CONTRIBUTION OF ENDOGENOUS ENDOTHELIN-1 TO THE MAINTENANCE OF VASCULAR TONE - ROLE OF NITRIC-OXIDE

Studies were designed to compare the effect of the nitric oxide inhibi tor, N-omega-nitro-L-arginine (L-NNA), and the novel ETB receptor anta gonist, RES-701-1, on changes in blood pressure and renal blood flow i nduced by exogenous endothelin receptor agonists and to determine the effect of L-NNA on basal hemodynamics in conscious, chronically instru mented rats. Infusion of low (nonpressor) doses of L-NNA or RES-701-1 potentiated systemic and renal vasoconstriction induced by bolus injec tions of endothelin-1 or sarafotoxin 6c. Bolus intravenous injection o r sustained infusion of L-NNA alone resulted in dose-dependent increas es in blood pressure and decreases in renal blood flow, similar to our recently reported results with RES-701-1. Vasoconstriction induced by inhibition of nitric oxide was attenuated by SE 209670, a mixed ETA/B receptor antagonist, but not by BQ123, an ETA receptor antagonist; ne ither antagonist altered basal hemodynamics. Collectively, the results indicate that: (1) endothelin plays an important role in the control of basal vascular tone by mediating both vasodilation and vasoconstric tion; (2) these effects are mediated by different ETB receptor subtype s in the rat, one located on the endothelium that mediates vasodilatio n via the nitric oxide pathway, the other located on the vascular smoo th muscle that mediates contraction.