The Experts below are selected from a list of 237 Experts worldwide ranked by ideXlab platform
Paul M Vanhoutte - One of the best experts on this subject based on the ideXlab platform.
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endothelial dysfunction the first step toward coronary arteriosclerosis
Circulation, 2009Co-Authors: Paul M VanhoutteAbstract:: The endothelium causes relaxations of the underlying vascular smooth muscle, by releasing nitric oxide (NO). The endothelial cells also can evoke Hyperpolarization of the vascular smooth muscle cells (endothelium-dependent Hyperpolarizations, endothelium-derived hyperpolarizing factors-mediated responses). Endothelium-dependent relaxations involve both pertussis toxin-sensitive Gi and pertussis toxin-insensitive Gq coupling proteins. The endothelial release of NO is reduced in diabetes and hypertension. Arteries covered with regenerated endothelium lose the pertussis-toxin sensitive pathway for NO-release. This dysfunction favors vasospasm, thrombosis, penetration of macrophages, cellular growth and the inflammatory reaction leading to atherosclerosis. Endothelial cells also release endothelium-derived contracting factors (EDCF). Most endothelium-dependent contractions are mediated by vasoconstrictor prostanoids (endoperoxides and prostacyclin), which activate thromboxane-prostanoid (TP)-receptors of the underlying vascular smooth muscle cells. EDCF-mediated responses are augmented by aging, hypertension and diabetes. Thus, endothelial dysfunction is the first step toward coronary arteriosclerosis.
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endothelial dysfunction the first step toward coronary arteriosclerosis
Circulation, 2009Co-Authors: Paul M VanhoutteAbstract:The endothelium causes relaxations of the underlying vascular smooth muscle, by releasing nitric oxide (NO). The endothelial cells also can evoke Hyperpolarization of the vascular smooth muscle cells (endothelium-dependent Hyperpolarizations, endothelium-derived hyperpolarizing factors-mediated responses). Endothelium-dependent relaxations involve both pertussis toxin-sensitive Gi and pertussis toxin-insensitive Gq coupling proteins. The endothelial release of NO is reduced in diabetes and hypertension. Arteries covered with regenerated endothelium lose the pertussis-toxin sensitive pathway for NO-release. This dysfunction favors vasospasm, thrombosis, penetration of macrophages, cellular growth and the inflammatory reaction leading to atherosclerosis. Endothelial cells also release endothelium-derived contracting factors (EDCF). Most endothelium-dependent contractions are mediated by vasoconstrictor prostanoids (endoperoxides and prostacyclin), which activate thromboxane-prostanoid (TP)-receptors of the underlying vascular smooth muscle cells. EDCF-mediated responses are augmented by aging, hypertension and diabetes. Thus, endothelial dysfunction is the first step toward coronary arteriosclerosis.
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Endothelial dysfunction and vascular disease
Acta Physiologica, 2009Co-Authors: Paul M Vanhoutte, E. H. C. Tang, Hirofumi Shimokawa, Michel FélétouAbstract:The endothelium can evoke relaxations (dilatations) of the underlying vascular smooth muscle, by releasing vasodilator substances. The best characterized endothelium-derived relaxing factor (EDRF) is nitric oxide (NO). The endothelial cells also evoke Hyperpolarization of the cell membrane of vascular smooth muscle (endothelium-dependent Hyperpolarizations, EDHF-mediated responses). Endothelium-dependent relaxations involve both pertussis toxin-sensitive Gi (e.g. responses to serotonin and thrombin) and pertussis toxin-insensitive Gq (e.g. adenosine diphosphate and bradykinin) coupling proteins. The release of NO by the endothelial cell can be up-regulated (e.g. by oestrogens, exercise and dietary factors) and down-regulated (e.g. oxidative stress, smoking and oxidized low-density lipoproteins). It is reduced in the course of vascular disease (e.g. diabetes and hypertension). Arteries covered with regenerated endothelium (e.g. following angioplasty) selectively loose the pertussis toxin-sensitive pathway for NO release which favours vasospasm, thrombosis, penetration of macrophages, cellular growth and the inflammatory reaction leading to atherosclerosis. In addition to the release of NO (and causing endothelium-dependent Hyperpolarizations), endothelial cells also can evoke contraction (constriction) of the underlying vascular smooth muscle cells by releasing endothelium-derived contracting factor (EDCF). Most endothelium-dependent acute increases in contractile force are due to the formation of vasoconstrictor prostanoids (endoperoxides and prostacyclin) which activate TP receptors of the vascular smooth muscle cells. EDCF-mediated responses are exacerbated when the production of NO is impaired (e.g. by oxidative stress, ageing, spontaneous hypertension and diabetes). They contribute to the blunting of endothelium-dependent vasodilatations in aged subjects and essential hypertensive patients.
