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Departments of 1Pharmacology and Toxicology and 2Pathology, Faculty of Medicine, Kuwait University, Safat 13110, Kuwait; and 3The Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina
Submitted 13 June 2005 ; accepted in final form 5 August 2005
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 µg·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.
angiotensin II; captopril; indomethacin; heart; AVE-0991
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