title: Angiotensin-(1-7) prevents development of severe hypertension and end-organ damage in spontaneously hypertensive rats treated with L-NAME.
abstract: 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 microg x kg(-1) x 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.
authors.affiliation: Dept. of Pharmacology and Toxicology, Faculty of Medicine, Kuwait Univ., PO Box 24923, Safat 13110, Kuwait. ibenter@hsc.edu.kw
authors.forename: Ibrahim F
authors.initials: IF
authors.lastname: Benter
authors.forename: Mariam H M
authors.initials: MH
authors.lastname: Yousif
authors.forename: J T
authors.initials: JT
authors.lastname: Anim
authors.forename: C
authors.initials: C
authors.lastname: Cojocel
authors.forename: D I
authors.initials: DI
authors.lastname: Diz
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004231:Diuresis / Q000187:drug effects; D004791:Enzyme Inhibitors; D006321:Heart / Q000503:physiopathology; D006973:Hypertension / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D007668:Kidney / Q000473:pathology; D008297:Male; D017202:Myocardial Ischemia / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester; D010446:Peptide Fragments / Q000494:pharmacology*; D011507:Proteinuria / Q000209:etiology / Q000503:physiopathology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D020127:Recovery of Function; D015427:Reperfusion Injury / Q000503:physiopathology; D012720:Severity of Illness Index; D014666:Vasomotor System / Q000503:physiopathology
chemical_list: D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D000803:Angiotensin I; C118790:angiotensin I (1-7); D019331:NG-Nitroarginine Methyl Ester