DEVELOPMENT OF PRESSURE-OVERLOAD INDUCED CARDIAC-HYPERTROPHY IS UNAFFECTED BY LONG-TERM TREATMENT WITH LOSARTAN

Left ventricular hypertrophy with adequate wall thickness, preserved a dult phenotype and extracellular matrix may be useful in the preventio n of heart failure. Because activation of subtype 1 of angiotensin II (AT(1)) receptors is thought to be involved in the hypertrophic respon se of cardiomyocytes, we tested the potential of systemic AT(1) blocka de to modify the development of left ventricular hypertrophy due to pr essure overload. Sham-operated rats and rats with ascending aorta cons triction were treated with losartan (30 mg/kg/day) for 8 weeks. Left v entricular geometry, dynamics of isovolumic contractions, hydroxyproli ne concentration as well as myosin isozymes (marker of fetal phenotype ) were assessed. Rats with aortic constriction exhibited a marked incr ease in left ventricular weight and the diastolic pressure-volume rela tionship was shifted to smaller volumes. An enlarged ventricular press ure-volume area and increased (p < 0.05) peak values of +dP/dt(max) an d -dP/dt(max) demonstrated an enhanced overall ventricular performance . Signs of congestive heart failure were not apparent. In contrast, pa rameters of myocardial function (normalized length-stress area, +d sig ma/dt(max) and -d sigma/dt(max)) were depressed (p < 0.05), indicating an impaired myocardial contractility. The hydroxyproline concentratio n remained unaltered. However, the proportion of beta-myosin heavy cha ins (MHC) was increased (p < 0.05). Administration of losartan decreas ed (p < 0.05) blood pressure and body weight in sham operated and pres sure overloaded rats. By contrast, neither the concentric left ventric ular hypertrophy or depressed myocardial function nor the increased be ta-MHC expression were significantly altered. Thus, activation of AT(1 ) receptors appears not to be involved in the initial expression of th e fetal phenotype of pressure overloaded heart which may be responsibl e for the progressive functional deterioration of the hypertrophied ve ntricle.