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

Evidence is increasing that therapeutic modulation of neurohormonal activation with vasopressin receptor antagonists via V1A and V2 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 V1A (SR-49059 or ((2S)1-[(2R3S)-5-chloro-3-(2-chlorophenyl)-1- (3,4-dimethoxybenzene-sulfonyl)-3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl]- pyrrolidine-2-carboxamide); 0.3 mg/kg/day) and a V2 (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 V1A (81±2 ml and 224±5 μl, respectively) but not V2 receptor antagonist. Improved cardiac output with the vasopressin V1A 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 μm2; P<0.05) and reduced capillary density (myocardial infarction: 2068±162 vs. sham: 2800±250 number/mm2; P<0.05) in the spared myocardium of myocardial infarcted rats, remained unaffected by the vasopressin V1A or V2 receptor antagonist. Thus, chronic vasopressin V1A but not V2 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.

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