IMMUNOSUPPRESSIVE PROPERTIES OF THE BENZOTHIAZEPINE CALCIUM-ANTAGONISTS DILTIAZEM AND CLENTIAZEM, WITH AND WITHOUT CYCLOSPORINE, IN HETEROTOPIC RAT-HEART TRANSPLANTATION

In vitro studies have shown that calcium channel blockers (CCB) exert inhibitory effects on immunocompetent cells but conflicting results ha ve been reported as to the translation of these effects into significa nt in vivo immunosuppression. In this study we evaluated the effects o f the benzothiazepine-like calcium blockers diltiazem and clentiazem, given alone or associated with cyclosporine on survival improvement of heterotopic rat heart transplants. Inbred male rats of the Lewis stra in were used as recipients and Wistar-Furth as donors. Following abdom inal implantation of the graft, recipients were randomly divided into 9 groups (n=5). Group 1 were control isografts (Lew-Lew); group 2 were control allografts (WFu-Lew), and group 3 were allografts treated wit h low-dose oral cyclosporine 2 mg/kg/day. Groups 4 and 5 were allograf ts treated with oral diltiazem 0.25 and 2.50 mg/kg/day. Groups 6 and 7 were treated with oral clentiazem, 0.25 and 2.50 mg/kg/day. Groups 8 and 9 consisted of allografts receiving low-dose cyclosporine with eit her diltiazem or clentiazem 2.50 mg/kg/day. all drugs were administere d daily by gavage. Graft function was monitored by transabdominal palp ation, and rejection was considered to be complete when no contraction of the graft could be detected. Mean survival time of untreated allog rafts was 6.4+/-0.5 days. Cyclosporine alone increased the mean surviv al time to 10.6+/-2.7 days (P<0.05 vs. group 2). At all doses studied, diltiazem and clentiazem significantly increased mean survival time o f allografts, clentiazem being slightly more potent than diltiazem. In addition, the observed beneficial effects of the benzothiazepine-like calcium channel blockers were dose-dependent. When combined with cycl osporine, diltiazem and clentiazem interacted synergistically (mean su rvival time increased to 16.8+/-3.4 days for diltiazem and 15.8+/-1.4 days for clentiazem). These results demonstrate that the benzothiazepi ne-like calcium channel blockers, as opposed to phenylalkylamines or d ihydropyridines, afford significant immunosuppression when used alone. These observations, and the fact that they beneficially interact with cyclosporine, suggest that the benzothiazepine-like calcium antagonis ts should be considered the drugs of choice when CCBs are to be select ed in transplanted patients.