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

Vascular Biology Center, Departments of Surgery, Physiology, and Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia 30912-2500

Renal clearance studies were conducted to determine the role of ET_B receptors in the renal response to big endothelin-1 (big ET-1). Two series of experiments were conducted on Inactin-anesthetized rats to contrast acute pharmacological blockade of ET_B receptors vs. genetic ET_B receptor deficiency. In the first series, Sprague-Dawley rats were given either ET_B-selective antagonist, 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 urine flow rate (0.5 ± 0.1 vs. 1.3 ± 0.2 µl/min, P < 0.05) without any effect on glomerular filtration rate (GFR) or effective renal plasma flow (ERPF). Big ET-1 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-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 ET_B blockade. Another series of experiments examined the response to big ET-1 in rats lacking functional renal ET_B receptors, known as spotting lethal (sl) rats. Surprisingly, rats heterozygous (sl/+) for ET_B receptor deficiency had a significantly higher baseline 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 significant change in MAP in either group. Urine flow, GFR, and ERPF were significantly decreased in both groups, although these changes were much larger in sl/sl rats. These experiments indicate that the ET_B receptor plays an important role in limiting the renal hemodynamic response to big ET-1. Furthermore, the diuretic actions of big ET-1 require a functional ET_B receptor.

endothelin; blood pressure; renal hemodynamics; water-electrolyte balance

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