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1
Hasunuma, K., T. Yamaguchi, D. M. Rodman, R. F. O'Brien, and I. F. McMurtry. "Effects of inhibitors of EDRF and EDHF on vasoreactivity of perfused rat lungs." American Journal of Physiology-Lung Cellular and Molecular Physiology 260, no. 2 (February 1, 1991): L97—L104. http://dx.doi.org/10.1152/ajplung.1991.260.2.l97.
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Recent studies indicate that the endothelium of isolated rat pulmonary arteries releases two different factors, endothelium-derived relaxing factor (EDRF) and hyperpolarizing factor (EDHF), which participate in histamine- and acetylcholine-induced relaxation. There is evidence for EDRF vasoreactivity in perfused lungs, but a role for EDHF, which hyperpolarizes vascular smooth muscle by activating membrane K+ channels, has not been reported. We used the inhibitors of EDRF, 20 microM hemoglobin, 200 microM NG-mono-methyl-L-arginine, and 2 mM L-canavanine, the nonselective blocker of K+ channels, 10 mM tetraethylammonium (TEA), and the inhibitor of ATP-sensitive K+ channels, 20 microM glibenclamide, to compare the roles of EDRF and EDHF in the vasoregulation of meclofenamate-treated, salt solution-perfused rat lungs. The three EDRF inhibitors had little or no effect on baseline perfusion pressure, but each potentiated the peak pressor response to airway hypoxia. Neither of them inhibited the pulmonary vasodilation to 5 microM histamine. TEA, but not glibenclamide, increased baseline pressure and potentiated the peak hypoxic response. Both K+ channel blockers, but not the EDRF inhibitors, also prolonged the hypoxic response by reducing the rate of spontaneous vasodilation. TEA, but not glibenclamide, inhibited histamine vasodilation. These results suggest roles for both EDRF and EDHF in the control of rat pulmonary vascular reactivity. EDRF is apparently not responsible for the low vascular tone of the normoxic lung and does not mediate the vasodilation to histamine, but it does modulate the hypoxic pressor response. The exact role of EDHF is uncertain, but it may also modulate hypoxic vasoconstriction and mediate at least part of the histamine vasodilation.
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Park, Yoonjung, Stefano Capobianco, Xue Gao, John R. Falck, Kevin C. Dellsperger, and Cuihua Zhang. "Role of EDHF in type 2 diabetes-induced endothelial dysfunction." American Journal of Physiology-Heart and Circulatory Physiology 295, no. 5 (November 2008): H1982—H1988. http://dx.doi.org/10.1152/ajpheart.01261.2007.
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Endothelium-derived hyperpolarizing factor (EDHF) plays a crucial role in modulating vasomotor tone, especially in microvessels when nitric oxide-dependent control is compromised such as in diabetes. Epoxyeicosatrienoic acids (EETs), potassium ions (K+), and hydrogen peroxide (H2O2) are proposed as EDHFs. However, the identity (or identities) of EDHF-dependent endothelial dilators has not been clearly elucidated in diabetes. We assessed the mechanisms of EDHF-induced vasodilation in wild-type (WT, normal), db/db (advanced type 2 diabetic) mice, and db/db mice null for TNF (dbTNF−/dbTNF−). In db/db mice, EDHF-induced vasodilation [ACh-induced vasodilation in the presence of NG-nitro-l-arginine methyl ester (l-NAME, 10 μmol/l) and prostaglandin synthase inhibitor indomethacin (Indo, 10 μmol/l)] was diminished after the administration of catalase (an enzyme that selectively dismutates H2O2 to water and oxygen, 1,000 U/ml); administration of the combination of charybdotoxin (a nonselective blocker of intermediate-conductance Ca2+-activated K+ channels, 10 μmol/l) and apamin (a selective blocker of small-conductance Ca2+-activated K+ channels, 50 μmol/l) also attenuated EDHF-induced vasodilation, but the inhibition of EETs synthesis [14,15-epoxyeicosa-5(Z)-enoic acid; 10 μmol/l] did not alter EDHF-induced vasodilation. In WT controls, EDHF-dependent vasodilation was significantly diminished after an inhibition of K+ channel, EETs synthesis, or H2O2 production. Our molecular results indicate that mRNA and protein expression of interleukin-6 (IL-6) were greater in db/db versus WT and dbTNF−/dbTNF− mice, but neutralizing antibody to IL-6 (anti-IL-6; 0.28 mg·ml−1·kg−1 ip for 3 days) attenuated IL-6 expression in db/db mice. The incubation of the microvessels with IL-6 (5 ng/ml) induced endothelial dysfunction in the presence of l-NAME and Indo in WT mice, but anti-IL-6 restored ACh-induced vasodilation in the presence of l-NAME and Indo in db/db mice. In dbTNF−/dbTNF− mice, EDHF-induced vasodilation was greater and comparable with controls, but IL-6 decreased EDHF-mediated vasodilation. Our results indicate that EDHF compensates for diminished NO-dependent dilation in IL-6-induced endothelial dysfunction by the activation of H2O2 or a K+ channel in type 2 diabetes.
3
Wang, Xuemei, Greg Trottier, and Rodger Loutzenhiser. "Determinants of renal afferent arteriolar actions of bradykinin: evidence that multiple pathways mediate responses attributed to EDHF." American Journal of Physiology-Renal Physiology 285, no. 3 (September 2003): F540—F549. http://dx.doi.org/10.1152/ajprenal.00127.2003.
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The determinants of bradykinin (BK)-induced afferent arteriolar vasodilation were investigated in the in vitro perfused hydronephrotic rat kidney. BK elicited a concentration-dependent vasodilation of afferent arterioles that had been preconstricted with ANG II (0.1 nmol/l), but this dilation was transient in character. Pretreatment with the nitric oxide synthase inhibitor Nω-nitro-l-arginine methyl ester (100 μmol/l) and the cyclooxygenase inhibitor ibuprofen (10 μmol/l) did not prevent this dilation when tone was established by ANG II but fully blocked the response when tone was established by elevated extracellular KCl, which suggests roles for both NO and endothelium-derived hyperpolarizing factor (EDHF). We had previously shown that the EDHF-like response of the afferent arteriole evoked by ACh was fully abolished by a combination of charybdotoxin (ChTX;10 nmol/l) and apamin (AP; 1 μmol/l). However, in the current study, treatment with ChTX plus AP only reduced the EDHF-like component of the BK response from 98 ± 5 to 53 ± 6% dilation. Tetraethylammonium (TEA; 1 mmol/l), which had no effect on the EDHF-induced vasodilation associated with ACh, reduced the EDHF-like response to BK to 88 ± 3% dilation. However, the combination of TEA plus ChTX plus AP abolished the response (0.3 ± 1% dilation). Similarly, 17-octadecynoic acid (17-ODYA) did not prevent the dilation when it was administered alone (77 ± 9% dilation) but fully abolished the EDHF-like response when added in combination with ChTX plus AP (-0.5 ± 4% dilation). These findings suggest that BK acts via multiple EDHFs: one that is similar to that evoked by ACh in that it is blocked by ChTX plus AP, and a second that is blocked by either TEA or 17-ODYA. Our finding that a component of the BK response is sensitive to TEA and 17-ODYA is consistent with previous suggestions that the EDHF released by BK is an epoxyeicosatrienoic acid.
4
Luksha, Leanid, Henry Nisell, Natallia Luksha, Marius Kublickas, Kjell Hultenby, and Karolina Kublickiene. "Endothelium-derived hyperpolarizing factor in preeclampsia: heterogeneous contribution, mechanisms, and morphological prerequisites." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 294, no. 2 (February 2008): R510—R519. http://dx.doi.org/10.1152/ajpregu.00458.2007.
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We hypothesized that in preeclampsia (PE), contribution of endothelium-derived hyperpolarizing factor (EDHF) and the mechanism/s of its action differ from that in normal pregnancy (NP). We aimed to assess endothelial function and morphology in arteries from NP and PE with particular focus on EDHF. Arteries (≈200 μm) were dissected from subcutaneous fat biopsies obtained from women undergoing cesarean section. With the use of wire myography, responses to the endothelium-dependent agonist bradykinin (BK) were determined before and after inhibition of pathways relevant to EDHF activity. The overall responses to BK in arteries from PE ( n = 13) and NP ( n = 17) were similar. However, in PE, EDHF-mediated relaxation was reduced ( P < 0.05). All women within the PE group were divided into two subgroups: with more ( group 1) or less ( group 2) than 50% reduction of EDHF-typed responses after 18-α-glycyrrhetinic acid (an inhibitor of myoendothelial gap junctions, MEGJs). The division showed that 1) MEGJs are principally involved when the EDHF contribution is reduced; and 2) when the EDHF contribution is similar to that in NP, the H2O2 and/or cytochrome P-450 epoxygenase products of arachidonic acid (AA), along with MEGJs, confer EDHF-mediated relaxation. In contrast, MEGJs were the main pathway for EDHF in NP. The abundant presence of MEGJs in arteries from NP but deficiency of them in PE was observed using transmission electron microscopy. We conclude that PE is associated with heterogeneous contribution of EDHF, and the mechanism behind EDHF-typed responses is mediated either by MEGJs alone or in combination with H2O2 or cytochrome P-450 epoxygenase metabolites of AA.
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Hayakawa, H., Y. Hirata, E. Suzuki, T. Sugimoto, H. Matsuoka, K. Kikuchi, T. Nagano, M. Hirobe, and T. Sugimoto. "Mechanisms for altered endothelium-dependent vasorelaxation in isolated kidneys from experimental hypertensive rats." American Journal of Physiology-Heart and Circulatory Physiology 264, no. 5 (May 1, 1993): H1535—H1541. http://dx.doi.org/10.1152/ajpheart.1993.264.5.h1535.