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Endothelium-dependent Hyperpolarizations: the history
Pharmacological research, 2004Co-Authors: Paul M VanhoutteAbstract:Endothelial cells control the tone and the growth of the underlying vascular smooth muscle by releasing Nitric Oxide (NO). This introduction summarizes the early experiments which first suggested and then demonstrated the existence of an alternative pathway, endothelium-dependent Hyperpolarization. It reviews why endothelium-derived hyperpolarizing factor (EDHF) is not likely to be either NO or prostacyclin. It sets the stage for the other contributions of this special issue devoted to EDHF that will discuss in depth the current knowledge concerning endothelium-dependent Hyperpolarizations.
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Third pathway: Endothelium‐dependent Hyperpolarization
Drug Development Research, 2003Co-Authors: Michel Félétou, Paul M VanhoutteAbstract:The mechanism of endothelium-dependent Hyperpolarizations, once attributed to an elusive endothelium-derived hyperpolarizing factor (EDHF), is better understood. The first steps involve an increase in the intracellular calcium concentration of the endothelial cells followed by the opening of endothelial calcium-activated potassium channels and the Hyperpolarization of the endothelial cells. In certain arteries, these endothelial events are under the control of the endothelial cytochrome P450 monooxygenase. Then, the endothelium-dependent Hyperpolarization of the smooth muscle cells can be evoked by direct electrical coupling through myo-endothelial junctions, accumulation of potassium ions in the intracellular space between the endothelial and the smooth muscle cells, and in rare occasions the release of a metabolite(s) of arachidonic acid via the cytochrome P450 pathway. These various mechanisms are not necessarily exclusive and can occur simultaneously and even in synergy.
Gillian Edwards - One of the best experts on this subject based on the ideXlab platform.
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Evidence for the presence of GPRC6A receptors in rat mesenteric arteries.
Cell Calcium, 2008Co-Authors: Erika Harno, Gillian Edwards, Annie R. Geraghty, Donald T. Ward, Robert H. Dodd, Philippe Dauban, Hélène Faure, Martial Ruat, Arthur H. WestonAbstract:In this study, the presence of GPRC6A receptors in rat mesenteric artery was investigated. In artery homogenates, GPRC6A mRNA was detected and Western blotting showed the presence of GPRC6A protein. Immunohistochemical studies revealed GPRC6A in both endothelial cells and myocytes. In whole vessel segments, the GPRC6A activators, 300 microM l-ornithine and 100 microM Al(3+), induced endothelium-dependent myocyte Hyperpolarizations sensitive to 10 microM TRAM-34, a blocker of intermediate conductance, Ca(2+)-sensitive K(+) channels (IK(Ca)). Activation of IK(Ca) with calindol (300 nM; a positive allosteric Ca(2+)-sensing receptor - CaR - modulator) was inhibited by 500 nM ouabain (inhibition of rat type 2 and type 3 Na(+)/K(+)-ATPases) but unaffected by 30 microM Ba(2+) (blockade of inwardly rectifying K(+) channels). Neither l-ornithine nor Al(3+) activated CaRs heterologously expressed in CHO or HEK293 cells. In the presence of 300 microM l-ornithine or 100 microM Al(3+), myocyte Hyperpolarizations to calindol were potentiated whereas this potentiation and Hyperpolarizations to l-ornithine were lost following incubation with an anti-GPRC6A antibody. It is concluded that GPRC6A receptors are present on mesenteric artery endothelial cells and myocytes and that their activation selectively opens IK(Ca) channels. This triggers a ouabain-sensitive myocyte Hyperpolarization suggesting a close functional relationship between GPRC6A, the IK(Ca) channel and type 2 and/or type 3 Na(+)/K(+)-ATPases.
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The expression and function of Ca(2+)-sensing receptors in rat mesenteric artery; comparative studies using a model of type II diabetes.
