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Liu, Zhipei, Liangkun Hu, Zefu Zhang, Lv Song, Peihua Zhang, Zhenzhen Cao y Jihua Ma. "Isoliensinine Eliminates Afterdepolarizations Through Inhibiting Late Sodium Current and L-Type Calcium Current". Cardiovascular Toxicology 21, n.º 1 (8 de agosto de 2020): 67–78. http://dx.doi.org/10.1007/s12012-020-09597-z.
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Ahern, Brooke, Andrea Sebastian, Douglas A. Andres y Jonathan Satin. "Myocardial RAD Deletion Increases Early L-type Calcium Current without Affecting Late Calcium Current through Multiple Mechanisms". Biophysical Journal 118, n.º 3 (febrero de 2020): 105a. http://dx.doi.org/10.1016/j.bpj.2019.11.726.
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Angelini, Marina, Arash Pezhouman, Nicoletta Savalli, Marvin Chang, Guillaume Calmettes, Federica Steccanella, Antonios Pantazis, Hrayr S. Karagueuzian, James N. Weiss y Riccardo Olcese. "Potent Suppression of Ventricular Arrhythmias by Selectively Targeting Late L-type Calcium Current". Biophysical Journal 118, n.º 3 (febrero de 2020): 104a. http://dx.doi.org/10.1016/j.bpj.2019.11.723.
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Protas, Lev, Dario DiFrancesco y Richard B. Robinson. "L-type but not T-type calcium current changes during postnatal development in rabbit sinoatrial node". American Journal of Physiology-Heart and Circulatory Physiology 281, n.º 3 (1 de septiembre de 2001): H1252—H1259. http://dx.doi.org/10.1152/ajpheart.2001.281.3.h1252.
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Although the neonatal sinus node beats at a faster rate than the adult, when a sodium current ( I Na) present in the newborn is blocked, the spontaneous rate is slower in neonatal myocytes than in adult myocytes. This suggests a possible functional substitution of I Na by another current during development. We used ruptured [T-type calcium current ( I Ca,T)] and perforated [L-type calcium current ( I Ca,L)] patch clamps to study developmental changes in calcium currents in sinus node cells from adult and newborn rabbits. I Ca,T density did not differ with age, and no significant differences were found in the voltage dependence of activation or inactivation. I Ca,L density was lower in the adult than newborn (12.1 ± 1.4 vs. 17.6 ± 2.5 pA/pF, P = 0.049). However, activation and inactivation midpoints were shifted in opposite directions, reducing the potential contribution during late diastolic depolarization in the newborn (activation midpoints −17.3 ± 0.8 and −22.3 ± 1.4 mV in the newborn and adult, respectively, P = 0.001; inactivation midpoints −33.4 ± 1.4 and −28.3 ± 1.7 mV for the newborn and adult, respectively, P = 0.038). Recovery of I Ca,L from inactivation was also slower in the newborn. The results suggest that a smaller but more negatively activating and rapidly recovering I Ca,L in the adult sinus node may contribute to the enhanced impulse initiation at this age in the absence of I Na.
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Baginskas, Armantas, Antanas Kuras y Artūras Grigaliūnas. "Inhibition of Dendritic L-Type Calcium Current by Memantine in Frog Tectum". Medicina 49, n.º 9 (4 de octubre de 2013): 64. http://dx.doi.org/10.3390/medicina49090064.
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The aim of the study was to explore the effects of memantine on responses elicited in the frog tectum by the bursts of spikes of moderate strength of a single retina ganglion cell and to gain an insight about the effect of memantine on the L-type Ca2+ current. Material and Methods. The experiments were performed in vivo on adult frogs (Rana temporaria). An individual retina ganglion cell (or its retinotectal fiber) was stimulated by current pulses delivered through a multichannel stimulating electrode positioned on the retina. Responses to the discharge of a single retinal ganglion cell were recorded in the tectum by an extracellular carbonfiber microelectrode positioned in the terminal arborization of the retinotectal fiber in the tectum layer F. The solution of memantine (1-amino-3,5-dimethyladamantane) hydrochloride (30 or 45 μM) was applied onto the surface of the tectum by perfusion at a rate of 0.4 mL/min. Results. Memantine (30–45 μM) largely inhibited the L-type Ca2+ channel-mediated slow negative wave and late discharges seen in the tectum responses without any effect on fast synaptic retinotectal transmission. Conclusions. Our results suggest that the neuroprotective effect of memantine could arise not only through the inhibition of the NMDA receptor current but also through the suppression of the L-type Ca2+ current.
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Blackwell, K. T. "Calcium Waves and Closure of Potassium Channels in Response to GABA Stimulation in Hermissenda Type B Photoreceptors". Journal of Neurophysiology 87, n.º 2 (1 de febrero de 2002): 776–92. http://dx.doi.org/10.1152/jn.00867.2000.
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Classical conditioning of Hermissenda crassicornisrequires the paired presentation of a conditioned stimulus (light) and an unconditioned stimulus (turbulence). Light stimulation of photoreceptors leads to production of diacylglycerol, an activator of protein kinase C, and inositol triphosphate (IP3), which releases calcium from intracellular stores. Turbulence causes hair cells to release GABA onto the terminal branches of the type B photoreceptor. One prior study has shown that GABA stimulation produces a wave of calcium that propagates from the terminal branches to the soma and raises the possibility that two sources of calcium are required for memory storage. GABA stimulation also causes an inhibitory postsynaptic potential (IPSP) followed by a late depolarization and increase in input resistance, whose cause has not been identified. A model was developed of the effect of GABA stimulation on the Hermissenda type B photoreceptor to evaluate the currents underlying the late depolarization and to evaluate whether a calcium wave could propagate from the terminal branches to the soma. The model included GABAA, GABAB, and calcium-sensitive potassium leak channels; calcium dynamics including release of calcium from intracellular stores; and the biochemical reactions leading from GABAB receptor activation to IP3 production. Simulations show that it is possible for a wave of calcium to propagate from the terminal branches to the soma. The wave is initiated by IP3-induced calcium release but propagation requires release through the ryanodine receptor channel where IP3 concentration is small. Wave speed is proportional to peak calcium concentration at the crest of the wave, with a minimum speed of 9 μm/s in the absence of IP3. Propagation ceases when peak concentration drops below 1.2 μM; this occurs if the rate of calcium pumping into the endoplasmic reticulum is too large. Simulations also show that both a late depolarization and an increase in input resistance occur after GABA stimulation. The duration of the late depolarization corresponds to the duration of potassium leak channel closure. Neither the late depolarization nor the increase in input resistance are observed when a transient calcium current and a hyperpolarization-activated current are added to the model as replacement for closure of potassium leak channels. Thus the late depolarization and input resistance elevation can be explained by a closure of calcium-sensitive leak potassium currents but cannot be explained by a transient calcium current and a hyperpolarization-activated current.
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Rivaud, Mathilde R., Gerard A. Marchal, Rianne Wolswinkel, John A. Jansen, Ingeborg van der Made, Leander Beekman, Adrián Ruiz-Villalba et al. "Functional modulation of atrio-ventricular conduction by enhanced late sodium current and calcium-dependent mechanisms in Scn5a1798insD/+ mice". EP Europace 22, n.º 10 (10 de agosto de 2020): 1579–89. http://dx.doi.org/10.1093/europace/euaa127.
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Abstract Aims SCN5A mutations are associated with arrhythmia syndromes, including Brugada syndrome, long QT syndrome type 3 (LQT3), and cardiac conduction disease. Long QT syndrome type 3 patients display atrio-ventricular (AV) conduction slowing which may contribute to arrhythmogenesis. We here investigated the as yet unknown underlying mechanisms. Methods and results We assessed electrophysiological and molecular alterations underlying AV-conduction abnormalities in mice carrying the Scn5a1798insD/+ mutation. Langendorff-perfused Scn5a1798insD/+ hearts showed prolonged AV-conduction compared to wild type (WT) without changes in atrial and His-ventricular (HV) conduction. The late sodium current (INa,L) inhibitor ranolazine (RAN) normalized AV-conduction in Scn5a1798insD/+ mice, likely by preventing the mutation-induced increase in intracellular sodium ([Na+]i) and calcium ([Ca2+]i) concentrations. Indeed, further enhancement of [Na+]i and [Ca2+]i by the Na+/K+-ATPase inhibitor ouabain caused excessive increase in AV-conduction time in Scn5a1798insD/+ hearts. Scn5a1798insD/+ mice from the 129P2 strain displayed more severe AV-conduction abnormalities than FVB/N-Scn5a1798insD/+ mice, in line with their larger mutation-induced INa,L. Transverse aortic constriction (TAC) caused excessive prolongation of AV-conduction in FVB/N-Scn5a1798insD/+ mice (while HV-intervals remained unchanged), which was prevented by chronic RAN treatment. Scn5a1798insD/+-TAC hearts showed decreased mRNA levels of conduction genes in the AV-nodal region, but no structural changes in the AV-node or His bundle. In Scn5a1798insD/+-TAC mice deficient for the transcription factor Nfatc2 (effector of the calcium-calcineurin pathway), AV-conduction and conduction gene expression were restored to WT levels. Conclusions Our findings indicate a detrimental role for enhanced INa,L and consequent calcium dysregulation on AV-conduction in Scn5a1798insD/+ mice, providing evidence for a functional mechanism underlying AV-conduction disturbances secondary to gain-of-function SCN5A mutations.
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Gross, R. A. y R. L. Macdonald. "Cyclic AMP selectively reduces the N-type calcium current component of mouse sensory neurons in culture by enhancing inactivation". Journal of Neurophysiology 61, n.º 1 (1 de enero de 1989): 97–105. http://dx.doi.org/10.1152/jn.1989.61.1.97.
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1. The single-electrode voltage-clamp technique was used to assess the effect of elevated intracellular cyclic AMP levels on the three calcium current components of mouse dorsal root ganglion (DRG) neurons in culture. 2. Neither forskolin, cholera toxin, nor 8-Br-cyclic AMP affected the isolated transient low-threshold (T) calcium current. 3. When calcium currents were evoked at clamp potentials (Vc) positive to -20 mV from holding potentials (Vh) near the resting membrane potential, the calcium current consisted primarily of the transient high-threshold (N) and the slowly inactivating high-threshold (L) calcium current components. Under these conditions forskolin, cholera toxin, and 8-Br-cyclic AMP reduced the peak calcium current but had little or no effect on the late (greater than or equal to 300 ms) calcium current. When calcium currents were evoked from very negative Vh, however, there was no effect of these compounds. 4. Forskolin had no effect on the voltage-dependence of the current-voltage relation, nor on the rate of recovery of the calcium current from inactivation. 5. In other experiments, current traces were fitted using a multiexponential curve-fitting program that determined the amplitudes and inactivation time constants (tau i) of the three calcium current components. Forskolin selectively reduced the magnitude of the (curve-fitted) N current, and reduced its tau i. 6. Forskolin also enhanced steady-state inactivation of the N current, producing a -7.5 mV shift in the steady-state inactivation curve. 7. Cholera toxin, forskolin, and 8-Br-cyclic AMP had similar effects on calcium currents in mouse DRG neurons in culture.(ABSTRACT TRUNCATED AT 250 WORDS)
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Song, Yejia, John C. Shryock y Luiz Belardinelli. "An increase of late sodium current induces delayed afterdepolarizations and sustained triggered activity in atrial myocytes". American Journal of Physiology-Heart and Circulatory Physiology 294, n.º 5 (mayo de 2008): H2031—H2039. http://dx.doi.org/10.1152/ajpheart.01357.2007.