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To study mechanisms for attenuated endothelium-dependent vasorelaxation in hypertension, we examined the effects of acetylcholine (ACh) on renal vascular resistance (RVR) and release rates of endothelium-derived relaxing factor (EDRF) in kidneys isolated from spontaneously hypertensive rats (SHR), deoxycorticosterone acetate (DOCA) salt-hypertensive (DOCA salt) rats, and Dahl salt-sensitive (Dahl S) rats. Decreases in RVR by ACh were smaller in hypertensive rats than in their normotensive controls. The release rate of nitric oxide into the perfusate, which was estimated using nitrite-nitrate as an index, did not differ between SHR and Wistar-Kyoto rats (WKY). However, the release rate of EDRF was markedly decreased in both DOCA salt rats and Dahl S rats compared with their normotensive controls (10(-7) M ACh: DOCA salt 45 +/- 6 vs. control 410 +/- 60 pmol.min-1.g-1 kidney wt, P < 0.001). In SHR, high-K+ perfusion or pretreatment with glibenclamide, inhibitors of endothelium-derived hyperpolarizing factor (EDHF), significantly reduced ACh-induced vasorelaxation only in WKY, resulting in no differences in the RVR reduction between SHR and WKY. Thus attenuated ACh-induced vasorelaxation in the SHR kidney may be attributed to a decrease in EDHF, but to a decrease in EDRF in DOCA salt rats and Dahl S rats.
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You, Junping, Elke M. Golding, and Robert M. Bryan. "Arachidonic acid metabolites, hydrogen peroxide, and EDHF in cerebral arteries." American Journal of Physiology-Heart and Circulatory Physiology 289, no. 3 (September 2005): H1077—H1083. http://dx.doi.org/10.1152/ajpheart.01046.2004.
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We tested the hypotheses that EDHF in rat middle cerebral arteries (MCAs) involves 1) metabolism of arachidonic acid through the epoxygenase pathway, 2) metabolism of arachidonic acid through the lipoxygenase pathway, or 3) reactive oxygen species. EDHF-mediated dilations were elicited in isolated and pressurized rat MCAs by activation of endothelial P2Y2 receptors with either UTP or ATP. All studies were conducted after the inhibition of nitric oxide synthase and cyclooxygenase with Nω-nitro-l-arginine methyl ester (10 μM) and indomethacin (10 μM), respectively. The inhibition of epoxygenase with miconazole (30 μM) did not alter EDHF dilations to UTP, whereas the structurally different epoxygenase inhibitor N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanoic acid (20 or 40 μM) only modestly inhibited EDHF at the highest concentration of UTP. An antagonist of epoxyeicosatrienoic acids, 14,15-epoxyeicosa-5( Z)-enoic acid, had no effect on EDHF dilations to UTP. Chronic inhibition of epoxygenase in the rat with 1-aminobenzotriazol (50 mg/kg twice daily for 5 days) did not alter EDHF dilations. The inhibition of the lipoxygenase pathway with either 10 μM baicalein or 10 μM nordihydroguaiaretic acid produced no major inhibitory effects on EDHF dilations. The combination of superoxide dismutase (200 U/ml) and catalase (140 U/ml) had no effect on EDHF dilations. Neither tiron (10 mM), a cell-permeable scavenger of reactive oxygen species, nor deferoxamine (1 or 10 mM), an iron chelator that blocks the formation of hydroxyl radicals, altered EDHF dilations in rat MCAs. We conclude that EDHF dilations in the rat MCA do not involve the epoxygenase pathway, lipoxygenase pathway, or reactive oxygen species including H2O2.
7
You, Junping, Sean P. Marrelli, and Robert M. Bryan. "Role of Cytoplasmic Phospholipase A2 in Endothelium-Derived Hyperpolarizing Factor Dilations of Rat Middle Cerebral Arteries." Journal of Cerebral Blood Flow & Metabolism 22, no. 10 (October 2002): 1239–47. http://dx.doi.org/10.1097/01.wcb.0000037996.34930.2e.
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Very little is known regarding the mechanism of action for the endothelium-derived hyperpolarizing factor (EDHF) response in cerebral vessels. The authors tested two hypotheses: (1) activation of the cytoplasmic form of phospholipase A2 (cPLA2) is involved with EDHF-mediated dilations in rat middle cerebral arteries; and (2) activation of the cPLA2 involves an increase in endothelial Ca2+ through activation of phospholipase C. Middle cerebral arteries were isolated from the rat, pressurized to 85 mm Hg, and luminally perfused. The EDHF response was elicited by luminal application of uridine triphosphate (UTP) after NO synthase and cyclooxygenase inhibition (10−5 mol/L N-nitro-l-arginine methyl ester and 10−5 mol/L indomethacin, respectively). AACOCF3 and PACOCF3, inhibitors of cPLA2 (Ca2+-sensitive) and Ca2+-insensitive PLA2 (iPLA2), dose dependently attenuated the EDHF response. A selective inhibitor for iPLA2, haloenol lactone suicide substrate, had no effect on the EDHF response. The EDHF response elicited by UTP was accompanied by an increase in endothelial Ca2+ (144 to 468 nmol/L), and the EDHF dilation was attenuated with U73122, a phospholipase C inhibitor. The authors conclude that the EDHF response elicited by luminal UTP in rat middle cerebral arteries involved activation of phospholipase C, an increase in endothelial Ca2+, and activation of cPLA2.
8
Chilian, William M., and Ryoji Koshida. "EDHF and NO." Circulation Research 89, no. 8 (October 12, 2001): 648–49. http://dx.doi.org/10.1161/res.89.8.648.
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Félétou, Michel, and Paul M. Vanhoutte. "EDHF: an update." Clinical Science 117, no. 4 (July 16, 2009): 139–55. http://dx.doi.org/10.1042/cs20090096.
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The endothelium controls vascular tone not only by releasing NO and prostacyclin, but also by other pathways causing hyperpolarization of the underlying smooth muscle cells. This characteristic was at the origin of the term ‘endothelium-derived hyperpolarizing factor’ (EDHF). However, this acronym includes different mechanisms. Arachidonic acid metabolites derived from the cyclo-oxygenases, lipoxygenases and cytochrome P450 pathways, H2O2, CO, H2S and various peptides can be released by endothelial cells. These factors activate different families of K+ channels and hyperpolarization of the vascular smooth muscle cells contribute to the mechanisms leading to their relaxation. Additionally, another pathway associated with the hyperpolarization of both endothelial and vascular smooth muscle cells contributes also to endothelium-dependent relaxations (EDHF-mediated responses). These responses involve an increase in the intracellular Ca2+ concentration of the endothelial cells, followed by the opening of SKCa and IKCa channels (small and intermediate conductance Ca2+-activated K+ channels respectively). These channels have a distinct subcellular distribution: SKCa are widely distributed over the plasma membrane, whereas IKCa are preferentially expressed in the endothelial projections toward the smooth muscle cells. Following SKCa activation, smooth muscle hyperpolarization is preferentially evoked by electrical coupling through myoendothelial gap junctions, whereas, following IKCa activation, K+ efflux can activate smooth muscle Kir2.1 and/or Na+/K+-ATPase. EDHF-mediated responses are altered by aging and various pathologies. Therapeutic interventions can restore these responses, suggesting that the improvement in the EDHF pathway contributes to their beneficial effect. A better characterization of EDHF-mediated responses should allow the determination of whether or not new drugable targets can be identified for the treatment of cardiovascular diseases.
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Félétou, Michel, and Paul M. Vanhoutte. "The Alternative: EDHF." Journal of Molecular and Cellular Cardiology 31, no. 1 (January 1999): 15–22. http://dx.doi.org/10.1006/jmcc.1998.0840.
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Parkington, Helena C., Marianne Tare, and Harold A. Coleman. "The EDHF Story." Circulation Research 102, no. 10 (May 23, 2008): 1148–50. http://dx.doi.org/10.1161/circresaha.108.177279.
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Takaki, Aya, Keiko Morikawa, Masato Tsutsui, Yoshinori Murayama, Ender Tekes, Hiroto Yamagishi, Junko Ohashi, Toyotaka Yada, Nobuyuki Yanagihara, and Hiroaki Shimokawa. "Crucial role of nitric oxide synthases system in endothelium-dependent hyperpolarization in mice." Journal of Experimental Medicine 205, no. 9 (August 11, 2008): 2053–63. http://dx.doi.org/10.1084/jem.20080106.
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The endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several relaxing factors, such as prostacyclin, nitric oxide (NO), and endothelium-derived hyperpolarizing factor (EDHF). We have previously demonstrated in animals and humans that endothelium-derived hydrogen peroxide (H2O2) is an EDHF that is produced in part by endothelial NO synthase (eNOS). In this study, we show that genetic disruption of all three NOS isoforms (neuronal [nNOS], inducible [iNOS], and endothelial [eNOS]) abolishes EDHF responses in mice. The contribution of the NOS system to EDHF-mediated responses was examined in eNOS−/−, n/eNOS−/−, and n/i/eNOS−/− mice. EDHF-mediated relaxation and hyperpolarization in response to acetylcholine of mesenteric arteries were progressively reduced as the number of disrupted NOS genes increased, whereas vascular smooth muscle function was preserved. Loss of eNOS expression alone was compensated for by other NOS genes, and endothelial cell production of H2O2 and EDHF-mediated responses were completely absent in n/i/eNOS−/− mice, even after antihypertensive treatment with hydralazine. NOS uncoupling was not involved, as modulation of tetrahydrobiopterin (BH4) synthesis had no effect on EDHF-mediated relaxation, and the BH4/dihydrobiopterin (BH2) ratio was comparable in mesenteric arteries and the aorta. These results provide the first evidence that EDHF-mediated responses are dependent on the NOSs system in mouse mesenteric arteries.
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Morio, Yoshiteru, Ethan P. Carter, Masahiko Oka, and Ivan F. McMurtry. "EDHF-mediated vasodilation involves different mechanisms in normotensive and hypertensive rat lungs." American Journal of Physiology-Heart and Circulatory Physiology 284, no. 5 (May 1, 2003): H1762—H1770. http://dx.doi.org/10.1152/ajpheart.00831.2002.
