Role of ET B Receptors in the Renal Response to Big Endothelin-1: Contrasting Pharmacologic ET B Receptor Blockade with Genetic ET B Deficiency

Abstract

Listen

Translate article

P98 Renal clearance studies were conducted to determine the role of ET B 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 ET B receptors versus genetic ET B receptor deficiency. In the first series, separate groups of normal SD rats were given the ET B -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). ET B 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 ET B blockade. An additional series of experiments examined the response to Big ET in rats lacking functional renal ET B receptors. Spotting lethal (sl) rats have a naturally occurring ET B deficiency but can be ”rescued“ from fatal intestinal aganglionosis by directed transgenic expression of ET B receptors. Rats heterozygous (sl/+) or homozygous (sl/sl) for ET B 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 ET B receptor plays an important role in limiting the renal hemodynamic response to Big ET. Furthermore, the diuretic actions of Big ET require a functional ET B receptor.