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This study determined the role of a slowly inactivating component of sodium current ( INa), late INa, to induce delayed afterdepolarizations (DADs) and triggered activity. We hypothesized that an increase of late INa may induce not only early afterdepolarizations (EADs), but also intracellular calcium overload and DADs. Guinea pig atrial myocytes were studied using the whole cell patch-clamp technique. Anemone toxin II (ATX-II) (5–10 nmol/l) was used to enhance late INa. Ranolazine (10 μmol/l) and TTX (2 μmol/l) were applied to block ATX-II-induced late INa. ATX-II prolonged action potential duration and induced EADs. In the continuous presence of ATX-II, following the appearance of EADs, both DADs and sustained triggered activity occurred. Triggered activity was abolished and DADs were reduced by either ranolazine or TTX. Consistent with induction of DADs, ATX-II induced the transient inward current ( ITI). The amplitude of ITI was significantly reduced by ranolazine. ATX-II induced only EADs, but no DADs, in the presence of the sodium-calcium exchange inhibitor KB-R7943 or the sarcoplasmic reticulum calcium release channel inhibitor ryanodine, or when the calcium chelator EGTA or BAPTA was included in the pipette solution. In conclusion, an increase of late INa, in addition to inducing EADs, can cause cellular calcium overload and induce DADs and sustained triggered activity in atrial myocytes. The data reveal that an increase of late INa is a novel mechanism for initiation of atrial arrhythmic activity.
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Shimamura, Keiichi, Masumi Kusaka y Nicholas Sperelakis. "Protein kinase C stimulates Ca2+ current in pregnant rat myometrial cells". Canadian Journal of Physiology and Pharmacology 72, n.º 11 (1 de noviembre de 1994): 1304–7. http://dx.doi.org/10.1139/y94-187.
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The factors that regulate the voltage-dependent Ca2+ channels in pregnant uterine smooth muscle cells have not been elucidated, including any roles for protein kinase C (PKC). Therefore, the role of PKC in the regulation of the slow (L type) Ca2+ channels was examined in myometrial cells isolated from late pregnant (18–19 day) rat uterus, using the nystatin-perforated whole-cell voltage clamp. A PKC activator, phorbol 12, 13-dibutyrate (PDB), increased the L-type Ca2+ current (ICa(L)). Bath application of PDB (0.03 and 0.3 μM) increased the peak amplitude of ICa(L) by 21 ± 14% (n = 6) and 37 ± 8% (n = 9, p < 0.01), respectively. PDB did not change the holding current or shift the current–voltage relationship for ICa(L). The PKC inhibitors, H-7 (20 μM) or staurosporine (10 nM), reversed the effect of PDB. These results indicate that PKC may play a role in regulating Ca2+ channel function in pregnant rat myometrial cells and, therefore, may be involved in control of uterine contraction.Key words: protein kinase C, phorbol ester, calcium current, myometrial cell, nystatin-perforated patch, whole-cell voltage clamp.
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Linz, Klaus W. y R. Meyer. "The late component of L-type calcium current during guinea-pig cardiac action potentials and its contribution to contraction". Pfl�gers Archiv European Journal of Physiology 436, n.º 5 (24 de agosto de 1998): 679–88. http://dx.doi.org/10.1007/s004240050689.
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Hung, Yuan, Yao-Chang Chen, Shih-Yu Huang, Yen-Yu Lu, Yung-Kuo Lin, Yu-Hsun Kao, Wei-Shiang Lin, Shih-Ann Chen y Yi-Jen Chen. "Klotho modulates electrical activity and calcium homeostasis in pulmonary vein cardiomyocytes via PI3K/Akt signalling". EP Europace 22, n.º 7 (30 de junio de 2020): 1132–41. http://dx.doi.org/10.1093/europace/euaa100.
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Abstract Aims Klotho, a potential antiageing protein has remarkable cardiovascular effects, which is lower in the patients with chronic kidney disease (CKD). Chronic kidney disease increases the risk of atrial fibrillation, majorly triggered by pulmonary vein (PV) arrhythmogenesis. This study investigated whether klotho protein can modulate PV electrical activity and the underlying potential mechanisms. Methods and results A conventional microelectrode and whole-cell patch clamp were used to investigate the action potentials and ionic currents in isolated rabbit PV tissue preparations and single cardiomyocytes before and after klotho administration. Phosphoinositide 3-kinase (PI3K)/Akt signalling was studied using western blotting. Klotho significantly reduced PV spontaneous beating rates in PV tissue preparations at 1.0 and 3.0 ng/mL (but not at 0.1 and 0.3 ng/mL). In the presence of the Akt inhibitor (10 µM), klotho (1.0 and 3.0 ng/mL) did not change PV electrical activities. Klotho (1.0 ng/mL) significantly decreased the late sodium current (INa-Late) and L-type calcium current (ICa-L), similar to the Akt inhibitor (10 µM). Western blots demonstrated that klotho (1.0 ng/mL)-treated PV cardiomyocytes had less phosphorylation of Akt (Ser473) compared with klotho-untreated cardiomyocytes. Compared with control PVs, klotho at relatively lower concentrations (0.1 and 0.3 ng/mL) significantly reduced beating rates and decreased the amplitudes of delay afterdepolarizations in CKD PVs. Conclusion Klotho modulated PV electrical activity by inhibiting PI3K/Akt signalling, which may provide a novel insight into CKD-induced arrhythmogenesis.
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Hadley, R. W. y W. J. Lederer. "Nifedipine inhibits movement of cardiac calcium channels through late, but not early, gating transitions". American Journal of Physiology-Heart and Circulatory Physiology 269, n.º 5 (1 de noviembre de 1995): H1784—H1790. http://dx.doi.org/10.1152/ajpheart.1995.269.5.h1784.
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L-type Ca2+ channels were studied in guinea pig ventricular myocytes by examining how photoinactivation of nifedipine affected the Ca2+ current (ICa) and the Ca2+ channel gating current (Ig). ICa, blocked by nifedipine, reappeared in qualitatively different phases (immediate and delayed) following photoinactivation of nifedipine. Immediate recovery was attributed to unblock of closed Ca2+ channels, while delayed recovery was attributed to unblock of inactivated channels. In contrast to the ICa results, photoinactivation of nifedipine produced only delayed recovery of Ig. Analysis of these results suggests the following conclusions. First, the actions of inhibitory dihydropyridines can be attributed to binding to either the inactivated or the closed conformation, but only binding to the inactivated state is associated with reduction of Ig. Second, the action of inhibitory dihydropyridines on closed channels is to retard their movement through a final, voltage-independent transition to the open state. This effect seems to be the converse of a major action of stimulatory dihydropyridines and thus is the principal mechanistic difference between stimulatory and inhibitory dihydropyridines.
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Gross, R. A. y R. L. MacDonald. "Activators of protein kinase C selectively enhance inactivation of a calcium current component of cultured sensory neurons in a pertussis toxin-sensitive manner". Journal of Neurophysiology 61, n.º 6 (1 de junio de 1989): 1259–69. http://dx.doi.org/10.1152/jn.1989.61.6.1259.
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1. Three calcium current components were recorded in mouse dorsal root ganglion (DRG) neurons using the single-electrode voltage-clamp technique, the transient low-threshold (T), the slowly inactivating high-threshold (L), and the transient high-threshold (N) calcium current components. 2. Two activators of protein kinase C, the phorbol ester, phorbol 12,13-dibutyrate (PDBu) and the diacylglycerol analogue, 1,2-oleoylacetylglycerol (OAG), were tested to determine their effects on the three calcium current components. Neither compound affected the isolated T current, but both had similar effects on calcium currents containing both the N and L current components. PDBu and OAG reduced the peak but had little effect on the late (greater than or equal to 300 ms) calcium current evoked at clamp potentials (Vc) positive to -20 mV from holding potentials (Vh) near the resting membrane potential (-70 to -55 mV). The reduction in peak calcium current ranged from 15 to 40% and was present in all neurons tested. In contrast, there was little or no effect of these compounds when calcium currents were evoked from Vh at or negative to -80 mV. A phorbol derivative, 4-alpha-phorbol, which does not activate protein kinase C, had no effect on calcium currents at any potential. 3. Pretreatment of cultures with pertussis toxin [(PTX); 100-200 ng/ml] for 4-24 h abolished the PDBu-induced reduction of calcium current. 4. Multiexponential curve-fitting of current traces was used to determine the amplitudes and inactivation time constants (tau i) of the T, N, and L current components. PDBu selectively reduced the amplitude of the N current component but had no effect on any of the tau i. 5. PDBu had no effect on the voltage dependence of the current-voltage relation or on the time dependence of recovery from inactivation at time intervals up to 500 ms. In contrast, PDBu produced a -7.5-mV shift in the steady-state inactivation curve, sufficient to account for its effect near the resting membrane potential. 6. PDBu and OAG had selective, voltage-dependent effects on the calcium current components of mouse DRG neurons in culture. We conclude that activation of protein kinase C caused a selective reduction of the N current component; this effect was due to increased steady-state inactivation at membrane potentials positive to -80 mV and was mediated by a G protein.
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Aoki, Takuya y Scott C. Baraban. "Properties of a Calcium-Activated K+ Current on Interneurons in the Developing Rat Hippocampus". Journal of Neurophysiology 83, n.º 6 (1 de junio de 2000): 3453–61. http://dx.doi.org/10.1152/jn.2000.83.6.3453.
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Calcium-activated potassium currents have an essential role in regulating excitability in a variety of neurons. Although it is well established that mature CA1 pyramidal neurons possess a Ca2+-activated K+ conductance ( I K(Ca)) with early and late components, modulation by various endogenous neurotransmitters, and sensitivity to K+ channel toxins, the properties of I K(Ca) on hippocampal interneurons (or immature CA1 pyramidal neurons) are relatively unknown. To address this problem, whole-cell voltage-clamp recordings were made from visually identified interneurons in stratum lacunosum-moleculare (L-M) and CA1 pyramidal cells in hippocampal slices from immature rats (P3–P25). A biphasic calcium-activated K+ tail current was elicited following a brief depolarization from the holding potential (−50 mV). Analysis of the kinetic properties of I K(Ca)suggests that an early current component differs between these two cell types. An early I K(Ca) with a large peak current amplitude (200.8 ± 13.2 pA, mean ± SE), slow time constant of decay (70.9 ± 3.3 ms), and relatively rapid time to peak (within 15 ms) was observed on L-M interneurons ( n = 88), whereas an early I K(Ca) with a small peak current amplitude (112.5 ± 7.3 pA), a fast time constant of decay (39.4 ± 1.6 ms), and a slower time-to-peak (within 26 ms) was observed on CA1 pyramidal neurons ( n = 85). Removal of extracellular calcium or addition of inorganic Ca2+ channel blockers (cadmium, nickel, or cobalt) was used to demonstrate the calcium dependence of these currents. Addition of norepinephrine, carbachol, and a variety of channel toxins (apamin, iberiotoxin, verruculogen, paxilline, penitrem A, and charybdotoxin) were used to further distinguish between I K(Ca) on these two hippocampal cell types. Verruculogen (100 nM), carbachol (100 μM), apamin (100 nM), TEA (1 mM), and iberiotoxin (50 nM) significantly reduced early I K(Ca) on CA1 pyramidal neurons; early I K(Ca) on L-M interneurons was inhibited by apamin and TEA. Combined with previous work showing that the firing properties of hippocampal interneurons and pyramidal cells differ, our kinetic and pharmacological data provide strong support for the hypothesis that different types of Ca2+-activated K+ current are present on these two cell types.
