ANTAGONISM OF RENAL AND SYSTEMIC RESPONSES TO ENDOTHELIN-1 INFUSION WITH PD-145065

The antagonism by PD 145065 (Ac-D-Bhg-L-Leu-L-Asp-L-Ile-L-Ile-L-Trp; D-Bhg = 5H-dibenzyl[a,d]cycloheptene-10,11-dihydroglycine), a non-selective endothelin ET(A) and ET(B) receptor antagonist, of the presser and renal haemodynamic responses to an infusion of endothelin-1 was investigated in the anaesthetised rat. Infusion of endothelin-1 at 2 or 4 pmol/min/rat for 2 h produced a significant increase in mean arterial blood pressure and renal vascular resistance. Glomerular filtration rate was reduced by both infusion rates of endothelin-1 (-34% for the lower rate and -72% for the higher rate), but only the high rate significantly reduced renal blood flow (-64%). These effects of endothelin-l were completely blocked by infusion of PD 145065 (0.05 mg/min/rat), demonstrating the efficacy of this antagonist in preventing the actions of endothelin-1 in vivo. These results lend support to an involvement of endothelin ET(B) receptors in the renal effects of endothelin-1.