Role of ETB Receptors in the Renal Response to Big Endothelin-1: Contrasting Pharmacologic ETB Receptor Blockade with Genetic ETB Deficiency
Renal clearance studies were conducted to determine the role of ETB receptors in the renal response to the endothelin-1 precursor, big endothelin-1 (Big ET). Two series of experiments were conducted on Inactin anesthetized rats to contrast acute pharmacologic blockade of ETB receptors versus genetic ETB receptor deficiency. In the first series, separate groups of normal SD rats were given the ETB-selective antagonist, A-192621, or vehicle (0.9% NaCl) prior to infusion of Big ET (20 pmol/kg/min) for a 60 min period (n=9 in each group). ETB receptor blockade alone significantly increased baseline mean arterial pressure (MAP; 102±4 vs. 141±6 mmHg, P<0.05) and urine flow rate (UV; 0.5±0.1 vs. 1.3±0.2, P<0.05) without any effect on GFR or renal plasma flow (RPF). Big ET significantly increased MAP in both groups but to a higher level in rats given antagonist (120±6 vs. 169±6 mmHg, P<0.05). Big ET increased UV in control rats but decreased in rats given antagonist. GFR and RPF were decreased in rats given Big ET, an effect which was exaggerated by ETB blockade. An additional series of experiments examined the response to Big ET in rats lacking functional renal ETB receptors. Spotting lethal (sl) rats have a naturally occurring ETB deficiency but can be ”rescued“ from fatal intestinal aganglionosis by directed transgenic expression of ETB receptors. Rats heterozygous (sl/+) or homozygous (sl/sl) for ETB receptor deficiency, were given Big ET as in the first series (n=5 in each group). Surprisingly, baseline MAP was significantly higher in sl/+ compared to sl/sl rats (147±3 vs. 111±11 mmHg, P<0.05) although other variables were similar. Big ET had no significant effect on MAP in either group although there was a tendency for MAP to increase in sl/+ rats (7±2%, P=0.052). UV was significantly decreased in both groups although the change was much larger in sl/sl rats. GFR and RPF were significantly decreased in sl/sl, but not sl/+ rats. Both series of experiments indicate that the ETB receptor plays an important role in limiting the renal hemodynamic response to Big ET. Furthermore, the diuretic actions of Big ET require a functional ETB receptor.