Contrasting pharmacological ETB receptor blockade with genetic ETB deficiency in renal responses to big ET-1

Renal clearance studies were conducted to determine the role of ETB recepto rs in the renal response to big endothelin-1 (big ET-1). Two series of expe riments were conducted on Inactin-anesthetized rats to contrast acute pharm acological blockade of ETB receptors vs. genetic ETB receptor deficiency. I n the first series, Sprague-Dawley rats were given either ETB-selective ant agonist, A-192621, or vehicle (0.9% NaCl) prior to infusion of big ET-1 (10 pmol.kg(-1).min(-1)) for 60 min. A-192621 significantly increased baseline mean arterial pressure (MAP; 102 +/- 4 vs. 141 +/- 6 mmHg, P < 0.05) and u rine flow rate (0.5 <plus/minus> 0.1 vs. 1.3 +/- 0.2 mul/ min, P < 0.05) wi thout any effect on glomerular filtration rate (GFR) or effective renal pla sma flow (ERPF). Big ET-1 significantly increased MAP in both groups but to a higher level in rats given antagonist (120 <plus/minus> 6 vs. 169 +/- 6 mmHg, P, 0.05). Big ET-1 increased urine flow in control rats but decreased in rats given antagonist. GFR and ERPF were decreased in rats given big ET -1, an effect that was exaggerated by ETB blockade. Another series of exper iments examined the response to big ET-1 in rats lacking functional renal E TB receptors, known as spotting lethal (sl) rats. Surprisingly, rats hetero zygous (sl/+) for ETB receptor deficiency had a significantly higher baseli ne MAP compared with homozygous (sl/sl) rats (134 +/- 6 vs. 112 +/- 7 mmHg, P < 0.05), although other variables were similar. Big ET-1 produced no sig nificant change in MAP in either group. Urine flow, GFR, and ERPF were sign ificantly decreased in both groups, although these changes were much larger in sl/sl rats. These experiments indicate that the ETB receptor plays an i mportant role in limiting the renal hemodynamic response to big ET-1. Furth ermore, the diuretic actions of big ET-1 require a functional ETB receptor.