Journal articles on the topic 'Calcium channel sensitizers'
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Lai, Tsung-Hsuan, Yuan-Feng Lin, Feng-Chang Wu, and Yu-Hui Tsai. "Follicle-Stimulating Hormone-Induced Gαh/Phospholipase C-δ1 Signaling Mediating a Noncapacitative Ca2+ Influx through T-Type Ca2+ Channels in Rat Sertoli Cells." Endocrinology 149, no. 3 (December 6, 2007): 1031–37. http://dx.doi.org/10.1210/en.2007-1244.
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Our previous study demonstrated that FSH-induced immediate Ca2+ influx in rat Sertoli cells (SCs) is mediated by the Gαh/phospholipase C-δ1 (PLC-δ1) signaling pathway. As to which Ca2+ channel is responsible for such Ca2+ influx was not understood. In this study, thapsigargin triggered an in-store calcium release and evoked a 1.5-fold elevation of intracellular Ca2+ in Ca2+-free media, whereas FSH exhibited no effect. The readdition of CaCl2 (2.5 mm) to FSH-pretreated or thapsigargin-sensitized SCs in Ca2+-free media immediately elicited a rapid Ca2+ influx or a 2-fold increase of second intracellular Ca2+ elevation, respectively. The addition of Ca2+ chelator EGTA (0.2 mm) reduced the FSH-induced elevation of intracellular Ca2+ in SCs incubated with CaCl2. However, pretreatment with dantrolene (25 μM), which inhibits in-store calcium release, did not affect the FSH-induced elevation of intracellular Ca2+. NiCl2 (10 μM), a T-type calcium channel blocker, abolished the FSH-induced SC Ca2+ influx. Furthermore, mibefradil (10 and 100 μm), another specific blocker for T-type Ca2+ channels, dose-dependently suppressed the FSH-induced Ca2+ influx. In contrast, nifedipine (10 and 50 μm) or ω-conotoxin GVIA (100 and 500 nm), blocker of L- or N-type Ca2+ channels, respectively, did not affect the FSH-induced SC Ca2+ influx. On the other hand, FSH-induced Ca2+ influx was significantly reduced by pretreatment of SCs with myristoylated synthetic peptide (0.1 and 1 μm) of PLC-δ1 fragment TIPWNSLKQGYRHVHLL but not affected by 2′,5′-dideoxyadenosine (3 and 15 μm), a selective inhibitor of adenylate cyclase. In conclusion, the FSH-induced Gαh/PLC-δ1 pathway-dependent Ca2+ influx of rat SCs is mediated by T-type Ca2+ channels and independent of in-store calcium release.
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Varpula, Tero, Janne Rapola, Marko Sallisalmi, and Jouni Kurola. "Treatment of Serious Calcium Channel Blocker Overdose With Levosimendan, a Calcium Sensitizer." Anesthesia & Analgesia 108, no. 3 (March 2009): 790–92. http://dx.doi.org/10.1213/ane.0b013e3181931737.
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Ham, Seok Won, Hee-Young Jeon, and Hyunggee Kim. "Verapamil augments carmustine- and irradiation-induced senescence in glioma cells by reducing intracellular reactive oxygen species and calcium ion levels." Tumor Biology 39, no. 5 (May 2017): 101042831769224. http://dx.doi.org/10.1177/1010428317692244.
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Resistance to conventional therapies and frequent recurrence are the major obstacles to the treatment of high-grade gliomas, including glioblastoma. Thus, the development of new therapeutic strategies to overcome these obstacles is necessary to improve the treatment outcomes. In this study, we found that verapamil, a pan–adenosine triphosphate–binding cassette transporter and L-type voltage-dependent calcium channel inhibitor, sensitized U87MG glioma cells to carmustine- and irradiation-induced senescence. Furthermore, our results indicated that verapamil treatment, in combination with carmustine and irradiation, rendered U87MG glioma cells and several patient-derived glioma stem cells more sensitive to therapy-induced senescence than individual or dual-combination treatments. When investigating the underlying mechanism, we found that verapamil treatment markedly decreased intracellular reactive oxygen species and calcium ion levels. Reactive oxygen species reduction with N-acetylcysteine, a reactive oxygen species scavenger, rendered U87MG glioma cells more sensitive to carmustine and irradiation whereas the protein kinase C agonist, phorbol 12-myristate 13-acetate, mitigated the effects of carmustine and irradiation. Taken together, our results indicate that verapamil may be a potent therapeutic sensitizer for increasing the effectiveness of glioblastoma treatment.
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Zaloga, G. P., P. R. Roberts, K. W. Black, M. Lin, G. Zapata-Sudo, R. T. Sudo, and T. E. Nelson. "Carnosine is a novel peptide modulator of intracellular calcium and contractility in cardiac cells." American Journal of Physiology-Heart and Circulatory Physiology 272, no. 1 (January 1, 1997): H462—H468. http://dx.doi.org/10.1152/ajpheart.1997.272.1.h462.
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Myocardial contractile failure is a common cause of morbidity and mortality in patients with ischemic heart disease and systemic inflammatory states such as sepsis. Accumulating evidence indicates that contractile failure is associated with dysregulation of myoplasmic calcium levels. In a search for biochemical causes for contractile dysfunction, we found that the dipeptide carnosine improves cardiac contractility and tested the possibility that carnosine plays a role in the regulation of intracellular calcium. Carnosine increased contractility in a dose-dependent manner (1-10 mM) in isolated perfused rat hearts. and it also increased free intracellular calcium levels in isolated myocytes. Carnosine increased myocyte tension via calcium release from the ryanodine receptor calcium release channel in skinned myocardial fibers and increased open-state probability and dwell time of the isolated ryanodine receptor calcium release channel in lipid bilayers. In addition. we report that carnosine sensitizes the contractile proteins so calcium. These results suggest a novel role for carnosine as a modulator of intracellular calcium and contractility in cardiac tissue.
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Babes, Alexandru, Cristian Neacsu, Michael JM Fischer, and Karl Messlinger. "Sumatriptan activates TRPA1." Cephalalgia Reports 2 (January 1, 2019): 251581631984715. http://dx.doi.org/10.1177/2515816319847155.
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Background: Migraine therapy with sumatriptan may cause adverse side effects like pain at the injection site, muscle pain, and transient aggravation of headaches. In animal experiments, sumatriptan excited or sensitized slowly conducting meningeal afferents. We hypothesized that sumatriptan may activate transduction channels of the “irritant receptor,” the transient receptor potential ankyrin type (TRPA1) expressed in nociceptive neurons. Methods: Calcium microfluorometry was performed in HEK293t cells transfected with human TRPA1 (hTRPA1) or a mutated channel (TRPA1-3C) and in dissociated trigeminal ganglion neurons. Membrane currents were recorded in the whole-cell patch clamp configuration. Results: Sumatriptan (10 and 400 µM) evoked calcium transients in hTRPA1-expressing HEK293t cells also activated by the TRPA1 agonist carvacrol (100 µM). In TRPA1-3C-expressing HEK293t cells, sumatriptan had hardly any effect. In rat trigeminal ganglion neurons, sumatriptan, carvacrol, and the transient receptor potential vanillod type 1 agonist capsaicin (1 µM) generated robust calcium signals. All sumatriptan-sensitive neurons (8% of the sample) were also activated by carvacrol (14%) and capsaicin (48%). In HEK293-hTRPA1 cells, sumatriptan (100 µM) evoked outwardly rectifying currents, which were almost completely inhibited by the TRPA1 antagonist HC-030031 (10 µM). Conclusion: Sumatriptan activates TRPA1 channels inducing calcium inflow and membrane currents. TRPA1-dependent activation of primary afferents may explain the painful side effects of sumatriptan.
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Daya, Hiba Abou, Sana Kouba, Hakim Ouled-Haddou, Nazim Benzerdjeb, Marie-Sophie Telliez, Charles Dayen, Henri Sevestre, Loïc Garçon, Frédéric Hague, and Halima Ouadid-Ahidouch. "Orai3-Mediates Cisplatin-Resistance in Non-Small Cell Lung Cancer Cells by Enriching Cancer Stem Cell Population through PI3K/AKT Pathway." Cancers 13, no. 10 (May 12, 2021): 2314. http://dx.doi.org/10.3390/cancers13102314.
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The development of the resistance to platinum salts is a major obstacle in the treatment of non-small cell lung cancer (NSCLC). Among the reasons underlying this resistance is the enrichment of cancer stem cells (CSCs) populations. Several studies have reported the involvement of calcium channels in chemoresistance. The Orai3 channel is overexpressed and constitutes a predictive marker of metastasis in NSCLC tumors. Here, we investigated its role in CSCs populations induced by Cisplatin (CDDP) in two NSCLC cell lines. We found that CDDP treatment increased Orai3 expression, but not Orai1 or STIM1 expression, as well as an enhancement of CSCs markers. Moreover, Orai3 silencing or the reduction of extracellular calcium concentration sensitized the cells to CDDP and led to a reduction in the expression of Nanog and SOX-2. Orai3 contributed to SOCE (Store-operated Calcium entry) in both CDDP-treated and CD133+ subpopulation cells that overexpress Nanog and SOX-2. Interestingly, the ectopic overexpression of Orai3, in the two NSCLC cell lines, lead to an increase of SOCE and expression of CSCs markers. Furthermore, CD133+ cells were unable to overexpress neither Nanog nor SOX-2 when incubated with PI3K inhibitor. Finally, Orai3 silencing reduced Akt phosphorylation. Our work reveals a link between Orai3, CSCs and resistance to CDDP in NSCLC cells.
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Sweet, Wendy E., and Christine S. Moravec. "Direct Measurement of Sarcoplasmic Reticulum Calcium Content Following Isoproterenol or Caffeine Treatment." Microscopy and Microanalysis 3, S2 (August 1997): 919–20. http://dx.doi.org/10.1017/s143192760001148x.
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The major storage site for calcium in cardiac muscle is the sarcoplasmic reticulum (SR). It has been shown using indirect methods that the amount of calcium stored in the SR can be altered by various agonists and anesthetics. The only technique to date which directly quantifies the amount of calcium in the SR is Electron Probe Microanalysis (EPMA). Using EPMA, an accurate measurement of the size of the SR calcium store can be made following treatments with known agonists.Isoproterenol (ISO) causes an increased inotropic response in cardiac muscle via the (3-adrenergic pathway. When ISO binds to the (β-receptor on the plasma membrane, it causes the activation of Protein Kinase A (PKA) through a cascade of events. PKA phosphorylates the sarcolemmal calcium channels causing an increase in the rate of calcium influx. PKA also phosphorylates Tnl, which sensitizes the myofilaments to calcium, thereby increasing the rate of calcium release from the myofilaments.
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FULCERI, Rosella, Jens KNUDSEN, Roberta GIUNTI, Pompeo VOLPE, Alessandra NORI, and Angelo BENEDETTI. "Fatty acyl-CoA–acyl-CoA-binding protein complexes activate the Ca2+ release channel of skeletal muscle sarcoplasmic reticulum." Biochemical Journal 325, no. 2 (July 15, 1997): 423–28. http://dx.doi.org/10.1042/bj3250423.