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The role of endothelium-derived hyperpolarizing factor (EDHF) in regulating the pulmonary circulation and the participation of cytochrome P-450 (CYP450) activity and gap junction intercellular communication in EDHF-mediated pulmonary vasodilation are unclear. We tested whether tonic EDHF activity regulated pulmonary vascular tone and examined the mechanism of EDHF-mediated pulmonary vasodilation induced by thapsigargin in salt solution-perfused normotensive and hypoxia-induced hypertensive rat lungs. After blockade of both cyclooxygenase and nitric oxide synthase, inhibition of EDHF with charybdotoxin plus apamin did not affect either normotensive or hypertensive vascular tone or acute hypoxic vasoconstriction but abolished thapsigargin vasodilation in both groups of lungs. The CYP450 inhibitors 7-ethoxyresorufin and sulfaphenazole and the gap junction inhibitor palmitoleic acid, but not 18α-glycyrrhetinic acid, inhibited thapsigargin vasodilation in normotensive lungs. None of these agents inhibited the vasodilation in hypertensive lungs. Thus tonic EDHF activity does not regulate either normotensive or hypertensive pulmonary vascular tone or acute hypoxic vasoconstriction. Whereas thapsigargin-induced EDHF-mediated vasodilation in normotensive rat lungs involves CYP450 activity and might act through gap junctions, the mechanism of vasodilation is apparently different in hypertensive lungs.
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Bryan, Robert M., Junping You, Elke M. Golding, and Sean P. Marrelli. "Endothelium-derived Hyperpolarizing Factor." Anesthesiology 102, no. 6 (June 1, 2005): 1261–77. http://dx.doi.org/10.1097/00000542-200506000-00028.
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There is now strong evidence that an endothelial mechanism, other than nitric oxide or prostacyclin, exists for dilating arteries and arterioles. This third pathway has been named endothelium-derived hyperpolarizing factor (EDHF) and should not be confused with endothelium-derived relaxing factor, which is nitric oxide. Currently, there are several ideas for the mechanism of EDHF, which may vary among vessels of different organs and species. During some pathologic states, EDHF can be up-regulated. This up-regulation often occurs as the dilator effects of endothelium-derived nitric oxide are suppressed. The up-regulated EDHF may serve in a protective capacity to help maintain blood flow to organs and tissues during these stressful states. Many anesthetics attenuate the dilator actions of EDHF; however, the full clinical implications of this anesthetic-related attenuation are not known. Like its cousins, nitric oxide and prostacyclin, EDHF is an important regulator of blood flow and should prove to be an important clinical consideration as we gain more knowledge of its mechanisms of action.
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Schildmeyer, Lisa A., and Robert M. Bryan. "Effect of NO on EDHF response in rat middle cerebral arteries." American Journal of Physiology-Heart and Circulatory Physiology 282, no. 2 (February 1, 2002): H734—H738. http://dx.doi.org/10.1152/ajpheart.00583.2001.
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Whereas the actual identity of endothelium-derived hyperpolarizing factor (EDHF) is still not certain, it involves a process requiring the endothelium and eliciting hyperpolarization and relaxation of smooth muscle. It is neither nitric oxide (NO) nor prostacyclin, and its presence has been demonstrated in a variety of vessels. Recent studies in peripheral vessels report that EDHF-mediated dilations were either attenuated or blocked by NO. Studies presented here demonstrate that NO does not block EDHF-mediated dilations in cerebral vessels. Rat middle cerebral arteries were cannulated, pressurized, and luminally perfused. EDHF-mediated dilations were elicited by the luminal application of ATP in the presence of N G-nitro-l-arginine methyl ester (l-NAME) and indomethacin (inhibitors of NO synthase and cyclooxygenase, respectively). These dilations persisted when S-nitroso- N-acetylpenicillamine, an NO donor, was added exogenously in the presence of l-NAME, or when endogenous NO was present but its cGMP actions were blocked by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, an inhibitor of guanylate cyclase. These findings demonstrate that the EDHF response is not suppressed by NO in cerebral vessels and suggests a role for EDHF during normal physiological conditions.
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Wigg, Susan J., Marianne Tare, Mary A. Tonta, Richard C. O'Brien, Ian T. Meredith, and Helena C. Parkington. "Comparison of effects of diabetes mellitus on an EDHF-dependent and an EDHF-independent artery." American Journal of Physiology-Heart and Circulatory Physiology 281, no. 1 (July 1, 2001): H232—H240. http://dx.doi.org/10.1152/ajpheart.2001.281.1.h232.
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The hypothesis tested in this study is that diabetes has a different impact on an artery in which endothelium-dependent responses derive from both nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) compared with responses in which NO predominates and EDHF is absent. The streptozotocin-treated rat model of diabetes was used, and the arteries were mounted on a wire myograph. In mesenteric arteries depolarized and constricted with phenylephrine, acetylcholine evoked hyperpolarization (31 ± 2 mV) and complete relaxation; these responses were attributed to EDHF and NO. In femoral arteries, acetylcholine evoked a small, NO-mediated hyperpolarization (5 ± 1 mV) and incomplete relaxation. Bradykinin evoked NO-dependent responses in mesenteric arteries. Whereas diabetes significantly impaired the EDHF-dependent hyperpolarization and relaxation in mesenteric arteries, NO-dependent responses in femoral and mesenteric arteries were preserved. 1-Ethyl-2-benzimidazolinone evoked hyperpolarization and relaxation in mesenteric arteries, and this was impaired in diabetes. In conclusion, NO-dependent responses are preserved in diabetes, whereas endothelial responses-dependent upon EDHF appear to be impaired. The putative channels responsible for mediating the EDHF response may be altered in diabetes.
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FELETOU, M. "EDHF: new therapeutic targets?" Pharmacological Research 49, no. 6 (June 2004): 565–80. http://dx.doi.org/10.1016/j.phrs.2003.10.017.
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PEARSON, J. "Caveolae and EDHF production." Cardiovascular Research 64, no. 2 (November 1, 2004): 189–91. http://dx.doi.org/10.1016/j.cardiores.2004.08.010.
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Villar, Inmaculada C., Adrian J. Hobbs, and Amrita Ahluwalia. "Sex differences in vascular function: implication of endothelium-derived hyperpolarizing factor." Journal of Endocrinology 197, no. 3 (March 31, 2008): 447–62. http://dx.doi.org/10.1677/joe-08-0070.
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The vascular endothelium plays a crucial role in the regulation of vascular homeostasis by controlling vascular tone, coagulation, and inflammatory responses. These actions are exerted by endothelial factors including nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF). The greater incidence of cardiovascular disease (CVD) in men and postmenopausal women compared with premenopausal women implies a vasoprotective phenotype of females, which may be influenced by sex hormones. These hormones, particularly estrogen, have modulatory effects on the endothelium and circulating cells that have been implicated in vascular inflammation and in the development of CVD. EDHF seems to be the predominant endothelial factor in the resistance vasculature of females and this mediator could afford the beneficial cardiovascular risk profile observed in premenopausal woman. In this review, we discuss sex differences in EDHF biology and how sex hormones can modulate EDHF responses. We also review the implication of sex hormone-dependent regulation of EDHF in inflammatory processes, platelet function, and repair after vascular damage, each of which have a critical role in several aspects of the pathogenesis of CVD.
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Loeb, A. L., I. Godeny, and D. E. Longnecker. "Anesthetics alter relative contributions of NO and EDHF in rat cremaster muscle microcirculation." American Journal of Physiology-Heart and Circulatory Physiology 273, no. 2 (August 1, 1997): H618—H627. http://dx.doi.org/10.1152/ajpheart.1997.273.2.h618.
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The contributions of the vasodilators nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) were investigated in the rat cremaster muscle microcirculation during halothane, isoflurane, or ketamine anesthesia. After inhibition of prostaglandin synthesis with indomethacin, changes in diameter of fourth-order arterioles to acetylcholine (ACh) or bradykinin (BK) were studied in the presence or absence of NG-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthase, and/or 20 mM K+, an inhibitor of EDHF action. L-NMMA inhibited ACh- and BK-induced vasodilation during isoflurane but not halothane or ketamine anesthesia. Superfusion of the muscle with buffer containing 20 mM K+ dilated arterioles. EDHF was responsible for most of the NO-independent response to ACh, because 20 mM K+ unmasked ACh-stimulated, NO-dependent relaxation during halothane or ketamine anesthesia. However, 20 mM K+ did not inhibit BK-induced vasodilation during halothane or ketamine anesthesia. Our data suggest that anesthetics can alter the balance between NO and EDHF vasodilation in the microcirculation and that NO-dependent mechanisms are enhanced and EDHF action inhibited during isoflurane anesthesia.
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Matsumoto, Takayuki, Tsuneo Kobayashi, and Katsuo Kamata. "Alterations in EDHF-type relaxation and phosphodiesterase activity in mesenteric arteries from diabetic rats." American Journal of Physiology-Heart and Circulatory Physiology 285, no. 1 (July 2003): H283—H291. http://dx.doi.org/10.1152/ajpheart.00954.2002.
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In isolated superior mesenteric artery rings from age-matched control rats and streptozotocin (STZ)-induced diabetic rats, we investigated the role of cAMP in endothelium-derived hyperpolarizing factor (EDHF)-type relaxation. The ACh-induced EDHF-type relaxation was significantly weaker in STZ-induced diabetic rats than in control rats, and in both groups of rats it was attenuated by 18α-glycyrrhetinic acid (18α-GA), an inhibitor of gap junctions, and enhanced by IBMX, a cAMP-phosphodiesterase (PDE) inhibitor. These enhanced EDHF-type responses were very similar in magnitude between diabetic and age-matched control rats. The EDHF-type relaxation was enhanced by cilostamide, a PDE3-selective inhibitor, but not by Ro 20–1724, a PDE4-selective inhibitor. The expression levels of the mRNAs and proteins for two cAMP PDEs (PDE3A, PDE3B) were significantly increased in STZ-induced diabetic rats, but those for PDE4D were not. We conclude that the impairment of EDHF-type relaxations in STZ-induced diabetic rats may be attributed to a reduction in the action of cAMP via increased PDE activity.
