In Vivo and In Vitro Effects of Vasopressin V2 Receptor Antagonism on Myocardial Fibrosis in Rats

Abstract

BackgroundMyocardial fibrosis is a major pathophysiologic substrate of heart failure with preserved ejection fraction. Vasopressin is an important therapeutic target in heart failure with preserved ejection fraction since it can modulate fluid balance, and based on a few studies, myocardial matrix deposition. Hence we examined the role of vasopressin antagonism in modulating myocardial matrix metabolism in vivo and in vitro. Materials and MethodsIn vivo studies utilized an established model of hyperhomocysteinemia-induced myocardial fibrosis in Sprague-Dawley rats combined with high salt diet; in vivo studies also utilized the same profibrotic stimuli of homocysteine and NaCl in cultured rat cardiac fibroblasts. ResultsHyperhomocysteinemia combined with high-salt diet promoted myocardial fibrosis, profibrotic and matrix gene expression and tolvaptan attenuated all these in vivo effects. In cultured cardiac fibroblasts, combined treatment with homocysteine and NaCl increased profibrotic and matrix gene expression and activation of PI3/Akt pathway; all these effects were attenuated by tolvaptan Vasopressin levels, gene expression and V2 receptor expression were increased in vivo and in vitro on exposure to profibrotic stimuli, and tolvaptan attenuated these in vivo and in vitro effects. ConclusionsAntagonism of vasopressin V2 receptor, via direct actions on cardiac fibroblast, attenuates myocardial matrix deposition.