British Journal of Pharmacology, 2008Co-Authors: Arthur H. Weston, Erika Harno, Annie R. Geraghty, Donald T. Ward, Robert H. Dodd, Philippe Dauban, Martial Ruat, Mais Absi, Gillian EdwardsAbstract:BACKGROUND AND PURPOSE: The extracellular calcium-sensing receptor (CaR) in vascular endothelial cells activates endothelial intermediate-conductance, calcium-sensitive K(+) channels (IK(Ca)) indirectly leading to myocyte Hyperpolarization. We determined whether CaR expression and function was modified in a rat model of type II diabetes. EXPERIMENTAL APPROACH: Pressure myography, western blotting, sharp microelectrode and K(+)-selective electrode recordings were used to investigate the functional expression of the CaR and IK(Ca) in rat mesenteric arteries. KEY RESULTS: Myocyte Hyperpolarization to the CaR activator calindol was inhibited by Calhex 231. U46619-induced vessel contraction elevated the extracellular [K(+)] around the myocytes, and inhibition of this 'K(+) cloud' by iberiotoxin was needed to reveal calindol-induced vasodilatations. These were antagonized by Calhex 231 and significantly smaller in Zucker diabetic fatty rat (ZDF) vessels than in Zucker lean (ZL) controls. Myocyte Hyperpolarizations to calindol were also smaller in ZDF than in ZL arteries. In ZDF vessels, endothelial cell CaR protein expression was reduced; IK(Ca) expression was also diminished, but IK(Ca)-generated Hyperpolarizations mediated by 1-EBIO were unaffected. CONCLUSIONS AND IMPLICATIONS: The reduced CaR-mediated hyperpolarizing and vasodilator responses in ZDF arteries result from a decrease in CaR expression, rather than from a modification of IK(Ca) channels. Detection of CaR-mediated vasodilatation required the presence of iberiotoxin, suggesting a CaR contribution to vascular diameter, that is, inversely related to the degree of vasoconstriction. Compromise of the CaR pathway would favour the long-term development of a higher basal vascular tone and could contribute to the vascular complications associated with type II diabetes.
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Evidence in favor of a calcium-sensing receptor in arterial endothelial cells: studies with calindol and Calhex 231.
Circulation Research, 2005Co-Authors: Arthur H. Weston, Donald T. Ward, Robert H. Dodd, Philippe Dauban, Martial Ruat, Mais Absi, Jacqueline Ohanian, Christophe Petrel, Gillian EdwardsAbstract:Small increases in extracellular Ca2+ dilate isolated blood vessels. In the present study, the possibility that a vascular, extracellular Ca2+-sensing receptor (CaSR) could mediate these vasodilator actions was investigated. Novel ligands that interact with the CaSR were used in microelectrode recordings from rat isolated mesenteric and porcine coronary arteries. The major findings were that (1) raising extracellular Ca2+ or adding calindol, a CaSR agonist, produced concentration-dependent Hyperpolarizations of vascular myocytes, actions attenuated by Calhex 231, a negative allosteric modulator of CaSR. (2) Calindol-induced Hyperpolarizations were inhibited by the intermediate conductance, Ca2+-sensitive K+ (IKCa) channel inhibitors, TRAM-34, and TRAM-39. (3) The effects of calindol were not observed in the absence of endothelium. (4) CaSR mRNA and protein were present in rat mesenteric arteries and in porcine coronary artery endothelial cells. (5) CaSR and IKCa proteins were restricted to caveolin-poor membrane fractions. We conclude that activation of vascular endothelial CaSRs opens endothelial cell IKCa channels with subsequent myocyte Hyperpolarization. The endothelial cell CaSR may have a physiological role in the control of arterial blood pressure.
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Differential effects of prostacyclin and iloprost in the isolated carotid artery of the guinea-pig.