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Tomioka, Hiroshi, Yuichi Hattori, Mitsuhiro Fukao, Hiroshi Watanabe, Yasuhiro Akaishi, Atsushi Sato, Tran Quang Kim, Ichiro Sakuma, Akira Kitabatake, and Morio Kanno. "Role of endothelial Ni2+-sensitive Ca2+entry pathway in regulation of EDHF in porcine coronary artery." American Journal of Physiology-Heart and Circulatory Physiology 280, no. 2 (February 1, 2001): H730—H737. http://dx.doi.org/10.1152/ajpheart.2001.280.2.h730.
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Elevation of intracellular Ca2+ concentration ([Ca2+]i) in endothelial cells is proposed to be required for generation of vascular actions of endothelium-derived hyperpolarizing factor (EDHF). This study was designed to determine the endothelial Ca2+ source that is important in development of EDHF-mediated vascular actions. In porcine coronary artery precontracted with U-46619, bradykinin (BK) and cyclopiazonic acid (CPA) caused endothelium-dependent relaxations in the presence of N G-nitro-l-arginine (l-NNA). The l-NNA-resistant relaxant responses were inhibited by high K+, indicating an involvement of EDHF. In the presence of Ni2+, which inhibits Ca2+ influx through nonselective cation channels, the BK-induced EDHF relaxant response was greatly diminished and the CPA-induced response was abolished. BK and CPA elicited membrane hyperpolarization of smooth muscle cells of porcine coronary artery. Ni2+ suppressed the hyperpolarizing responses in a manner analogous to removal of extracellular Ca2+. EDHF-mediated relaxations and hyperpolarizations evoked by BK and CPA in porcine coronary artery showed a temporal correlation with the increases in [Ca2+]i in porcine aortic endothelial cells. The extracellular Ca2+-dependent rises in [Ca2+]i in endothelial cells stimulated with BK and CPA were completely blocked by Ni2+. These results suggest that Ca2+ influx into endothelial cells through nonselective cation channels plays a crucial role in the regulation of EDHF.
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Cheng, Zhongjian, Xiaohua Jiang, Warren D. Kruger, Domenico Praticò, Sapna Gupta, Karthik Mallilankaraman, Muniswamy Madesh, et al. "Hyperhomocysteinemia impairs endothelium-derived hyperpolarizing factor–mediated vasorelaxation in transgenic cystathionine beta synthase–deficient mice." Blood 118, no. 7 (August 18, 2011): 1998–2006. http://dx.doi.org/10.1182/blood-2011-01-333310.
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Abstract Hyperhomocysteinemia (HHcy) is associated with endothelial dysfunction (ED), but the mechanism is largely unknown. In this study, we investigated the role and mechanism of HHcy-induced ED in microvasculature in our newly established mouse model of severe HHcy (plasma total homocysteine, 169.5μM). We found that severe HHcy impaired nitric oxide (NO)– and endothelium-derived hyperpolarizing factor (EDHF)–mediated, endothelium-dependent relaxations of small mesenteric arteries (SMAs). Endothelium-independent and prostacyclin-mediated endothelium-dependent relaxations were not changed. A nonselective Ca2+-activated potassium channel (KCa) inhibitor completely blocked EDHF-mediated relaxation. Selective blockers for small-conductance KCa (SK) or intermediate-conductance KCa (IK) failed to inhibit EDHF-mediated relaxation in HHcy mice. HHcy increased the levels of SK3 and IK1 protein, superoxide (O2−), and 3-nitrotyrosine in the endothelium of SMAs. Preincubation with antioxidants and peroxynitrite (ONOO−) inhibitors improved endothelium-dependent and EDHF-mediated relaxations and decreased O2− production in SMAs from HHcy mice. Further, EDHF-mediated relaxation was inhibited by ONOO− and prevented by catalase in the control mice. Finally, L-homocysteine stimulated O2− production, which was reversed by antioxidants, and increased SK/IK protein levels and tyrosine nitration in cultured human cardiac microvascular endothelial cells. Our results suggest that HHcy impairs EDHF relaxation in SMAs by inhibiting SK/IK activities via oxidation- and tyrosine nitration–related mechanisms.
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Baragatti, Barbara, Michal Laniado Schwartzman, Debora Angeloni, Francesca Scebba, Enrica Ciofini, Daria Sodini, Virginia Ottaviano, et al. "EDHF function in the ductus arteriosus: evidence against involvement of epoxyeicosatrienoic acids and 12S-hydroxyeicosatetraenoic acid." American Journal of Physiology-Heart and Circulatory Physiology 297, no. 6 (December 2009): H2161—H2168. http://dx.doi.org/10.1152/ajpheart.00576.2009.
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We have previously shown (Ref. 2 ) that endothelium-derived hyperpolarizing factor (EDHF) becomes functional in the fetal ductus arteriosus on removal of nitric oxide and carbon monoxide. From this, it was proposed that EDHF originates from a cytochrome P-450 (CYP450)-catalyzed reaction being inhibited by the two agents. Here, we have examined in the mouse ductus whether EDHF can be identified as an arachidonic acid product of a CYP450 epoxygenase and allied pathways. We did not detect transcripts of the mouse CYP2C subfamily in vessel, while CYP2J subfamily transcripts were expressed with CYP2J6 and CYP2J9. These CYP2J hemoproteins were also detected in the ductus by immunofluorescence microscopy, being colocalized with the endoplasmic reticulum in both endothelial and muscle cells. Distinct CYP450 transcripts were also detected and were responsible for ω-hydroxylation (CYP4A31) and 12R-hydroxylation (CYP4B1). Mass spectrometric analysis showed formation of epoxyeicosatrienoic acids (EETs) in the intact ductus, with 11,12- and 14,15-EETs being more prominent than 5,6- and 8,9-EETs. However, their yield did not increase with nitric oxide/carbon monoxide suppression, nor did it abate with endothelium removal. No evidence was obtained for formation of 12R-hydroxyeicosatrienoic acid and ω-hydroxylation products. 2S-hydroxyeicosatetraenoic acid was instead detected, and, contrary to data implicating this compound as an alternative EDHF, its suppression with baicalein did not modify the EDHF-mediated relaxation to bradykinin. We conclude that none of the more common CYP450-linked arachidonic acid metabolites appears to qualify as EDHF in mouse ductus. We speculate that some novel eicosanoid or a totally unrelated compound requiring CYP450 for its synthesis accounts for EDHF in this vessel.
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Osei-Owusu, Patrick, Rasna Sabharwal, Kevin M. Kaltenbronn, Man-Hee Rhee, Mark W. Chapleau, Hans H. Dietrich, and Kendall J. Blumer. "Regulator of G Protein Signaling 2 Deficiency Causes Endothelial Dysfunction and Impaired Endothelium-derived Hyperpolarizing Factor-mediated Relaxation by Dysregulating Gi/o Signaling." Journal of Biological Chemistry 287, no. 15 (February 21, 2012): 12541–49. http://dx.doi.org/10.1074/jbc.m111.332130.
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Regulator of G protein signaling 2 (RGS2) is a GTPase-activating protein for Gq/11α and Gi/oα subunits. RGS2 deficiency is linked to hypertension in mice and humans, although causative mechanisms are not understood. Because endothelial dysfunction and increased peripheral resistance are hallmarks of hypertension, determining whether RGS2 regulates microvascular reactivity may reveal mechanisms relevant to cardiovascular disease. Here we have determined the effects of systemic versus endothelium- or vascular smooth muscle-specific deletion of RGS2 on microvascular contraction and relaxation. Contraction and relaxation of mesenteric resistance arteries were analyzed in response to phenylephrine, sodium nitroprusside, or acetylcholine with or without inhibitors of nitric oxide (NO) synthase or K+ channels that mediate endothelium-derived hyperpolarizing factor (EDHF)-dependent relaxation. The results showed that deleting RGS2 in vascular smooth muscle had minor effects. Systemic or endothelium-specific deletion of RGS2 strikingly inhibited acetylcholine-evoked relaxation. Endothelium-specific deletion of RGS2 had little effect on NO-dependent relaxation but markedly impaired EDHF-dependent relaxation. Acute, inducible deletion of RGS2 in endothelium did not affect blood pressure significantly. Impaired EDHF-mediated vasodilatation was rescued by blocking Gi/oα activation with pertussis toxin. These findings indicated that systemic or endothelium-specific RGS2 deficiency causes endothelial dysfunction resulting in impaired EDHF-dependent vasodilatation. RGS2 deficiency enables endothelial Gi/o activity to inhibit EDHF-dependent relaxation, whereas RGS2 sufficiency facilitates EDHF-evoked relaxation by squelching endothelial Gi/o activity. Mutation or down-regulation of RGS2 in hypertension patients therefore may contribute to endothelial dysfunction and defective EDHF-dependent relaxation. Blunting Gi/o signaling might improve endothelial function in such patients.
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Luksha, Leonid, Henry Nisell, and Karolina Kublickiene. "The mechanism of EDHF-mediated responses in subcutaneous small arteries from healthy pregnant women." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 286, no. 6 (June 2004): R1102—R1109. http://dx.doi.org/10.1152/ajpregu.00550.2003.
