Inhibition of vascular smooth muscle relaxation by LY83583

The ability of LY83583 to antagonize vascular smooth muscle relaxation elicited by a number of vasodilators was examined in rings of rat aorta. LY83583 (0.3-10 microM) inhibited relaxant responses to acetylcholine, calimycin (A23187), adenosine triphosphate (ATP) and sodium nitroprusside, whereas responses to atriopeptin III an activator of particulate guanylate cyclase, and papaverine were unaffected. For acetylcholine and calimycin the major effect of LY83583 (0.3-10 microM) was to reduce the maximal response without appreciably altering the EC50 values whereas for ATP the EC50 values were markedly increased by low concentrations of LY83583 (0.3-1 microM) with depression of maximal responses occurring at higher concentrations (10 microM) of the antagonist. In contrast LY83583 produced nonparallel rightward shifts of the curve for sodium nitroprusside without altering the maximal response. In addition, LY83583 (10 microM) reduced basal levels of cyclic GMP and prevented acetylcholine and sodium nitroprusside-induced elevations of cyclic GMP, in parallel with reductions in the relaxant responses. In the presence of LY83583 (10 microM) higher concentrations of sodium nitroprusside restored both the relaxant response and the elevation of cyclic GMP. The results of this study show that LY83583 antagonises only those vasodilators which are thought to act via stimulation of soluble guanylate cyclase. The nonsurmountable inhibition of relaxation to acetylcholine, calimycin and ATP probably reflects a limited maximal capacity of the endothelium to release EDRF in response to these agents.