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Tzeng, Huei-Ping, Jinping Fan, Jesus G. Vallejo, Jian Wen Dong, Xiongwen Chen, Steven R. Houser y Douglas L. Mann. "Negative inotropic effects of high-mobility group box 1 protein in isolated contracting cardiac myocytes". American Journal of Physiology-Heart and Circulatory Physiology 294, n.º 3 (marzo de 2008): H1490—H1496. http://dx.doi.org/10.1152/ajpheart.00910.2007.
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High-mobility group box 1 (HMGB1) released from necrotic cells or macrophages functions as a late inflammatory mediator and has been shown to induce cardiovascular collapse during sepsis. Thus far, however, the effect(s) of HMGB1 in the heart are not known. We determined the effects of HMGB1 on isolated feline cardiac myocytes by measuring sarcomere shortening in contracting cardiac myocytes, intracellular Ca2+ transients by using fluo-3, and L-type calcium currents by using whole cell perforate configuration of the patch-clamp technique. Treatment of isolated myocytes with HMGB1 (100 ng/ml) resulted in a 70% decrease in sarcomere shortening and a 50% decrease in the height of the peak Ca2+ transient within 5 min ( P < 0.01). The immediate negative inotropic effects of HMGB1 on cell contractility and calcium homeostasis were partially reversible upon washout of HMGB1. A significant inhibition of the inward l-type calcium currents was also documented by the patch-clamp technique. HMGB1 induced the PKC-ε translocation, and a PKC inhibitor significantly attenuated the negative inotropic effects of HMGB1. These studies show for the first time that HMGB1 impairs sarcomere shortening by decreasing calcium availability in cardiac myocytes through modulating membrane calcium influx and suggest that HMGB1 maybe acts as a novel myocardial depressant factor during cardiac injury.
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Tai, Buh-Yuan, Ming-Kun Lu, Hsiang-Yu Yang, Chien-Sung Tsai y Chih-Yuan Lin. "Ziprasidone Induces Rabbit Atrium Arrhythmogenesis via Modification of Oxidative Stress and Sodium/Calcium Homeostasis". Biomedicines 10, n.º 5 (23 de abril de 2022): 976. http://dx.doi.org/10.3390/biomedicines10050976.
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Background: Atypical antipsychotics increase the risk of atrial arrhythmias and sudden cardiac death. This study investigated whether ziprasidone, a second-generation antipsychotic, affected intracellular Ca2+ and Na+ regulation and oxidative stress, providing proarrhythmogenic substrates in atriums. Methods: Electromechanical analyses of rabbit atrial tissues were conducted. Intracellular Ca2+ monitoring using Fluo-3, the patch-clamp method for ionic current recordings, and a fluorescence study for the detection of reactive oxygen species and intracellular Na+ levels were conducted in enzymatically dissociated atrial myocytes. Results: Ziprasidone-treated atriums showed sustained triggered activities after rapid pacing, which were inhibited by KN-93 and ranolazine. A reduced peak L-type Ca2+ channel current and enhanced late Na+ current were observed in ziprasidone-treated atrial myocytes, together with an increased cytosolic Na+ level. KN-93 suppressed the enhanced late Na+ current in ziprasidone-treated atrial myocytes. Atrial myocytes treated with ziprasidone showed reduced Ca2+ transient amplitudes and sarcoplasmic reticulum (SR) Ca2+ stores, and increased SR Ca2+ leakage. Cytosolic and mitochondrial reactive oxygen species production was increased in atrial myocytes treated with ziprasidone. TNF-α and NLRP3 were upregulated in ziprasidone-treated myocytes, and the level of phosphorylated calcium/calmodulin-dependent protein kinase II protein was increased. Conclusions: Our results suggest that ziprasidone increases the occurrence of atrial triggered activity and causes intracellular Ca2+ and Na+ dysregulation, which may result from enhanced oxidative stress and activation of the TNF-α/NLRP3 inflammasome pathway in ziprasidone-treated myocytes.
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Prudencio, Tomas M., Luther M. Swift, Devon Guerrelli, Blake Cooper, Marissa Reilly, Nina Ciccarelli, Jiansong Sheng, Rafael Jaimes y Nikki Gillum Posnack. "Bisphenol S and Bisphenol F Are Less Disruptive to Cardiac Electrophysiology, as Compared With Bisphenol A". Toxicological Sciences 183, n.º 1 (8 de julio de 2021): 214–26. http://dx.doi.org/10.1093/toxsci/kfab083.
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Abstract Bisphenol A (BPA) is a high-production volume chemical used to manufacture consumer and medical-grade plastic products. Due to its ubiquity, the general population can incur daily environmental exposure to BPA, whereas heightened exposure has been reported in intensive care patients and industrial workers. Due to health concerns, structural analogs are being explored as replacements for BPA. This study aimed to examine the direct effects of BPA on cardiac electrophysiology compared with recently developed alternatives, including BPS (bisphenol S) and BPF (bisphenol F). Whole-cell voltage-clamp recordings were performed on cell lines transfected to express the voltage-gated sodium channel (Nav1.5), L-type voltage-gated calcium channel (Cav1.2), or the rapidly activating delayed rectifier potassium channel (hERG). Cardiac electrophysiology parameters were measured using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) and intact, whole rat heart preparations. BPA was the most potent inhibitor of fast/peak (INa-P) and late (INa-L) sodium channel (IC50 = 55.3, 23.6 µM, respectively), L-type calcium channel (IC50 = 30.8 µM), and hERG channel current (IC50 = 127 µM). Inhibitory effects on L-type calcium channels were supported by microelectrode array recordings, which revealed a shortening of the extracellular field potential (akin to QT interval). BPA and BPF exposures slowed atrioventricular (AV) conduction and increased AV node refractoriness in isolated rat heart preparations, in a dose-dependent manner (BPA: +9.2% 0.001 µM, +95.7% 100 µM; BPF: +20.7% 100 µM). BPS did not alter any of the cardiac electrophysiology parameters tested. Results of this study demonstrate that BPA and BPF exert an immediate inhibitory effect on cardiac ion channels, whereas BPS is markedly less potent. Additional studies are necessary to fully elucidate the safety profile of bisphenol analogs on the heart.
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Kaplan, Aaron D., Humberto C. Joca, Liron Boyman y Maura Greiser. "Calcium Signaling Silencing in Atrial Fibrillation: Implications for Atrial Sodium Homeostasis". International Journal of Molecular Sciences 22, n.º 19 (29 de septiembre de 2021): 10513. http://dx.doi.org/10.3390/ijms221910513.
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Atrial fibrillation (AF) is the most common type of cardiac arrhythmia, affecting more than 33 million people worldwide. Despite important advances in therapy, AF’s incidence remains high, and treatment often results in recurrence of the arrhythmia. A better understanding of the cellular and molecular changes that (1) trigger AF and (2) occur after the onset of AF will help to identify novel therapeutic targets. Over the past 20 years, a large body of research has shown that intracellular Ca2+ handling is dramatically altered in AF. While some of these changes are arrhythmogenic, other changes counteract cellular arrhythmogenic mechanisms (Calcium Signaling Silencing). The intracellular Na+ concentration ([Na+])i is a key regulator of intracellular Ca2+ handling in cardiac myocytes. Despite its importance in the regulation of intracellular Ca2+ handling, little is known about [Na+]i, its regulation, and how it might be changed in AF. Previous work suggests that there might be increases in the late component of the atrial Na+ current (INa,L) in AF, suggesting that [Na+]i levels might be high in AF. Indeed, a pharmacological blockade of INa,L has been suggested as a treatment for AF. Here, we review calcium signaling silencing and changes in intracellular Na+ homeostasis during AF. We summarize the proposed arrhythmogenic mechanisms associated with increases in INa,L during AF and discuss the evidence from clinical trials that have tested the pharmacological INa,L blocker ranolazine in the treatment of AF.
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Lee, Ting-I., Yao-Chang Chen, Yung-Kuo Lin, Cheng-Chih Chung, Yen-Yu Lu, Yu-Hsun Kao y Yi-Jen Chen. "Empagliflozin Attenuates Myocardial Sodium and Calcium Dysregulation and Reverses Cardiac Remodeling in Streptozotocin-Induced Diabetic Rats". International Journal of Molecular Sciences 20, n.º 7 (4 de abril de 2019): 1680. http://dx.doi.org/10.3390/ijms20071680.
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Diabetes mellitus (DM) has significant effects on cardiac calcium (Ca2+) and sodium (Na+) regulation. Clinical studies have shown that empagliflozin (Jardiance™) has cardiovascular benefits, however the mechanisms have not been fully elucidated. This study aimed to investigate whether empagliflozin modulates cardiac electrical activity as well as Ca2+/Na+ homeostasis in DM cardiomyopathy. Electrocardiography, echocardiography, whole-cell patch-clamp, confocal microscopic examinations, and Western blot, were performed in the ventricular myocytes of control and streptozotocin-induced DM rats, with or without empagliflozin (10 mg/kg for 4 weeks). The results showed that the control and empagliflozin-treated DM rats had smaller left ventricular end-diastolic diameters and shorter QT intervals than the DM rats. In addition, the prolonged action potential duration in the DM rats was attenuated in the empagliflozin-treated DM rats. Moreover, the DM rats had smaller sarcoplasmic reticular Ca2+ contents, intracellular Ca2+ transients, L-type Ca2+, reverse mode Na+-Ca2+exchanger currents, lower protein expressions of sarcoplasmic reticulum ATPase, ryanodine receptor 2 (RyR2), but higher protein expressions of phosphorylated RyR2 at serine 2808 than the control and empagliflozin-treated DM rats. The incidence and frequency of Ca2+ sparks, cytosolic and mitochondrial reactive oxygen species, and late Na+ current and Na+/hydrogen-exchanger currents were greater in the DM rats than in the control and empagliflozin-treated DM rats. Empagliflozin significantly changed Ca2+ regulation, late Na+ and Na+/hydrogen-exchanger currents and electrophysiological characteristics in DM cardiomyopathy, which may contribute to its cardioprotective benefits in DM patients.
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Tai, Buh-Yuan, Zhi-Hong Wen, Pao-Yun Cheng, Hsiang-Yu Yang, Chang-Yih Duh, Ping-Nan Chen y Chih-Hsueng Hsu. "Lemnalol Modulates the Electrophysiological Characteristics and Calcium Homeostasis of Atrial Myocytes". Marine Drugs 17, n.º 11 (30 de octubre de 2019): 619. http://dx.doi.org/10.3390/md17110619.
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Sepsis, an inflammatory response to infection provoked by lipopolysaccharide (LPS), is associated with high mortality, as well as ischemic stroke and new-onset atrial arrhythmia. Severe bacterial infections causing sepsis always result in profound physiological changes, including fever, hypotension, arrhythmia, necrosis of tissue, systemic multi-organ dysfunction and finally death. LPS challenge-induced inflammatory responses during sepsis may increase the likelihood of the arrhythmogenesis. Lemnalol is known to possess potent anti-inflammatory effects. This study examined whether Lemnalol (0.1 μM) could modulate the electrophysiological characteristics and calcium homeostasis of atrial myocytes under the influence of LPS (1μg/mL). Under challenge with LPS, Lemnalol-treated LA myocytes, had a longer AP duration at 20%, 50% and 90% repolarization of the amplitude, compared to the LPS-treated cells. LPS-challenged LA myocytes showed increased late sodium current, Na+-Ca2+ exchanger current, transient outward current, rapid component of delayed rectifier potassium current, tumor necrosis factor-α, NF-κB and increased phosphorylation of ryanodine receptor (RyR), but a lower L-type Ca2+ current than the control LA myocytes. Exposure to Lemnalol reversed the LPS-induced effects. The LPS-treated and control groups of LA myocytes, with or without the existence of Lemnalol. showed no apparent alterations in the sodium current amplitude or Cav1.2 expression. The expression of sarcoendoplasmic reticulum calcium transport ATPase (SERCA2) was reduced by LPS treatment, while Lemnalol ameliorated the LPS-induced alterations. The phosphorylation of RyR was enhanced by LPS treatment, while Lemnalol attenuated the LPS-induced alterations. In conclusion, Lemnalol modulates LPS-induced alterations of LA calcium homeostasis and blocks the NF-κB pathways, which may contribute to the attenuation of LPS-induced arrhythmogenesis.