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We studied the importance of endothelium-derived hyperpolarizing factor (EDHF) vs. nitric oxide (NO) and prostacyclin (PGI2) in bradykinin (BK)-induced relaxation in isolated small subcutaneous arteries from normal pregnant women. We also explored the contribution of cytochrome P-450 (CYP450) product of arachidonic acid (AA) metabolism, hydrogen peroxide (H2O2), and gap junctions that have been suggested to be involved in EDHF-mediated responses. Isolated arteries obtained from subcutaneous fat biopsies of normal pregnant women ( n = 30) undergoing planned cesarean section were mounted in a wire-myography system. In norepinephrine-constricted vessels, incubation with NG-nitro-l-arginine methyl ester (l-NAME) resulted in a significant reduction in relaxation to BK. Simultaneous incubation with l-NAME and indomethacin failed to modify this response further. BK-mediated dilatation in the presence of K+-modified solution was decreased to similar level as obtained after incubation with l-NAME. Incubation with l-NAME abolished BK-induced responses in K+-modified solution. Sulfaphenazole, a specific inhibitor of CYP450 epoxygenase, and catalase (an enzyme that decomposes H2O2) did not affect the EDHF-mediated relaxation because concentration-response curves to BK were similar in arteries after incubation with l-NAME vs. l-NAME + sulfaphenazole and l-NAME + catalase. The inhibitor of gap junctions, 18α-glycyrrhetinic acid, significantly reduced BK-mediated relaxation both without and with incubation with l-NAME. We found that both NO and EDHF, but not PGI2, are involved in the endothelium-dependent dilatation to BK. BK-induced relaxation is almost equally mediated by NO and EDHF. CYP450 epoxygenase metabolites of AA or H2O2 do not account for EDHF-mediated response; however, gap junctions are involved in the EDHF-mediated responses to BK in subcutaneous small arteries in normal pregnancy.
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Nishikawa, Yasuhiro, David W. Stepp, and William M. Chilian. "Nitric oxide exerts feedback inhibition on EDHF-induced coronary arteriolar dilation in vivo." American Journal of Physiology-Heart and Circulatory Physiology 279, no. 2 (August 1, 2000): H459—H465. http://dx.doi.org/10.1152/ajpheart.2000.279.2.h459.
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We tested the hypothesis that nitric oxide (NO) inhibits endothelium-derived hyperpolarizing factor (EDHF)-induced vasodilation via a negative feedback pathway in the coronary microcirculation. Coronary microvascular diameters were measured using stroboscopic fluorescence microangiography. Bradykinin (BK)-induced dilation was mediated by EDHF, when NO and prostaglandin syntheses were inhibited, or by NO when EDHF and prostaglandin syntheses were blocked. Specifically, BK (20, 50, and 100 ng · kg−1 · min−1 ic) caused dose-dependent vasodilation similarly before and after administration of N G-monomethyl-l-arginine (l-NMMA) (3 μmol/min ic for 10 min) and indomethacin (Indo, 10 mg/kg iv). The residual dilation to BK withl-NMMA and Indo was completely abolished by suffusion of miconazole or an isosmotic buffer containing high KCl (60 mM), suggesting that this arteriolar vasodilation is mediated by the cytochrome P-450 derivative EDHF. BK-induced dilation was reduced by 39% after inhibition of EDHF and prostaglandin synthesis, and dilation was further inhibited by combined blockade withl-NMMA to a 74% reduction in the response. This suggests an involvement for NO in the vasodilation. After dilation to BK was assessed with l-NMMA and Indo, sodium nitroprusside (SNP, 1–3 μg · kg−1 · min−1ic), an exogenous NO donor, was administered in a dose to increase the diameter to the original control value. Dilation to BK was virtually abolished when administered concomitantly with SNP duringl-NMMA and Indo ( P < 0.01 vs. before SNP), suggesting that NO inhibits EDHF-induced dilation. SNP did not affect adenosine- or papaverine-induced arteriolar dilation in the presence ofl-NMMA and Indo, demonstrating that the effect of SNP was not nonspecific. In conclusion, our data are the first in vivo evidence to suggest that NO inhibits the production and/or action of EDHF in the coronary microcirculation.
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Gokina, N. I., O. Y. Kuzina, and A. M. Vance. "Augmented EDHF signaling in rat uteroplacental vasculature during late pregnancy." American Journal of Physiology-Heart and Circulatory Physiology 299, no. 5 (November 2010): H1642—H1652. http://dx.doi.org/10.1152/ajpheart.00227.2010.
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A successful pregnancy outcome relies on extensive maternal cardiovascular adaptation, including enhanced uteroplacental vasodilator mechanisms. The objective of the present study was to determine the contribution of the endothelium-derived hyperpolarizing factor (EDHF) signaling in pregnancy-enhanced uterine vasodilation, to define the role of Ca2+-activated K+ channels in mediating EDHF effects, and to explore the impact of endothelial Ca2+ signaling in pregnancy-specific upregulation of EDHF. Fura 2-based measurements of smooth muscle cell (SMC) and endothelial cell cytosolic Ca2+ concentration ([Ca2+]i) were performed simultaneously with measurements of the diameter of uterine radial arteries from nonpregnant (NP) and late pregnant (LP) rats. Changes in SMC membrane potential of pressurized arteries from LP rats were assessed using glass microelectrodes. After blockade of nitric oxide and prostacyclin production, a cumulative application of ACh induced rapid and effective dilatation of uterine vessels from both NP and LP rats. This vasodilation was associated with SMC hyperpolarization and SMC [Ca2+]i reduction and was abolished by a high-K+ solution, demonstrating that NG-nitro-l-arginine (l-NNA)- and indomethacin-resistant responses are attributable to EDHF. Pregnancy significantly potentiates EDHF-mediated vasodilation in part due to enhanced endothelial Ca2+ signaling. l-NNA- and indomethacin-resistant responses were insensitive to iberiotoxin but abolished by a combined treatment with apamin and charybdotoxin, supporting the key role of small- and intermediate-conductance K+ channels in mediating EDHF signaling in the maternal uterine resistance vasculature.
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AHLUWALIA, Amrita. "To b'EET or not to b'EET? That is the question!" Clinical Science 105, no. 4 (October 1, 2003): 399–401. http://dx.doi.org/10.1042/cs20030232.
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Since the discovery of endothelium-derived hyperpolarizing factor (EDHF), several different candidates and pathways have been proposed as mediators of endothelium-dependent hyperpolarization of vascular smooth muscle. In particular, there has been considerable support for a role for the cytochrome P450 metabolites, the epoxyeicosatrienoic acids (EETs). However, more recently, this hypothesis has come under severe scrutiny. In this issue of Clinical Science, Passauer et al. demonstrate that an EET cannot be EDHF in the human forearm, and add further to the growing belief that an EET is not a candidate for a ubiquitous EDHF.
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Harrington, Louise S., Martin J. Carrier, Nicola Gallagher, Derek Gilroy, Chris J. Garland, and Jane A. Mitchell. "Elucidation of the temporal relationship between endothelial-derived NO and EDHF in mesenteric vessels." American Journal of Physiology-Heart and Circulatory Physiology 293, no. 3 (September 2007): H1682—H1688. http://dx.doi.org/10.1152/ajpheart.00389.2007.
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Although the endothelium co-generates both nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF), the relative contribution from each vasodilator is not clear. In studies where the endothelium is stimulated acutely, EDHF responses predominate in small arteries. However, the temporal relationship between endothelial-derived NO and EDHF over more prolonged periods is unclear but of major physiological importance. Here we have used a classical pharmacological approach to show that EDHF is released transiently compared with NO. Acetylcholine (3 × 10−6 mol/l) dilated second- and/or third-order mesenteric arteries for prolonged periods of up to 1 h, an effect that was reversed fully and immediately by the subsequent addition of l-NAME (10−3 mol/l) but not TRAM-34 (10−6 mol/l) plus apamin (5 × 10−7 mol/l). When vessels were pretreated with l-NAME, acetylcholine induced relatively transient dilator responses (declining over ∼5 min), and vessels were sensitive to TRAM-34 plus apamin. When measured in parallel, the dilator effects of acetylcholine outlasted the smooth muscle hyperpolarization. However, in the presence of l-NAME, vasodilatation and hyperpolarization followed an identical time course. In vessels from NOSIII−/− mice, acetylcholine induced small but detectable dilator responses that were transient in duration and blocked by TRAM-34 plus apamin. EDHF responses in these mouse arteries were inhibited by an intracellular calcium blocker, TMB-8, and the phospholipase A2 inhibitor AACOCF3, suggesting a role for lipid metabolites. These data show for the first time that EDHF is released transiently, whereas endothelial-derived NO is released in a sustained manner.
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Xu, H. L., R. A. Santizo, V. L. Baughman, and D. A. Pelligrino. "Nascent EDHF-mediated cerebral vasodilation in ovariectomized rats is not induced by eNOS dysfunction." American Journal of Physiology-Heart and Circulatory Physiology 285, no. 5 (November 2003): H2045—H2053. http://dx.doi.org/10.1152/ajpheart.00439.2003.
