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 center dot kg-1 center dot day-1) or a
V2 receptor antagonist,
OPC-31260 (20 mg center dot kg-1 center dot 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.