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Wei, X., L. Wu, S. Huang, Q. Yang, L. Ren y Y. Huo. "ASSA14-03-46 Inhibition of late sodium current reduces the reverse rate dependence of action potential duration prolongation induced by L-type calcium channel activator". Heart 101, Suppl 1 (1 de diciembre de 2014): A25.2—A26. http://dx.doi.org/10.1136/heartjnl-2014-307109.64.
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Gu, Huaiyu, Shaojuan Amy Jiang, Jorge M. Campusano, Jorge Iniguez, Hailing Su, Andy An Hoang, Monica Lavian, Xicui Sun y Diane K. O'Dowd. "Cav2-Type Calcium Channels Encoded by cac Regulate AP-Independent Neurotransmitter Release at Cholinergic Synapses in Adult Drosophila Brain". Journal of Neurophysiology 101, n.º 1 (enero de 2009): 42–53. http://dx.doi.org/10.1152/jn.91103.2008.
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Voltage-gated calcium channels containing α1 subunits encoded by Cav2 family genes are critical in regulating release of neurotransmitter at chemical synapses. In Drosophila, cac is the only Cav2-type gene. Cacophony (CAC) channels are localized in motor neuron terminals where they have been shown to mediate evoked, but not AP-independent, release of glutamate at the larval neuromuscular junction (NMJ). Cultured embryonic neurons also express CAC channels, but there is no information about the properties of CAC-mediated currents in adult brain nor how these channels regulate transmission in central neural circuits where fast excitatory synaptic transmission is predominantly cholinergic. Here we report that wild-type neurons cultured from late stage pupal brains and antennal lobe projection neurons (PNs) examined in adult brains, express calcium currents with two components: a slow-inactivating current sensitive to the spider toxin Plectreurys toxin II (PLTXII) and a fast-inactivating PLTXII-resistant component. CAC channels are the major contributors to the slow-inactivating PLTXII-sensitive current based on selective reduction of this component in hypomorphic cac mutants ( NT27 and TS3). Another characteristic of cac mutant neurons both in culture and in whole brain recordings is a reduced cholinergic miniature excitatory postsynaptic current frequency that is mimicked in wild-type neurons by acute application of PLTXII. These data demonstrate that cac encoded Cav2-type calcium channels regulate action potential (AP)-independent release of neurotransmitter at excitatory cholinergic synapses in the adult brain, a function not predicted from studies at the larval NMJ.
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Mercer, Alison R. y John G. Hildebrand. "Developmental Changes in the Density of Ionic Currents in Antennal-Lobe Neurons of the Sphinx Moth, Manduca sexta". Journal of Neurophysiology 87, n.º 6 (1 de junio de 2002): 2664–75. http://dx.doi.org/10.1152/jn.2002.87.6.2664.
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Early in metamorphic adult development, action potentials elicited from Manduca sexta antennal lobe neurons are small in amplitude, long in duration, and calcium dependent. As development proceeds, the action potential waveform becomes larger in amplitude, shorter in duration, and increasingly sodium dependent. Whole cell voltage-clamp analysis of Manduca antennal-lobe neurons in vitro has been used to identify voltage-activated currents that contribute to developmental changes in the electrical excitability of these cells. Proximal Branching neurons [putative projection (output) neurons] and Rick Rack neurons (putative local antennal-lobe interneurons) are examined in detail early (pupal stage 5) and late (pupal stage 14) in adult metamorphosis. In both cell types, four voltage-gated and two calcium-dependent ionic currents have been identified. Cell-type–specific changes in the density of sodium, calcium, and potassium currents correlate temporally with changes in cell excitability and spike waveform. Developmental changes in ionic current profiles are accompanied also by the emergence of cell-type–specific response characteristics in the cells. Together with the accompanying paper, this study provides an important foundation for examining the impact of developmental changes in electrical excitability on the growth, electrical properties and connectivity of neurons in central olfactory pathways of the moth.
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Livshitz, Leonid M. y Yoram Rudy. "Regulation of Ca2+ and electrical alternans in cardiac myocytes: role of CAMKII and repolarizing currents". American Journal of Physiology-Heart and Circulatory Physiology 292, n.º 6 (junio de 2007): H2854—H2866. http://dx.doi.org/10.1152/ajpheart.01347.2006.
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Alternans of cardiac repolarization is associated with arrhythmias and sudden death. At the cellular level, alternans involves beat-to-beat oscillation of the action potential (AP) and possibly Ca2+ transient (CaT). Because of experimental difficulty in independently controlling the Ca2+ and electrical subsystems, mathematical modeling provides additional insights into mechanisms and causality. Pacing protocols were conducted in a canine ventricular myocyte model with the following results: 1) CaT alternans results from refractoriness of the sarcoplasmic reticulum Ca2+ release system; alternation of the L-type calcium current has a negligible effect; 2) CaT-AP coupling during late AP occurs through the sodium-calcium exchanger and underlies AP duration (APD) alternans; 3) increased Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity extends the range of CaT and APD alternans to slower frequencies and increases alternans magnitude; its decrease suppresses CaT and APD alternans, exerting an antiarrhythmic effect; and 4) increase of the rapid delayed rectifier current ( IKr) also suppresses APD alternans but without suppressing CaT alternans. Thus CaMKII inhibition eliminates APD alternans by eliminating its cause (CaT alternans) while IKr enhancement does so by weakening CaT-APD coupling. The simulations identify combined CaMKII inhibition and IKr enhancement as a possible antiarrhythmic intervention.
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Horváth, Balázs, Bence Hegyi, Kornél Kistamás, Krisztina Váczi, Tamás Bányász, János Magyar, Norbert Szentandrássy y Péter P. Nánási. "Cytosolic calcium changes affect the incidence of early afterdepolarizations in canine ventricular myocytes". Canadian Journal of Physiology and Pharmacology 93, n.º 7 (julio de 2015): 527–34. http://dx.doi.org/10.1139/cjpp-2014-0511.
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This study was designed to investigate the influence of cytosolic Ca2+ levels ([Ca2+]i) on action potential duration (APD) and on the incidence of early afterdepolarizations (EADs) in canine ventricular cardiomyocytes. Action potentials (AP) of isolated cells were recorded using conventional sharp microelectrodes, and the concomitant [Ca2+]i was monitored with the fluorescent dye Fura-2. EADs were evoked at a 0.2 Hz pacing rate by inhibiting the rapid delayed rectifier K+ current with dofetilide, by activating the late sodium current with veratridine, or by activating the L-type calcium current with BAY K8644. These interventions progressively prolonged the AP and resulted in initiation of EADs. Reducing [Ca2+]i by application of the cell-permeant Ca2+ chelator BAPTA-AM lengthened the AP at 1.0 Hz if it was applied alone, in the presence of veratridine, or in the presence of BAY K8644. However, BAPTA-AM shortened the AP if the cells were pretreated with dofetilide. The incidence of the evoked EADs was strongly reduced by BAPTA-AM in dofetilide, moderately reduced in veratridine, whereas EAD incidence was increased by BAPTA-AM in the presence of BAY K8644. Based on these experimental data, changes in [Ca2+]i have marked effects on APD as well as on the incidence of EADs; however, the underlying mechanisms may be different, depending on the mechanism of EAD generation. As a consequence, reduction of [Ca2+]i may eliminate EADs under some, but not all, experimental conditions.
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Santini, Lorenzo, Raffaele Coppini y Elisabetta Cerbai. "Ion Channel Impairment and Myofilament Ca2+ Sensitization: Two Parallel Mechanisms Underlying Arrhythmogenesis in Hypertrophic Cardiomyopathy". Cells 10, n.º 10 (18 de octubre de 2021): 2789. http://dx.doi.org/10.3390/cells10102789.
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Life-threatening ventricular arrhythmias are the main clinical burden in patients with hypertrophic cardiomyopathy (HCM), and frequently occur in young patients with mild structural disease. While massive hypertrophy, fibrosis and microvascular ischemia are the main mechanisms underlying sustained reentry-based ventricular arrhythmias in advanced HCM, cardiomyocyte-based functional arrhythmogenic mechanisms are likely prevalent at earlier stages of the disease. In this review, we will describe studies conducted in human surgical samples from HCM patients, transgenic animal models and human cultured cell lines derived from induced pluripotent stem cells. Current pieces of evidence concur to attribute the increased risk of ventricular arrhythmias in early HCM to different cellular mechanisms. The increase of late sodium current and L-type calcium current is an early observation in HCM, which follows post-translation channel modifications and increases the occurrence of early and delayed afterdepolarizations. Increased myofilament Ca2+ sensitivity, commonly observed in HCM, may promote afterdepolarizations and reentry arrhythmias with direct mechanisms. Decrease of K+-currents due to transcriptional regulation occurs in the advanced disease and contributes to reducing the repolarization-reserve and increasing the early afterdepolarizations (EADs). The presented evidence supports the idea that patients with early-stage HCM should be considered and managed as subjects with an acquired channelopathy rather than with a structural cardiac disease.
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Xu, Qiang, Xuemei Huang, Zenghui Meng, Yingrui Li, Rujia Zhong, Xin Li, Lukas Cyganek et al. "Antiarrhythmic Effects of Vernakalant in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes from a Patient with Short QT Syndrome Type 1". Journal of Cardiovascular Development and Disease 9, n.º 4 (9 de abril de 2022): 112. http://dx.doi.org/10.3390/jcdd9040112.
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(1) Background: Short QT syndrome (SQTS) may result in sudden cardiac death. So far, no drugs, except quinidine, have been demonstrated to be effective in some patients with SQTS type 1 (SQTS1). This study was designed to examine the potential effectiveness of vernakalant for treating SQTS1 patients, using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a patient with SQTS1. (2) Methods: Patch clamp and calcium imaging techniques were used to examine the drug effects. (3) Results: Vernakalant prolonged the action potential duration (APD) in hiPSC-CMs from a SQTS1-patient (SQTS1-hiPSC-CMs). In spontaneously beating SQTS1-hiPSC-CMs, vernakalant reduced the arrhythmia-like events induced by carbachol plus epinephrine. Vernakalant failed to suppress the hERG channel currents but reduced the outward small-conductance calcium-activated potassium channel current. In addition, it enhanced Na/Ca exchanger currents and late sodium currents, in agreement with its APD-prolonging effect. (4) Conclusions: The results demonstrated that vernakalant can prolong APD and reduce arrhythmia-like events in SQTS1-hiPSC-CMs and may be a candidate drug for treating arrhythmias in SQTS1-patients.
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Abrahamsson, Niclas, Britt Edén Engström, Magnus Sundbom y F. Anders Karlsson. "GLP1 analogs as treatment of postprandial hypoglycemia following gastric bypass surgery: a potential new indication?" European Journal of Endocrinology 169, n.º 6 (diciembre de 2013): 885–89. http://dx.doi.org/10.1530/eje-13-0504.
