Properties and Mechanisms of Production and Action of Endothelium-Derived Relaxing Factor

A brief review is given of the vasodilators that require an intact vascular endothelium to exert their relaxing effect. Then some major issues of the phenomenon of endothelium-dependent smooth muscle relaxation are discussed in more detail: (a) The chemical structure of the endothelium-derived relaxing factor (EDRF), which mediates this type of vasodilation, is still unclear. There is agreement that EDRF is chemically unstable, but determinations of its biological half-life have yielded discrepant values (6–50 s). Recent evidence suggests that oxygen and/or activated oxygen species accelerate the evanescence of the factor, (b) The biochemical mechanisms involved in the production of EDRF are still largely unknown. Both stimulators of phospholipase A2 and inhibitors of lysolecithin acyl-transferase were found to induce EDRF-mediated relaxation, while several phospholipase inhibitors block these relaxations. These findings suggest that cleavage of phospholipids (and formation of free fatty acids and lysophos-phatides) play an important role in EDRF production. (c) EDRF-mediated relaxations are associated with increased levels of cyclic GMP in vascular smooth muscle cells. Endothelial cells were found to produce a factor that directly stimulates the enzymatic activity of soluble guanylate cyclase. This stimulating factor is likely to be identical with EDRF. (d) The significance of the endothelium-dependent relaxing mechanism in resistance vessels is still largely unclear. In the blood-perfused hind limb of the rabbit, two irreversible inhibitors of endothelium-dependent vasodilation (gossypol and p-bromophenacyl-bromide) blocked the vasodilation induced by the endothelium-dependent agent acetylcholine, but not the response to the endothelium-independent vasodilator prostaglandin E1. This suggests that the EDRF mechanism is also active in the microcirculation. (e)The relevance of endothelium for the regulation of human coronary artery tone has also been investigated. In coronary arteries from recipient hearts of transplant patients, the endothelium could mediate complete vasodilation. Interestingly, acetylcholine proved little effective as a stimulator of the EDRF mechanism in this tissue and generally produced contractions, despite a histologically and functionally intact endothelium. Severe atherosclerosis attenuated endothelium-dependent relaxations in response to different agents.