Angiotensin-(1-7) prevents development of severe hypertension and end-organ damage in spontaneously hypertensive rats treated with L-NAME

We examined the influence of chronic treatment with ANG-( 1 - 7) on development of hypertension and end-organ damage in spontaneously hypertensive rats ( SHR) chronically treated with the nitric oxide synthesis inhibitor L-NAME ( SHR-L-NAME). L-NAME administered orally ( 80 mg/l) for 4 wk significantly elevated mean arterial pressure ( MAP) compared with SHR controls drinking regular water ( 269 +/- 10 vs. 196 +/- 6 mmHg). ANG-( 1 - 7) ( 24 mu g (.) kg(-1) (.) h(-1)) or captopril ( 300 mg/l) significantly attenuated the elevation in MAP due to L-NAME ( 213 +/- 7 and 228 +/- 8 mmHg, respectively), and ANG-( 1 7) + captopril completely reversed the L-NAME-dependent increase in MAP ( 193 +/- 5 mmHg). L-NAME-induced increases in urinary protein were significantly lower in ANG-( 1 - 7)- treated animals ( 226 +/- 6 vs. 145 +/- 12 mg/day). Captopril was more effective ( 96 +/- 12 mg/day), and there was no additional effect of captopril + ANG-( 1 - 7) ( 87 +/- 5 mg/day). The abnormal vascular responsiveness to endothelin-1, carbachol, and sodium nitroprusside in perfused mesenteric vascular bed of SHR-L-NAME was improved by ANG( 1 - 7) or captopril, with no additive effect of ANG-( 1 - 7) + captopril. In isolated perfused hearts, recovery of left ventricular function from 40 min of global ischemia was significantly better in ANG-( 1 - 7)- or captopril-treated SHR-L-NAME, with additive effects of combined treatment. The beneficial effects of ANG-( 1 - 7) on MAP and cardiac function were inhibited when indomethacin was administered with ANG-( 1 - 7), but indomethacin did not reverse the protective effects on proteinuria or vascular reactivity. The protective effects of the ANG( 1 - 7) analog AVE-0991 were qualitatively comparable to those of ANG-( 1 - 7) but were not improved over those of captopril alone. Thus, during reduced nitric oxide availability, ANG-( 1 - 7) attenuates development of severe hypertension and end-organ damage; prostaglandins participate in the MAP- lowering and cardioprotective effects of ANG-( 1 - 7); and additive effects of captopril + ANG-( 1 - 7) on MAP, but not proteinuria or endothelial function, suggest common, as well as different, mechanisms of action for the two treatments. Together, the results provide further evidence of a role for ANG-( 1 - 7) in protective effects of angiotensin-converting enzyme inhibition and suggest dissociation of factors influencing MAP and those influencing end-organ damage.