BENEFICIAL EFFECT OF AMRINONE ON MURINE CARDIAC ALLOGRAFT SURVIVAL

Amrinone is a non-glycoside positive inotropic agent with an inhibitor y effect on a cyclic adenosine monophosphate (AMP) phosphodiesterase i soenzyme. In the present study, we examined the immunosuppressive acti on of amrinone, since several other cyclic AMP-elevating agents have b een shown to suppress T lymphocyte activation. First, the in vivo effe cts of amrinone were investigated. Oral amrinone treatment, at 40 mg/k g per day, significantly prolonged median cardiac allograft survival c ompared with non-treated controls (22.0 days versus 10.5 days, P < 0.0 1) when DBA/2 mouse hearts (H-2(d)) were heterotopically transplanted into C57B1/6 mice (H-2(b)). Histopathological examination showed that there was less prominent cellular infiltration in the amrinone-treated than in the non-treated allografts. Plasma amrinone concentrations of mice after a single oral dose of 40 mg/kg were within the range of cl inical relevance. To clarify the mechanism of action, in vitro studies were done. The generation of specific cytotoxic T lymphocytes after m ixed lymphocyte culture was significantly suppressed by addition of am rinone to the culture medium at 5 mu g/ml. The production of IL-2 and the interferon-gamma during mixed lymphocyte culture was also suppress ed by amrinone at 5 mu g/ml. However, the level of intracellular cycli c AMP in mouse splenic lymphocytes was not affected significantly by t he same dose of amrinone. In conclusion, amrinone has immunosuppressiv e actions at the therapeutic doses, and it may be a beneficial agent f or therapy against acute cardiac allograft rejection.