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1.
Cardiovasc Res ; 46(1): 102-10, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10727658

ABSTRACT

OBJECTIVE: We investigated the effect of chronic treatment with the new Na(+)/H(+)-exchange inhibitor, cariporide, on cardiac function and remodelling 6 weeks after myocardial infarction (MI) in rats. METHODS: Treatment with cariporide was commenced either 1 week pre or 30 min, 3 h, 24 h or 7 days after ligation of the left ventricular artery and was continued until haemodynamic parameters were obtained 6 weeks after MI in conscious rats. RESULTS: Compared to sham animals, untreated MI-controls developed pronounced heart failure after 6 weeks. Basal left ventricular end-diastolic pressure (in mmHg) was reduced in the groups in which cariporide was started 1 week pre (16.0+/-1.7) or 30 min (12.5+/-1.1), 3 h (11.8+/-1.0) and 24 h (13.0+/-2.5) after MI compared to untreated MI-controls (22. 4+/-1.5; P<0.01). Basal myocardial contractility (in 1000 mmHg/s) was only increased when treatment was initiated after 30 min (9. 0+/-0.7), 3 h (8.5+/-0.3) and 24 h (8.0+/-0.7) compared to untreated MI-controls (5.8+/-0.7; P<0.05-0.01). Infarct size (in % of left ventricular circumference) was 40.0+/-2.1 in MI-controls and was decreased when treatment was begun after 30 min (32.6+/-2.7) or 3 h (32.4+/-2.3) (P<0.05). In animals, in which cariporide was started 3 h after induction of MI, heart weight/body weight ratio was significantly decreased, indicating reduced cardiac hypertrophy. When treatment started 7 days after MI, cariporide did not exert any beneficial actions on structural and functional cardiac parameters. CONCLUSION: Our results show for the first time that chronic treatment with the Na(+)/H(+)-exchange inhibitor cariporide engendered marked cardioprotective effects when commenced before and up to 24 h after MI. The optimal time for the start of treatment was between 30 min and 3 h post MI.


Subject(s)
Guanidines/therapeutic use , Heart Failure/prevention & control , Myocardial Infarction/drug therapy , Sodium-Hydrogen Exchangers/antagonists & inhibitors , Sulfones/therapeutic use , Analysis of Variance , Animals , Heart Failure/etiology , Male , Myocardial Contraction/drug effects , Myocardial Infarction/complications , Random Allocation , Rats , Rats, Wistar , Ventricular Pressure/drug effects , Ventricular Remodeling/drug effects
2.
Eur J Pharmacol ; 385(2-3): 171-9, 1999 Dec 03.
Article in English | MEDLINE | ID: mdl-10607873

ABSTRACT

Cardiac remodeling after myocardial infarction is associated with impaired ventricular function and heart failure and has important implications for survival. The purpose of the present study was to assess the effects of chronic treatment with a novel angiotensin AT(1) receptor antagonist 2-butyl-4-(methylthio-)-1-[[2'[[[(propylamino)carbonyl]amino]sulfonyl ](1,1'-biphenyl)-4-yl]methyl]-1H-imidazole-5-carboxylate (HR720), on cardiac remodeling and left ventricular dysfunction in a rat model of large myocardial infarction. Rats were subjected to permanent ligation of the left coronary artery and were treated for six weeks with placebo or HR720 (3 mg/kg/day) initiated 24 h after surgery. Sham-operated rats served as normal controls. Mean arterial blood pressure, the maximum rate of rise of the left ventricular systolic pressure (dP/dt(max)), left ventricular end-diastolic pressure, left ventricular inner diameter and circumference, septal thickness, left ventricular collagen content and heart weight were measured at the end of the treatment. HR720 treatment versus placebo attenuated the cardiac hypertrophy (heart weight/body weight: 2.88+/-0.08 mg/g vs. 3.16+/-0.09 mg/g, P<0.05), reduced interstitial collagen content (3. 47+/-0.28% vs. 5.25+/-0.45%, P<0.01), limited infarct size (33.0+/-3. 0% vs. 41.5+/-2.3%, P<0.05), decreased left ventricular end-diastolic pressure (13.7+/-2.2 vs. 21.4+/-1.6 mm Hg, P<0.01) and improved dP/dt(max) (9000+/-430 vs. 6000+/-840 mm Hg/s, P<0.05). The present results demonstrate that chronic treatment with the angiotensin AT(1) receptor antagonist HR720 can limit infarct size, partially prevent cardiac hypertrophic remodeling and improve left ventricular function in rats with myocardial infarction.


Subject(s)
Angiotensin Receptor Antagonists , Biphenyl Compounds/pharmacology , Imidazoles/pharmacology , Myocardial Infarction/prevention & control , Animals , Blood Pressure/drug effects , Body Weight/drug effects , Cardiomegaly/prevention & control , Heart Rate/drug effects , Heart Ventricles/drug effects , Heart Ventricles/pathology , Heart Ventricles/physiopathology , Hemodynamics/drug effects , Male , Myocardial Contraction/drug effects , Myocardial Infarction/pathology , Myocardial Infarction/physiopathology , Rats , Rats, Wistar , Receptor, Angiotensin, Type 1 , Receptor, Angiotensin, Type 2 , Ventricular Function, Left/drug effects
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