Prostacyclin and EDHF

Abstract

In response to various neurohumoral substances endothelial cells release nitric oxide (NO), prostacyclin and produce hyperpolarization of the underlying vascular smooth muscle cells by a yet unknown mechanism attributed to an endothelium-derived hyperpolarizing factor (EDHF). NO and prostacyclin stimulate soluble guanylate and adenylate cyclase, respectively, in smooth muscle and can activate, depending on the vascular tissue studied, ATP-sensitive potassium (KATP) and large conductance calcium-activated potassium channels (BKCa). In isolated carotid arteries of the guinea-pig, prostacyclin and iloprost induced a concentration-dependent hyperpolarization of the smooth muscle cells. Iloprost activates IP receptors on the smooth muscle cells and produces hyperpolarization by opening KATP. Prostacyclin produces additional endothelium-dependent and -independent effects that are sensitive to Bay U4605 (an inhibitor of TP receptors). In this tissue, the release of prostacyclin by the endothelial cells contributes to the endothelium-dependent hyperpolarization evoked by acetylcholine. EDHF-mediated responses are observed, in the presence of the combination of inhibitors of NO synthase and cyclooxygenase, in isolated blood vessels from various species including human and eNOS knock-out mice. These responses are sensitive to the combination of the potassium channel blockers charybdotoxin plus apamin, but not to glibenclamide or to the combination of iberiotoxin plus apamin. This indicates that, in contrast to NO and prostacyclin, endothelium-dependent hyperpolarizations do not involve KATP or BKCa. The targets of charybdotoxin and apamin are most likely situated on the endothelial cells. Indeed, hyperpolarization of the latter appears to be required in order to observe endothelium-dependent hyperpolarization of the vascular smooth muscle cells. Whether or not endothelium-dependent hyperpolarization involves the release of an endothelial factor or could be attributed to an electrical coupling through myo-endothelial gap junctions, is a matter of debate. The elucidation of the mechanism underlying endothelium-dependent hyperpolarizations and the discovery of specific inhibitors of the phenomenon are a prerequisite for the understanding of the possible role of this alternative endothelial pathway in the control of vascular tone in health and disease.