DIFFERENTIAL BLOCKADE OF THE RENAL VASOCONSTRICTOR AND DIURETIC RESPONSES TO ENDOTHELIN-1 BY ENDOTHELIN ANTAGONIST

1. The effect of cyclo(D-Trp-D-Asp-Pro-D-Val-Leu) (or BQ123), a selective ET(A) receptor antagonist, on the vasoconstrictor and diuretic responses elicited by endothelin-1 (ET-1) was examined in conscious sheep with chronic indwelling renal arterial cannulae. 2. Using low dose close renal arterial infusion, ET-1 has potent effects on the kidney causing a marked decrease in effective renal plasma flow and an increase in urine output and free water clearance in the normally hydrated animal. 3. The vasoconstrictor response to renal arterial infusion of ET-1 at 5 mu g/h was blunted by renal arterial infusion of the ET(A) receptor selective antagonist, BQ123 (400 mu g/h). 4. In contrast, the effect of ET-1 on urine production and free water clearance was not affected by this dose of BQ123. 5. The differential effect of BQ123 on renal blood flow and urine production suggests that these effects of endothelin on the kidney are mediated through different receptor mechanisms.