Endothelin-A-receptor blockade improves renal function and doubles the lifespan of stroke-prone spontaneously hypertensive rats

This study assessed whether the orally active endotheLin-A- (ETA) receptor antagonist, EMS 182874 (BMS), affects systolic blood pressure (SBP), renal function and survival in salt-loaded stroke-prone spontaneously hypertensiv e rats (SHRSPs). Eight-week-old male and female SHRSPs were given a high-sa lt diet (4% NaCl) (n = 6/group). The treatment groups (n = 6/group), also o n a high-salt diet, were administered EMS (40 mg/kg/day) which was mixed in the food. In untreated SHRSPs, mean survival was 136 days (range 96-194 da ys) in males, and 98 days (range 74-112 days) in females. Treatment with EM S increased survival to 223 days in males (range 129-280 days, p < 0.01 vs controls) and 156 days (range 124-180, p < 0.05 vs controls) in females. SE P increased to similar to 240 mmHg in all groups. EMS had no effect on SEP in females and a small, but significant (p < 0.05), SEP-lowering effect in males. In control rats, severe renal disease was evident at 16 weeks (prote inuria, 161 +/- 1.3 mg/day). In the treated group, development of proteinur ia was significantly delayed (13 +/- 0.5 mg/day at 16 weeks). In conclusion ETA-receptor antagonism prolongs survival and improves renal status, but h as little effect on the progression of hypertension. These data suggest tha t interruption of the endothelin (ET) system by blockade of ETA-receptors m ay achieve protection from target-organ damage despite lack of a reduction in blood pressure.