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In estrogen-depleted [i.e., ovariectomized (Ovx)] animals, an endothelium-derived hyperpolarizing factor (EDHF)-like mechanism may arise to, at least partially, replace endothelial nitric oxide (NO) synthase (eNOS)-derived NO in modulating cerebral arteriolar tone. Additional findings show that eNOS expression and function is restored in estrogen-treated Ovx female rats, while the nascent EDHF-like activity disappears. Because NO has been linked to repression of EDHF activity in the periphery, the current study was undertaken to examine whether the nascent EDHF role in cerebral vessels of Ovx females relates to a chronically repressed eNOS-derived NO-generating function. We compared the effects of chronic NOS inhibition with Nω-nitro-l-arginine-methyl ester (l-NAME; 100 mg · kg–1 · day–1 for 3 wk) on EDHF-mediated pial arteriolar vasodilation in anesthetized intact, Ovx, and 17β-estradiol-treated (0.1 mg · kg–1 · day–1 ip, 1 wk) Ovx (OVE) female rats as well as in male rats that were prepared with closed cranial windows. In the chronic NOS inhibition groups, pial arteriolar responses were monitored in the absence (all groups) and presence (females only) of indomethacin (Indo; 10 mg/kg iv). Finally, the gap junction inhibitory peptide Gap 27 (300 μM) was applied to block EDHF-related vasodilation. NO donor ( S-nitroso- N-acetyl-penicillamine) responses were similar in all rats studied. Acetylcholine (ACh) reactivity was virtually absent in control Ovx rats and chronically NOS-inhibited intact female, OVE, and male rats. However, a partial recovery of ACh reactivity was seen in l-NAME-treated Ovx females. In addition, in the presence of l-NAME, a normal CO2 reactivity was observed in all females, whereas a 50% reduction in CO2 reactivity was seen in males. In intact and OVE rats, both chronic and acute ( NG-nitro-l-arginine suffusion) NOS inhibition, combined with Indo, depressed ADP-induced dilation by ≥50%, and subsequent application of Gap 27 had no further effect on ADP-induced vasodilation. ADP reactivity was retained in Ovx rats after combined chronic NOS inhibition and acute Indo, but was attenuated significantly by Gap 27. In males, Gap 27 had no effect on arteriolar reactivity. Taken together, our data demonstrate that in the cerebral microcirculation, NO does not have an inhibitory effect on EDHF production or action. The increased EDHF-like function in chronic estrogen-depleted animals is not due to eNOS deficiency, suggesting a more direct effect of estrogen in modulating EDHF-mediated cerebral vasodilation.
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Suzuki, H., and G. Chen. "Endothelium-Derived Hyperpolarizing Factor (EDHF): An Endogenous Potassium-Channel Activator." Physiology 5, no. 5 (October 1, 1990): 212–15. http://dx.doi.org/10.1152/physiologyonline.1990.5.5.212.
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Acetylcholine hyperpolarizes the membrane of vascular smooth muscles by increasing potassium permeability, the response being mediated by an endothelium-derived hyperpolarizing factor (EDHF). The membrane hyperpolarization produced by EDHF is therefore one of the components contributing to endothelium-dependent relaxation of vascular smooth muscles.
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Lischke, Volker, Rudi Busse, and Markus Hecker. "Inhalation Anesthetics Inhibit the Release of Endothelium-derived Hyperpolarizing Factor in the Rabbit Carotid Artery." Anesthesiology 83, no. 3 (September 1, 1995): 574–82. http://dx.doi.org/10.1097/00000542-199509000-00017.
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Background Inhalation anesthetics may interfere with the synthesis or action of endothelium-derived vasoactive factors. We investigated the effects of desflurane, enflurane, halothane, isoflurane, and sevoflurane on the release of nitric oxide and endothelium-derived hyperpolarizing factor (EDHF) in the isolated endothelium-intact carotid artery of the rabbit. Methods Isolated segments of the carotid artery were suspended in Krebs-Henseleit solution (37 degrees C) and preconstricted with phenylephrine (1 microM). Relaxations caused by acetylcholine (ACh) (0.03-10 microM) or sodium nitroprusside (0.01-10 microM) were compared in the presence or absence of the nitric oxide synthase inhibitor NG-nitro-L-arginine (0.1 mM) in segments exposed to desflurane (8%), enflurane (2-4%), halothane (2-3.5%), isoflurane (2-4%), or sevoflurane (2%) as well as in NG-nitro-L- arginine-treated segments exposed to enflurane (2%) in combination with the KCa(+)-channel blocker tetrabutylammonium (0.3 mM) or the cytochrome P450 inhibitor clotrimazole (3 microM). Results Desflurane, enflurane, and sevoflurane selectively inhibited the ACh-induced release of EDHF. Halothane and isoflurane also weakly affected the nitric oxide-mediated relaxant response to ACh. The inhibitory effect of these two anesthetics on EDHF release was concentration-dependent. Relaxations induced by sodium nitroprusside were not inhibited by any of the anesthetics tested. Three structurally unrelated cytochrome P450 inhibitors clotrimazole (0.1 mM), metyrapone (1 mM), and SKF525a (proadifen, 0.1 mM) abolished the EDHF-mediated relaxation elicited by ACh. The pharmacologic profile of the inhibitory effect of enflurane on the release of EDHF closely resembled that of clotrimazole but not that of tetrabutylammonium. Moreover, all anesthetics inhibited the cytochrome P450-catalyzed O-dealkylation of 7-ethoxycoumarin by rabbit liver microsomes in a concentration-dependent manner. Conclusions Inhalation anesthetics significantly attenuate the EDHF-mediated relaxant response to ACh in the rabbit carotid artery. This effect appears to be attributable to inhibition of the cytochrome P450-dependent synthesis of EDHF by the endothelium.
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de Wit, Cor, Norbert Esser, Hans-Anton Lehr, Steffen-Sebastian Bolz, and Ulrich Pohl. "Pentobarbital-sensitive EDHF comediates ACh-induced arteriolar dilation in the hamster microcirculation." American Journal of Physiology-Heart and Circulatory Physiology 276, no. 5 (May 1, 1999): H1527—H1534. http://dx.doi.org/10.1152/ajpheart.1999.276.5.h1527.
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It is unclear to what extent the endothelium-derived hyperpolarizing factor (EDHF) contributes to the control of microcirculatory blood flow in vivo. We analyzed, by intravital microscopy in hamster muscles, the potential role of EDHF along the vascular tree under stimulated (ACh) or basal conditions. Experiments were performed in conscious as well as anesthetized (pentobarbital, urethan) animals. Additionally, cellular effects of the potential EDHF were studied in isolated small arteries. In pentobarbital-anesthetized animals, treatment with N ω-nitro-l-arginine (l-NNA; 30 μmol/l) and indomethacin (3 μmol/l) reduced the dilation in response to 10 μmol/l ACh from 60 ± 6 to 20 ± 4%. This nitric oxide/prostaglandin-independent dilation (NPID), which was of a similar magnitude in large and small arterioles, was abolished by potassium depolarization or charybdotoxin (ChTX, 1 μmol/l) but not by glibenclamide. In conscious animals, NPID amounted to 33 ± 3%. The inhibitor of the P-450 monooxygenase 17-octadecynoic acid (ODYA) reduced NPID further to 9 ± 4%. ChTX abolished the NPID and also reduced basal diameters (by −11 ± 3%). The induction of anesthesia with pentobarbital reduced NPID (to 12 ± 6%), whereas urethan anesthesia was without effect. Pentobarbital also reduced the ACh-induced hyperpolarization of vascular smooth muscle in isolated arteries, whereas ChTX abolished it. This study suggests that a considerable part of the ACh dilation in the microcirculation is mediated by EDHF, which also contributes to the control of basal tone in conscious animals. The direct inhibitory effect of pentobarbital and ODYA supports the idea that “microcirculatory” EDHF is a product of the cytochrome P-450 pathway. The role of EDHF might be underestimated in pentobarbital-anesthetized animals.
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Matsumoto, Takayuki, Eri Noguchi, Keiko Ishida, Tsuneo Kobayashi, Nobuhiro Yamada, and Katsuo Kamata. "Metformin normalizes endothelial function by suppressing vasoconstrictor prostanoids in mesenteric arteries from OLETF rats, a model of type 2 diabetes." American Journal of Physiology-Heart and Circulatory Physiology 295, no. 3 (September 2008): H1165—H1176. http://dx.doi.org/10.1152/ajpheart.00486.2008.
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We previously reported that in mesenteric arteries from aged Otsuka Long-Evans Tokushima fatty (OLETF) rats (a type 2 diabetes model) endothelium-derived hyperpolarizing factor (EDHF)-type relaxation is impaired while endothelium-derived contracting factor (EDCF)-mediated contraction is enhanced (Matsumoto T, Kakami M, Noguchi E, Kobayashi T, Kamata K. Am J Physiol Heart Circ Physiol 293: H1480–H1490, 2007). Here we investigated whether acute and/or chronic treatment with metformin might improve this imbalance between the effects of the above endothelium-derived factors in mesenteric arteries isolated from OLETF rats. In acute studies on OLETF mesenteric arteries, ACh-induced relaxation was impaired and the relaxation became weaker at high ACh concentrations. Both metformin and 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside [AICAR, an AMP-activated protein kinase (AMPK) activator that is also activated by metformin] 1) diminished the tendency for the relaxation to reverse at high ACh concentrations and 2) suppressed both ACh-induced EDCF-mediated contraction and ACh-stimulated production of prostanoids (thromboxane A2 and PGE2). In studies on OLETF arteries from chronically treated animals, metformin treatment (300 mg·kg−1·day−1 for 4 wk) 1) improved ACh-induced nitric oxide- or EDHF-mediated relaxation and cyclooxygenase (COX)-mediated contraction, 2) reduced EDCF-mediated contraction, 3) suppressed production of prostanoids, and 4) reduced superoxide generation. Metformin did not alter the protein expressions of endothelial nitric oxide synthase (eNOS), phospho-eNOS (Ser1177), or COX-1, but it increased COX-2 protein. These results suggest that metformin improves endothelial functions in OLETF mesenteric arteries by suppressing vasoconstrictor prostanoids and by reducing oxidative stress. Our data suggest that within the timescale studied here, metformin improves endothelial function through this direct mechanism, rather than by improving metabolic abnormalities.
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Woodley, N., R. L. Meunier, and J. K. Barclay. "EDHF mediates the relaxation of stretched canine femoral arteries to acetylcholine." Canadian Journal of Physiology and Pharmacology 79, no. 11 (November 1, 2001): 924–31. http://dx.doi.org/10.1139/y01-079.
