Prolongation of Murine Cardiac Allograft Survival with Vesnarinone

Abstract

Vesnarinone is a non-glycoside positive inotropic drug that has immunomodulating actions. In the present study, the effects of vesnarinone on both cardiac allografts and lymphocytes were investigated. First, in a mouse model of primary vascularized heterotopic cardiac transplantation, the oral vesnarinone treatment at a dose of 50 mg/kg/day prolonged median graft survival time significantly as compared with the vehicle-treated control. Histopathological examination revealed that cellular infiltration and interstitial edema were less prominent in the vesnarinone-treated than in the vehicle-treated allografts. The plasma concentrations of vesnarinone in mice treated with a single dose of 50 mg/kg were within the range of clinical relevance. To clarify the mechanism of action,in vitrostudies were performed. The generation of specific cytotoxic T lymphocytes in mixed lymphocyte culture was significantly suppressed by the treatment with vesnarinone, especially at 3 and 10μg/ml. The production of interferon-γin the co-culture was also suppressed by 10μg/ml vesnarinone. However, the level of cyclic adenosine monophosphate was not significantly affected by vesnarinone at 10μg/ml. The results suggest that vesnarinone acts beneficially on rejecting cardiac allografts through its lymphocyte-suppressive property, although this property may not be closely associated with the inhibiting action of the drug on the cyclic adenosine monophosphate-phosphodiesterase enzyme.