Platelets, endothelium-derived vasoactive factors, and coronary disease.

Abstract

Endothelial cells can release both relaxing and contracting substances. The former include prostacyclin, endothelium-derived relaxing factor (EDRF, which most likely is nitric oxide, or a nitrosoderivative releasing nitric oxide, derived from 1-arginine), and endothelium-derived hyperpolarizing factor (EDHF, which possibly is a labile metabolite of arachidonic acid formed through the P-450 pathway). Possible endothelium-derived contracting factors (EDCF) include superoxide anions, thrombox-ane A2, and the peptide endothelin. Endothelium-derived relaxing factor causes relaxation of vascular smooth muscle by activation of the soluble form of guanylate cyclase, which leads to an accumulation of cyclic GMP; it also reduces platelet adhesion and aggregation. The latter effect is synergistic with the inhibition evoked by prostacyclin. The release of endothelium-derived relaxing factor and prostacyclin plays a key role in the protective role of the endothelium against vasospasm and unwanted coagulation of blood. Indeed, thrombin and aggregating platelets are potent stimuli for the release of endothelium-derived relaxing factor. The platelet products responsible are the adenine nucleotides, ADP and ATP, which activate P2-purinegic receptors on the endothelial cells, and 5-hydroxytryptamine (serotonin) which stimulates 5HT1-like serotonergic receptors. The response to serotonin, but not to the adenine nucleotides, is mediated by a pertussis toxin-sensitive mechanism. When endothelial cells regenerate, or are cultured, they selectively lose the pertussis toxin-sensitive mechanism of release, which results in a marked decrease in sensitivity to exogenous and platelet-released serotonin. As a consequence, the endothelial cells exhibit a considerably reduced response to aggregating platelets. This phenomemon, which can be exacerbated by hypercholesterolemia, favors ongoing platelet aggregation and vasospasm, and constitutes a first step toward atheroscerosis.