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We previously reported that fatty acyl-CoA esters activate ryanodine receptor/Ca2+ release channels in a terminal cisternae fraction from rabbit skeletal muscle [Fulceri, Nori, Gamberucci, Volpe, Giunti and Benedetti (1994) Cell Calcium 15, 109–116]. Skeletal muscle cytosol contains a high-affinity fatty acyl-CoA-binding protein (ACBP) [Knudsen, Hojrup, Hansen, H. O., Hansen, H. F. and Roepstorff (1989) Biochem. J. 262, 513–519]. We show here that palmitoyl-CoA (PCoA) in a complex with a molar excess of bovine ACBP causes a discrete Ca2+ efflux or allows Ca2+ release from the Ca2+-preloaded terminal cisternae fraction by sub-optimal caffeine concentrations. Both effects were abolished by elevating the free [Mg2+] in the system, which inhibits the Ca2+ release channel activity. Sensitization towards caffeine was a function of both the concentration of the complex and the [PCoA]-to-[ACBP] ratio. In all experimental conditions the calculated free [PCoA] was no more than 50 nM, and such concentrations by themselves were inactive on Ca2+ release channels. The KD for PCoA binding was approx. 2 nM for bovine and yeast ACBP, and slightly higher (8 nM) for rat ACBP. The PCoA–rat ACBP complex behaved in the same manner as the PCoA–bovine ACBP complex, whereas the ester complexed with yeast ACBP was more active in activating/sensitizing Ca2+ efflux. A non-hydrolysable analogue of PCoA bound to (bovine) ACBP also sensitized the Ca2+ release channel towards caffeine. These findings indicate that fatty acyl-CoA–ACBP complexes either interact directly with one or more components in the terminal cisternae membranes or, through interaction with the component(s), donate the fatty acyl-CoA esters to high-affinity binding sites of the membrane, thus affecting (and possibly regulating) Ca2+ release channel activity.
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Liu, Zhenyu, Youtian Hu, Xiaoyun Yu, Jiefeng Xi, Xiaoming Fan, Chung-Ming Tse, Allen C. Myers, Pankaj J. Pasricha, Xingde Li, and Shaoyong Yu. "Allergen challenge sensitizes TRPA1 in vagal sensory neurons and afferent C-fiber subtypes in guinea pig esophagus." American Journal of Physiology-Gastrointestinal and Liver Physiology 308, no. 6 (March 15, 2015): G482—G488. http://dx.doi.org/10.1152/ajpgi.00374.2014.
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Transient receptor potential A1 (TRPA1) is a newly defined cationic ion channel, which selectively expresses in primary sensory afferent nerve, and is essential in mediating inflammatory nociception. Our previous study demonstrated that TRPA1 plays an important role in tissue mast cell activation-induced increase in the excitability of esophageal vagal nodose C fibers. The present study aims to determine whether prolonged antigen exposure in vivo sensitizes TRPA1 in a guinea pig model of eosinophilic esophagitis (EoE). Antigen challenge-induced responses in esophageal mucosa were first assessed by histological stains and Ussing chamber studies. TRPA1 function in vagal sensory neurons was then studied by calcium imaging and by whole cell patch-clamp recordings in 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI)-labeled esophageal vagal nodose and jugular neurons. Extracellular single-unit recordings were performed in vagal nodose and jugular C-fiber neuron subtypes using ex vivo esophageal-vagal preparations with intact nerve endings in the esophagus. Antigen challenge significantly increased infiltrations of eosinophils and mast cells in the esophagus. TRPA1 agonist allyl isothiocyanate (AITC)-induced calcium influx in nodose and jugular neurons was significantly increased, and current densities in esophageal DiI-labeled nodose and jugular neurons were also significantly increased in antigen-challenged animals. Prolonged antigen challenge decreased esophageal epithelial barrier resistance, which allowed intraesophageal-infused AITC-activating nodose and jugular C fibers at their nerve endings. Collectively, these results demonstrated that prolonged antigen challenge sensitized TRPA1 in esophageal sensory neurons and afferent C fibers. This novel finding will help us to better understand the molecular mechanism underlying esophageal sensory and motor dysfunctions in EoE.
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Takenaka, Tsuneo, Yoichi Ohno, Koichi Hayashi, Takao Saruta, and Hiromichi Suzuki. "Governance of arteriolar oscillation by ryanodine receptors." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 285, no. 1 (July 2003): R125—R131. http://dx.doi.org/10.1152/ajpregu.00711.2002.
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To investigate the role of ryanodine receptors in glomerular arterioles, experiments were performed using an isolated perfused hydronephrotic kidney model. In the first series of studies, BAYK-8644 (300 nM), a calcium agonist, constricted afferent (19.6 ± 0.6 to 17.6 ± 0.5 μm, n = 6, P < 0.01) but not efferent arterioles. Furthermore, BAYK-8644 elicited afferent arteriolar oscillatory movements. Subsequent administration of nifedipine (1 μM) inhibited both afferent arteriolar oscillation and constriction by BAYK-8644 (to 19.4 ± 0.5 μm). In the second group, although BAYK-8644 constricted afferent arterioles treated with 1 μM of thapsigargin (19.7 ± 0.6 to 16.8 ± 0.6 μm, n = 5, P < 0.05), it failed to induce rhythmic contraction. Removal of extracellular calcium with EGTA (2 mM) reversed BAYK-8644-induced afferent arteriolar constriction (to 20.0 ± 0.5 μm). In the third series of investigations, ryanodine (10 μM) but not 2-aminoethoxyphenyl borate (100 μM) abolished afferent arteriolar vasomotion by BAYK-8644. In the fourth series of experiments, in the presence of caffeine (1 mM), the stronger activation of voltage-dependent calcium channels by higher potassium media resulted in greater afferent arteriolar constriction and faster oscillation. Our results indicate that L-type calcium channels are rich in preglomerular but not postglomerular microvessels. Furthermore, the present findings suggest that either prolonged calcium influx through voltage-dependent calcium channels (BAYK-8644) or sensitized ryanodine receptors (caffeine) is required to trigger periodic calcium release through ryanodine receptors in afferent arterioles.
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Binz-Lotter, Julia, Christian Jüngst, Markus M. Rinschen, Sybille Koehler, Peter Zentis, Astrid Schauss, Bernhard Schermer, Thomas Benzing, and Matthias J. Hackl. "Injured Podocytes Are Sensitized to Angiotensin II–Induced Calcium Signaling." Journal of the American Society of Nephrology 31, no. 3 (January 10, 2020): 532–42. http://dx.doi.org/10.1681/asn.2019020109.
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BackgroundInhibition of angiotensin II (AngII) signaling, a therapeutic mainstay of glomerular kidney diseases, is thought to act primarily through regulating glomerular blood flow and reducing filtration pressure. Although extravascular actions of AngII have been suggested, a direct effect of AngII on podocytes has not been demonstrated in vivo.MethodsTo study the effects of AngII on podocyte calcium levels in vivo, we used intravital microscopy of the kidney in mice expressing the calcium indicator protein GCaMP3.ResultsIn healthy animals, podocytes displayed limited responsiveness to AngII stimulation. In contrast, in animals subjected to either adriamycin-induced acute chemical injury or genetic deletion of the podocin-encoding gene Nphs2, the consequent podocyte damage and proteinuria rendered the cells responsive to AngII and resulted in AngII-induced calcium transients in significantly more podocytes. The angiotensin type 1 receptor blocker losartan could fully inhibit this response. Also, responsiveness to AngII was at least partly mediated through the transient receptor potential channel 6, which has been implicated in podocyte calcium handling. Interestingly, loss of a single Nphs2 allele also increased podocytes’ responsiveness to AngII signaling. This direct effect of AngII on injured podocytes results in increased calcium transients, which can further aggravate the underlying kidney disease.ConclusionsOur discovery that podocytes become sensitized to AngII-induced calcium signaling upon injury might explain results from large, randomized, controlled trials in which improved renal outcomes occur only in the subgroup of patients with proteinuria, indicating podocyte damage. Our findings also emphasize the need to treat every patient with a glomerular disease with either an angiotensin-converting enzyme inhibitor or an angiotensin type 1 receptor blocker.
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Zhang, Ying, Nichola Cruickshanks, Julia Wulfkuhle, Isela Gallagher, David Schiff, Emanuel Petricoin, Lloyd Gray, and Roger Abounader. "ATPS-01INHIBITION OF T-TYPE CALCIUM CHANNELS SENSITIZES GLIOBLASTOMA STEM CELLS TO CHEMOTHERAPY." Neuro-Oncology 17, suppl 5 (November 2015): v18.1—v18. http://dx.doi.org/10.1093/neuonc/nov204.01.
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Rojo-Ruiz, Jonathan, Macarena Rodríguez-Prados, Alba Delrio-Lorenzo, María Teresa Alonso, and Javier García-Sancho. "Caffeine chelates calcium in the lumen of the endoplasmic reticulum." Biochemical Journal 475, no. 22 (November 28, 2018): 3639–49. http://dx.doi.org/10.1042/bcj20180532.
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Cytosolic Ca2+ signals are often amplified by massive calcium release from the endoplasmic reticulum (ER). This calcium-induced calcium release (CICR) occurs by activation of an ER Ca2+ channel, the ryanodine receptor (RyR), which is facilitated by both cytosolic- and ER Ca2+ levels. Caffeine sensitizes RyR to Ca2+ and promotes ER Ca2+ release at basal cytosolic Ca2+ levels. This outcome is frequently used as a readout for the presence of CICR. By monitoring ER luminal Ca2+ with the low-affinity genetic Ca2+ probe erGAP3, we find here that application of 50 mM caffeine rapidly reduces the Ca2+ content of the ER in HeLa cells by ∼50%. Interestingly, this apparent ER Ca2+ release does not go along with the expected cytosolic Ca2+ increase. These results can be explained by Ca2+ chelation by caffeine inside the ER. Ca2+-overloaded mitochondria also display a drop of the matrix Ca2+ concentration upon caffeine addition. In contrast, in the cytosol, with a low free Ca2+ concentration (10−7 M), no chelation is observed. Expression of RyR3 sensitizes the responses to caffeine with effects both in the ER (increase in Ca2+ release) and in the cytosol (increase in Ca2+ peak) at low caffeine concentrations (0.3–1 mM) that have no effects in control cells. Our results illustrate the fact that simultaneous monitoring of both cytosolic- and ER Ca2+ are necessary to understand the action of caffeine and raise concerns against the use of high concentrations of caffeine as a readout of the presence of CICR.
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Sayers, L. G., G. R. Brown, R. H. Michell, and F. Michelangeli. "The effects of thimerosal on calcium uptake and inositol 1,4,5-trisphosphate-induced calcium release in cerebellar microsomes." Biochemical Journal 289, no. 3 (February 1, 1993): 883–87. http://dx.doi.org/10.1042/bj2890883.
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Thimerosal inhibits calcium uptake in skeletal muscle sarcoplasmic reticulum and rat cerebellar microsomes by inhibiting the Ca(2+)-ATPase. In the presence of 5 mM dithiothreitol (DTT), Ca2+ uptake and ATPase activity were not inhibited by thimerosal, indicating that thimerosal modifies cysteine residues of the Ca(2+)-ATPase. Low thimerosal concentrations (2 microM) sensitize the inositol 1,4,5-trisphosphate (InsP3)-sensitive Ca2+ channel, making it open at lower InsP3 concentrations. Higher concentrations of thimerosal, however, cause inhibition of InsP3-induced Ca2+ release. Both sensitization and inhibition of the InsP3 receptor by thimerosal can be prevented by DTT. The binding and metabolism of InsP3 by cerebellar microsomes is not affected by thimerosal. The amount of InsP3-induced Ca2+ release is co-operatively linked to the InsP3 concentration with a Hill coefficient of 2.0 +/- 0.3. This is decreased to 1.0 +/- 0.2 at inhibitory concentrations of thimerosal. Under our experimental conditions, we observed no dependence of quantal Ca2+ release on intraluminal Ca2+ concentration.
