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 μg/kg/day), amlodipine (25 μg/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 μg/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.

Influence of cytomegalovirus infection in the development of cardiac allograft vasculopathy after heart transplantation

“…Transmembrane calcium movement plays a critical role in lymphocyte function, and numerous investigators have demonstrated that diltiazem inhibits lymphocyte functions and depresses the immune response. [36][37][38] We speculate whether through any of these mechanisms diltiazem may explain the protective effect against CAV that we have found in our analysis.…”

Piperidine Mediated Synthesis of Prenylated Chalcones and 8-Substituted -2, 5-Dihydro-2-(4- