ENDOTHELIN MODULATES THE PRESSOR ACTIONS OF ACUTE SYSTEMIC NITRIC-OXIDE BLOCKADE

Acute nitric oxide blockade not only potentiates the vasoconstrictor actions of endothelin but also enhances the synthesis and release of endothelin. To investigate whether the vasoconstrictor actions of acute nitric oxide blockade are modulated by endothelin, studies were conducted in the conscious, chronically catheterized rat. Renal function was measured before and during acute nitric oxide blockade with nitro-L-arginine methylester (L-NAME), L-NAME + endothelin blockade with the endothelin-converting enzyme inhibitor phosphoramidon, or L-NAME + the nonpeptide ET(A) and ET(B) receptor antagonist Bosentan. The increases in blood pressure and RVR seen with acute nitric oxide blockade were attenuated by either method of concomitant endothelin blockade. The falls in RPF and GFR were not blunted because endothelin blockade produced parallel reductions of both presser and renal vasoconstrictor responses to acute nitric oxide blockade. Endothelin blockade alone with either endothelin-converting enzyme inhibitor or the nonpeptide ET(A) and ET(B) receptor antagonist had little effect on blood pressure, RPF, or RVR, but increases in urinary sodium excretion and a small decline in GFR were observed with Bosentan. These observations indicate that endogenous endothelin exerts a tonic antinatriuretic action in the normal conscious rat and partially mediates the presser actions of acute nitric oxide blockade.