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Yang, Hua, Huisheng Liu, Zhitao Hu, Hongliang Zhu, and Tao Xu. "PKC-induced Sensitization of Ca2+-dependent Exocytosis Is Mediated by Reducing the Ca2+ Cooperativity in Pituitary Gonadotropes." Journal of General Physiology 125, no. 3 (February 14, 2005): 327–34. http://dx.doi.org/10.1085/jgp.200409230.
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The highly cooperative nature of Ca2+-dependent exocytosis is very important for the precise regulation of transmitter release. It is not known whether the number of binding sites on the Ca2+ sensor can be modulated or not. We have previously reported that protein kinase C (PKC) activation sensitizes the Ca2+ sensor for exocytosis in pituitary gonadotropes. To further unravel the underlying mechanism of how the Ca2+ sensor is modulated by protein phosphorylation, we have performed kinetic modeling of the exocytotic burst and investigated how the kinetic parameters of Ca2+-triggered fusion are affected by PKC activation. We propose that PKC sensitizes exocytosis by reducing the number of calcium binding sites on the Ca2+ sensor (from three to two) without significantly altering the Ca2+-binding kinetics. The reduction in the number of Ca2+-binding steps lowers the threshold for release and up-regulates release of fusion-competent vesicles distant from Ca2+ channels.
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Donoso, Paulina, José Pablo Finkelstein, Luis Montecinos, Matilde Said, Gina Sánchez, Leticia Vittone, and Ricardo Bull. "Stimulation of NOX2 in isolated hearts reversibly sensitizes RyR2 channels to activation by cytoplasmic calcium." Journal of Molecular and Cellular Cardiology 68 (March 2014): 38–46. http://dx.doi.org/10.1016/j.yjmcc.2013.12.028.
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Montaño, Luis M., Julia Espinoza, Edgar Flores-Soto, Jaime Chávez, and Mercedes Perusquía. "Androgens are bronchoactive drugs that act by relaxing airway smooth muscle and preventing bronchospasm." Journal of Endocrinology 222, no. 1 (April 29, 2014): 1–13. http://dx.doi.org/10.1530/joe-14-0074.
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Changes in the androgen levels in asthmatic men may be associated with the severity of asthma. Androgens induce a nongenomic relaxation in airway smooth muscle, but the underlying mechanisms remain unclear. The aim of this study was to investigate the potential bronchorelaxing action of testosterone (TES) and its metabolites (5α- and 5β-dihydrotestosterone (DHT). A preventive effect on ovalbumin (OVA)-induced bronchospasm was observed in sensitized guinea pigs for each androgen. Androgens were studied in response to bronchoconstrictors: carbachol (CCh) and KCl in isolated trachea rings with and without epithelium from non-sensitized and sensitized animals as well as on OVA-induced contraction. Androgens concentration-dependently abolished the contraction in response to CCh, KCl, and OVA. There were significant differences in the sensitivity to the relaxation induced by each androgen. 5β-DHT was more potent for relaxing KCl-induced contraction, while TES and 5α-DHT were more potent for CCh- and OVA-induced contraction. No differences were found in preparations with and without epithelium or in the presence of a nitric oxide (NO) synthase inhibitor or an inhibitor of K+channels. These data indicate the absence of involvement of the epithelium-, NO- and K+channels-dependent pathway in androgen-induced relaxation. However, in dissociated tracheal myocytes loaded with the calcium-binding fluorescent dye Fura -2, physiological concentrations of androgens decreased the KCl-induced [Ca2+]iincrement. 5β-DHT was the most potent at decreasing KCl-induced [Ca2+]iincrement and preventing bronchospasm. We suggest that androgen-induced brochorelaxation was mediated via decreased Ca2+influx through L-type Ca2+channels but additional Ca2+entry blockade may be involved. Molecular changes in androgen structure may determine its preferential site of action.
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Damiano, Melissa A., and Edward J. Barbieri. "The release of slow-reacting substance of anaphylaxis from guinea pig lung: effects of calcium antagonists." Canadian Journal of Physiology and Pharmacology 63, no. 1 (January 1, 1985): 23–29. http://dx.doi.org/10.1139/y85-004.
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The effects of three calcium antagonists, verapamil, lanthanum, and 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8) were studied on the release of slow-reacting substance of anaphylaxis (SRS-A) from ovalbumin-sensitized chopped guinea pig lung parenchyma in calcium-containing and calcium-free media. The SRS-A levels (mean ± SEM) obtained from tissues incubated in normal and calcium-free Krebs–bicarbonate buffer were 51 ± 8 (N = 19) and 21 ± 4 (N = 14) U/mL, respectively. TMB-8 (0.1–10 μM) a reported intracellular calcium antagonist, reduced antigen-stimulated SRS-A release from lung tissue incubated in calcium-containing, but not calcium-free, medium; A23187-induced SRS-A release from normal guinea pig lung was not significantly altered by TMB-8 at concentrations up to 10 μM. Verapamil and lanthanum consistently reduced SRS-A release only at high concentrations (100 μM and 1 mM, respectively). The quantities of SRS-A released from lung tissue incubated in the presence of verapamil in normal medium were similar to those obtained in calcium-free medium. Tissues incubated in the presence of potassium chloride (60 and 100 mM) did not release significant quantities of SRS-A, and release which did occur was not blocked by verapamil, suggesting that antigen-induced SRS-A release is not dependent on membrane depolarization and that verapamil was not exerting inhibition via blockade of voltage-dependent calcium channels. These data suggest that although intracellular calcium is important for the regulation of SRS-A secretion from guinea pig lung tissue, extracellular calcium is necessary for optimal release of SRS-A.
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Pei, Zhen-Ming, John M. Ward, and Julian I. Schroeder. "Magnesium Sensitizes Slow Vacuolar Channels to Physiological Cytosolic Calcium and Inhibits Fast Vacuolar Channels in Fava Bean Guard Cell Vacuoles." Plant Physiology 121, no. 3 (November 1, 1999): 977–86. http://dx.doi.org/10.1104/pp.121.3.977.
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Liu, Shuyuan, Yinglong Hou, Weiguo Liu, Chunyan Lu, Weixin Wang, and Shujuan Sun. "Components of the Calcium-Calcineurin Signaling Pathway in Fungal Cells and Their Potential as Antifungal Targets." Eukaryotic Cell 14, no. 4 (January 30, 2015): 324–34. http://dx.doi.org/10.1128/ec.00271-14.
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ABSTRACTIn recent years, the emergence of fungal resistance has become frequent, partly due to the widespread clinical use of fluconazole, which is minimally toxic and effective in the prevention and treatment ofCandida albicansinfections. The limited selection of antifungal drugs for clinical fungal infection therapy has prompted us to search for new antifungal drug targets. Calcium, which acts as the second messenger in both mammals and fungi, plays a direct role in controlling the expression patterns of its signaling systems and has important roles in cell survival. In addition, calcium and some of the components, mainly calcineurin, in the fungal calcium signaling pathway mediate fungal resistance to antifungal drugs. Therefore, an overview of the components of the fungal calcium-calcineurin signaling network and their potential roles as antifungal targets is urgently needed. The calcium-calcineurin signaling pathway consists of various channels, transporters, pumps, and other proteins or enzymes. Many transcriptional profiles have indicated that mutant strains that lack some of these components are sensitized to fluconazole or other antifungal drugs. In addition, many researchers have identified efficient compounds that exhibit antifungal activity by themselves or in combination with antifungal drugs by targeting some of the components in the fungal calcium-calcineurin signaling pathway. This targeting disrupts Ca2+homeostasis, which suggests that this pathway contains potential targets for the development of new antifungal drugs.
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Cosentino, Nicola, Giampaolo Niccoli, Francesco Fracassi, Antonio Rebuzzi, Piergiuseppe Agostoni, and Giancarlo Marenzi. "Rationale, experimental data, and emerging clinical evidence on early and preventive use of levosimendan in patients with ventricular dysfunction." European Heart Journal - Cardiovascular Pharmacotherapy 6, no. 5 (November 5, 2019): 310–16. http://dx.doi.org/10.1093/ehjcvp/pvz065.
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Abstract Acute ventricular dysfunction (AVD) is a complex condition with substantial morbidity and mortality, still featuring unique therapeutic challenges. Levosimendan is a calcium sensitizer and ATP-dependent potassium channel opener that was developed as an inodilating drug for the treatment of acute heart failure and cardiogenic shock. Differently from other more widely used inotropic agents, levosimendan has some exclusive characteristics, in terms of mechanisms of action, pharmacodynamic profile, and haemodynamic effects. This may have important clinical implications. In particular, in patients with AVD or in patients with pre-existing severe ventricular impairment undergoing planned myocardial stress, the administration of levosimendan before the onset of overt symptoms or before cardiovascular therapeutic procedures may have the potential to bridge the patient through the critical phase. In this review, we will focus on the rationale, the existing experimental data, and the emerging clinical experience supporting an early, even preventive use of levosimendan in severe ventricular dysfunction, beyond its recognized indications.
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Enomoto, Nobuyuki, Shunhei Yamashina, Moritaka Goto, Peter Schemmer, and Ronald G. Thurman. "Desensitization to LPS after ethanol involves the effect of endotoxin on voltage-dependent calcium channels." American Journal of Physiology-Gastrointestinal and Liver Physiology 277, no. 6 (December 1, 1999): G1251—G1258. http://dx.doi.org/10.1152/ajpgi.1999.277.6.g1251.
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Hepatic macrophages are sensitized to alcohol in 24 h due to increases in the endotoxin receptor, CD14; however, desensitization to lipopolysaccharide (LPS), which occurred earlier, could not be explained by changes in CD14. Therefore, the purpose of this work was to attempt to understand factors responsible for ethanol-induced desensitization to LPS in hepatic macrophages. Rats were given ethanol (5 g/kg body wt) intragastrically, and hepatic macrophages were isolated 2 h later. After addition of endotoxin, intracellular Ca2+concentration ([Ca2+]i) was measured using fura 2 and tumor necrosis factor (TNF)-α was measured by ELISA. Ethanol given 2 h before injection of LPS totally prevented liver injury and blunted LPS-induced increases in [Ca2+]i and TNF-α in hepatic macrophages. Furthermore, the protein kinase C (PKC) agonist phorbol 12-myristate 13-acetate and acute ethanol treatment both activated PKC and largely prevented the influx of [Ca2+]i caused by LPS. Sterilization of the gut with antibiotics completely blocked all effects of ethanol on [Ca2+]i and TNF-α release. Thus ethanol-induced desensitization of hepatic macrophages correlates with gut-derived endotoxin after ethanol and involves the effect of PKC on voltage-dependent Ca2+channels.
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Liu, Zhong-Jie, Wei Zhao, Hong-Yi Lei, Hua-Li Xu, Lu-Ying Lai, Rui Xu, and Shi-Yuan Xu. "High Glucose Enhances Bupivacaine-Induced Neurotoxicity via MCU-Mediated Oxidative Stress in SH-SY5Y Cells." Oxidative Medicine and Cellular Longevity 2019 (February 18, 2019): 1–11. http://dx.doi.org/10.1155/2019/7192798.
