Angiotensin-(1-7) prevents diabetes-induced cardiovascular dysfunction.
The aim of this study was to test the hypothesis that treatment with angiotensin-(1-7) [ANG-(1-7)] or ANG-(1-7) nonpeptide analog AVE-0991 can produce protection against diabetes-induced cardiovascular dysfunction. We examined the influence of chronic treatment (4 wk) with ANG-(1-7) (576 microg.kg(-1).day(-1) ip) or AVE-0991 (576 microg.kg(-1).day(-1) ip) on proteinuria, vascular responsiveness of isolated carotid and renal artery ring segments and mesenteric bed to vasoactive agonists, and cardiac recovery from ischemia-reperfusion in streptozotocin-treated rats (diabetes). Animals were killed 4 wk after induction of diabetes and/or treatment with ANG-(1-7) or AVE-0991. There was a significant increase in urine protein (231 +/- 2 mg/24 h) in diabetic animals compared with controls (88 +/- 6 mg/24 h). Treatment of diabetic animals with ANG-(1-7) or AVE-0991 resulted in a significant reduction in urine protein compared with vehicle-treated diabetic animals (183 +/- 16 and 149 +/- 15 mg/24 h, respectively). Treatment with ANG-(1-7) or AVE-0991 also prevented the diabetes-induced abnormal vascular responsiveness to norepinephrine, endothelin-1, angiotensin II, carbachol, and histamine in the perfused mesenteric bed and isolated carotid and renal arteries. In isolated perfused hearts, recovery of left ventricular function from 40 min of global ischemia was significantly better in ANG-(1-7)- or AVE-0991-treated animals. These results suggest that activation of ANG-(1-7)-mediated signal transduction could be an important therapeutic strategy to reduce cardiovascular events in diabetic patients.
Benter
Ibrahim F
IF
Dept. of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, P. O. Box 24923, Safat 13110, Kuwait. ibenter@hsc.edu.kw
Yousif
Mariam H M
MH
Cojocel
Constantin
C
Al-Maghrebi
May
M
Diz
Debra I
DI
D000803:Angiotensin I / Q000008:administration & dosage*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000008:administration & dosage; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D008297:Male; D010446:Peptide Fragments / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control*
D002316:Cardiotonic Agents; D010446:Peptide Fragments; D013311:Streptozocin; D000803:Angiotensin I; C118790:angiotensin I (1-7)