European Journal of Pharmacology, 2001Co-Authors: Catherine Corriu, Michel Félétou, Gillian Edwards, Arthur H. Weston, Paul M VanhoutteAbstract:The effects on membrane potential of prostacyclin and iloprost were compared in smooth muscle cells of the guinea pig carotid artery. Both prostacyclin and iloprost induced Hyperpolarization of the smooth muscle cells. In the presence of (3R)-3-(4-fluorophenyl-sulfonamido)-1,2,3,4-tetrahydro-9-carbazolepropanoic acid (Bay U3405), an antagonist of TP receptors, the response to iloprost was unaffected while that to prostacyclin was increased. Iloprost-induced Hyperpolarizations were abolished by glibenclamide while those to prostacyclin were either not affected, or converted to either depolarization or to rhythmic electrical activity. The latter effects of prostacyclin were abolished by Bay U3405. After removal of the endothelium, iloprost and prostacyclin produced Hyperpolarizations similar to those observed in control blood vessels. However, in the presence of glibenclamide, prostacyclin produced only depolarizations inhibited by Bay U3405. These results suggest that iloprost activates IP receptors and K(ATP) channels in smooth muscle. In contrast, prostacyclin produces additional endothelium-dependent and -independent effects via activation of TP receptors.
Michel Félétou - One of the best experts on this subject based on the ideXlab platform.
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Endothelial dysfunction and vascular disease
Acta Physiologica, 2009Co-Authors: Paul M Vanhoutte, E. H. C. Tang, Hirofumi Shimokawa, Michel FélétouAbstract:The endothelium can evoke relaxations (dilatations) of the underlying vascular smooth muscle, by releasing vasodilator substances. The best characterized endothelium-derived relaxing factor (EDRF) is nitric oxide (NO). The endothelial cells also evoke Hyperpolarization of the cell membrane of vascular smooth muscle (endothelium-dependent Hyperpolarizations, EDHF-mediated responses). Endothelium-dependent relaxations involve both pertussis toxin-sensitive Gi (e.g. responses to serotonin and thrombin) and pertussis toxin-insensitive Gq (e.g. adenosine diphosphate and bradykinin) coupling proteins. The release of NO by the endothelial cell can be up-regulated (e.g. by oestrogens, exercise and dietary factors) and down-regulated (e.g. oxidative stress, smoking and oxidized low-density lipoproteins). It is reduced in the course of vascular disease (e.g. diabetes and hypertension). Arteries covered with regenerated endothelium (e.g. following angioplasty) selectively loose the pertussis toxin-sensitive pathway for NO release which favours vasospasm, thrombosis, penetration of macrophages, cellular growth and the inflammatory reaction leading to atherosclerosis. In addition to the release of NO (and causing endothelium-dependent Hyperpolarizations), endothelial cells also can evoke contraction (constriction) of the underlying vascular smooth muscle cells by releasing endothelium-derived contracting factor (EDCF). Most endothelium-dependent acute increases in contractile force are due to the formation of vasoconstrictor prostanoids (endoperoxides and prostacyclin) which activate TP receptors of the vascular smooth muscle cells. EDCF-mediated responses are exacerbated when the production of NO is impaired (e.g. by oxidative stress, ageing, spontaneous hypertension and diabetes). They contribute to the blunting of endothelium-dependent vasodilatations in aged subjects and essential hypertensive patients.
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Third pathway: Endothelium‐dependent Hyperpolarization
Drug Development Research, 2003Co-Authors: Michel Félétou, Paul M VanhoutteAbstract:The mechanism of endothelium-dependent Hyperpolarizations, once attributed to an elusive endothelium-derived hyperpolarizing factor (EDHF), is better understood. The first steps involve an increase in the intracellular calcium concentration of the endothelial cells followed by the opening of endothelial calcium-activated potassium channels and the Hyperpolarization of the endothelial cells. In certain arteries, these endothelial events are under the control of the endothelial cytochrome P450 monooxygenase. Then, the endothelium-dependent Hyperpolarization of the smooth muscle cells can be evoked by direct electrical coupling through myo-endothelial junctions, accumulation of potassium ions in the intracellular space between the endothelial and the smooth muscle cells, and in rare occasions the release of a metabolite(s) of arachidonic acid via the cytochrome P450 pathway. These various mechanisms are not necessarily exclusive and can occur simultaneously and even in synergy.
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Differential effects of prostacyclin and iloprost in the isolated carotid artery of the guinea-pig.