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Bupivacaine, a typical local anesthetic, induces neurotoxicity via reactive oxygen species regulation of apoptosis. High glucose could enhance bupivacaine-induced neurotoxicity through regulating oxidative stress, but the mechanism of it is not clear. Mitochondrial calcium uniporter (MCU), a key channel for regulating the mitochondrial Ca2+ (mCa2+) influx, is closely related to oxidative stress via disruption of mCa2+ homeostasis. Whether MCU is involved in high glucose-sensitized bupivacaine-induced neurotoxicity remains unknown. In this study, human neuroblastoma (SH-SY5Y) cells were cultured with high glucose and/or bupivacaine, and the data showed that high glucose enhanced bupivacaine-induced MCU expression elevation, mCa2+ accumulation, and oxidative damage. Next, Ru360, an inhibitor of MCU, was employed to pretreated SH-SY5Y cells, and the results showed that it could decrease high glucose and bupivacaine-induced mCa2+ accumulation, oxidative stress, and apoptosis. Further, with the knockdown of MCU with a specific small interfering RNA (siRNA) in SH-SY5Y cells, we found that it also could inhibit high glucose and bupivacaine-induced mCa2+ accumulation, oxidative stress, and apoptosis. We propose that downregulation expression or activity inhibition of the MCU channel might be useful for restoring the mitochondrial function and combating high glucose and bupivacaine-induced neurotoxicity. In conclusion, our study demonstrated the crucial role of MCU in high glucose-mediated enhancement of bupivacaine-induced neurotoxicity, suggesting the possible use of this channel as a target for curing bupivacaine-induced neurotoxicity in diabetic patients.
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Lieu, Tina Marie, Allen C. Myers, Sonya Meeker, and Bradley J. Undem. "TRPV1 induction in airway vagal low-threshold mechanosensory neurons by allergen challenge and neurotrophic factors." American Journal of Physiology-Lung Cellular and Molecular Physiology 302, no. 9 (May 1, 2012): L941—L948. http://dx.doi.org/10.1152/ajplung.00366.2011.
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We addressed the hypothesis that allergic inflammation in guinea pig airways leads to a phenotypic switch in vagal tracheal cough-causing, low-threshold mechanosensitive Aδ neurons, such that they begin expressing functional transient receptor potential vanilloid (TRPV1) channels. Guinea pigs were actively sensitized to ovalbumin (OVA) and beginning 21 days later exposed via aerosol to OVA daily for 3 days. Tracheal-specific neurons were identified in the nodose ganglion using retrograde tracing techniques. Tracheal specific neurons were isolated, and mRNA expression was evaluated at the single-neuron level using RT-PCR analysis. Electrophysiological studies have revealed that the vast majority of vagal nodose afferent nerves innervating the trachea are capsaicin-insensitive Aδ-fibers. Consistent with this, we found <20% of these neurons express TRPV1 mRNA or respond to capsaicin in a calcium assay. Allergen exposure induced de novo TRPV1 mRNA in a majority of the tracheal-specific nodose neurons ( P < 0.05). The allergen-induced TRPV1 induction was mimicked by applying either brain-derived neurotrophic factor (BDNF) or glial-derived neurotrophic factor (GDNF) to the tracheal lumen. The BDNF-induced phenotypic change observed at the level of mRNA expression was mimicked using a calcium assay to assess functional TRPV1 ion channels. Finally, OVA exposure induced BDNF and GDNF production in the tracheal epithelium, the immediate vicinity of the nodose Aδ -fibers terminations. The induction of TRPV1 in nodose tracheal Aδ -fibers would substantively expand the nature of stimuli capable of activating these cough-causing nerves.
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Pierre, Ophélie, Maxime Fouchard, Nelig Le Goux, Paul Buscaglia, Raphaël Leschiera, Richard J. Lewis, Olivier Mignen, Joachim W. Fluhr, Laurent Misery, and Raphaële Le Garrec. "Pacific-Ciguatoxin-2 and Brevetoxin-1 Induce the Sensitization of Sensory Receptors Mediating Pain and Pruritus in Sensory Neurons." Marine Drugs 19, no. 7 (July 6, 2021): 387. http://dx.doi.org/10.3390/md19070387.
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Ciguatera fish poisoning (CFP) and neurotoxic shellfish poisoning syndromes are induced by the consumption of seafood contaminated by ciguatoxins and brevetoxins. Both toxins cause sensory symptoms such as paresthesia, cold dysesthesia and painful disorders. An intense pruritus, which may become chronic, occurs also in CFP. No curative treatment is available and the pathophysiology is not fully elucidated. Here we conducted single-cell calcium video-imaging experiments in sensory neurons from newborn rats to study in vitro the ability of Pacific-ciguatoxin-2 (P-CTX-2) and brevetoxin-1 (PbTx-1) to sensitize receptors and ion channels, (i.e., to increase the percentage of responding cells and/or the response amplitude to their pharmacological agonists). In addition, we studied the neurotrophin release in sensory neurons co-cultured with keratinocytes after exposure to P-CTX-2. Our results show that P-CTX-2 induced the sensitization of TRPA1, TRPV4, PAR2, MrgprC, MrgprA and TTX-r NaV channels in sensory neurons. P-CTX-2 increased the release of nerve growth factor and brain-derived neurotrophic factor in the co-culture supernatant, suggesting that those neurotrophins could contribute to the sensitization of the aforementioned receptors and channels. Our results suggest the potential role of sensitization of sensory receptors/ion channels in the induction or persistence of sensory disturbances in CFP syndrome.
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Nelson, M. T., J. Woo, H. W. Kang, I. Vitko, P. Q. Barrett, E. Perez-Reyes, J. H. Lee, H. S. Shin, and S. M. Todorovic. "Reducing Agents Sensitize C-Type Nociceptors by Relieving High-Affinity Zinc Inhibition of T-Type Calcium Channels." Journal of Neuroscience 27, no. 31 (August 1, 2007): 8250–60. http://dx.doi.org/10.1523/jneurosci.1800-07.2007.
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Wang, Meng, Ugur Eskiocak, Michalis Agathokleous, Stacy Yuan, Charles Crawley, and Sean J. Morrison. "Therapeutic Synergy from Combined Inhibition of the SERCA Channel and MAPK Signaling Pathway in MAPK-Dependent Leukemia." Blood 126, no. 23 (December 3, 2015): 1264. http://dx.doi.org/10.1182/blood.v126.23.1264.1264.
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Abstract Background The generation and maintenance of electrochemical gradients by ion transporters are vital in almost all cellular processes. Ion transporters are often dysregulated in cancer cells and play important roles in cancer cell function. For example, aberrant expression of voltage gated potassium channels Kv10.1 (Eag1) and Kv11.1, (hERG) have been associated with increased proliferation and worse prognosis in hematological malignancies. Targeting ion transporters may thus offer a novel therapeutic strategy against cancer. To this end, we identified ion transporters that when inhibited, result in selective toxicity in hematological malignancies with a focus on acute myeloid leukaemia (AML). Method and Results Ion transporter inhibitors exhibiting selective activity against leukaemia/lymphoma cells were identified from screening compound libraries targeting ion transporters (total 126 inhibitors) against 7 leukaemia/lymphoma cell lines (HL-60, Kasumi-1, HuT-78, BC-2, U266B1, K562 and Raji). Eight unique compounds were selected (Antibiotic A-23187; Niguldipine; Ouabain; Penitrem A; SKF-96365; Tetrandrine; Thapsigargin; Triamterene). The most potent compound was thapsigargin, exhibiting toxicity at nano-molar concentrations against leukemia cells (IC50 1.8 nM - 8.4 nM) whilst sparing human umbilical cord blood cells (IC50 20 nM). In AML cell lines dependent on activated MAPK signaling pathway (HL-60, Kasumi-1), the potency of thapsigargin was enhanced when combined with MEK inhibitor trametinib (thapsigargin IC50 0.7 nM - 2.6 nM in presence of trametinib), with significantly increased apoptosis as measured by both caspase 3 activation and Annexin-V surface binding. The therapeutic activity of thapsigargin likely acted through the inhibition of sarco-endoreticulum calcium ATPase (SERCA) channel as similar efficacy against the AML cells could be reproduced by treatment with trametinib combined with other SERCA inhibitors (CPA and BHQ). SERCA is ubiquitously expressed on the endoplasmic reticulum (ER) and functions to sequester cytoplasmic calcium into the ER. SERCA inhibition by thapsigargin is known to trigger ER stress and to activate the unfolded protein response (UPR), which we postulated might underlie the mechanism of activity from combined trametinib/thapsigargin treatment. Compared to human umbilical cord blood cells, inhibition of the MAPK pathway in AML cell lines by trametinib reduced the expression of GRP-78, a major chaperone protein acting both as an initiator and effector of UPR. When trametinib was combined with thapsigargin, the downregulation of GRP-78 was associated with increased level of CHOP, a pro-apoptotic effector downstream of UPR activation. Taken together, these data suggested the downregulation of GRP-78 by trametinib in the AML cells potentially reduces cellular capacity to adapt to the ER stress induced by thapsigargin, thus triggering UPR mediated apoptosis pathway. Indeed, the addition of the chemical chaperone tauro-ursodeoxycholic acid (TUDCA) rescued for the loss of GRP-78 and the toxicity from combined trametinib and thapsigargin treatment. Conclusion Inhibition of SERCA channel either alone or in combination with MAPK pathway inhibition was selectively toxic in MAPK-dependent AML cell lines. The combination-induced toxicity resulted from a deficiency in GRP-78 chaperone protein that sensitized the cells to ER stress mediated apoptosis. The combined inhibition of SERCA channel and MAPK signaling may thus offer a novel therapeutic opportunity in MAPK-dependent leukemia. Disclosures No relevant conflicts of interest to declare.
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SETHI, Jaswinder K., Ruth M. EMPSON, and Antony GALIONE. "Nicotinamide inhibits cyclic ADP-ribose-mediated calcium signalling in sea urchin eggs." Biochemical Journal 319, no. 2 (October 15, 1996): 613–17. http://dx.doi.org/10.1042/bj3190613.
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Cyclic ADP ribose (cADPR) is a potent Ca2+-releasing agent, and putative second messenger, the endogenous levels of which are tightly regulated by synthetic (ADP-ribosyl cyclases) and degradative (cADPR hydrolase) enzymes. These enzymes have been characterized in a number of mammalian and invertebrate tissues and their activities are often found on a single polypeptide. β-NAD+, cGMP and nitric oxide (NO) have been reported to mobilize Ca2+ in the sea urchin egg via the cADPR-mediated pathway. We now report that in sea urchin egg homogenates, nicotinamide inhibits the Ca2+-mobilizing action of β-NAD+, cGMP and NO, but has no effect on cADPR-induced Ca2+ release. Moreover, nicotinamide inhibits cGMP-induced regenerative Ca2+ waves in the intact sea urchin egg. By successfully separating the cADPR-metabolizing machinery from that which releases Ca2+, we have shown that nicotinamide inhibits cADPR-mediated Ca2+ signalling at the level of cADPR generation. Importantly, nicotinamide had no effect upon the hydrolysis of cADPR, and its selective action on cyclase activity was supported by its inhibition of purified Aplysia ADP-ribosyl cyclase, which does not exhibit detectable hydrolytic activity. The action of nicotinamide in blocking Ca2+ release by β-NAD+, cGMP and NO strongly suggests that these agents act as modulators of cADPR synthesis rather than to sensitize calcium release channels to cADPR.
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Connern, C. P., and A. P. Halestrap. "Recruitment of mitochondrial cyclophilin to the mitochondrial inner membrane under conditions of oxidative stress that enhance the opening of a calcium-sensitive non-specific channel." Biochemical Journal 302, no. 2 (September 1, 1994): 321–24. http://dx.doi.org/10.1042/bj3020321.