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ObjectiveThe number of morbidly obese subjects submitted to bariatric surgery is rising worldwide. In a fraction of patients undergoing gastric bypass (GBP), episodes with late postprandial hypoglycemia (PPHG) develop 1–3 years after surgery. The pathogenesis of this phenomenon is not fully understood; meal-induced rapid and exaggerated increases of circulating incretins and insulin appear to be at least partially responsible. Current treatments include low-carbohydrate diets, inhibition of glucose intestinal uptake, reduction of insulin secretion with calcium channel blockers, somatostatin analogs, or diazoxide, a KATP channel opener. Even partial pancreatectomy has been advocated. In type 2 diabetes, GLP1 analogs have a well-documented effect of stabilizing glucose levels without causing hypoglycemia.DesignWe explored GLP1 analogs as open treatment in five consecutive GBP cases seeking medical attention because of late postprandial hypoglycemic symptoms.ResultsGlucose measured in connection with the episodes in four of the cases had been 2.7, 2.5, 1.8, and 1.6 mmol/l respectively. The patients consistently described that the analogs eliminated their symptoms, which relapsed in four of the five patients when treatment was reduced/discontinued. The drug effect was further documented in one case by repeated 24-h continuous glucose measurements.ConclusionThese open, uncontrolled observations suggest that GLP1 analogs might provide a new treatment option in patients with problems of late PPHG.
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Sridhar, N. L., Sreeram S. y Madoori Srinivas. "Is calcium a concern in neonates undergoing phototherapy?" International Journal of Contemporary Pediatrics 5, n.º 3 (20 de abril de 2018): 988. http://dx.doi.org/10.18203/2349-3291.ijcp20181527.
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Background: Neonatal hypocalcemia is defined as total serum calcium concentration of < 7 mg/dl or ionized calcium concentration of <4 mg/dl (<1 mmol/L). The current aim was to look the effect of phototherapy on ionized calcium levels before and after phototherapy in otherwise healthy term and late preterm (35 to 37 weeks) neonates.Methods: The study group included 50 neonates. Measurement of serum ionized calcium levels was done before and at the end of phototherapy.Results: At the end of phototherapy in study group, a significant fall in calcium level in 64% of term and 76% of late preterm neonates was observed, but almost all except one remained asymptomatic.Conclusions: The efficacy of phototherapy in the prevention and treatment of hyperbilirubinemia in newborn infants has been well established. The mean duration of phototherapy in our study was 32 hours. Duration of phototherapy may influence the severity of hypocalcaemia. The regulation of calcium homeostasis in the newborn period has been of considerable interest. Phototherapy increases calcium absorption by the bones and leads to the reduction of melatonin levels. Changes in melatonin levels affect the incidence of hypocalcaemia-induced phototherapy. The mechanism of hypocalcaemia effect of phototherapy was reported by inhibition of pineal gland via transcranial illumination, resulting to decline of melatonin secretion; which blocks the effect of cortisol on bone calcium. It is suggested that serum calcium levels be assessed in neonates treated with phototherapy. Neonatal Jaundice is one of the most common problems that can occur in the newborn. Hypocalcaemia during phototherapy has been reported in literature.
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García, Antonio G., Antonio M. García-De-Diego, Luis Gandía, Ricardo Borges y Javier García-Sancho. "Calcium Signaling and Exocytosis in Adrenal Chromaffin Cells". Physiological Reviews 86, n.º 4 (octubre de 2006): 1093–131. http://dx.doi.org/10.1152/physrev.00039.2005.
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At a given cytosolic domain of a chromaffin cell, the rate and amplitude of the Ca2+ concentration ([Ca2+]c) depends on at least four efficient regulatory systems: 1) plasmalemmal calcium channels, 2) endoplasmic reticulum, 3) mitochondria, and 4) chromaffin vesicles. Different mammalian species express different levels of the L, N, P/Q, and R subtypes of high-voltage-activated calcium channels; in bovine and humans, P/Q channels predominate, whereas in felines and murine species, L-type channels predominate. The calcium channels in chromaffin cells are regulated by G proteins coupled to purinergic and opiate receptors, as well as by voltage and the local changes of [Ca2+]c. Chromaffin cells have been particularly useful in studying calcium channel current autoregulation by materials coreleased with catecholamines, such as ATP and opiates. Depending on the preparation (cultured cells, adrenal slices) and the stimulation pattern (action potentials, depolarizing pulses, high K+, acetylcholine), the role of each calcium channel in controlling catecholamine release can change drastically. Targeted aequorin and confocal microscopy shows that Ca2+ entry through calcium channels can refill the endoplasmic reticulum (ER) to nearly millimolar concentrations, and causes the release of Ca2+ (CICR). Depending on its degree of filling, the ER may act as a sink or source of Ca2+ that modulates catecholamine release. Targeted aequorins with different Ca2+ affinities show that mitochondria undergo surprisingly rapid millimolar Ca2+ transients, upon stimulation of chromaffin cells with ACh, high K+, or caffeine. Physiological stimuli generate [Ca2+]c microdomains in which the local subplasmalemmal [Ca2+]c rises abruptly from 0.1 to ∼50 μM, triggering CICR, mitochondrial Ca2+ uptake, and exocytosis at nearby secretory active sites. The fact that protonophores abolish mitochondrial Ca2+ uptake, and increase catecholamine release three- to fivefold, support the earlier observation. This increase is probably due to acceleration of vesicle transport from a reserve pool to a ready-release vesicle pool; this transport might be controlled by Ca2+ redistribution to the cytoskeleton, through CICR, and/or mitochondrial Ca2+ release. We propose that chromaffin cells have developed functional triads that are formed by calcium channels, the ER, and the mitochondria and locally control the [Ca2+]c that regulate the early and late steps of exocytosis.
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He, Miaomiao, Jie Qiu, Yan Wang, Yang Bai y Guangzhi Chen. "Caveolin-3 and Arrhythmias: Insights into the Molecular Mechanisms". Journal of Clinical Medicine 11, n.º 6 (14 de marzo de 2022): 1595. http://dx.doi.org/10.3390/jcm11061595.
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Caveolin-3 is a muscle-specific protein on the membrane of myocytes correlated with a variety of cardiovascular diseases. It is now clear that the caveolin-3 plays a critical role in the cardiovascular system and a significant role in cardiac protective signaling. Mutations in the gene encoding caveolin-3 cause a broad spectrum of clinical phenotypes, ranging from persistent elevations in the serum levels of creatine kinase in asymptomatic humans to cardiomyopathy. The influence of Caveolin-3(CAV-3) mutations on current density parallels the effect on channel trafficking. For example, mutations in the CAV-3 gene promote ventricular arrhythmogenesis in long QT syndrome 9 by a combined decrease in the loss of the inward rectifier current (IK1) and gain of the late sodium current (INa-L). The functional significance of the caveolin-3 has proved that caveolin-3 overexpression or knockdown contributes to the occurrence and development of arrhythmias. Caveolin-3 overexpression could lead to reduced diastolic spontaneous Ca2+ waves, thus leading to the abnormal L-Type calcium channel current-induced ventricular arrhythmias. Moreover, CAV-3 knockdown resulted in a shift to more negative values in the hyperpolarization-activated cyclic nucleotide channel 4 current (IHCN4) activation curve and a significant decrease in IHCN4 whole-cell current density. Recent evidence indicates that caveolin-3 plays a significant role in adipose tissue and is related to obesity development. The role of caveolin-3 in glucose homeostasis has attracted increasing attention. This review highlights the underlining mechanisms of caveolin-3 in arrhythmia. Progress in this field may contribute to novel therapeutic approaches for patients prone to developing arrhythmia.
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Dienes, Csaba, Tamás Hézső, Dénes Zsolt Kiss, Dóra Baranyai, Zsigmond Máté Kovács, László Szabó, János Magyar et al. "Electrophysiological Effects of the Transient Receptor Potential Melastatin 4 Channel Inhibitor (4-Chloro-2-(2-chlorophenoxy)acetamido) Benzoic Acid (CBA) in Canine Left Ventricular Cardiomyocytes". International Journal of Molecular Sciences 22, n.º 17 (31 de agosto de 2021): 9499. http://dx.doi.org/10.3390/ijms22179499.
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Transient receptor potential melastatin 4 (TRPM4) plays an important role in many tissues, including pacemaker and conductive tissues of the heart, but much less is known about its electrophysiological role in ventricular myocytes. Our earlier results showed the lack of selectivity of 9-phenanthrol, so CBA ((4-chloro-2-(2-chlorophenoxy)acetamido) benzoic acid) was chosen as a new, potentially selective inhibitor. Goal: Our aim was to elucidate the effect and selectivity of CBA in canine left ventricular cardiomyocytes and to study the expression of TRPM4 in the canine heart. Experiments were carried out in enzymatically isolated canine left ventricular cardiomyocytes. Ionic currents were recorded with an action potential (AP) voltage-clamp technique in whole-cell configuration at 37 °C. An amount of 10 mM BAPTA was used in the pipette solution to exclude the potential activation of TRPM4 channels. AP was recorded with conventional sharp microelectrodes. CBA was used in 10 µM concentrations. Expression of TRPM4 protein in the heart was studied by Western blot. TRPM4 protein was expressed in the wall of all four chambers of the canine heart as well as in samples prepared from isolated left ventricular cells. CBA induced an approximately 9% reduction in AP duration measured at 75% and 90% of repolarization and decreased the short-term variability of APD90. Moreover, AP amplitude was increased and the maximal rates of phase 0 and 1 were reduced by the drug. In AP clamp measurements, CBA-sensitive current contained a short, early outward and mainly a long, inward current. Transient outward potassium current (Ito) and late sodium current (INa,L) were reduced by approximately 20% and 47%, respectively, in the presence of CBA, while L-type calcium and inward rectifier potassium currents were not affected. These effects of CBA were largely reversible upon washout. Based on our results, the CBA induced reduction of phase-1 slope and the slight increase of AP amplitude could have been due to the inhibition of Ito. The tendency for AP shortening can be explained by the inhibition of inward currents seen in AP-clamp recordings during the plateau phase. This inward current reduced by CBA is possibly INa,L, therefore, CBA is not entirely selective for TRPM4 channels. As a consequence, similarly to 9-phenanthrol, it cannot be used to test the contribution of TRPM4 channels to cardiac electrophysiology in ventricular cells, or at least caution must be applied.
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Chen, Haiyan y Erika S. Piedras-Rentería. "Altered frequency-dependent inactivation and steady-state inactivation of polyglutamine-expanded α1A in SCA6". American Journal of Physiology-Cell Physiology 292, n.º 3 (marzo de 2007): C1078—C1086. http://dx.doi.org/10.1152/ajpcell.00353.2006.
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Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease of the cerebellum and inferior olives characterized by a late-onset cerebellar ataxia and selective loss of Purkinje neurons ( 15 , 16 ). SCA6 arises from an expansion of the polyglutamine tract located in exon 47 of the α1A (P/Q-type calcium channel) gene from a nonpathogenic size of 4 to 18 glutamines (CAG4–18) to CAG19–33 in SCA6. The molecular basis of SCA6 is poorly understood. To date, the biophysical properties studied in heterologous systems support both a gain and a loss of channel function in SCA6. We studied the behavior of the human α1A isoform, previously found to elicit a gain of function in disease ( 41 ), focusing on properties in which the COOH terminus of the channel is critical for function: we analyzed the current properties in the presence of β4- and β2a-subunits (both known to interact with the α1A COOH terminus), current kinetics of activation and inactivation, calcium-dependent inactivation and facilitation, voltage-dependent inactivation, frequency dependence, and steady-state activation and inactivation properties. We found that SCA6 channels have decreased activity-dependent inactivation and a depolarizing shift (+6 mV) in steady-state inactivation properties consistent with a gain of function.
