Inhibition of endothelium-derived relaxing factor enhances endothelin-mediated vasoconstriction

Background. The endothelium possesses the ability to modulate vascular tone by the release of vasodilators and vasoconstrictors, among them endothelium-derived relaxing factor (EDRF) and endothelin (ET). Abnormalities in EDRF generation have been demonstrated in various cardiovascular pathophysiological states. Moreover, a twofold increase in plasma ET concentration was reported in these disease states. Recent in vitro studies have suggested the interaction between these two endothelium-derived substances, suggesting that imbalance between the two may contribute to alternation in vascular tone characteristic of these disease states. Thus, the hypothesis of this study was that inhibition of endogenous EDRF will enhance the vasoconstrictor response to a twofold increase in plasma ET concentrations. Methods and Results. Experiments were conducted in three groups of anesthetized dogs. In group 1, ET-1 was infused intravenously to double circulating ET concentrations. Group 2 received both ET and N^G-monomethyl L-arginine (L-NMMA), a competitive inhibitor of EDRF generation, and group 3 received a continuous infusion of L-NMMA alone. Twofold increase in plasma ET concentrations was characterized by an increase in systemic and renal vasoconstriction. The inhibition of EDRF markedly enhanced the vasoconstriction to ET specifically involving the systemic, pulmonary, coronary, and renal arterial circulations. Conclusions. The present study demonstrates that inhibition of endogenous EDRF augments the vasoconstrictor property of ET and supports a functional role for the balance between endothelium-derived vasodilating and vasoconstricting factors in the regulation of vascular tone.