Chronic vasopressin V1A but not V2 receptor antagonism prevents heart failure in chronically infarcted rats

Abstract Evidence is increasing that therapeutic modulation of neurohormonal activation with vasopressin receptor antagonists via V 1A and V 2 receptors may favourably affect prognosis of heart failure. This study was designed to compare in vivo hemodynamic effects of early treatment (1–21 days after infarction) with a V 1A (SR-49059 or ((2 S )1-[(2 R 3 S )-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxybenzene-sulfonyl)-3-hydroxy-2,3-dihydro-1 H -indole-2-carbonyl]-pyrrolidine-2-carboxamide); 0.3 mg/kg/day) and a V 2 (SR-121463B or (1-[4-( N - tert -Butylcarbamoyl)-2-methoxybenzene sulfonyl]-5-ethoxy-3-spiro-[4-(2-morpholinoethyoxy)-cyclo-hexane]indol-2one,furmate; 0.5 mg/kg/day) receptor antagonist in myocardial infarcted rats, chronically instrumented for hemodynamic measurements. Left ventricular dysfunction in conscious myocardial infarcted rats, which was evidenced by a significantly decreased cardiac output (myocardial infarction: 70±3 vs. sham: 81±3 ml/min) and stroke volume (myocardial infarction: 190±10 vs. sham: 221±7 μl), was restored by the vasopressin V 1A (81±2 ml and 224±5 μl, respectively) but not V 2 receptor antagonist. Improved cardiac output with the vasopressin V 1A receptor antagonist resulted from an increased stroke volume at a reduced myocardial infarction induced tachycardia. In addition to the hemodynamic measurements, left ventricular hypertrophy and capillary density were determined, histologically measured as the cross-sectional area of Gomori-stained myocytes and Lectin-stained capillaries per tissue area, respectively. The observed left ventricular concentric hypertrophy (myocardial infarction: 525±38 vs. sham: 347±28 μm 2 ; P 2 ; P 1A or V 2 receptor antagonist. Thus, chronic vasopressin V 1A but not V 2 receptor blockade prevents heart failure in 3-week-old infarcted rats. Moreover, the improved cardiac function could not attributed to changes in left ventricular hypertrophy and/or capillary density.