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 ((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 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 microl), was restored by the
vasopressin V(1A) (81+/-2 ml and 224 +/- 5 microl, 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 microm(2); P < 0.05) and reduced capillary density (
myocardial infarction: 2068 +/- 162 vs.
sham: 2800 +/- 250 number/mm(2); P<0.05) in the spared myocardium of myocardial infarcted rats, remained unaffected by the
vasopressin V(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.