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, BMS 182874 (BMS), affects systolic blood pressure (SBP), renal function and survival in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSPs). Eight-week-old male and female SHRSPs were given a high-salt diet (4% NaCl) (n = 6/group). The treatment groups (n = 6/group), also on a high-salt diet, were administered BMS (40 mg/kg/day) which was mixed in the food. In untreated SHRSPs, mean survival was 136 days (range 96-194 days) in males, and 98 days (range 74-112 days) in females. Treatment with BMS 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. SBP increased to approximately 240 mmHg in all groups. BMS had no effect on SBP in females and a small, but significant (p < 0.05), SBP-lowering effect in males. In control rats, severe renal disease was evident at 16 weeks (proteinuria, 161 +/- 1.3 mg/day). In the treated group, development of proteinuria was significantly delayed (13 +/- 0.5 mg/day at 16 weeks). In conclusion ETA-receptor antagonism prolongs survival and improves renal status, but has little effect on the progression of hypertension. These data suggest that interruption of the endothelin (ET) system by blockade of ETA-receptors may achieve protection from target-organ damage despite lack of a reduction in blood pressure.
Touyz
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MRC Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, Quebec, Canada. touyzr@ircm.qc.ca
Turgeon
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Schiffrin
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D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001794:Blood Pressure; D001835:Body Weight; D003619:Dansyl Compounds / Q000627:therapeutic use*; D065128:Endothelin Receptor Antagonists; D005260:Female; D006973:Hypertension / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D044022:Receptor, Endothelin A; D020521:Stroke / Q000517:prevention & control*
D000959:Antihypertensive Agents; D003619:Dansyl Compounds; D065128:Endothelin Receptor Antagonists; D044022:Receptor, Endothelin A; C085754:5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide