Abstract 9412: Vasopressin V2 Receptor Antagonist Tolvaptan Prevents The Development of Chronic Heart Failure via Its Anti-inflammatory and Anti-fibrotic Actions

Abstract

Introduction: Arginine vasopressin (AVP), which promotes the reabsorption of renal water via the AVP V2 receptor, is overexpressed in chronic heart failure (CHF). A non-peptide V2 receptor antagonist, tolvaptan (TLV), induces aquaresis without affecting electrolyte. A recent clinical study indicates that the TLV-treated patients had significantly lower rates of mortality or hospitalization for worsening heart failure than those administered the placebo. Hypothesis: TLV has more beneficial effects than furosemide (FRS), a loop diuretic, on CHF after myocardial infarction (MI). Methods: Ten weeks after MI induction, rats were divided into 3 groups (n=9-10) adjusted to the infarct size as determined by echocardiography: a vehicle group (V), a group treated with 15 mg/kg/day of FRS (F), a group treated with 10 mg/kg/day of TLV (T). Control rats were subjected to a sham operation, and each treatment agent was administered for four weeks. After treatment, we compared the effects of TLV with FRS in hemodynamics, cardiac function, inflammation, and fibrosis. Results: Although no significant intergroup differences were noted in the blood pressure, heart rate and infarct size, echocardiographic study revealed that both end-diastolic and systolic volumes in the T group was lower levels than those in the V group (P<0.01). The ejection fraction was also improved in the T group (p<0.05) but not in the F group, compared with the V group. TLV treatment significantly attenuated MI-induced interstitial fibrosis and macrophage infiltration in the marginal area of the infarct by sirius red staining and and ED-1 immunostaining (p<0.01, respectively), but FRS did not affect them. Compared with the V group, mRNA expressions of atrial natriuretic peptides, brain natriuretic peptides, monocyte chemotactic protein-1, and transforming growth factor-β1 were significantly attenuated in the marginal area of the T group (approximately 60%, 50%, 36%, and 35% decrease, p<0.05, respectively). In contrast, FRS failed to decrease the expressions. Conclusions: Tolvaptan may prevent cardiac remodeling in CHF. This effect may be attributed to its volume-reducing effect as well as its anti-inflammatory and anti-fibrotic actions.