European Journal of Pharmacology, 2001Co-Authors: Catherine Corriu, Michel Félétou, Gillian Edwards, Arthur H. Weston, Paul M VanhoutteAbstract:The effects on membrane potential of prostacyclin and iloprost were compared in smooth muscle cells of the guinea pig carotid artery. Both prostacyclin and iloprost induced Hyperpolarization of the smooth muscle cells. In the presence of (3R)-3-(4-fluorophenyl-sulfonamido)-1,2,3,4-tetrahydro-9-carbazolepropanoic acid (Bay U3405), an antagonist of TP receptors, the response to iloprost was unaffected while that to prostacyclin was increased. Iloprost-induced Hyperpolarizations were abolished by glibenclamide while those to prostacyclin were either not affected, or converted to either depolarization or to rhythmic electrical activity. The latter effects of prostacyclin were abolished by Bay U3405. After removal of the endothelium, iloprost and prostacyclin produced Hyperpolarizations similar to those observed in control blood vessels. However, in the presence of glibenclamide, prostacyclin produced only depolarizations inhibited by Bay U3405. These results suggest that iloprost activates IP receptors and K(ATP) channels in smooth muscle. In contrast, prostacyclin produces additional endothelium-dependent and -independent effects via activation of TP receptors.
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Endothelium-derived hyperpolarizing factor.
Clinical and experimental pharmacology & physiology, 1996Co-Authors: Michel Félétou, Paul M VanhoutteAbstract:1. Not all endothelium-dependent relaxations can be fully explained by the release of either nitric oxide (NO) and/or prostacyclin. Another unidentified substance(s) that hyperpolarizes the underlying vascular smooth muscle cells (endothelium-derived hyperpolarizing factor; EDHF) contributes to endothelium-dependent relaxations. 2. In blood vessels from various species these Hyperpolarizations are resistant to inhibitors of NO synthase (NOS) and cyclo-oxygenase. In canine, porcine and human blood vessels the Hyperpolarization cannot be mimicked by nitrovasodilators or exogeneous NO. However, in other species (rat, guinea-pig, rabbit) endothelium-dependent Hyperpolarizations resistant to inhibitors of NOS and cyclo-oxygenase and Hyperpolarizations to endothelium-derived or exogeneous NO can be observed in the same vascular smooth muscle cells. 3. In blood vessels where NO causes Hyperpolarization, the response is blocked by glibenclamide, suggesting the involvement of ATP-dependent potassium channels. Hyperpolarizations caused by EDHF are insensitive to glibenclamide but, depending on the tissue, are inhibited by relatively small concentrations of tetraethylammonium (TEA) or by apamin or the combination of charybdotoxin plus apamin, indicating that calcium-dependent potassium channels are likely to be involved. 4. Metabolites of arachidonic acid, through the cytochrome P450 mono-oxygenase pathway (epoxyeicosatrienoic acids), are produced by the endothelial cells, increase the open-state probability of calcium-activated potassium channels sensitive to TEA or charybdotoxin, and induce the Hyperpolarization of arterial smooth muscle cells, indicating that epoxyeicosatrienoic acids could be EDHF. However, in blood vessels from various species, cytochrome P450 inhibitors do not affect endothelium-dependent Hyperpolarizations, indicating that EDHF is not yet identified with certainty. 5. Endothelium-derived hyperpolarizing factor released from cultured endothelial cells reduces the intracellular calcium concentration in vascular smooth muscle cells and the EDHF component of the relaxation is proportionally more important in smaller than larger arteries. In aging animals and in various models of diseases, endothelium-dependent Hyperpolarizations are diminished. 6. The identification of EDHF and/or the discovery of specific inhibitors of its synthesis and its action may allow a better understanding of its physiological and pathophysiological role(s).
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Endothelium-Dependent Hyperpolarization and Potassium Channels
Pharmacological Control of Calcium and Potassium Homeostasis, 1995Co-Authors: Mikio Nakashima, Michel Félétou, Paul M VanhoutteAbstract:In response to various neurohumoral mediators and physical stimuli, the endothelium elicits relaxations or contractions of the underlying vascular smooth muscle. Endothelium-dependent relaxations can be mediated by the release of the endothelium-derived nitric oxide and prostacyclin [1-2]. In addition, endothelial cells release a yet unidentified endothelium-derived hyperpolarizing factor (EDHF), which causes membrane Hyperpolarization by opening potassium channels in vascular smooth muscle [3-4]. However, the possibility that EDHF may contribute to endothelium-dependent Hyperpolarization and the mechanism underlying this response is the subject of some controversy. Since both NO and some synthesized prostanoids [5] can cause membrane Hyperpolarization under certain conditions, depending on the tissues and/or the species studied, the electrophysiological changes attributed to EDHF have to be distinguished from those of either NO or prostanoids by demonstrating its occurrence during combined inhibition of NO synthase and cyclooxygenase [6]. This brief review focuses on endothelium-dependent Hyperpolarizations which cannot be attributed to the release of nitric oxide or prostanoids.