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Binding of mitochondrial matrix cyclophilin (CyP) to the rat liver mitochondrial membranes was detected by SDS/PAGE and Western blotting with suitable antipeptide antibodies. Binding was not affected by prior exposure of mitochondria to Ca2+, adenine nucleotides or inhibitors of the adenine nucleotide translocase, but was greatly increased by t-butyl hydroperoxide (tBH), phenylarsine oxide or diamide. These all sensitized the opening of the non-specific mitochondrial pore to [Ca2+], and the effect of tBH was shown to be maintained after washing away the tBH, consistent with it being caused by the enhanced CyP binding. The bound CyP did not demonstrate peptidyl-prolyl cis-trans isomerase activity. CyP-binding was prevented by 5 microM cyclosporin A, but not reversed by cyclosporin treatment of the membranes. The effect of tBH on binding was concentration-dependent and maximal within 30 s.
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Liu, Lieju, Lei Chen, Wolfgang Liedtke, and S. A. Simon. "Changes in Osmolality Sensitize the Response to Capsaicin in Trigeminal Sensory Neurons." Journal of Neurophysiology 97, no. 3 (March 2007): 2001–15. http://dx.doi.org/10.1152/jn.00887.2006.
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Changes in tonicity in the peripheral nervous system can activate nociceptors and produce pain. Under local inflammatory conditions the peripheral terminals of nociceptors are subject to deviations from isotonicity. Previously it was shown that several members of the TRP(V) family of ion channels are responsive to changes in tonicity. Here we explore how changes in tonicity affect TRPV1 receptor-mediated responses to capsaicin in dissociated rat trigeminal ganglion (TG) neurons. Using whole cell patch-clamp and calcium imaging, we found that mild anisotonicity (260 and 348 mOsm/kg for hypotonicity and hypertonicity, respectively) strikingly sensitized the capsaicin-evoked current, Icaps. Confocal immunolocalization studies also revealed a modest anisotonicity-mediated redistribution of TRPV1 toward the plasma membrane of TG neurons. With respect to downstream signaling pathways, tonicity-induced sensitization of Icaps was dependent on whether hypo- or hypertonic stimuli were applied. Specifically, antagonism of PKA- and PI3K-activated pathways appreciably reduced the hypertonicity-induced sensitization of Icaps, whereas inhibition of PKC-mediated pathways selectively reduced the sensitization produced by hypotonic solutions. In summary, whereas the overall effects of hypo- and hypertonicity resulted in a similar pattern of potentiation of Icaps, intracellular signaling pathways were selective for hypo- versus hypertonicity-induced tuning of capsaicin-activated currents.
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Panneerpandian, Ponmathi, Divya Bhaskar Rao, and Kumaresan Ganesan. "Calcium channel blockers lercanidipine and amlodipine inhibit YY1/ERK/TGF-β mediated transcription and sensitize the gastric cancer cells to doxorubicin." Toxicology in Vitro 74 (August 2021): 105152. http://dx.doi.org/10.1016/j.tiv.2021.105152.
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Dhaliwal, Vikramjit Singh, Manpreet Singh Gill, and Monika . "Levosimendan: a remedy for treating the patients of decompensated heart failure." International Journal of Advances in Medicine 7, no. 8 (July 21, 2020): 1280. http://dx.doi.org/10.18203/2349-3933.ijam20203129.
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Background: Levosimendan is a new-fangled calcium based sensitizer which is used to treat the patients with congestive or decompensated heart failure. The empirical study reveals that it intensifies myocardial contractility and expands coronary and peripheral vessels without affecting the diastolic function adversely. Levosimendan also performs as an opener of ATP-based K channels in vascular smooth muscle. The empirical research study shows the benefits of usage of levosimendan over other drugs in the treatment of decompensated and congestive heart failure.Methods: Levosimendan has been administered to patients with decompensated heart failure conditions. Infusion of levosimendan started with a dose of 0.1 µg/kg/min and titrated to 0.2 µg/kg/min. The systolic BP has been monitored after the administration of levosimendan to maintain stability in the patient’s BP for the initial 2-3 hours. The suggested duration of infusion of levosimendan in critical heart failure is twenty-four hours. Initially levosimendan is infused in the patients with systolic BP is more than hundred mmHg and diastolic BP is more than sixty mmHg.Results: The outcomes of the usage of Levosimendan have been studied on 80 patients with decompensated heart problems and the comparative study has also been made with other inotropes, respectively. We have also performed a trial on two groups of people named as LIVO and NON-LIVO groups. The research study proves that the usage of levosimendan is better than other inotropes. Levosimendan can be recommended in the standard treatment of patients with acute heart conditions.Conclusions: Levosimendan is offering an effective remedy to treat the patients with decompensated heart failure. In comparison to other inotropes available for the treatment of patients suffering from congestive heart ailments, levosimendan can be considered to be a safe and efficient sensitizer.
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Rossetti, M., J. P. Savineau, H. Crevel, and R. Marthan. "Role of protein kinase C in nonsensitized and passively sensitized human isolated bronchial smooth muscle." American Journal of Physiology-Lung Cellular and Molecular Physiology 268, no. 6 (June 1, 1995): L966—L971. http://dx.doi.org/10.1152/ajplung.1995.268.6.l966.
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To examine the role of protein kinase C (PKC) activation in the control of the mechanical activity of human isolated bronchial smooth muscle obtained at thoracotomy, the effect of the phorbol ester phorbol 12,13-dibutyrate (PDB) was evaluated. PDB produced slowly developing and sustained contractions that were reduced 1) by the PKC inhibitor staurosporine and 2) after long-term (12 h) exposure to PDB, which downregulates PKC. Moreover, the inactive phorbol ester 4 alpha-phorbol 12,13 didecanoate had no contractile effect. Removal of external Ca2+ or addition of the Ca(2+)-channel antagonist verapamil reduced the PDB-induced contraction. Passive sensitization of human isolated bronchial rings, i.e., incubation overnight of tissues in serum from atopic asthmatic patients, decreased the maximal response to PDB to 28.9 +/- 8% of the maximal response to acetylcholine (ACh) when compared with that of paired nonsensitized rings, i.e., tissues incubated overnight in serum from normal subjects (46.7 +/- 9.4% of the maximal response to ACh, n = 5, P < 0.05). The decrease in the response to PDB induced by either long-term preexposure to PDB or passive sensitization was reversed when both types of tissues were allowed to recover unstimulated for 3 h before PDB application. These results show that 1) PKC activation induces maintained contractions in human isolated airway smooth muscle that are largely dependent on extracellular calcium; 2) passive sensitization alters the PKC-mediated response in a way similar to that induced by prolonged stimulation of PKC.
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Jian, Tunyu, Niuniu Yang, Yan Yang, Chan Zhu, Xiaolin Yuan, Guang Yu, Changming Wang, et al. "TRPV1 and PLC Participate in Histamine H4 Receptor-Induced Itch." Neural Plasticity 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/1682972.
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Histamine H4 receptor has been confirmed to play a role in evoking peripheral pruritus. However, the ionic and intracellular signaling mechanism of activation of H4 receptor on the dorsal root ganglion (DRG) neurons is still unknown. By using cell culture and calcium imaging, we studied the underlying mechanism of activation of H4 receptor on the DRG neuron. Immepip dihydrobromide (immepip)—a histamine H4 receptor special agonist under cutaneous injection—obviously induced itch behavior of mice. Immepip-induced scratching behavior could be blocked by TRPV1 antagonist AMG9810 and PLC pathway inhibitor U73122. Application of immepip (8.3–50 μM) could also induce a dose-dependent increase in intracellular Ca2+(Ca2+i) of DRG neurons. We found that 77.8% of the immepip-sensitized DRG neurons respond to the TRPV1 selective agonist capsaicin. U73122 could inhibit immepip-induced Ca2+responses. In addition, immepip-inducedCa2+iincrease could be blocked by ruthenium red, capsazepine, and AMG9810; however it could not be blocked by TRPA1 antagonist HC-030031. These results indicate that TRPV1 but not TRPA1 is the important ion channel to induce the DRG neurons’ responses in the downstream signaling pathway of histamine H4 receptor and suggest that TRPV1 may be involved in the mechanism of histamine-induced itch response by H4 receptor activation.
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Fellner, Susan K., and William J. Arendshorst. "Voltage-gated Ca2+ entry and ryanodine receptor Ca2+-induced Ca2+ release in preglomerular arterioles." American Journal of Physiology-Renal Physiology 292, no. 5 (May 2007): F1568—F1572. http://dx.doi.org/10.1152/ajprenal.00459.2006.
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We have previously shown that in afferent arterioles, angiotensin II (ANG II) involves activation of the inositol trisphosphate receptor (IP3R), activation of adenine diphosphoribose (ADPR) cyclase, and amplification of the initial IP3R-stimulated release of cytosolic Ca2+ ([Ca2+]i) from the sarcoplasmic reticulum (SR) (Fellner SK, Arendshorst WJ. Am J Physiol Renal Physiol 288: F785–F791, 2004). The response of the ryanodine receptor (RyR) to local increases in [Ca2+]i is defined as calcium-induced calcium release (CICR). To investigate whether Ca2+ entry via voltage-gated channels (VGCC) can stimulate CICR, we treated fura 2-loaded, freshly isolated afferent arterioles with KCl (40 mM; high KCl). In control arterioles, peak [Ca2+]i increased by 165 ± 10 nM. Locking the RyR in the closed position with ryanodine (100 μM) inhibited the [Ca2+]i response by 59% ( P < 0.01). 8-Br cADPR, a specific blocker of the ability of cyclic ADPR (cADPR) to sensitize the RyR to Ca2+, caused a 43% inhibition. We suggest that the lower inhibition by 8-Br cADPR ( P = 0.02, ryanodine vs. 8-Br cADPR) represents endogenously active ADPR cyclase. Depletion of SR Ca2+ stores by inhibiting the SR Ca2+-ATPase with cyclopiazonic acid or thapsigargin blocked the [Ca2+]i responses to KCl by 51% ( P not significant vs. ryanodine or 8-Br cADPR). These data suggest that about half of the increase in [Ca2+]i induced by high KCl is accomplished by activation of CICR through the ability of entered Ca2+ to expose the RyR to high local concentrations of Ca2+ and that endogenous cADPR contributes to the process.
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Stehlin, Ellyce, Simon C. Malpas, David M. Budgett, Carolyn J. Barrett, Daniel McCormick, Gillian Whalley, Fumin Fu, Michael Beil, Dean F. Rigel, and Sarah-Jane Guild. "Chronic measurement of left ventricular pressure in freely moving rats." Journal of Applied Physiology 115, no. 11 (December 1, 2013): 1672–82. http://dx.doi.org/10.1152/japplphysiol.00683.2013.
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Measurements of left ventricular pressure (LVP) in conscious freely moving animals are uncommon, yet could offer considerable opportunity for understanding cardiovascular disease progression and treatment. The aim of this study was to develop surgical methods and validate the measurements of a new high-fidelity, solid-state pressure-sensor telemetry device for chronically measuring LVP and dP/d t in rats. The pressure-sensor catheter tip (2-Fr) was inserted into the left ventricular chamber through the apex of the heart, and the telemeter body was implanted in the abdomen. Data were measured up to 85 days after implant. The average daytime dP/d t max was 9,444 ± 363 mmHg/s, ranging from 7,870 to 10,558 mmHg/s ( n = 7). A circadian variation in dP/d t max and heart rate (HR) was observed with an average increase during the night phase in dP/d t max of 918 ± 84 mmHg/s, and in HR of 38 ± 3 bpm. The β-adrenergic-agonist isoproterenol, β1-adrenergic agonist dobutamine, Ca2+ channel blocker verapamil, and the calcium sensitizer levosimendan were administered throughout the implant period, inducing dose-dependent time course changes and absolute changes in dP/d t max of −6,000 to +13,000 mmHg/s. The surgical methods and new technologies demonstrated long-term stability, sensitivity to circadian variation, and the ability to measure large drug-induced changes, validating this new solution for chronic measurement of LVP in conscious rats.
