A role for endothelin ETA receptors in regulation of renal function in spontaneously hypertensive rats.

Abstract While there is evidence to suggest that endothelin-1 is involved in regulation of kidney function and blood pressure, the importance of endothelin ET A receptors in this area has not been clearly defined. The novel, non-peptide endothelin ET A receptor antagonist, BMS-182874, (5-(dimethylamino)- N -(3,4-dimethyl-5-isoxazolyl)-l-naphthalene sulfonamide) was used to examine effects of endothelin ET A receptor blockade on renal function in spontaneously hypertensive rats. Preliminary studies were conducted to determine an effective dose of BMS-182874. Infusion of BMS-182874 (10 μmol/kg/min, i.v.) inhibited effects of exogenous endothelin-1 on glomerular filtration rate, renal blood flow, and mean arterial pressure in Sprague-Dawley rats. Administration of BMS-182874 (10 μmol/kg/min, i.v.) to anesthetized, male, spontaneously hypertensive rats decreased renal blood flow by ~ 50% (1.2 ± 0.11 ml/min/100 g body weight) compared to vehicle (2.7 ± 0.23). There was no effect of BMS-182874 on glomerular filtration rate (0.5 ± 0.05 ml/min/100 g body weight; vehicle: 0.7 ± 0.06). Mean arterial pressure decreased significantly after BMS-182874 (123 ± 3.8 mm Hg; vehicle: 162 ± 4.8). Urine flow and renal vascular resistance were unchanged by BMS-182874. Endothelin ET A receptor density was increased ~ 50% in spontaneously hypertensive rat kidneys compared to normotensive kidneys, with no change in equilibrium dissociation constant. Endothelin ET B receptor density and equilibrium dissociation constant were similar in the two rat strains. Plasma immunoreactive endothelin was higher in hypertensive (5.9 ± 0.31 fmol/ml) than normotensive rats (2.8 ± 0.15). The results suggest endothelin ET A receptors may play a role in the regulation of renal function in this model of hypertension.