title: Immunomodulating effects of second-generation calcium channel blockers on experimental heart transplantation.
abstract: The administration of second-generation calcium channel blockers (CCBs) to counteract the adverse effects of conventional immunosuppression gains more and more acceptance. Since these newly developed molecules differ in their chemical structure and possess specific pharmacokinetic profiles, we hypothesized that exposure to clinically relevant concentrations may have a significant immunomodulatory potential. The effects of various second-generation CCBs, felodipine, amlodipine, mibefradil and clentiazem, on cardiac allograft survival were therefore evaluated. Inbred male Lewis rats were used as recipients and Brown-Norway rats as donors. After abdominal implantation of the donor heart, allograft recipients were exposed to felodipine (31 microg/kg/day), amlodipine (25 microg/kg/day), mibefradil (3 mg/kg/day) or clentiazem (2.5 mg/kg/day). Other allograft recipients were treated with low-dose cyclosporine (CsA) alone (2 mg/kg/day) or with low-dose CsA combined with amlodipine (25 microg/kg/day), mibefradil (3 mg/kg/day) or clentiazem (2.5 mg/kg/day). All drugs were given daily by gavage. Median survival time of untreated cardiac allografts was 6.5 days. When given alone, not all the second-generation CCBs elicited a positive effect: the dihydropyridines felodipine and amlodipine were ineffective (median survival time was 6.5 and 7.0 days, respectively), the T- and L-type CCB mibefradil had a significant but minor impact (median survival time = 9.0 days, p <0.0015) while the benzothiazepine clentiazem produced the most significant result (median survival time = 16.0 days, p <0.0033). Neither amlodipine nor mibefradil modified the extent of survival provided by low-dose CsA (median survival time = 9.0 days), while clentiazem had a significant positive effect. These data indicate that second-generation CCBs differ in their immunomodulatory potential. These observations of pharmacodynamic specificity appear to be related to differences in their chemical structure as well as their interaction with other sites than the calcium channel.
authors.affiliation: Département de Pharmacologie, Faculté de Médecine, Université de Montréal, Montréal, Que., Canada.
authors.forename: N
authors.initials: N
authors.lastname: Lapointe
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.forename: S
authors.initials: S
authors.lastname: Qi
authors.forename: D
authors.initials: D
authors.lastname: Xu
authors.forename: P
authors.initials: P
authors.lastname: Daloze
authors.forename: L
authors.initials: L
authors.lastname: Dumont
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D017311:Amlodipine / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology; D004110:Diltiazem / Q000031:analogs & derivatives / Q000494:pharmacology; D004359:Drug Therapy, Combination; D015736:Felodipine / Q000494:pharmacology; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D020748:Mibefradil; D051381:Rats; D011917:Rats, Inbred Lew; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000276:Adjuvants, Immunologic; D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D007166:Immunosuppressive Agents; D013764:Tetrahydronaphthalenes; D017311:Amlodipine; D020748:Mibefradil; C056595:clentiazem; D016572:Cyclosporine; D004110:Diltiazem; D015736:Felodipine