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Khare, Ekta y Zeeshan Fatima. "Recent advances and current perspectives in treatment of Alzheimer’s disease". Environment Conservation Journal 21, n.º 1&2 (10 de junio de 2020): 183–86. http://dx.doi.org/10.36953/ecj.2020.211224.
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Dementia is a disorder which is associated with disruption of cerebral neurons, resulting in its characteristic symptomatology. Acetylcholine neurotransmitter is found to be significant for processing memory and learning. However it is diminished in both concentration and function in patients with Alzheimer disease. Nootropics are the drugs which is used to improve memory and learning by acting as AChEI (Acetyl cholineesterase inhibitors). Cognitive enhancers include drugs interacting with receptors (e.g. NMDA receptor antagonist: memantine), Enzymes (e.g. AChE inhibitors: tacrine, donepezil, galantamine), Antioxidants (e.g. resveratrol, curcumin, and acetyl-L-carnitine), Metal chelators (e.g. calcium and zinc chelator: DP-b99), Vaccines, Monoclonal antibodies (e.g. A beta-Amyloid: solanezumab under Phase III clinical trial). Apart from the pharmacological approaches, supplementation of a healthy diet and healthy physical & mental lifestyle impact cognitive research in the future. There is no remedy for AD. Contemporary treatments just relive the behaviourial symptoms.Treatment centers around making a superior personal satisfaction for the individuals with Alzheimer infection. As of late, undifferentiated cell innovation (stem cell technology), and Nanotechnology has given new bits of knowledge into the treatment of Alzheimer's disease. In this review, we talk about current indicative medicines and future difficulties for new potential illness altering treatments.
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Kim, Hyun Jong, Yu Ran Nam, Eun-Jung Kim, Joo Hyun Nam y Woo Kyung Kim. "Spirodela polyrhiza and its Chemical Constituent Vitexin Exert Anti-Allergic Effect via ORAI1 Channel Inhibition". American Journal of Chinese Medicine 46, n.º 06 (enero de 2018): 1243–61. http://dx.doi.org/10.1142/s0192415x18500659.
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Intracellular calcium signaling cascades are integral to early and late allergic responses involving mast cell degranulation and type 2 helper T cell activation, respectively. Both the responses are accompanied by the movement of calcium through the calcium release-activated calcium (CRAC) channel, encoded by the ORAI1 gene. Spirodela polyrhiza (L.) Schleid (SP) has anti-inflammatory and anti-allergic effects, but its effect on calcium signaling has not been reported. This study investigated whether a 30% ethanolic SP extract (SPEtOH) and its constituents can reduce CRAC currents ([Formula: see text]), and thus inhibit mast cell degranulation and T cell activation. In Jurkat T lymphocytes, we found that 3[Formula: see text]mg/mL SPEtOH inhibited the [Formula: see text] by [Formula: see text]%, whereas one of its constituents vitexin (100[Formula: see text][Formula: see text]M) inhibited the [Formula: see text] by [Formula: see text]%. Furthermore, in the RBL-2H3 mast cell, the [Formula: see text] was inhibited by 3[Formula: see text]mg/mL SPEtOH ([Formula: see text]%) and 100[Formula: see text][Formula: see text]M vitexin ([Formula: see text]%). Investigation of human primary T cell proliferation induced by co-stimulation with antibodies to cluster of differentiation 3 and 28, and of RBL-2H3 mast cell degranulation following IgE-antigen complex stimulation revealed that 100[Formula: see text][Formula: see text]M vitexin inhibited both T-cell proliferation (by [Formula: see text]%) and mast cell degranulation (by [Formula: see text]%). These effects were concentration-dependent, and no cytotoxicity was observed. Our findings suggest that vitexin is a promising candidate compound for the development of therapeutic agents to prevent and treat allergic diseases.
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Huang, Jingbo, Leif Hove-Madsen y Glen F. Tibbits. "SR Ca2+ refilling upon depletion and SR Ca2+ uptake rates during development in rabbit ventricular myocytes". American Journal of Physiology-Cell Physiology 293, n.º 6 (diciembre de 2007): C1906—C1915. http://dx.doi.org/10.1152/ajpcell.00241.2007.
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While it has been reported that a sparse sarcoplasmic reticulum (SR) and a low SR Ca2+ pump density exist at birth, we and others have recently shown that significant amounts of Ca2+ are stored in the neonatal rabbit heart SR. Here we try to determine developmental changes in SR Ca2+ loading mechanisms and Ca2+ pump efficacy in rabbit ventricular myocytes. SR Ca2+ loading (loadSR) and k0.5 (Ca2+ concentration at half-maximal SR Ca2+ uptake) were higher and lower, respectively, in younger age groups. Inhibition of the L-type calcium current ( ICa) with 15 μM nifedipine dramatically reduced loadSR in older but not in younger age groups. In contrast, subsequent inhibition of the Na+/Ca2+ exchanger (NCX) with 10 μM KB-R7943 strongly reduced loadSR in the younger but not the older age groups. Accordingly, the time integral of the inward NCX current (tail INCX) elicited on repolarization was highly sensitive to nifedipine in the older groups and sensitive to KB-R7943 in the younger groups. Interestingly, slow SR loading took place in the presence of both nifedipine and KB-R7943 in all age groups, although it was less prominent in the older groups. We conclude that the SR loading capacity at the earliest postnatal stages is at least as large as that of adult myocytes. However, reverse-mode NCX plays a prominent role in SR Ca2+ loading at early postnatal stages while ICa is the main source of SR Ca2+ loading at late postnatal and adult stages.
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Hussain, Syed Ashaq, Sanjeev Kumar Uppal, Naresh Kumar Sood y Shashi Kant Mahajan. "Clinico Hemato Biochemical Findings, Clinical Management, and Production Performance of Bovines with Late Pregnancy Indigestion (Type IV Vagal Indigestion)". Veterinary Medicine International 2014 (2014): 1–6. http://dx.doi.org/10.1155/2014/525607.
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This prospective study was conducted on 15 animals (eight buffaloes and seven cows), diagnosed with late pregnancy indigestion. Ten buffaloes and 10 cows served as the control group. The animals were in advanced pregnancy and had partial or complete anorexia, reduced water intake, loss of defecation or scanty faecal output, and mild to moderate dehydration. Heart and respiration rates were increased and rumen motility was reduced. Five animals had persistent tympany and moderate distension of left abdomen, and two animals each had bilateral abdominal distension and papple shaped abdomen. Neutrophil and lymphocyte counts were significantly higher and lower than the control values. Total bilirubin, AST, total protein, globulin, BUN, glucose, and lactate were significantly higher, and chloride and calcium were significantly lower than the control values. Levels of ALP, GGT, albumin, creatinine, cholesterol, triglyceride, fibrinogen, fibrinogen ratio, sodium, potassium, phosphorus, and magnesium did not differ significantly from the control values. Rumen chloride concentration was higher than the reference range. Majority of animals were managed symptomatically until parturition. There was no effect on fetal survival or milk yield in current and subsequent lactation. So, late pregnancy indigestion causes clinical and hemato biochemical alterations which require special consideration when treating diseased animals.
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Parveen, Saltanat y Altaf H. Ganai. "Physico-chemical conditions at Watlab ghat in Wular lake, Kashmir". Environment Conservation Journal 14, n.º 3 (21 de diciembre de 2013): 1–7. http://dx.doi.org/10.36953/ecj.2013.14301.
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The present limnological investigations include analysis of various physico- chemical parameters at the selected site in Wular lake, Kashmir (a Ramsar site) from March, 2007 to February, 2008. The aim of current study was to evaluate the status of the Wular lake water on the basis of different physico-chemical conditions. The water depth ranged from 1.35 (m) to 2.60 (m). The pH of the water was on alkaline side throughout the study period. The lake depicted the usual cation progression: Ca > Mg. The lake can be categorized as calcium rich after Ohle (1934). Specific conductance was found low in spring and summer. High values of transparency were recorded in winter. The lake water is typical hard water type. The alkalinity was due to bicarbonates only. High values of both NO3–N (338 ?g/L) and PO4–P (203 ?g/L) were recorded during summer. Statistical analysis was also carried out to find out the degree of relationship between various abiotic factors. Dissolved oxygen showed significant negative correlation with water temperature (r = –0.839), whereas significant positive correlation with pH (r = 0.854) at the selected site. pH showed significant negative correlation with water temperature (r = –0.777) and CO2 (r = –0.854) respectively, at the selected site.
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Lee, J. K., I. Kodama, H. Honjo, T. Anno, K. Kamiya y J. Toyama. "Stage-dependent changes in membrane currents in rats with monocrotaline-induced right ventricular hypertrophy". American Journal of Physiology-Heart and Circulatory Physiology 272, n.º 6 (1 de junio de 1997): H2833—H2842. http://dx.doi.org/10.1152/ajpheart.1997.272.6.h2833.
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Sequential changes in action potential configuration, 4-amino-pyridine-sensitive transient outward current (Ito), and L-type calcium current (ICa) in association with hypertrophy were investigated in ventricular myocytes from rats with monocrotaline (MCT)-induced pulmonary hypertension. The tissue weight ratio of right ventricle (RV) to left ventricle plus septum 14 and 28 days after a subcutaneous injection of MCT increased by 29.7 and 77.2%, respectively. Action potential duration (APD) of RV cells from MCT rats increased progressively, prolonged by 73.2 and 92.2% on days 14 and 28, respectively. The current density of Ito in RV cells from MCT rats on day 14 (32.5 +/- 4.5 pA/pF, n = 13) was significantly larger than in controls (26.8 +/- 4.5 pA/pF, n = 8; P < 0.05). On day 28, however, Ito density in MCT rats (15.3 +/- 4.6 pA/pF, n = 9) was significantly less than in controls (27.3 +/- 4.2 pA/pF, n = 10; P < 0.05). There were no differences in the voltage dependence of steady-state activation and inactivation of Ito between MCT and control rats. ICa density in MCT rats on day 14 (15.7 +/- 2.6 pA/pF, n = 10) was significantly larger than in controls (10.0 +/- 2.3 pA/pF, n = 10; P < 0.05), but there was no significant difference in Ito density between MCT rats (8.3 +/- 3.7 pA/pF, n = 10) and controls (11.6 +/- 3.0 pA/pF, n = 10) on day 28. These findings suggest that hypertrophy of mammalian hearts may cause stage-dependent changes in Ito and ICa density of ventricular myocytes. The APD prolongation in the early stage of hypertrophy may be caused mainly by an increase in ICa density, whereas the APD prolongation in the late stage may be ascribed to a reduction in Ito density.
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THOMAS, David, Hak Yong KIM y Michael R. HANLEY. "Regulation of inositol trisphosphate-induced membrane currents in Xenopus oocytes by a Jurkat cell calcium influx factor". Biochemical Journal 318, n.º 2 (1 de septiembre de 1996): 649–56. http://dx.doi.org/10.1042/bj3180649.
