Tolvaptan Attenuates Left Ventricular Fibrosis After Acute Myocardial Infarction in Rats

Abstract

Tolvaptan, a non-peptide V₂-receptor antagonist, is a newly developed diuretic agent. Recently, we reported that tolvaptan has diuretic as well as anti-inflammatory and anti-fibrotic actions in chronic heart failure. In this study, we investigated whether tolvaptan has a cardioprotective effect in acute heart failure after myocardial infarction (MI). After MI induction, rats were randomized into 6 groups as follows: vehicle group, group treated with 15 mg∙kg⁻¹∙day⁻¹ furosemide, 2 groups treated with 3 or 10 mg∙kg⁻¹∙day⁻¹ tolvaptan, and 2 groups treated with 15 mg∙kg⁻¹∙day⁻¹ furosemide combined with 3 or 10 mg∙kg⁻¹∙day⁻¹ tolvaptan. Each agent was administered for 2 weeks, and blood pressure levels and infarct sizes were similar in all MI groups. Lower left ventricular end-systolic volumes and greater improvement of left ventricular ejection fraction were observed in the tolvaptan-treated groups compared with the vehicle group. In contrast, furosemide alone did not improve them. Sirius red staining revealed that tolvaptan significantly repressed MI-induced interstitial fibrosis in the left ventricle. MI-induced mRNA expressions related to cardiac load, inflammation, and fibrosis were significantly attenuated in the combination group. The combination treatment also repressed MI-induced mineralocorticoid receptor expression. Tolvaptan, or combination of furosemide and tolvaptan, may improve cardiac function in acute MI.