PROLONGATION OF MURINE CARDIAC ALLOGRAFT SURVIVAL WITH VESNARINONE

Vesnarinone is a non-glycoside positive inotropic drug that has immuno modulating actions, In the present study, the effects of vesnarinone o n both cardiac allografts and lymphocytes were investigated, First, in a mouse model of primary vascularized heterotopic cardiac transplanta tion, the oral vesnarinone treatment at a dose of 50 mg/kg/day prolong ed median graft survival time significantly as compared with the vehic le-treated control. Histopathological examination revealed that cellul ar infiltration and interstitial edema were less prominent in the vesn arinone-treated than in the vehicle-treated allografts. The plasma con centrations of vesnarinone in mice treated with a single dose of 50 mg /kg were within the range of clinical relevance. To clarify the mechan ism of action, in vitro studies were performed, The generation of spec ific cytotoxic T lymphocytes in mixed lymphocyte culture was significa ntly suppressed by the treatment with vesnarinone, especially at 3 and 10 mu g/ml. The production of interferon-gamma in the co-culture was also suppressed by 10 mu g/ml vesnarinone. However, the level of cycli c adenosine monophosphate was not significantly affected by vesnarinon e at 10 mu g/ml. The results suggest that vesnarinone acts beneficiall y on rejecting cardiac allografts through its lymphocyte-suppressive p roperty, although this property may not be closely associated with the inhibiting action of the drug on the cyclic adenosine monophosphate-p hosphodiesterase enzyme. (C) 1997 Academic Press Limited.