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The functional interactions of a Jurkat cell-derived calcium influx factor (CIF) with Ins(1,4,5)P3 were examined by microinjection and voltage-clamp recording of current responses in Xenopus oocytes. CIF, which stimulates Ca2+ entry directly on microinjection, was active at dilutions at which it had no direct effect by augmenting both initial rapid Ins(1,4,5)P3-mediated Ca2+ discharge-activated currents and later sustained Ca2+ entry-activated currents. Augmented initial membrane currents were 3–5-fold greater in peak amplitude than currents evoked by injection of the same dose of Ins(1,4,5)P3 alone. The augmented initial response was not decreased by removal of extracellular Ca2+, suggesting that there is potentiation of Ins(1,4,5)P3-mediated discharge from intracellular Ca2+ stores. However, the augmentation of Ins(1,4,5)P3-mediated discharge cannot be due to an enhanced production of endogenous Ins(1,4,5)P3 because maximal Ins(1,4,5)P3-activated currents saturate (approx. 500 nA) with supramaximal levels of Ins(1,4,5)P3 (10–50 µM). Depletion of Ca2+ stores, by pretreatment with thapsigargin or by prior injection with the Ins(1,4,5)P3 receptor antagonist heparin, abolished membrane currents elicited by Ins(1,4,5)P3/CIF co-injection, further suggesting that the Ins(1,4,5)P3 receptor was the target for the initial-current-potentiating actions of CIF. In this regard, CIF also induced augmented initial currents with co-injection of either Ins(2,4,5)P3 or Ins(1,3,4,5)P4. The augmentation of Ins(1,4,5)P3-mediated currents by CIF was bell-shaped with regard to Ins(1,4,5)P3 concentration, reminiscent of the regulatory influence of Ca2+ on Ins(1,4,5)P3 responses. Co-injection of Ins(1,4,5)P3 and CIF also augmented (2–3-fold) later current responses arising from sustained Ca2+ entry. The augmented late-current responses were not due to enhanced Ca2+ store depletion because supramaximal levels of Ins(1,4,5)P3 (50 µM) or injection of the poorly metabolized Ins(1,4,5)P3 analogue, Ins(2,4,5)P3, cannot activate the same magnitude of Ca2+-entry-dependent currents. These results suggest that CIF at low levels interacts with Ins(1,4,5)P3 to sensitize two pathways of Ca2+ signalling: initial discharge and later Ca2+ entry. Thus under physiological conditions CIF might be more potent as a co-messenger than as a direct Ca2+ entry signal and might provide a novel type of direct feedback regulation between the stores-activated influx pathway and the Ins(1,4,5)P3 receptor. Moreover these results suggest that CIF modulation of the receptor for Ins(1,4,5)P3 may underlie control of both augmentation of discharge and Ca2+ entry, as has been predicted from the conformational coupling model of Ca2+ entry.
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da Silva, Maria Vitoria, Artur Santos-Miranda, Julliane V. Joviano-Santos, Diego Santos Souza, Leisiane Pereira Marques, Jaqueline Oliveira Sarmento, Samuel Santos Beserra y Danilo Roman-Campos. "The insecticide β-Cyfluthrin induces acute arrhythmic cardiotoxicity through interaction with NaV1.5 and ranolazine reverses the phenotype". Clinical Science 136, n.º 5 (marzo de 2022): 329–43. http://dx.doi.org/10.1042/cs20211151.
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Abstract β-Cyfluthrin, a class II Pyrethroid, is an insecticide used worldwide in agriculture, horticulture (field and protected crops), viticulture, and domestic applications. β-Cyfluthrin may impair the function of biological systems; however, little information is available about its potential cardiotoxic effect. Here, we explored the acute toxicity of β-Cyfluthrin in isolated heart preparations and its cellular basis, using isolated cardiomyocytes. Moreover, β-Cyfluthrin effects on the sodium current, especially late sodium current (INa-L), were investigated using human embryonic kidney cells (HEK-293) cells transiently expressing human NaV1.5 channels. We report that β-Cyfluthrin raised INa-L in a dose-dependent manner. β-Cyfluthrin prolonged the repolarization of the action potential (AP) and triggered oscillations on its duration. Cardiomyocytes contraction and calcium dynamics were disrupted by the pesticide with a marked incidence of non-electronic-stimulated contractions. The antiarrhythmic drug Ranolazine was able to reverse most of the phenotypes observed in isolated cells. Lastly, ventricular premature beats (VPBs) and long QT intervals were found during β-Cyfluthrin exposure, and Ranolazine was able to attenuate them. Overall, we demonstrated that β-Cyfluthrin can cause significant cardiac alterations and Ranolazine ameliorated the phenotype. Understanding the insecticides’ impacts upon electromechanical properties of the heart is important for the development of therapeutic approaches to treat cases of pesticides intoxication.
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Chandler, S. H., C. F. Hsaio, T. Inoue y L. J. Goldberg. "Electrophysiological properties of guinea pig trigeminal motoneurons recorded in vitro". Journal of Neurophysiology 71, n.º 1 (1 de enero de 1994): 129–45. http://dx.doi.org/10.1152/jn.1994.71.1.129.
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1. Intracellular recording and stimulation were made from guinea pig trigeminal motoneurons (TMNs) in brain stem slices. Electrophysiological properties were examined and the underlying currents responsible for motoneuron excitability were investigated by the use of current clamp and single electrode voltage clamp (SEVC) techniques. 2. The voltage responses to subthreshold hyperpolarizing or depolarizing current pulses showed voltage- and time-dependent inward rectification. SEVC analysis demonstrated that the hyperpolarizing inward rectification resulted from the development of a slowly occurring voltage-dependent inward current activated at hyperpolarized membrane potentials. This current persisted in solutions containing low Ca2+/Mn2+, tetraethylammonium (TEA), and Ba2+, whereas it was reduced by 1–3 mM cesium. The depolarizing inward rectification was mediated by a persistent sodium current (INa-P) that was completely abolished by bath application of tetrodotoxin (TTX). 3. Action potential characteristics were studied by intracellular stimulation with brief current pulses (< 3 ms) in combination with ionic substitutions or application of specific ionic conductance blocking agents. Bath application of TTX abolished the action potential, whereas 1–10 mM TEA or 0.5–2 mM 4-aminopyridine (4-AP) increased, significantly, the spike duration, suggesting participation of the delayed rectifier and A-current type conductances in spike repolarization. SEVC analysis revealed a TEA-sensitive sustained outward current and a fast, voltage-dependent, transient current with properties consistent with their roles in spike repolarization. 4. TMN afterhyperpolarizing potentials (AHPs) that followed a single spike consisted of fast and slow components usually separated by a depolarizing hump [afterdepolarization (ADP)]. The fast component was abolished by TEA or 4-AP but not by Mn2+, Co2+, or the bee venom apamin. In contrast, the slow AHP was readily reduced by Mn2+, Co2+, or apamin, suggesting participation of an apamin-sensitive, calcium-dependent K+ conductance in the production of the slow AHP. SEVC analysis and ionic substitutions demonstrated a slowly activating and deactivating calcium-dependent K+ current with properties that could account for the slow AHP observed in these neurons. 5. Repetitive discharge was examined with long depolarizing current pulses (1 s) and analysis of frequency-current plots. When evoked from resting potential (about -55 mV), spike onset from rheobase occurred rapidly and was maintained throughout the current pulse. At higher current intensities, early and late adaptations in spike discharge were observed. Frequency-current plots exhibited a bilinear relationship for the first interspike interval (ISI) in approximately 50% of the neurons tested and in most neurons tested during steady-state discharge (SS).(ABSTRACT TRUNCATED AT 400 WORDS)
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Kuijpers, Nico H. L., Evelien Hermeling, Joost Lumens, Huub M. M. ten Eikelder, Tammo Delhaas y Frits W. Prinzen. "Mechano-electrical coupling as framework for understanding functional remodeling during LBBB and CRT". American Journal of Physiology-Heart and Circulatory Physiology 306, n.º 12 (15 de junio de 2014): H1644—H1659. http://dx.doi.org/10.1152/ajpheart.00689.2013.
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It is not understood why, after onset of left bundle-branch block (LBBB), acute worsening of cardiac function is followed by a further gradual deterioration of function, whereas most adverse cardiac events lead to compensatory adaptations. We investigated whether mechano-electrical coupling (MEC) can explain long-term remodeling with LBBB and cardiac resynchronization therapy (CRT). To this purpose, we used an integrative modeling approach relating local ventricular electrophysiology, calcium handling, and excitation-contraction coupling to global cardiovascular mechanics and hemodynamics. Each ventricular wall was composed of multiple mechanically and electrically coupled myocardial segments. MEC was incorporated by allowing adaptation of L-type Ca2+ current aiming at minimal dispersion of local external work, an approach that we previously applied to replicate T-wave memory in a synchronous heart after a period of asynchronous activation. LBBB instantaneously decreased left-ventricular stroke work and increased end-diastolic volume. During sustained LBBB, MEC reduced intraventricular dispersion of mechanical workload and repolarization. However, MEC-induced reduction in contractility in late-activated regions was larger than the contractility increase in early-activated regions, resulting in further decrease of stroke work and increase of end-diastolic volume. Upon the start of CRT, stroke work increased despite a wider dispersion of mechanical workload. During sustained CRT, MEC-induced reduction in dispersion of workload and repolarization coincided with a further reduction in end-diastolic volume. In conclusion, MEC may represent a useful framework for better understanding the long-term changes in cardiac electrophysiology and contraction following LBBB as well as CRT.
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Vaidyanathan, Ravi, Yogananda S. Markandeya, Timothy J. Kamp, Jonathan C. Makielski, Craig T. January y Lee L. Eckhardt. "IK1-enhanced human-induced pluripotent stem cell-derived cardiomyocytes: an improved cardiomyocyte model to investigate inherited arrhythmia syndromes". American Journal of Physiology-Heart and Circulatory Physiology 310, n.º 11 (1 de junio de 2016): H1611—H1621. http://dx.doi.org/10.1152/ajpheart.00481.2015.
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Currently available induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) do not ideally model cellular mechanisms of human arrhythmic disease due to lack of a mature action potential (AP) phenotype. In this study, we create and characterize iPS-CMs with an electrically mature AP induced by potassium inward rectifier ( IK1) enhancement. The advantages of IK1-enhanced iPS-CMs include the absence of spontaneous beating, stable resting membrane potentials at approximately −80 mV and capability for electrical pacing. Compared with unenhanced, IK1-enhanced iPS-CMs calcium transient amplitudes were larger ( P < 0.05) with a typical staircase pattern. IK1-enhanced iPS-CMs demonstrated a twofold increase in cell size and membrane capacitance and increased DNA synthesis compared with control iPS-CMs ( P < 0.05). Furthermore, IK1-enhanced iPS-CMs expressing the F97C-CAV3 long QT9 mutation compared with wild-type CAV3 demonstrated an increase in AP duration and late sodium current. IK1-enhanced iPS-CMs represent a more mature cardiomyocyte model to study arrhythmia mechanisms.
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Mercer, Alison R. y John G. Hildebrand. "Developmental Changes in the Electrophysiological Properties and Response Characteristics of Manduca Antennal-Lobe Neurons". Journal of Neurophysiology 87, n.º 6 (1 de junio de 2002): 2650–63. http://dx.doi.org/10.1152/jn.2002.87.6.2650.
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Using whole cell patch-clamp recordings, we have examined changes in the electrophysiological properties and response characteristics of antennal lobe (AL) neurons associated with the metamorphic adult development of the sphinx moth, Manduca sexta. Whole cell current profiles and electrical excitability were examined in dispersed AL neurons in vitro, and in medial-group AL neurons in situ in semi-intact brain preparations. Around stages 2–4 of the 18 stages of metamorphic adult development, whole cell current profiles were dominated by large outward (K+) currents. Calcium-dependent action potentials could be elicited at this stage, but only a small percentage of cells exhibited sodium spikes. From stages 3 to 10, there was a rapid increase in the proportion of AL neurons exhibiting rapidly activating, transient sodium currents, and many cells in vitro exhibited spontaneous bursts of spike activity at this time. As development progressed, action-potential waveforms became shorter in duration and larger in amplitude. Cell-type–specific differences in the prevalence of spontaneous activity, and in the electrophysiological properties and response characteristics of AL neurons, were most apparent late in metamorphosis. While removal of antennal sensory input to the ALs early (stage 1–2) in metamorphosis had no detectable effect on the development of cell excitability, a significantly higher percentage of neurons in vitro from stage 4 pupae exhibited sodium-based action potentials following the addition of serotonin to the culture medium. Characteristic forms of electrical excitability in developing Manduca AL neurons, and their modulation by serotonin, seem likely to play a central role in the functional development of the ALs.
