Endothelin-1-induced constriction inhibits nitric-oxide-mediated dilation in isolated rat resistance arteries

Vascular endothelial cells release dilatory compounds like nitric oxide and prostacyclin, as well as contractile factors like endothelin-l (ET-1). We investigated the interaction of ET-I with nitric-oxide-mediated dilation in cannulated pressurized (75 mm Hg) arterioles from rat cremaster muscle (180 +/- 3 mu m). Arterioles constricted spontaneously to 101 +/- 3 mu m, while ET-1 (0.4 mM) increased constriction to 78 +/- 3 mu m. Acetylcholine, an endothelium-dependent nitric-oxide-mediated vasodilator induced a dose-dependent dilation during spontaneous tone. After addition of ET-1, the response to acetylcholine was significantly impaired. Nitroprusside, an endothelium-independent nitric oxide donor, induced a dose-dependent dilation that was almost completely inhibited by ET-1. In contrast, 8-Br-cGMP-induced dilation was unaffected. Thus, ET-I appears to inhibit nitric-oxide-mediated dilation at the level of cGMP formation or degradation. The effect of ET-1 appears to be specific for nitric oxide as responses to a prostacyclin analogue were impaired at low doses only. The inhibitory effect of ET-1 on nitric-oxide-mediated dilation could be mimicked with high potassium (65 +/- 6 mu m), but not with phenylephrine (74 +/- 8 mu m)induced constriction. These data show a direct inhibitory effect of ET-1 on nitric-oxide-mediated dilation in isolated skeletal muscle arterioles.