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To test the hypothesis that mechanically stretched arteries relax to endothelium-derived vasodilators, we challenged endothelium-intact dog femoral artery rings stretched from 1 to 16 g total initial tension (active force and passive elastic) with 106 M acetylcholine (ACh), an endothelium-dependent dilator. The relaxation to 106 M sodium nitroprusside (SNP), an endothelium-independent dilator, increased with the total initial tension. The relaxation to ACh averaged approximately 65% of the relaxation to SNP at total initial tensions of 4 to 16 g. To determine the nature of the endothelial-derived products involved, we compared the ACh-induced relaxation of stretched rings (6.5 ± 0.2 g total initial tension) with rings chemically contracted with phenylephrine (Phe, 107 to 105 M) (6.5 ± 0.3 g total initial tension). ACh-induced relaxation was evaluated before and after the inhibition of the synthesis of eicosanoids [cyclooxygenase (105 M indomethacin) and lipoxygenase (105 M nordihydroguariaretic acid)] and nitric oxide [nitric oxide synthase (105 M Nw-nitro-L-arginine)]. The contribution of endothelium-derived hyperpolarizing factor (EDHF) was identified by blocking calcium-activated potassium channels (108 M iberiotoxin). SNP (106 M) relaxed stretched rings by 1.7 ± 0.1 g and chemically-activated rings by 4.8 ± 0.2 g. ACh relaxed stretched rings to 73 ± 3% of the SNP relaxation and this was only attenuated in the presence of iberiotoxin. ACh relaxed Phe-activated rings to 60 ± 3% of the SNP relaxation. This relaxation was attenuated by inhibition of the synthesis of nitric oxide and (or) eicosanoids. Therefore, ACh relaxed stretched rings through the release of EDHF whereas the relaxation of chemically activated rings to ACh involved multiple endothelium-derived vasodilators.Key words: endothelium-derived relaxing factor (EDRF), endothelium-derived hyperpolarizing factor (EDHF), arachidonic acid metabolites.
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Quilley, John, and John C. McGiff. "Is EDHF an epoxyeicosatrienoic acid?" Trends in Pharmacological Sciences 21, no. 4 (April 2000): 121–24. http://dx.doi.org/10.1016/s0165-6147(00)01445-0.
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Busse, Rudi, Gillian Edwards, Michel Félétou, Ingrid Fleming, Paul M. Vanhoutte, and Arthur H. Weston. "EDHF: bringing the concepts together." Trends in Pharmacological Sciences 23, no. 8 (August 2002): 374–80. http://dx.doi.org/10.1016/s0165-6147(02)02050-3.
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SUZUKI, HIKARU, GUIFA CHEN, and YOSHIMICHI YAMAMOTO. "Endothelium-Derived Hyperpolarizing Factor (EDHF)." Japanese Circulation Journal 56, no. 2 (1992): 170–74. http://dx.doi.org/10.1253/jcj.56.170.
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Campbell, William B., and David R. Harder. "Prologue: EDHF–what is it?" American Journal of Physiology-Heart and Circulatory Physiology 280, no. 6 (June 1, 2001): H2413—H2416. http://dx.doi.org/10.1152/ajpheart.2001.280.6.h2413.
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Suzuki, Hikaru. "Endothelium-derived hyperpolarizing factor (EDHF)." Journal of Molecular and Cellular Cardiology 24 (May 1992): 43. http://dx.doi.org/10.1016/0022-2828(92)90160-2.
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Matsumoto, Takayuki, Tsuneo Kobayashi, Kentaro Wakabayashi, and Katsuo Kamata. "Cilostazol improves endothelium-derived hyperpolarizing factor-type relaxation in mesenteric arteries from diabetic rats." American Journal of Physiology-Heart and Circulatory Physiology 289, no. 5 (November 2005): H1933—H1940. http://dx.doi.org/10.1152/ajpheart.00303.2005.
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We previously reported that in mesenteric arteries from streptozotocin (STZ)-induced diabetic rats that 1) endothelium-derived hyperpolarizing factor (EDHF)-type relaxation is impaired, possibly due to a reduced action of cAMP via increased phosphodiesterase 3 (PDE3) activity (Matsumoto T, Kobayashi T, and Kamata K. Am J Physiol Heart Circ Physiol 285: H283–H291, 2003) and that 2) PKA activity is decreased (Matsumoto T, Wakabayashi K, Kobayashi T, and Kamata K. Am J Physiol Heart Circ Physiol 287: H1064–H1071, 2004). Here we investigated whether chronic treatment with cilostazol, a PDE3 inhibitor, improves EDHF-type relaxation in mesenteric arteries isolated from STZ rats. We found that in such arteries 1) cilostazol treatment (2 wk) improved ACh-, A-23187-, and cyclopiazonic acid-induced EDHF-type relaxations; 2) the ACh-induced cAMP accumulation was transient and sustained in arteries from cilostazol-treated STZ rats; 3) the EDHF-type relaxation was significantly decreased by a PKA inhibitor in the cilostazol-treated group, but not in the cilostazol-untreated group; 4) cilostazol treatment improved both the relaxations induced by cAMP analogs and the PKA activity level; and 5) PKA catalytic subunit (Cat-α) protein was significantly decreased, but the regulatory subunit RII-β was increased (and the latter effect was significantly decreased by cilostazol treatment). These results strongly suggest that cilostazol improves EDHF-type relaxations in STZ rats via an increase in cAMP and PKA signaling.
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Burger, Natalie Z., Olga Y. Kuzina, George Osol, and Natalia I. Gokina. "Estrogen replacement enhances EDHF-mediated vasodilation of mesenteric and uterine resistance arteries: role of endothelial cell Ca2+." American Journal of Physiology-Endocrinology and Metabolism 296, no. 3 (March 2009): E503—E512. http://dx.doi.org/10.1152/ajpendo.90517.2008.
Full textAbstract:
Endothelium-derived hyperpolarizing factor (EDHF) plays an important role in the regulation of vascular microcirculatory tone. This study explores the role of estrogen in controlling EDHF-mediated vasodilation of uterine resistance arteries of the rat and also analyzes the contribution of endothelial cell (EC) Ca2+ signaling to this process. A parallel study was also performed with mesenteric arteries to provide comparison with a nonreproductive vasculature. Mature female rats underwent ovariectomy, with one half receiving 17β-estradiol replacement (OVX+E) and the other half serving as estrogen-deficient controls (OVX). Uterine or mesenteric resistance arteries were harvested, cannulated, and pressurized. Nitric oxide and prostacyclin production were inhibited with 200 μM NG-nitro-l-arginine and 10 μM indomethacin, respectively. ACh effectively dilated the arteries preconstricted with phenylephrine but failed to induce dilation of vessels preconstricted with high-K+ solution. ACh EC50 values were decreased by estrogen replacement by five- and twofold in uterine and mesenteric arteries, respectively. As evidenced by fura-2-based measurements of EC cytoplasmic Ca2+ concentration ([Ca2+]i), estrogen replacement was associated with increased basal and ACh-stimulated EC [Ca2+]i rise in uterine, but not mesenteric, vessels. These data demonstrate that EDHF contributes to endothelium-dependent vasodilation of uterine and mesenteric resistance arteries and that estrogen controls EDHF-related mechanism(s) more efficiently in reproductive vs. nonreproductive vessels. Enhanced endothelial Ca2+ signaling may be an important underlying mechanism in estrogenic modulation of EDHF-mediated vasodilation in small resistance uterine arteries.
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Coleman, H. A., Marianne Tare, and Helena C. Parkington. "EDHF is not K+ but may be due to spread of current from the endothelium in guinea pig arterioles." American Journal of Physiology-Heart and Circulatory Physiology 280, no. 6 (June 1, 2001): H2478—H2483. http://dx.doi.org/10.1152/ajpheart.2001.280.6.h2478.
Full textAbstract:
Endothelium-derived hyperpolarizing factor (EDHF)-attributed hyperpolarizations and relaxations were recorded simultaneously from submucosal arterioles of guinea pigs with the use of intracellular microelectrodes and a video-based system, respectively. Membrane currents were recorded from electrically short segments of arterioles under single-electrode voltage clamp. Substance P evoked an outward current with a current-voltage relationship that was well described by the Goldman-Hodgkin-Katz equation for a K+ current, consistent with the involvement of intermediate- and small-conductance Ca2+-activated K+ channels. 1-Ethyl-2-benzimidazolinone relaxed the arterioles and evoked hyperpolarizations that were blocked by charybdotoxin, but not by iberiotoxin. Application of K+induced depolarization under conditions in which EDHF evoked hyperpolarization. The Ba2+-sensitive component of the K+-induced current was inwardly rectifying, in contrast to the outwardly rectifying current evoked by substance P. EDHF-attributed hyperpolarizations in dye-identified smooth muscle cells were indistinguishable from those recorded from dye-identified endothelial cells in the same arterioles. These results provide evidence that EDHF is not K+ but may involve electrotonic spread of hyperpolarization from the endothelial cells to the smooth muscle cells.
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Moreno, Juan Manuel, Rosemary Wangensteen, Juan Sainz, Isabel Rodríguez-Gomez, Virginia Chamorro, Antonio Osuna, and Félix Vargas. "Role of endothelium-derived relaxing factors in the renal response to vasoactive agents in hypothyroid rats." American Journal of Physiology-Endocrinology and Metabolism 285, no. 1 (July 2003): E182—E188. http://dx.doi.org/10.1152/ajpendo.00558.2002.
Full textAbstract:
This study analyzed the role of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) in the abnormal renal vascular reactivity of hypothyroid rats. Renal responses to vasoconstrictors [VC: phenylephrine (PHE) and ANG II] and vasodilators [VD: ACh, sodium nitroprusside (SNP), and papaverine (PV)] were studied in kidneys from control and hypothyroid rats under normal conditions and after NO or EDHF blockade. NO was blocked by the administration of Nω-nitro-l-arginine methyl ester (l-NAME) and EDHF by the administration of tetraethylammonium (TEA) or by an increased extracellular K+. The response to VC was also evaluated after endothelium removal. Hypothyroid kidneys showed reduced responsiveness to PHE and a normal response to ANG II. l-NAME and TEA administration produced an increased sensitivity to PHE and to ANG II in control preparations. l-NAME also increased the response to PHE in hypothyroid kidneys, but the differences between control and hypothyroid kidneys were maintained. TEA administration did not change the response to either VC in hypothyroid preparations. In endothelium-removed preparations, TEA was unable to increase pressor responsiveness to VC. Hypothyroid kidneys showed reduced responsiveness to ACh and SNP and normal response to PV. The differences between hypothyroid and control preparations in the responses to ACh and SNP were maintained after l-NAME or increased K+. In conclusion, this study shows that 1) the attenuated response to PHE in hypothyroidism is not related to an increased production of endothelium-derived relaxing factors NO and EDHF; 2) the response to VC in hypothyroid preparations is insensitive to EDHF blockade; and 3) hypothyroid preparations have a reduced reactivity to the NO donor, and NO-independent vasodilatation remains unaffected.