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Mourtzi, Niki, Amalia Sertedaki, Athina Markou, George P. Piaditis, Nicholas Katsanis, Joanne Traeger-Synodinos, Constantine Tsigos, and Evangelia Charmandari. "Unravelling the Genetic Basis of ACTH-Mediated Aldosterone Hypersecretion in Hypertensive Patients Without Primary Aldosteronism." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A73—A74. http://dx.doi.org/10.1210/jendso/bvab048.148.
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Abstract Introduction: Primary aldosteronism (PA), a condition characterized by autonomous aldosterone hypersecretion, constitutes the most common cause of secondary hypertension. PA includes both sporadic and familial forms, inherited in an autosomal dominant manner. Recent evidence suggests a higher prevalence of aldosterone excess among hypertensive patients than previously thought, while chronic stress-related ACTH-mediated aldosterone hypersecretion has also been implicated in the pathogenesis of essential hypertension. Objective: To determine whether genetic variations of aldosterone regulating genes could be implicated in the ACTH-mediated aldosterone hypersecretion in hypertensive patients without PA. Methods: Twenty-one hypertensive patients without PA, who exhibited ACTH-mediated aldosterone hypersecretion, underwent Whole Exome Sequencing (WES) on Novaseq 6000 platform (Illumina). As hyper-responders were defined patients whose aldosterone (ALD) and aldosterone-to-renin ratio (ARR) response to ultra-low ACTH stimulation test was above the 97.5th percentile values of controls. The cutoff levels for ALD and ARR were 1300 pmol/L and 77 pmol/mIU, respectively. Variant calling was performed according to GATK best practices and VCF files were filtered for variants in 25 genes associated with PA. To identify new susceptibility genes for PA, VCF files were also intersected for variants in ion channels encoding genes involved in pathways responsible for PA. The analysis was restricted to rare variants with gnomAD frequency < 1%. Qualifying variants and pathogenicity were established by employing in silico tools. Copy Number Variant analysis was performed using ExomeDepth algorithm. Results: Eight out of twenty-one patients were heterozygous for rare variants in genes associated with PA, while two patients carried potentially damaging variants in genes encoding ion channels. Specifically, one patient was heterozygous for p.V259M in KCNK5 and one patient was heterozygous for the novel variant p.V221M in KCNK9. Two additional patients carried a predicted pathogenic variant p.R492W in SLC26A2, a gene that has been associated with PA through GWAS. Germline variants in calcium channel genes were also detected in three patients: p.V249I in CACNA1H, p.R462Q in CACNA1D and p.L1801M in CACNA1I, while one patient carried an ultra-rare variant (p.R26L) in ATP13A3. Finally, in two patients we identified rare, likely pathogenic variants in two new susceptibility genes for PA: KCNK16 (p.P255H) and CACNA2D3 (p.V55I). Conclusion: These findings support the notion that mutations in aldosterone synthesis/secretion regulating genes may sensitize zone glomerulosa cells to ACTH stimulation, leading to aldosterone hypersecretion under conditions of stress. We also report two novel candidate susceptibility genes for PA, KCNK16 and CACNA2D3, and one novel variant in KCNK9.
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Doliba, Nicolai M., Wei Qin, Marko Z. Vatamaniuk, Changhong Li, Dorothy Zelent, Habiba Najafi, Carol W. Buettger, et al. "Restitution of defective glucose-stimulated insulin release of sulfonylurea type 1 receptor knockout mice by acetylcholine." American Journal of Physiology-Endocrinology and Metabolism 286, no. 5 (May 2004): E834—E843. http://dx.doi.org/10.1152/ajpendo.00292.2003.
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Inhibition of ATP-sensitive K+ (KATP) channels by an increase in the ATP/ADP ratio and the resultant membrane depolarization are considered essential in the process leading to insulin release (IR) from pancreatic β-cells stimulated by glucose. It is therefore surprising that mice lacking the sulfonylurea type 1 receptor (SUR1−/−) in β-cells remain euglycemic even though the knockout is expected to cause hypoglycemia. To complicate matters, isolated islets of SUR1−/− mice secrete little insulin in response to high glucose, which extrapolates to hyperglycemia in the intact animal. It remains thus unexplained how euglycemia is maintained. In recognition of the essential role of neural and endocrine regulation of IR, we evaluated the effects of acetylcholine (ACh) and glucagon-like peptide-1 (GLP-1) on IR and free intracellular Ca2+ concentration ([Ca2+]i) of freshly isolated or cultured islets of SUR1−/− mice and B6D2F1 controls (SUR1+/+). IBMX, a phosphodiesterase inhibitor, was also used to explore cAMP-dependent signaling in IR. Most striking, and in contrast to controls, SUR1−/− islets are hypersensitive to ACh and IBMX, as demonstrated by a marked increase of IR even in the absence of glucose. The hypersensitivity to ACh was reproduced in control islets by depolarization with the SUR1 inhibitor glyburide. Pretreatment of perifused SUR1−/− islets with ACh or IBMX restored glucose stimulation of IR, an effect expectedly insensitive to diazoxide. The calcium channel blocker verapamil reduced but did not abolish ACh-stimulated IR, supporting a role for intracellular Ca2+ stores in stimulus-secretion coupling. The effect of ACh on IR was greatly potentiated by GLP-1 (10 nM). ACh caused a dose-dependent increase in [Ca2+]i at 0.1–1 μM or biphasic changes (an initial sharp increase in [Ca2+]i followed by a sustained phase of low [Ca2+]i) at 1–100 μM. The latter effects were observed in substrate-free medium or in the presence of 16.7 mM glucose. We conclude that SUR1 deletion depolarizes the β-cells and markedly elevates basal [Ca2+]i. Elevated [Ca2+]i in turn sensitizes the β-cells to the secretory effects of ACh and IBMX. Priming by the combination of high [Ca2+]i, ACh, and GLP-1 restores the defective glucose responsiveness, precluding the development of diabetes but not effectively enough to cause hyperinsulinemic hypoglycemia.
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Suttorp, N., W. Seeger, S. Zinsky, and S. Bhakdi. "Complement complex C5b-8 induces PGI2 formation in cultured endothelial cells." American Journal of Physiology-Cell Physiology 253, no. 1 (July 1, 1987): C13—C21. http://dx.doi.org/10.1152/ajpcell.1987.253.1.c13.
Full textAbstract:
The effects of the terminal complement sequence on prostacyclin (PGI2) generation in antibody-sensitized pulmonary arterial endothelial cells were examined. Whereas C5b-7 complement complexes induced no PGI2 formation, addition of purified complement component C8 resulted in a time- and dose-dependent burst of PGI2 release in the absence of overt cell damage. Formation of the complete terminal complement complex C5b-9 enhanced PGI2 release but was accompanied by cytolysis. Extracellular Ca2+ was required for C5b-8-dependent PGI2 formation. Three different blockers of physiological calcium channels failed to suppress the observed stimulatory effect. In contrast, W7 [N-(6-amino-hexyl)-5-chloro-1-naphthalene sulfonamide] and trifluoperazine, inhibitors of calmodulin activity, all reduced the C5b-8-dependent PGI2 generation. None of the inhibitors used impaired Ca2+ flux into the cells. One minute after addition of C8 to endothelial cells carrying C5b-7 complexes, a six- to seven-fold enhanced passive influx of 45Ca2+ into the cells was noted. An enhanced passive influx was also observed for 51Cr O4(2-), [3H] aminobutyric acid, and [3H]sucrose, but not for [3H]inulin and [3H]dextran. These data together suggest that complement C5b-8 complexes may serve as Ca2+ bypass gates in endothelial cells, the ensuing influx of Ca2+ leading to subsequent activation of the arachidonic acid pathway.
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Fang, Jing, Xiaona Liu, Lyndsey Bolanos, Brenden Barker, Carmela Rigolino, Agostino Cortelezzi, Esther Natalie Oliva, Kyle J. MacBeth, Kakajan Komurov, and Daniel T. Starczynowski. "A Calcium-Dependent Pathway Determines Response to Lenalidomide in Del(5q) Myelodysplastic Syndromes." Blood 124, no. 21 (December 6, 2014): 1898. http://dx.doi.org/10.1182/blood.v124.21.1898.1898.
Full textAbstract:
Abstract Deletions of the long arm of chromosome 5 (del(5q)) are common cytogenetic alterations in myelodysplastic syndrome (MDS), a disease characterized by refractory anemia, megakaryocyte dysplasia, and thrombocytosis. The thalidomide analogue lenalidomide (LEN) produces durable erythroid responses in ~60% of del(5q) MDS patients, including a majority of cytogenetic responses in which the del(5q) clone becomes undetectable in the bone marrow. Despite high response rates, clinical and cytogenetic relapse occur within 2-3 years. Mechanisms of clinical response, resistance and relapse with LEN therapy remain to be elucidated. The target of LEN has recently been identified as the cereblon (CRBN) component of the cullin 4 RING E3 ubiquitin ligase complex (CRL4-CRBN). Upon LEN binding, the substrate-specificity of the CRL4-CRBN complex is altered, and LEN-regulated substrates are beginning to be identified. An RNA interference screen was performed to identify genes/pathways that mediate LEN sensitivity and resistance in del(5q) MDS. The LEN-sensitive del(5q) MDS patient-derived cell line MDSL was screened with a genome-wide shRNA library (SBI GeneNet Human 50K Library) in the presence and absence of LEN treatment (0 and 10 μM) for 7 days. Three independent shRNAs targeting the proton-sensing G protein-coupled receptor 1 (GPR68 or OGR1) were among the most enriched shRNAs in LEN-treated cells, suggesting that loss of GPR68 expression conferred resistance to LEN. This finding was validated in MDSL cells, using an independent set of shRNAs. Conversely, a GPR68 agonist (N-cyclopropoyl-5-[thiophen-2-yl]-isoxazole-3-carboxamid) enhanced LEN-induced cytotoxicity to MDSL cells. GPR68 is a proton-sensing G-protein coupled receptor that stimulates inositol phosphate production and/or intracellular calcium (Ca2+) mobilization. Curiously, CRBN was originally identified as a binding protein of calcium-activated potassium channels. These data led us to hypothesize that Ca2+ signaling may be responsible for LEN-mediated cytotoxic effect in MDS cells. Reducing intracellular Ca2+ level with chelators reversed LEN’s cytotoxic effects, while increasing intracellular Ca2+ level with ionomycin enhanced LEN’s cytotoxic effect, indicating that intracellular Ca2+ levels determine cellular responsiveness to LEN. Although LEN did not induce an instant burst of Ca2+ influx, a gradual increase of basal intracellular free Ca2+ was observed following LEN treatment in LEN-sensitive cell lines and primary MDS marrow cells, but not in LEN-resistant cells, suggesting that LEN cytotoxicity was dependent on the cell’s ability to release Ca2+ from intracellular stores. GPR68 and CRBN were both necessary for the LEN-induced increase in Ca2+, as knockdown of GPR68 or CRBN in LEN-sensitive cells prevented the Ca2+increase. To identify the Ca2+-dependent signaling pathway responsible for mediating the cytotoxic effect of LEN, a panel of seven inhibitors that blocked mitochondrial/caspase-, calpain-, autophagy-, or lysosomal-dependent cell death pathways was tested in combination with LEN on MDSL cells. Only the inhibitor of calpains (PD150606) prevented LEN-induced cytotoxic effects in MDSL cells, indicating that calpain activation was necessary for mediating cell death in LEN-treated cells. Calpains are Ca2+-dependent cysteine proteases that can induce apoptotic and necrotic cell death by proteolytic cleavage of protein substrates. Calpastatin, the only endogenous calpain inhibitor, is localized to 5q15 and its expression is haploinsufficient in del(5q) MDS as compared to normal karyotype MDS. Taken together, our results show that LEN increased intracellular Ca2+ levels by a CRBN- and GPR68-dependent mechanism, leading to calpain-mediated cytotoxicity in del(5q) MDS cells. We propose a model in which haploinsufficient expression of calpastatin in del(5q) MDS sensitizes cells to cytotoxic effects of LEN. Further studies are required to identify the direct LEN-modulated substrates of CRBN that mediate this effect. Disclosures Oliva: Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy, Honoraria. MacBeth:Celgene: Employment, Equity Ownership. Starczynowski:Celgene: Research Funding.
