Interactions between nitric oxide and endothelin in the regulation of vascular tone of human resistance vessels in vivo

Endothelial release of nitric oxide (NO) contributes to the regulation of v ascular tone by inducing vascular relaxation. In addition, NO may inhibit t he synthesis and hemodynamic effects of endothelin-1 (ET-1), a powerful end othelium-derived vasoconstrictor peptide that may stimulate NO production. However, whether NO and ET-1 physiologically interact to regulate vascular tone in humans has not been defined. In this study, the interactions betwee n the L-arginine NO pathway and the ET-1 system in the regulation of vascul ar tone in human forearm resistance vessels were examined in vivo. Vasomoto r response to the NO synthase inhibitor N-G-monomethyl-L-arginine (L-NMMA, 4 mu mol/min for 30 minutes) was measured during either saline infusion or blockade of ET-1 receptors, Endothelin-A (ETA) and endothelin-B (ETB) recep tor blockade was achieved by infusion of BQ-123 (100 nmol/min) and BQ-788 ( 50 nmol/min), respectively, separately and in combination. Drugs were infus ed into the brachial artery, and the forearm blood flow (FBF) response was measured by strain-gauge plethysmography. During saline infusion, L-NMMA ad ministration significantly decreased FBF (25%, P<0.01 versus baseline). Thi s effect was significantly blunted during nonselective blockade of ET-1 rec eptors (7% decrease in FBF, P=0.02 versus the effect of L-NMMA during salin e infusion). Selective ETA blockade did not modify the vasoconstrictor resp onse to L-NMMA (26% decrease in FBF, P=0.66 versus the effect of L-NMMA dur ing saline infusion), but selective ETB receptor antagonism caused signific ant diminution of the hemodynamic response to NO inhibition (8% decrease in FBF, P=0.04 versus the effect of L-NMMA during saline infusion), Thus ET-1 contributes to the regulation of vascular tone by stimulating NO activity. This effect is mediated through endothelial ETB receptors and may be relev ant in conditions associated with endothelial dysfunction.