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Torondel, B., JM Vila, G. Segarra, P. Lluch, P. Medina, J. Martinez-Leon, J. Ortega, and S. Lluch. "Endothelium-dependent responses in human isolated thyroid arteries from donors." Journal of Endocrinology 181, no. 3 (June 1, 2004): 379–84. http://dx.doi.org/10.1677/joe.0.1810379.
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The functional properties of the endothelium of human thyroid arteries remain unexplored. We investigated the intervention of nitric oxide (NO), prostacyclin (PGI(2)) and endothelium-derived hyperpolarizing factor (EDHF) in the responses to acetylcholine and noradrenaline in isolated thyroid arteries obtained from multi-organ donors. Artery rings were suspended in organ baths for isometric recording of tension. The contribution of NO, PGI(2) and EDHF to endothelium-dependent relaxation was determined by the inhibitory effects of N(G)-monomethyl-L-arginine (L-NMMA), indomethacin, and K(+) channel inhibitors respectively. Acetylcholine induced concentration-dependent relaxation; this effect was not modified by indomethacin and was only partly reduced by L-NMMA, but was abolished in endothelium-denuded rings. The relaxation resistant to indomethacin and L-NMMA was abolished by using either apamin combined with charybdotoxin, ouabain plus barium, or a high-K(+) solution. Noradrenaline induced concentration-dependent contractions which were of greater magnitude in arteries denuded of endothelium or in the presence of L-NMMA.In conclusion, the results indicate that in human thyroid arteries the endothelium significantly modulates responses to acetylcholine and noradrenaline through the release of NO and EDHF. EDHF plays a dominant role in acetylcholine-induced relaxation through activation of Ca(2+)-activated K(+) channels, inwardly rectifying K(+) channels and Na(+)-K(+)-ATPase.
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Olmos, L., J. V. Mombouli, S. Illiano, and P. M. Vanhoutte. "cGMP mediates the desensitization to bradykinin in isolated canine coronary arteries." American Journal of Physiology-Heart and Circulatory Physiology 268, no. 2 (February 1, 1995): H865—H870. http://dx.doi.org/10.1152/ajpheart.1995.268.2.h865.
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The relaxation to bradykinin in canine coronary arteries is mediated by endothelium-derived nitric oxide (NO) and hyperpolarizing factor (EDHF). Desensitization to the kinin was induced by incubation of canine coronary arteries with endothelium with 10(-8) M bradykinin for 30 min. After washout, tissues were contracted with prostaglandin F2 alpha, and concentration-relaxation curves to bradykinin were obtained in control and desensitized arteries treated with indomethacin. After desensitization, there was a shift to the right of the concentration-relaxation curves to bradykinin. However, the elevation in guanosine 3',5'-cyclic monophosphate (cGMP) levels evoked by bradykinin was similar in both groups of tissues. The curves to bradykinin obtained in the presence of NG-nitro-L-arginine (an NO synthase inhibitor) were depressed, whereas those obtained in arteries contracted with potassium (to eliminate the EDHF-mediated relaxation) were not affected by the desensitization. Addition of NG-nitro-L-arginine, oxyhemoglobin, or methylene blue before the desensitization procedure preserved, whereas 3-morpholinosydnonimine (SIN-1, a donor of NO) and 8-bromoguanosine 3',5'-cyclic monophosphate impaired, the EDHF-mediated relaxation to bradykinin. Thus the selective impairment of the EDHF-dependent relaxation to bradykinin may be mediated by NO, acting mainly through increased production of cGMP.
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Marrelli, Sean P. "Mechanisms of endothelial P2Y1- and P2Y2-mediated vasodilatation involve differential [Ca2+]i responses." American Journal of Physiology-Heart and Circulatory Physiology 281, no. 4 (October 1, 2001): H1759—H1766. http://dx.doi.org/10.1152/ajpheart.2001.281.4.h1759.
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The present study was designed to evaluate the role of endothelial intracellular Ca2+ concentration ([Ca2+]i) in the difference between P2Y1- and P2Y2-mediated vasodilatations in cerebral arteries. Rat middle cerebral arteries were cannulated, pressurized, and luminally perfused. The endothelium was selectively loaded with fura 2, a fluorescent Ca2+indicator, for simultaneous measurement of endothelial [Ca2+]i and diameter. Luminal administration of 2-methylthioadenosine 5′-triphosphate (2-MeS-ATP), an endothelial P2Y1 agonist, resulted in purely nitric oxide (NO)-dependent dilation and [Ca2+]i increases up to ∼300 nM (resting [Ca2+]i = 145 nM). UTP, an endothelial P2Y2 agonist, resulted in dilations that were both endothelium-derived hyperpolarizing factor (EDHF)- and NO-dependent with [Ca2+]iincreases to >400 nM. In the presence of N G-nitro-l-arginine-indomethacin to inhibit NO synthase and cyclooxygenase, UTP resulted in an EDHF-dependent dilation alone. The [Ca2+]ithreshold for NO-dependent dilation was 220 vs. 340 nM for EDHF. In summary, the differences in the mechanism of vasodilatation resulting from stimulation of endothelial P2Y1 and P2Y2purinoceptors result in part from differential [Ca2+]i responses. Consistent with this finding, these studies also demonstrate a higher [Ca2+]i threshold for EDHF-dependent responses compared with NO.
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Ogawa, Koji, Satoru Tanaka, and Paul A. Murray. "Inhibitory Effects of Etomidate and Ketamine on Endothelium-dependent Relaxation in Canine Pulmonary Artery." Anesthesiology 94, no. 4 (April 1, 2001): 668–77. http://dx.doi.org/10.1097/00000542-200104000-00022.
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Background The authors recently demonstrated that acetylcholine-induced pulmonary vasorelaxation had two primary components, nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). The goal was to investigate the effects of etomidate and ketamine on the NO- and EDHF-mediated components of pulmonary vasorelaxation in response to acetylcholine, bradykinin, and the calcium ionophore, A23187. Methods Canine pulmonary arterial rings with an intact endothelium were suspended in organ chambers for isometric tension recording. The effects of etomidate and ketamine (10(-5) M and 10(-4) M) on vasorelaxation responses to acetylcholine, bradykinin, and A23187 were assessed in phenylephrine-contracted rings. The NO- and EDHF-mediated components of relaxation were assessed using a NO synthase inhibitor (N-nitro-L-arginine methylester [L-NAME]: 10(-4) M) and a Ca2+-activated potassium channel inhibitor (tetrabutylammonium hydrogen sulfate [TBA]: 10(-3) M) in rings pretreated with a cyclooxygenase inhibitor (ibuprofen: 10(-5) M). Intracellular calcium concentration ([Ca2+]i) was measured in cultured bovine pulmonary artery endothelial cells loaded with acetoxylmethyl ester of fura-2. Results Etomidate and ketamine attenuated pulmonary vasorelaxation in response to acetylcholine and bradykinin, whereas they had no effect on the response to A23187. The relaxant responses to acetylcholine and bradykinin were attenuated by L-NAME or TBA alone and were abolished by combined inhibition in rings pretreated with ibuprofen. Etomidate and ketamine further attenuated both L-NAME-resistant and TBA-resistant relaxation. These anesthetics also inhibited increases in endothelial [Ca2+]i in response to bradykinin, but not A23187. Conclusion These results indicate that etomidate and ketamine attenuated vasorelaxant responses to acetylcholine and bradykinin by inhibiting both NO- and EDHF-mediated components. Moreover, our results suggest that these anesthetics do not directly suppress NO or EDHF activity, but rather inhibit the endothelial [Ca2+]i transient in response to receptor activation.
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Golding, Elke M., and Tara E. Kepler. "Role of estrogen in modulating EDHF-mediated dilations in the female rat middle cerebral artery." American Journal of Physiology-Heart and Circulatory Physiology 280, no. 6 (June 1, 2001): H2417—H2423. http://dx.doi.org/10.1152/ajpheart.2001.280.6.h2417.
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We tested the hypothesis that endothelium-derived hyperpolarizing factor (EDHF) plays a less dominant role in the female cerebrovasculature. The contribution of EDHF to the ATP-mediated dilation was determined in middle cerebral arteries (MCAs) isolated from male and female rats. Four groups of rats were tested: intact male ( n = 12), intact female ( n= 13), estrogen-treated ovariectomized female ( n = 13), and vehicle-treated ovariectomized female ( n = 20) rats. Maximal dilation to ATP was similar in all groups. However, in the presence of N ω-nitro-l-arginine methyl ester (l-NAME, 3 × 10−5 M) and indomethacin (10−5 M), the maximal dilation to ATP was significantly reduced in intact female (24 ± 9%) and estrogen-treated ovariectomized female (29 ± 9%) rats compared with intact male (95 ± 4%) and vehicle-treated ovariectomized female (96 ± 2%) rats. The ATP-mediated dilation in l-NAME- and indomethacin-treated MCAs isolated from male and ovariectomized female rats was inhibited by charybdotoxin (10−7 M), an inhibitor of large-conductance Ca2+-sensitive K+channels. We have defined EDHF as the l-NAME- and indomethacin-insensitive component of the ATP-mediated dilation. Our findings indicate that EDHF-mediated dilations are negligible in the female rat MCA; these dilations can be significantly enhanced after ovariectomy, suggesting that this effect is mediated by estrogen.