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Liu, Shangqin, Hideaki Ishikawa, Naohiro Tsuyama, Saeid Abroun, Fu-Jun Li, Ken-ichiro Otsuyama, Xu Zheng, et al. "CD45 Defines Signaling Thresholds Critical for Proliferation and Apoptosis in Myeloma Cells." Blood 104, no. 11 (November 16, 2004): 3345. http://dx.doi.org/10.1182/blood.v104.11.3345.3345.
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Abstract Expression of the common leukocyte antigen, CD45 is quite variable in human myeloma cells and cell lines, such as U266, and CD45+ U266 proliferates in response to a growth factor, interleukin-6 (IL-6). IL-6 as a mitogenic stimulus, activated a src family kinase, Lyn and phospholipase C (PLC)-g2 followed by Ca2+ influxes and protein kinase C (PKC) activation in CD45+ U266. Here we show that compared with CD45− U266, CD45+ U266 was more sensitive to various apoptotic stimuli, such as oxidative stress and endoplasmic reticulum (ER)-stress. Both release of apoptosis-inducing factor or cytochrome c and the activation of caspase-9 and caspase-3 were enhanced in CD45+ U266 more than in CD45− U266. Increased susceptibility to the stress-induced apoptosis was also observed in other CD45-expressing myeloma cell lines and the CD45-transfected U266. Reactive oxygen species (ROS) and calcium ion (Ca2+) seem to be involved in the susceptibility to apoptosis of CD45+ U266 because either an anti-oxidant, DTT or a Ca2+ chelating agent, BAPTA blocked the apoptosis. As the oxidative stress-induced Ca2+ influxes and apoptosis of CD45+ U266 were blocked by a src family kinase inhibitor, PP2, CD45 phosphatase regulating the src family kinase activity plays an important role in the augmented apoptosis in CD45+ U266 by oxidative stress. The intracellular accumulation of ROS may activate src associated with CD45, and the activated src kinases accelerate the Ca2+ influxes followed by calicineurin activation, mitochondrial translocation of Bad, and inhibition of Bcl-2 function. These results indicate that the CD45-expression renders myeloma cells competent with not only mitogenic but also apoptotic stimuli, resulting in either proliferation or apoptosis of CD45+ myeloma cells dependently upon the stimuli. Furthermore, voltage-dependent anion channel (VDAC)-1 was identified as a gene highly expressed in CD45+ U266 by cDNA subtraction. The increased expression of VDAC-1 seemed to augment the sensitivity to the ER-stress because the VDAC-1-transfected CD45− U266 was confirmed to be susceptible to the thapsigargin-induced apoptosis. Thus, CD45 may define the signaling thresholds that are critical for the IL-6-induced proliferation and the oxidative stress-induced apoptosis of myeloma cells, and the CD45 expression accompanied by the increased VDAC-1 expression sensitizes myeloma cells to the various extracellular stimuli triggering apoptosis via the mitochondrial pathways.
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Loskutov, O. A. "Emergency care for life-threatening arrhythmias." Infusion & Chemotherapy, no. 3.2 (December 15, 2020): 183–85. http://dx.doi.org/10.32902/2663-0338-2020-3.2-183-185.
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Background. Sepsis is often accompanied by arrhythmias and conduction disorders. It can be assumed that pacemaker cells of the sinoatrial node, strongly sensitized by massive stimulation with β1-adrenergic catecholamines, tend to trigger arrhythmias. The importance of the inflammatory component in the development of new atrial fibrillation (AF) events is also confirmed by the existence of a strong correlation between increased levels of C-reactive protein, interleukin-6 and tumor necrosis factor and the onset of fibrillation. Under the conditions of the new-onset AF, the hospital mortality of patients of general profile in the intensive care unit (ICU) significantly exceeds that for people without AF.
Objective. To describe the features of treatment of life-threatening arrhythmias.
Materials and methods. Analysis of literature data on this issue.
Results and discussion. Amiodarone, diltiazem and lidocaine are the most commonly used treatments for life-threatening arrhythmias. According to a UK-wide study, amiodarone is used to treat new-onset AF in ICU in 80.94 % of cases, β-blockers (BB) – in 11.60 %, other antiarrhythmic drugs (AAD) – in 3.87 %, and digoxin – in 3.31 %. However, this tactic is not in line with the existing guidelines. According to the recommendations for the heart rate (HR) control in emergency care for AF (Bokeria L.A. et al., 2017), in an acute situation in the absence of ventricular pre-excitation syndrome intravenous administration of BB or non-dihydropyridine calcium channel blockers (CCB) is recommended to slow ventricular rhythm in patients with AF. Caution should be taken in patients with hypotension or heart failure. For the last group of patients intravenous administration of cardiac glycosides or amiodarone is recommended. In patients with ventricular pre-excitation syndrome, class I AAD or amiodarone are the drugs of choice. In presence of the pre-excitation syndrome and AF BB, non-dihydropyridine CCB, digoxin and adenosine are contraindicated. The guidelines for the management of AF patients, developed in 2017 by the European Society of Cardiology in collaboration with the European Association of Cardiothoracic Surgery, recommend to use different management tactics depending on the left ventricular ejection fraction (LV EF). In case of LV EF <40 % or signs of heart failure, the lowest effective dose of BB should be prescribed to achieve rhythm control. Amiodarone is prescribed to hemodynamically unstable patients or to individuals with severely reduced LV EF. The primary goal of treatment is to achieve a HR <110 beats/min. In the absence of this result, digoxin should be added. In case of LV EF ≥40 %, BB, or diltiazem, or verapamil should be administered. In the absence of clinical result, digoxin should be added. Practical models of AF treatment in sepsis have demonstrated the superiority of BB over CCB, digoxin and amiodarone (Walkey A.J. et al., 2016). BB weaken the stimulating effect of the sympathetic part of the autonomic nervous system on the myocardium, have a negative chronotropic effect, improve the contractility of ischemized cardiomyocytes, slow atrioventricular conduction, reduce myocardial oxygen demand, and apoptosis. Esmolol (Biblok, “Yuria-Pharm”) is indicated for supraventricular tachycardia (except for ventricular pre-excitation syndrome) and for the rapid control of ventricular rhythm in patients with AF or atrial flutter in the pre- and postoperative periods or in other circumstances when it is necessary to normalize ventricular rhythm with a short-acting drug. Studies show that esmolol inhibits inflammation in sepsis by increasing the expression of the antimicrobial peptide cathelicidin. Kaplan – Mayer analysis shows better survival for experimental animals with sepsis receiving esmolol compared to animals in the 0.9 % NaCl group (Ibrahim-Zada I. et al., 2014).
Conclusions. 1. Sepsis is often accompanied by arrhythmias and conduction disorders. 2. Under the conditions of new-onset AF, the hospital mortality of patients of general somatic profile in ICU significantly exceeds the number for people without AF. 3. In case of AF and LV EF <40 % or signs of heart failure, the lowest effective dose of BB should be prescribed to achieve rhythm control. 4. In case of LV EF ≥40 %, BB, or diltiazem, or verapamil should be administered. 5. Esmolol is indicated for supraventricular tachycardia and for the rapid control of ventricular rhythm in patients with AF or atrial flutter. 6. Esmolol inhibits inflammation in sepsis by increasing the expression of the antimicrobial peptide cathelicidin.
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Wang, Haiyuan, Pu Yang, Yungang Lu, Jin Wang, Jaepyo Jeon, Qiaochu Wang, Jin-Bin Tian, Bin Zang, Ye Yu, and Michael X. Zhu. "Mechanisms of proton inhibition and sensitization of the cation channel TRPV3." Journal of General Physiology 153, no. 2 (December 15, 2020). http://dx.doi.org/10.1085/jgp.202012663.
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TRPV3 is a temperature-sensitive, nonselective cation channel expressed prominently in skin keratinocytes. TRPV3 plays important roles in hair morphogenesis and maintenance of epidermal barrier function. Gain-of-function mutations of TRPV3 have been found in both humans and rodents and are associated with hair loss, pruritus, and dermatitis. Here, we study the mechanisms of acid regulation of TRPV3 by using site-directed mutagenesis, fluorescent intracellular calcium measurement, and whole-cell patch-clamp recording techniques. We show that, whereas extracellular acid inhibits agonist-induced TRPV3 activation through an aspartate residue (D641) in the selectivity filter, intracellular protons sensitize the channel through cytoplasmic C-terminal glutamate and aspartate residues (E682, E689, and D727). Neutralization of the three C-terminal residues presensitizes the channel to agonist stimulation. Molecular dynamic simulations revealed that charge neutralization of the three C-terminal residues stabilized the sensitized channel conformation and enhanced the probability of α-helix formation in the linker between the S6 transmembrane segment and TRP domain. We conclude that acid inhibits TRPV3 function from the extracellular side but facilitates it from the intracellular side. These novel mechanisms of TRPV3 proton sensing can offer new insights into the role of TRPV3 in the regulation of epidermal barrier permeability and skin disorders under conditions of tissue acidosis.
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Alaimo, Alessandro, Marco Lorenzoni, Paolo Ambrosino, Arianna Bertossi, Alessandra Bisio, Alice Macchia, Eugenio Zoni, et al. "Calcium cytotoxicity sensitizes prostate cancer cells to standard-of-care treatments for locally advanced tumors." Cell Death & Disease 11, no. 12 (December 2020). http://dx.doi.org/10.1038/s41419-020-03256-5.
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AbstractTherapy resistance is a major roadblock in oncology. Exacerbation of molecular dysfunctions typical of cancer cells have proven effective in twisting oncogenic mechanisms to lethal conditions, thus offering new therapeutic avenues for cancer treatment. Here, we demonstrate that selective agonists of Transient Receptor Potential cation channel subfamily M member 8 (TRPM8), a cation channel characteristic of the prostate epithelium frequently overexpressed in advanced stage III/IV prostate cancers (PCa), sensitize therapy refractory models of PCa to radio, chemo or hormonal treatment. Overall, our study demonstrates that pharmacological-induced Ca2+ cytotoxicity is an actionable strategy to sensitize cancer cells to standard therapies.
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Hou, Peiwei. "HIIT sensitizes the arterial baroreflex by activating GSH-Px and downregulating calcium channel." Journal of Sports Medicine and Physical Fitness 60, no. 4 (May 2020). http://dx.doi.org/10.23736/s0022-4707.20.10393-1.
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Shuba, Yaroslav M. "Beyond Neuronal Heat Sensing: Diversity of TRPV1 Heat-Capsaicin Receptor-Channel Functions." Frontiers in Cellular Neuroscience 14 (February 5, 2021). http://dx.doi.org/10.3389/fncel.2020.612480.
