Angiotensin-converting enzyme inhibition and angiogenesis in myocardium of obese Zucker rats.
BACKGROUND
Obesity, hypertension, and non-insulin-dependent diabetes mellitus (NIDDM) are associated with microvascular rarefaction in the myocardium and this contributes to increase cardiovascular morbidity and mortality. At present, controversial data exist in medical literature regarding the specific role of angiotensin-converting enzyme (ACE) inhibitors concerning angiogenesis in different tissues. The present study was designed to determine the possible beneficial effects of an ACE inhibitor perindopril on myocardial angiogenesis in an animal model of obesity, hypertension, and NIDDM, such as the obese Zucker rat (OZR) and control lean Zucker rats (LZR).


RESULTS
Ten-week-old male OZR (fa/fa) and LZR (Fa/fa) were used in this study: OZR group (G1, n = 10), OZR with perindopril group (G2, n = 10); LZR group (G3, n = 10). For 6 months, G2 received a daily dose of 3 mg/kg of perindopril, by gavage, and G1 and G3 received an equal volume of vehicle throughout the experiment. After 6 months of treatment, all rats were killed, hearts were harvested for pathology studies, including immunohistochemistry, using monoclonal antibodies against rat endothelial cell (RECA-1) and endothelial nitric oxide synthase. At the end of the study, OZR treated with perindopril presented: 1) lower blood pressure (BP) (127 +/- 3.2 v 152.4 +/- 3 mm Hg, P <.01) and 2) lower heart weight/100 g body weight (0.22 +/- 0.02 v 0.36 +/- 0.04 g, P <.01) than OZR untreated. Moreover, OZR that received perindopril showed higher: 1) myocyte density (2044 +/- 67 v 847 +/- 91 myocytes/mm(2), P <.01) and 2) capillary density (1348 +/- 118 v 436 +/- 78 capillaries/mm(2), P <.01); higher amount of: 1) vascular endothelial growth factor (VEGF) in the myocardium (P <.01) and higher percentage of capillaries with positive immunostaining for eNOS (P <.01), compared with untreated OZR. There was a correlation between both the amount of VEGF in myocardium and the number of capillaries (r = 0.88; P <.01) and VEGF and eNOS expression in myocardial capillaries (r = 0.93; P <.01) in OZR treated with perindopril. Finally, OZR that received P showed an improvement in insulin/glucose ratio (P <.01) when compared with untreated OZR.


CONCLUSIONS
These results suggest that ACE inhibition by perindopril improves myocardial angiogenesis in this animal model of human metabolic syndrome. The pathway that involves bradykinin, eNOS, and VEGF could be involved in this effect; however, because no additional antihypertensive treatment group was included in our study, the BP-lowering effect cannot be excluded.
Toblli
Jorge E
JE
Laboratory of Experimental Medicine, Hospital Alemán, CONICET, Av. Pueyrredon 1640, Buenos Aires 1118, Argentina. jtoblli@hospitalaleman.com
Cao
Gabriel
G
DeRosa
Graciela
G
Di Gennaro
Federico
F
Forcada
Pedro
P
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001786:Blood Glucose; D001794:Blood Pressure; D003326:Coronary Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D008297:Male; D017566:Microvascular Angina / Q000188:drug therapy* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism; D009929:Organ Size; D020913:Perindopril / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011924:Rats, Zucker
D000806:Angiotensin-Converting Enzyme Inhibitors; D001786:Blood Glucose; D020913:Perindopril