Effect of Long-Term Treatment with Selective Vasopressin V1 and V2 Receptor Antagonist on the Development of Heart Failure in Rats

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Abstract
Summary: Vasopressin has been implicated in the pathogenesis of heart failure as one of the most potent vasoconstrictors. However, whether the increase in plasma vasopressin levels modifies the pathophysiology of heart failure remains unknown. To investigate the effect of long-term inhibition of vasopressin in the development of heart failure, we administered a selective, orally effective, nonpeptide vasopressin antagonist, the V1 receptor antagonist OPC-21268 (100 mg · kg-1 · day-1) or a V2 receptor antagonist, OPC-31260 (20 mg · kg-1 · day-1) to rats with heart failure induced by the creation of an aortocaval fistula (AVF) and to sham-operated rats for 4 weeks, beginning on the first postoperative day. The heart failure in this experiment was characterized by an increase in the weights of the right and left ventricles, the lungs, and the right and left appendage, increase in left ventricular end-diastolic pressure (LVEDP), increase in right ventricular systolic pressure (RVSP), increase in right atrial pressure (RAP), and an increase in the plasma level of atrial natriuretic peptide (ANP) as compared with no change in sham-operated rats. There were no differences in shunt ratio between treated and untreated heart failure groups. Chronic administration of the V2 receptor antagonist OPC-31260 significantly reduced the weight of the right ventricle (1.17 ± 0.39 vs. 0.90 ± 0.13 g/kg, p < 0.05), RVSP (53 ± 18 vs. 39 ± 4 mm Hg, p < 0.05), LVEDP (11.8 ± 5.2 vs. 6.5 ± 2.8 mm Hg, p < 0.05) and the plasma concentrations of ANP (554 ± 271 vs. 193 ± 39 pg/ml, p < 0.05) as compared with the values of rats with untreated HF. Chronic treatment with the V1 receptor antagonist OPC-21268 did not alter hemodynamics, organ weights, or hormone concentrations. These results suggest that vasopressin did not contribute mainly to the maintenance of systemic hemodynamics through the V1 receptor in this heart failure model. Vasopressin may play a role, at least in part, in the fluid retention in the development of heart failure through the V2 receptor. OPC-31260 may present a new approach to the treatment of heart failure.