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Transient receptor potential vanilloid 1 (TRPV1) is a calcium-permeable ion channel best known for its ability to be gated by the pungent constituent of red chili pepper, capsaicin, and related chemicals from the group of vanilloids as well as by noxious heat. As such, it is mostly expressed in sensory neurons to act as a detector of painful stimuli produced by pungent chemicals and high temperatures. Its activation is also sensitized by the numerous endogenous inflammatory mediators and second messengers, making it an important determinant of nociceptive signaling. Except for such signaling, though, neuronal TRPV1 activation may influence various organ functions by promoting the release of bioactive neuropeptides from sensory fiber innervation organs. However, TRPV1 is also found outside the sensory nervous system in which its activation and function is not that straightforward. Thus, TRPV1 expression is detected in skeletal muscle; in some types of smooth muscle; in epithelial and immune cells; and in adipocytes, where it can be activated by the combination of dietary vanilloids, endovanilloids, and pro-inflammatory factors while the intracellular calcium signaling that this initiates can regulate processes as diverse as muscle constriction, cell differentiation, and carcinogenesis. The purpose of the present review is to provide a clear-cut distinction between neurogenic TRPV1 effects in various tissues consequent to its activation in sensory nerve endings and non-neurogenic TRPV1 effects due to its expression in cell types other than sensory neurons.
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Kumar, Dhanesh, Om Prakash Yadava, Vikas Ahlawat, Anirban Kundu, Amita Yadav, and Arvind Prakash. "Pre-bypass levosimendan in ventricular dysfunction-effect on right ventricle." Asian Cardiovascular and Thoracic Annals, November 3, 2020, 021849232097289. http://dx.doi.org/10.1177/0218492320972891.
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Background Levosimendan is an effective calcium sensitizer with complementary mechanisms of action: calcium sensitization and opening of adenosine triphosphate-dependent potassium channels, both on the sarcolemma of the smooth muscle cells in the vasculature and on the mitochondria of cardiomyocytes. Levosimendan has a long-acting metabolite with a half-life of approximately 80 h. There have been a few small studies on this drug regarding right ventricular function. In view of this, we investigated the effect of levosimendan on right ventricular function in patients with coronary artery disease. Methods This was a prospective, randomized, double-blind study on 50 patients with coronary artery disease and severe left ventricular dysfunction (left ventricular ejection fraction ≤35%) undergoing elective off-pump coronary artery bypass. Results Levosimendan had an inotropic effect on right ventricular myocardium and a vasodilatory effect on blood vessels. It caused a decline in pulmonary vascular resistance ( p < 0.018), right ventricular systolic pressure ( p < 0.001), and pulmonary artery systolic pressure ( p < 0.001), and improved right ventricular diastolic function as shown by the decrease in right ventricular Tei index ( p < 0.001), right ventricular end-diastolic pressure, and the ratio of early diastolic tricuspid inflow to tricuspid lateral annular velocity ( p < 0.006). However, we found no beneficial effects on intensive care unit or hospital stay ( p = 0.164, p = 0.349, respectively) nor a mortality benefit. Conclusions Levosimendan has salutary effects on right ventricular function in patients with severe left ventricular dysfunction undergoing coronary artery bypass, in terms of improved hemodynamic parameters.
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Paterno Marchioli, C. A. "P4559Assess of angiotensin receptor blockers therapy associated to mineralocorticoid receptor antagonists or to calcium channel blockers plus hydrochlorothiazide according central haemodynamic parameters." European Heart Journal 40, Supplement_1 (October 1, 2019). http://dx.doi.org/10.1093/eurheartj/ehz745.0950.
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Abstract Background Protective effect of Angiotensin-II Receptor Blockers (ARBs) on major cardiovascular events might be partly independent of the degree of blood pressure reduction. Calcium channel blockers (CCBs), lower arterial pressure by decreasing total peripheral resistance without reducing cardiac output. Hydrochlorothiazide (Hctz) is one of the most commonly prescribed antihypertensive drugs worldwide, but associated with more frequent adverse effects, such as hypokalaemia, hyponatraemia, hyperuricaemia and may increase the glycaemia, It sensitizes the endothelium to the action of angiotensin II, might act on the aldosterone release. The phenomenon of “aldosterone escape” occurs even in the presence of combination therapy with ARBs. The harmful effects of aldosterone are innumerable: induced cardiac and renal fibrosis, sodium and water retention, inflammation, oxidative stress, arrhythmias, glucose intolerance, insulin resistance, among others, that are involved in arterial and myocardium remodelling. Mineralocorticoid Receptor Antagonists (MRAs) therapy improve diastolic function, decrease plasma volume and vascular/myocardial fibrosis. Purpose This study aimed to assess the responses of two groups of therapy such as ARBs associated to MRAs or to CCBs+Hctz according to central haemodynamic parameters (CHPs) in hypertensive patients, both genders, with normal kidney function. Methods For this cross-sectional retrospective study, data were collected from 391 hypertensive patients who were assisted in the hypertension centre. Female/male 239/152, each gender divided into two groups of therapy: ARB+MRA/ARB+CCB+Hctz. Female 210/29 (average age 57/70) and male 125/27 (average age 55/61). The CHPs were measured with a SphygmoCor System PVX (AtCor-Medical Australia), a validated device employing the high-fidelity technique of applanation tonometry according to established protocols. Also, the difference of Augmentation Index (Diff-AIx) between the observed values and the expected levels was assessed according to normal range by age. No patients had cardiovascular, endocrine, renal and metabolic decompensated diseases. Results After measuring the body mass index, waist circumference and heart rate, the two therapy groups were confronted, both genders, had not found the statistically significant difference. The results of CHPs (Central Aortic Pressure, End-Systolic Pressure, Mean Arterial Pressure, Pulse Pressure, Augmentation Pressure), systolic and diastolic blood pressure during association of ARBs+MRAs therapy compared to ARBs+CCBs+Hctz, both genders, showed the lowest values with a highly statistically significant difference. In the female/male the Diff-AIx was found p=0.05/0.04. Conclusion These findings suggest that ARBs+MRAs treatment reaches the best haemodynamic conditions because improve the levels of CHPs and arterial stiffness (Diff-AIx) giving an adequate reduction of the stress to the arterial-ventricular coupling.
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Wanderer, Stefan, Lukas Andereggen, Jan Mrosek, Sepide Kashefiolasl, Gerrit Alexander Schubert, Serge Marbacher, and Jürgen Konczalla. "Levosimendan as a therapeutic strategy to prevent neuroinflammation after aneurysmal subarachnoid hemorrhage?" Journal of NeuroInterventional Surgery, May 26, 2021, neurintsurg—2021–017504. http://dx.doi.org/10.1136/neurintsurg-2021-017504.
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BackgroundPoor patient outcomes after aneurysmal subarachnoid hemorrhage (SAH) occur due to a multifactorial process, mainly involving cerebral inflammation (CI), delayed cerebral vasospasm (DCVS), and delayed cerebral ischemia, followed by neurodegeneration. CI is mainly triggered by enhanced synthesis of serotonin (5-HT), prostaglandin F2alpha (PGF2a), and cytokines such as interleukins. Levosimendan (LV), a calcium-channel sensitizer, has already displayed anti-inflammatory effects in patients with severe heart failure. Therefore, we wanted to elucidate its potential anti-inflammatory role on the cerebral vasculature after SAH.MethodsExperimental SAH was induced by using an experimental double-hemorrhage model. Sprague Dawley rats were harvested on day 3 and day 5 after the ictus. The basilar artery was used for isometric investigations of the muscular media tone. Vessel segments were either preincubated with LV or without, with precontraction performed with 5-HT or PGF2a followed by application of acetylcholine (ACh) or LV.ResultsAfter preincubation with LV 10−4 M and 5-HT precontraction, ACh triggered a strong vasorelaxation in sham segments (LV 10−4 M, Emax 65%; LV 10−5 M, Emax 48%; no LV, Emax 53%). Interestingly, SAH D3 (LV 10−4, Emax 76%) and D5 (LV 10−4, Emax 79%) segments showed greater vasorelaxation compared with sham. An LV series after PGF2a precontraction showed significantly enhanced relaxation in the sham (P=0.004) and SAH groups (P=0.0008) compared with solvent control vessels.ConclusionsLV application after SAH seems to beneficially influence DCVS by antagonizing 5-HT- and PGF2a-triggered vasoconstriction. Considering this spasmolytic effect, LV might have a role in the treatment of SAH, additionally in selected patients suffering takotsubo cardiomyopathy.
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de Oliveira, Amanda A., Fernanda Priviero, Rita C. Tostes, R. Clinton Webb, and Kenia P. Nunes. "Dissecting the interaction between HSP70 and vascular contraction: role of $$\hbox{Ca}^{2+}$$ handling mechanisms." Scientific Reports 11, no. 1 (January 14, 2021). http://dx.doi.org/10.1038/s41598-021-80966-6.
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AbstractHeat-shock protein 70 (HSP70) is a ubiquitously expressed molecular chaperone with various biological functions. Recently, we demonstrated that HSP70 is key for adequate vascular reactivity. However, the specific mechanisms targeted by HSP70 to assist in this process remain elusive. Since there is a wealth of evidence connecting HSP70 to calcium ($$\hbox {Ca}^{2+}$$ Ca 2 + ), a master regulator of contraction, we designed this study to investigate whether blockade of HSP70 disrupts vascular contraction via impairment of $${\text{Ca}}^{2+}$$ Ca 2 + handling mechanisms. We performed functional studies in aortas isolated from male Sprague Dawley rats in the presence or absence of exogenous $$\hbox {Ca}^{2+}$$ Ca 2 + , and we determined the effects of VER155008, an inhibitor of HSP70, on $$\hbox {Ca}^{2+}$$ Ca 2 + handling as well as key mechanisms that regulate vascular contraction. Changes in the intracellular concentration of $$\hbox {Ca}^{2+}$$ Ca 2 + were measured with a biochemical assay kit. We report that blockade of HSP70 leads to $$\hbox {Ca}^{2+}$$ Ca 2 + mishandling in aorta stimulated with phenylephrine, decreasing both phasic and tonic contractions. Importantly, in $$\hbox {Ca}^{2+}$$ Ca 2 + free Krebs’ solution, inhibition of HSP70 only reduced the $$\hbox {E}_{\mathrm{max}}$$ E max of the phasic contraction if the protein was blocked before IP3r-mediated $$\hbox {Ca}^{2+}$$ Ca 2 + release, suggesting that HSP70 has a positive effect towards this receptor. Corroborating this statement, VER155008 did not potentiate an IP3r inhibitor’s outcomes, even with partial blockade. In another set of experiments, the inhibition of HSP70 attenuated the amplitude of the tonic contraction independently of the moment VER155008 was added to the chamber (i.e., whether it was before or after IP3r-mediated phasic contraction). More compelling, following re-addition of $$\hbox {Ca}^{2+}$$ Ca 2 + , VER155008 amplified the inhibitory effects of a voltage-dependent $$\hbox {Ca}^{2+}$$ Ca 2 + channel blocker, but not of a voltage-independent $$\hbox {Ca}^{2+}$$ Ca 2 + channel inhibitor, indicating that HSP70 has a positive impact on the latter. Lastly, the mechanism by which HSP70 modulates vascular contraction does not involve the $$\hbox {Ca}^{2+}$$ Ca 2 + sensitizer protein, Rho-kinase, nor the SERCA pump, as blockade of these proteins in the presence of VER155008 almost abolished contraction. In summary, our findings shed light on the processes targeted by HSP70 during vascular contraction and open research avenues for potential new mechanisms in vascular diseases.