Endothelium-dependent hyperpolarization of vascular smooth muscle cells.
In response to various neurohumoral substances endothelial cells release nitric oxide (NO) and prostacyclin, and produce hyperpolarization of the underlying vascular smooth muscle cells, possibly by releasing another factor termed endothelium-derived hyperpolarizing factor (EDHF). NO and prostacyclin stimulate smooth muscle soluble guanylate and adenylate cyclase respectively and can activate, depending on the vascular tissue studied, ATP-sensitive potassium (KATP) and large conductance calcium-activated potassium channels (BKCa). Furthermore, NO directly activates BKCa. In contrast to NO and prostacyclin, EDHF-mediated responses are sensitive to the combination of charybdotoxin plus apamin but do not involve KATP or BKCa. As hyperpolarization of the endothelial cells is required to observe endothelium-dependent hyperpolarization, an electric coupling through myoendothelial gap junctions may explain the phenomenon. An alternative explanation is that the hyperpolarization of the endothelial cells causes an efflux of potassium that in turn activates the inwardly rectifying potassium conductance and the Na+/K+ pump of the smooth muscle cells. Therefore, in some vascular tissue K+ could be EDHF. Endothelial cells produce metabolites of the cytochrome P-450-monooxygenase that activate BKCa, and induce hyperpolarization of coronary arterial smooth muscle cells. Whether or not EDHF could be an epoxyeicosatrienoic acid is still a matter of debate. The elucidation of the mechanism underlying endothelium-dependent hyperpolarizations and the discovery of specific inhibitors of the phenomenon are prerequisite for the understanding of the physiologic role of this alternative endothelial pathway involved in the control of vascular tone in health and disease.
Département de Diabétologie, Institut de Recherches Servier, 11 rue des Moulineaux, 92150 Suresnes, France.
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Vanhoutte
D000818:Animals; D001685:Biological Factors / Q000378:metabolism* / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D011464:Epoprostenol / Q000494:pharmacology*; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology*; D009569:Nitric Oxide / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects
D001685:Biological Factors; D015221:Potassium Channels; C067410:endothelium-dependent hyperpolarization factor; D009569:Nitric Oxide; D011464:Epoprostenol