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McBeath, T. M., M. J. McLaughlin, R. D. Armstrong, M. Bell, M. D. A. Bolland, M. K. Conyers, R. E. Holloway y S. D. Mason. "Predicting the response of wheat (Triticum aestivum L.) to liquid and granular phosphorus fertilisers in Australian soils". Soil Research 45, n.º 6 (2007): 448. http://dx.doi.org/10.1071/sr07044.
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Liquid forms of phosphorus (P) have been shown to be more effective than granular P for promoting cereal growth in alkaline soils with high levels of free calcium carbonate on Eyre Peninsula, South Australia. However, the advantage of liquid over granular P forms of fertiliser has not been fully investigated across the wide range of soils used for grain production in Australia. A glasshouse pot experiment tested if liquid P fertilisers were more effective for growing spring wheat (Triticum aestivum L.) than granular P (monoammonium phosphate) in 28 soils from all over Australia with soil pH (H2O) ranging from 5.2 to 8.9. Application of liquid P resulted in greater shoot biomass, as measured after 4 weeks’ growth (mid to late tillering, Feeks growth stage 2–3), than granular P in 3 of the acidic to neutral soils and in 3 alkaline soils. Shoot dry matter responses of spring wheat to applied liquid or granular P were related to soil properties to determine if any of the properties predicted superior yield responses to liquid P. The calcium carbonate content of soil was the only soil property that significantly contributed to predicting when liquid P was more effective than granular P. Five soil P test procedures (Bray, Colwell, resin, isotopically exchangeable P, and diffusive gradients in thin films (DGT)) were assessed to determine their ability to measure soil test P on subsamples of soil collected before the experiment started. These soil test values were then related to the dry matter shoot yields to assess their ability to predict wheat yield responses to P applied as liquid or granular P. All 5 soil test procedures provided a reasonable prediction of dry matter responses to applied P as either liquid or granular P, with the resin P test having a slightly greater predictive capacity on the range of soils tested. The findings of this investigation suggest that liquid P fertilisers do have some potential applications in non-calcareous soils and confirm current recommendations for use of liquid P fertiliser to grow cereal crops in highly calcareous soils. Soil P testing procedures require local calibration for response to the P source that is going to be used to amend P deficiency.
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Boulay, Emmanuel, Matthew M. Abernathy, Ray Chui, Gregory S. Friedrichs, Nicolas Gendron-Parra, Andrea Greiter-Wilke, Jean-Michel Guillon et al. "A Proof-of-Concept Evaluation of JTPc and Tp-Tec as Proarrhythmia Biomarkers in Preclinical Species: A Retrospective Analysis by an HESI-Sponsored Consortium". International Journal of Toxicology 38, n.º 1 (19 de diciembre de 2018): 23–32. http://dx.doi.org/10.1177/1091581818813601.
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Introduction: Based on the ICH S7B and E14 guidance documents, QT interval (QTc) is used as the primary in vivo biomarker to assess the risk of drug-induced torsades de pointes (TdP). Clinical and nonclinical data suggest that drugs that prolong the corrected QTc with balanced multiple ion channel inhibition (most importantly the l-type calcium, Cav1.2, and persistent or late inward sodium current, Nav1.5, in addition to human Ether-à-go-go-Related Gene [hERG] IKr or Kv11.1) may have limited proarrhythmic liability. The heart rate-corrected J to T-peak (JTpc) measurement in particular may be considered to discriminate selective hERG blockers from multi-ion channel blockers. Methods: Telemetry data from Beagle dogs given dofetilide (0.3 mg/kg), sotalol (32 mg/kg), and verapamil (30 mg/kg) orally and Cynomolgus monkeys given medetomidine (0.4 mg/kg) orally were retrospectively analyzed for effects on QTca, JTpca, and T-peak to T-end covariate adjusted (Tpeca) interval using individual rate correction and super intervals (calculated from 0-6, 6-12, 12-18, and 18-24 hours postdose). Results: Dofetilide and cisapride (IKr or Kv11.1 blockers) were associated with significant increases in QTca and JTpca, while sotalol was associated with significant increases in QTca, JTpca, and Tpeca. Verapamil (a Kv11.1 and Cav1.2 blocker) resulted in a reduction in QTca and JTpca, however, and increased Tpeca. Medetomidine was associated with a reduction in Tpeca and increase in JTpca. Discussion: Results from this limited retrospective electrocardiogram analysis suggest that JTpca and Tpeca may discriminate selective IKr blockers and multichannel blockers and could be considered in the context of an integrated comprehensive proarrhythmic risk assessment.
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Kinney, Gregory A., Linda S. Overstreet y N. Traverse Slater. "Prolonged Physiological Entrapment of Glutamate in the Synaptic Cleft of Cerebellar Unipolar Brush Cells". Journal of Neurophysiology 78, n.º 3 (1 de septiembre de 1997): 1320–33. http://dx.doi.org/10.1152/jn.1997.78.3.1320.
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Kinney, Gregory A., Linda S. Overstreet, and N. Traverse Slater. Prolonged physiological entrapment of glutamate in the synaptic cleft of cerebellar unipolar brush cells. J. Neurophysiol. 78: 1320–1333, 1997. The cellular mechanism underlying the genesis of the long-lasting α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptor-mediated excitatory postsynaptic currents (EPSCs) at the mossy fiber (MF)–unipolar brush cell (UBC) synapse in rat vestibular cerebellum was examined with the use of whole cell and excised patch-clamp recording methods in thin cerebellar slices. Activation of MFs evokes an all-or-none biphasic AMPA-receptor-mediated synaptic current with a late component that peaks at 100–800 ms, which has been proposed to originate from an entrapment of glutamate in the MF-UBC synaptic cleft and is generated by the steady-state activation of AMPA receptors. Bath application of cyclothiazide, which blocks desensitization of AMPA receptors, produced a dose-dependent enhancement of the amplitude of the synaptic current (median effective dose 30 μM) and slowing of the rise time of the fast EPSC. N-methyl-d-aspartate-receptor-mediated EPSCs in UBCs were not potentiated in amplitude or time course by cyclothiazide (100 μM). The dose-response relations for the steady-state current evoked by glutamate acting at AMPA receptors in excised outside-out patches from UBC and granule somatic membranes was biphasic, peaking at 50 μM and declining to 50–70% of this value at 1 mM glutamate. When glutamate was slowly washed from patches to simulate the gradual decline of glutamate in the synapse, a late hump in the transmembrane current was observed in patches from both cell types. The delivery of a second MF stimulus at the peak of the slow EPSC evoked a fast EPSC of reduced amplitude followed by an undershoot of the subsequent slow current, consistent with the hypothesis that the peak of the slow EPSC reflects the peak of the biphasic steady-state dose-response curve. Estimates of receptor occupancy and glutamate concentration derived from the ratio of fast EPSC amplitudes, and the amplitude and polarity of the initial steady-state current in paired-pulse experiments, predict a slow decline of glutamate with a time constant of 800 ms, declining to ineffective concentrations at 5.4 s. Manipulation of cleft glutamate concentration by lowered extracellular calcium or delivery of brief stimulus trains abolished the slow EPSC and restored the undershoot to paired stimuli, respectively, in a manner consistent with a prolonged lifetime of glutamate in the cleft. The slow component of the EPSC was prolonged in duration by the glutamate reuptake inhibitor l- trans-pyrrolidine-2,4-dicarboxylate, suggesting that glutamate transport contributes to the time course of the synaptic current in UBCs. The data support the notion that the MF-UBC synapse represents an ultrastructural specialization to effectively entrap glutamate for unusually prolonged periods of time following release from MF terminals. The properties of the postsynaptic receptors and constraints on diffusional escape of glutamate imposed by synaptic ultrastructure and glutamate transporters act in concert to sculpt the time course of the resulting slow EPSC. This in turn drives a long-lasting train of action potentials in response to single presynaptic stimuli.
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Strik, Bernadine C. y Amanda J. Vance. "Seasonal Variation in Leaf Nutrient Concentration of Northern Highbush Blueberry Cultivars Grown in Conventional and Organic Production Systems". HortScience 50, n.º 10 (octubre de 2015): 1453–66. http://dx.doi.org/10.21273/hortsci.50.10.1453.
Texto completoResumen
Northern highbush blueberry (Vaccinium corymbosum L.) cultivars were evaluated for leaf and fruit nutrient concentration at two production sites in 2013–14. The treatments included cultivar (Duke, Bluecrop, Draper, Legacy, Liberty, and Aurora), site [“conventional” (conventionally managed, grower-collaborator site) and “organic” (certified organic research site)], and amendment–mulch [at the organic site only; “organic mulch” (included preplant amendment and a surface mulch of yard debris compost and sawdust); and “weed mat” (no preplant amendments but with a sawdust mulch topped with weed mat)]. Leaf samples were collected every 2 weeks in all treatment plots from late April through early October of each year. Ripe fruit were subsampled from the second harvest for each cultivar. Fruiting season varied from 22 June to 19 Sept. and the highest yielding cultivar, Legacy, had 114% to 330% greater yield than the lowest, Duke, depending on year and site. Cultivar had a significant effect on all fruit nutrients except for phosphorus (P) at the conventional site. Nitrogen (N) and potassium (K) accounted for the largest proportion of nutrient content in the fruit, with 10 to 52 kg·ha–1 and 7 to 34 kg·ha–1 removed in the harvested fruit, respectively, depending on cultivar and site. Fruit carbon concentration ranged from 32% to 44% dry weight with 0.5 to 3.2 t·ha–1 removed in harvested fruit. There were significant year, site, and cultivar effects on leaf nutrient concentrations on many sample dates throughout the season. Despite relatively large differences in management between sites and yield and fruiting season among cultivars, the pattern in leaf nutrient concentration over sampling time was relatively similar between sites and years. Leaf manganese (Mn) and aluminum (Al) concentrations were higher when plants were grown with weed mat as compared with the organic mulch treatment, because soil pH was lower under weed mat than in the organic mulch treatment. ‘Liberty’ had the highest leaf N throughout much of the season at the conventional site. There were relatively large differences among cultivars in leaf magnesium (Mg), calcium (Ca), and K when sampling from mid-July to autumn at both sites. ‘Duke’ and ‘Bluecrop’ tended to have the highest leaf K during this period, whereas ‘Legacy’ and ‘Liberty’ had the lowest. There were greater differences in leaf Ca among cultivars at the conventional site than at the organic site. ‘Draper’ and ‘Legacy’ had higher leaf Ca than ‘Duke’. Leaf nutrient concentrations were within the current published sufficiency levels on many sample dates throughout the season for P, Mg, sulfur (S), Mn, and zinc (Zn), on many dates in midseason for K and Ca, and from mid- to late-season for boron (B) and iron (Fe). However, only when sampled in late July to early August, the current recommended sampling time, was leaf N within sufficiency range. Moreover, there was an effect of cultivar on the concentration of most leaf nutrients at both sites when sampled in late July to early August. The recommended sampling time to determine plant nutrient status in northern highbush blueberry should remain at late July to mid-August, regardless of cultivar, when most nutrients are relatively stable. We recommend lowering the leaf sufficiency range for P and copper (Cu) based on our findings.