Cardiovascular protective role of a low-dose antihypertensive combination in obese Zucker rats.
OBJECTIVE
Obesity, non-insulin-dependent diabetes mellitus (NIDDM) and hypertension are leading causes associated with increased cardiovascular morbidity and mortality. In modern times, the combined first line antihypertensive therapy with at least two drugs with a different mechanism of action to achieve a better blood pressure control, is increasing in acceptance worldwide. The aim of the present study was to determine possible beneficial effects of the low-dose combination (LDC) of an angiotensin-converting enzyme (ACE) inhibitor, perindopril (PER), and the diuretic indapamide (IND), regarding myocardial and vessels protection in an animal model of hypertension, obesity and NIDDM, such as the obese Zucker rat (OZR), and control lean Zucker rats (LZR).


METHODS
Ten-week-old male OZR (fa/fa) and LZR (Fa/fa) were used in this study. OZR group (G1, n=8), OZR with LDC group (G2, n=8); LZR group (G3, n=8) and LZR with LDC group (G4, n=8). During 6 months, G2 and G4 received a daily dose of 1 mg/kg combination of 0.76 mg/kg PER + 0.24 mg/kg IND, (ratio of doses 0.32), by gavage, and G1 and G3 received an equal volume of vehicle throughout the experiment. In order to evaluate cardiac dimensions and left ventricular mass (LVM) transthoracic echocardiograms were performed, at baseline and at the end of the experiment. Urine and blood samples for biochemical determination were obtained. After 6 months of treatment all rats were sacrificed, hearts were harvested for light microscopy (LM), high-resolution light microscopy (HRLM), immunohistochemistry including monoclonal antibodies against transforming growth factor beta (TGFbeta1) and anti-collagen type I (COL I) and type III (COL III) and electron microscopy (EM) studies.


RESULTS
At the end of the study OZR treated with LDC presented: (1) lower blood pressure (128.9 +/- 4 versus 150.3 +/- 3.6 mmHg, P< 0.05); (2) smaller cardiac dimensions (P< 0.01); (3) lower LVM/100 g body weight (0.17 +/- 0.02 versus 0.30 +/- 0.05, P< 0.01); (4) higher fractional shortening (34.5 +/- 3.2 versus 23.3 +/- 5.9%, P< 0.01) than OZR untreated. Moreover, OZR that received LDC showed higher: (1) myocyte density (48 +/- 1.5 versus 20 +/- 2.5 myocytes/area, P< 0.01); (2) capillary density (30.5 +/- 3.1 versus 9.5 +/- 1.6 capillaries/area, P<0.01); (3) myofilament thickness (12.05 +/- 0.27 versus 9.83 +/- 0.39 nm, P<0.01); and lower amounts of: (1) TGFbeta1 in myocytes (P< 0.01), interstitium (P< 0.01) and vessel wall (P< 0.05); (2) COL I and COL III (P< 0.01), and COL I /COL III ratio (P< 0.01), compared with untreated OZR. Finally, OZR-treated with LDC showed not only unsubstantial modification in carbohydrate and lipid metabolism when compared with untreated OZR, but also an improvement in insulin/glucose ratio (P< 0.05).


CONCLUSIONS
These results suggest that LDC of PER + IND can control cardiovascular damage in OZR providing an additional help in the metabolic scenario likewise.
Toblli
Jorge E
JE
Laboratory of Experimental Medicine, Hospital Alemán, CONICET, Av. Pueyrredon 1640, Buenos Aires 1118, Argentina. jtobili@hospitalaleman.com
DeRosa
Graciela
G
Rivas
Carlos
C
Cao
Gabriel
G
Piorno
Pablo
P
Pagano
Patricia
P
Forcada
Pedro
P
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D001794:Blood Pressure / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000517:prevention & control*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D004232:Diuretics / Q000008:administration & dosage; D006321:Heart / Q000187:drug effects; D006973:Hypertension / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D007190:Indapamide / Q000008:administration & dosage; D008297:Male; D009206:Myocardium / Q000473:pathology; D009765:Obesity / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D020913:Perindopril / Q000008:administration & dosage; D051381:Rats; D011924:Rats, Zucker; D016277:Ventricular Function, Left / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D004232:Diuretics; D007190:Indapamide; D020913:Perindopril