Tolvaptan Improves Left Ventricular Dysfunction after Myocardial Infarction in Rats

Abstract

Background— Arginine vasopressin, which promotes the reabsorption of renal water is increased in chronic heart failure. Here, we compared the effects of tolvaptan, a newly developed nonpeptide V 2 receptor antagonist, with those of furosemide, a loop diuretic, and a combination of these 2 agents in rats with left ventricular dysfunction after myocardial infarction (MI). Methods and Results— After 10 weeks of MI induction, the rats were separated them into the following 6 groups adjusted to the infarct size: a vehicle group, a group treated with 15 mg·kg -1 ·day -1 of furosemide, 2 groups treated with 3 or 10 mg·kg −1 ·day −1 of tolvaptan; and 2 groups treated with 15 mg·kg −1 ·day −1 of furosemide plus 3 or 10 mg·kg −1 ·day −1 tolvaptan. Each treatment agent was administered for 4 weeks, and all groups had similar blood pressure levels and infarct size. The tolvaptan-treated groups were found to have lower levels of left ventricular end-diastolic and systolic cardiac volumes than the vehicle group did. Furthermore, the improvement in the ejection fraction in the tolvaptan-treated groups was significantly greater than those in the vehicle group. ED-1 immunostaining and Sirius red staining revealed that tolvaptan significantly repressed MI-induced macrophage infiltration and interstitial fibrosis in the left ventricle, respectively. Tolvaptan attenuated the MI-induced mRNA expressions of atrial and brain natriuretic peptides, monocyte chemotactic protein-1, transforming growth factor-β1, arginine vasopressin V 1a receptor, and endothelin-1 in the marginal infarct region. Conclusions— Tolvaptan may improve cardiac dysfunction after MI, which is partially mediated by the suppression of V 1a receptor, neurohumoral activation and inflammation.