G. D. S. Hirst - One of the best experts on this subject based on the ideXlab platform.
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Ionophoretically applied acetylcholine and vagal stimulation in the arrested sinus venosus of the toad, Bufo marinus.
The Journal of Physiology, 1994Co-Authors: Narelle J. Bramich, James A. Brock, F. R. Edwards, G. D. S. HirstAbstract:1. The effects of acetylcholine (ACh), applied by ionophoresis, on the isolated arrested sinus venosus of the toad, Bufo marinus, were examined. 2. At each position where ACh was applied across the surface of sinus venosus preparations, a Hyperpolarization was produced. These responses were abolished by hyoscine, indicating that muscarinic cholinoceptors are widely distributed over the surface of these muscle cells. 3. Vagal stimulation produced Hyperpolarizations which were mimicked, to some extent, by ionophoretically applied ACh. 4. The responses to ionophoretically applied ACh were abolished by adding barium ions to the perfusion fluid, whereas responses to vagal stimulation persisted. 5. The responses to ionophoretically applied ACh were consistently slower than those to vagal stimulation. It is argued that the pathways activated by neural and applied ACh have different kinetics of activation.
Arthur H. Weston - One of the best experts on this subject based on the ideXlab platform.
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Evidence for the presence of GPRC6A receptors in rat mesenteric arteries.
Cell Calcium, 2008Co-Authors: Erika Harno, Gillian Edwards, Annie R. Geraghty, Donald T. Ward, Robert H. Dodd, Philippe Dauban, Hélène Faure, Martial Ruat, Arthur H. WestonAbstract:In this study, the presence of GPRC6A receptors in rat mesenteric artery was investigated. In artery homogenates, GPRC6A mRNA was detected and Western blotting showed the presence of GPRC6A protein. Immunohistochemical studies revealed GPRC6A in both endothelial cells and myocytes. In whole vessel segments, the GPRC6A activators, 300 microM l-ornithine and 100 microM Al(3+), induced endothelium-dependent myocyte Hyperpolarizations sensitive to 10 microM TRAM-34, a blocker of intermediate conductance, Ca(2+)-sensitive K(+) channels (IK(Ca)). Activation of IK(Ca) with calindol (300 nM; a positive allosteric Ca(2+)-sensing receptor - CaR - modulator) was inhibited by 500 nM ouabain (inhibition of rat type 2 and type 3 Na(+)/K(+)-ATPases) but unaffected by 30 microM Ba(2+) (blockade of inwardly rectifying K(+) channels). Neither l-ornithine nor Al(3+) activated CaRs heterologously expressed in CHO or HEK293 cells. In the presence of 300 microM l-ornithine or 100 microM Al(3+), myocyte Hyperpolarizations to calindol were potentiated whereas this potentiation and Hyperpolarizations to l-ornithine were lost following incubation with an anti-GPRC6A antibody. It is concluded that GPRC6A receptors are present on mesenteric artery endothelial cells and myocytes and that their activation selectively opens IK(Ca) channels. This triggers a ouabain-sensitive myocyte Hyperpolarization suggesting a close functional relationship between GPRC6A, the IK(Ca) channel and type 2 and/or type 3 Na(+)/K(+)-ATPases.
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The expression and function of Ca(2+)-sensing receptors in rat mesenteric artery; comparative studies using a model of type II diabetes.
British Journal of Pharmacology, 2008Co-Authors: Arthur H. Weston, Erika Harno, Annie R. Geraghty, Donald T. Ward, Robert H. Dodd, Philippe Dauban, Martial Ruat, Mais Absi, Gillian EdwardsAbstract:BACKGROUND AND PURPOSE: The extracellular calcium-sensing receptor (CaR) in vascular endothelial cells activates endothelial intermediate-conductance, calcium-sensitive K(+) channels (IK(Ca)) indirectly leading to myocyte Hyperpolarization. We determined whether CaR expression and function was modified in a rat model of type II diabetes. EXPERIMENTAL APPROACH: Pressure myography, western blotting, sharp microelectrode and K(+)-selective electrode recordings were used to investigate the functional expression of the CaR and IK(Ca) in rat mesenteric arteries. KEY RESULTS: Myocyte Hyperpolarization to the CaR activator calindol was inhibited by Calhex 231. U46619-induced vessel contraction elevated the extracellular [K(+)] around the myocytes, and inhibition of this 'K(+) cloud' by iberiotoxin was needed to reveal calindol-induced vasodilatations. These were antagonized by Calhex 231 and significantly smaller in Zucker diabetic fatty rat (ZDF) vessels than in Zucker lean (ZL) controls. Myocyte Hyperpolarizations to calindol were also smaller in ZDF than in ZL arteries. In ZDF vessels, endothelial cell CaR protein expression was reduced; IK(Ca) expression was also diminished, but IK(Ca)-generated Hyperpolarizations mediated by 1-EBIO were unaffected. CONCLUSIONS AND IMPLICATIONS: The reduced CaR-mediated hyperpolarizing and vasodilator responses in ZDF arteries result from a decrease in CaR expression, rather than from a modification of IK(Ca) channels. Detection of CaR-mediated vasodilatation required the presence of iberiotoxin, suggesting a CaR contribution to vascular diameter, that is, inversely related to the degree of vasoconstriction. Compromise of the CaR pathway would favour the long-term development of a higher basal vascular tone and could contribute to the vascular complications associated with type II diabetes.
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Evidence in favor of a calcium-sensing receptor in arterial endothelial cells: studies with calindol and Calhex 231.
Circulation Research, 2005Co-Authors: Arthur H. Weston, Donald T. Ward, Robert H. Dodd, Philippe Dauban, Martial Ruat, Mais Absi, Jacqueline Ohanian, Christophe Petrel, Gillian EdwardsAbstract:Small increases in extracellular Ca2+ dilate isolated blood vessels. In the present study, the possibility that a vascular, extracellular Ca2+-sensing receptor (CaSR) could mediate these vasodilator actions was investigated. Novel ligands that interact with the CaSR were used in microelectrode recordings from rat isolated mesenteric and porcine coronary arteries. The major findings were that (1) raising extracellular Ca2+ or adding calindol, a CaSR agonist, produced concentration-dependent Hyperpolarizations of vascular myocytes, actions attenuated by Calhex 231, a negative allosteric modulator of CaSR. (2) Calindol-induced Hyperpolarizations were inhibited by the intermediate conductance, Ca2+-sensitive K+ (IKCa) channel inhibitors, TRAM-34, and TRAM-39. (3) The effects of calindol were not observed in the absence of endothelium. (4) CaSR mRNA and protein were present in rat mesenteric arteries and in porcine coronary artery endothelial cells. (5) CaSR and IKCa proteins were restricted to caveolin-poor membrane fractions. We conclude that activation of vascular endothelial CaSRs opens endothelial cell IKCa channels with subsequent myocyte Hyperpolarization. The endothelial cell CaSR may have a physiological role in the control of arterial blood pressure.
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Differential effects of prostacyclin and iloprost in the isolated carotid artery of the guinea-pig.
European Journal of Pharmacology, 2001Co-Authors: Catherine Corriu, Michel Félétou, Gillian Edwards, Arthur H. Weston, Paul M VanhoutteAbstract:The effects on membrane potential of prostacyclin and iloprost were compared in smooth muscle cells of the guinea pig carotid artery. Both prostacyclin and iloprost induced Hyperpolarization of the smooth muscle cells. In the presence of (3R)-3-(4-fluorophenyl-sulfonamido)-1,2,3,4-tetrahydro-9-carbazolepropanoic acid (Bay U3405), an antagonist of TP receptors, the response to iloprost was unaffected while that to prostacyclin was increased. Iloprost-induced Hyperpolarizations were abolished by glibenclamide while those to prostacyclin were either not affected, or converted to either depolarization or to rhythmic electrical activity. The latter effects of prostacyclin were abolished by Bay U3405. After removal of the endothelium, iloprost and prostacyclin produced Hyperpolarizations similar to those observed in control blood vessels. However, in the presence of glibenclamide, prostacyclin produced only depolarizations inhibited by Bay U3405. These results suggest that iloprost activates IP receptors and K(ATP) channels in smooth muscle. In contrast, prostacyclin produces additional endothelium-dependent and -independent effects via activation of TP receptors.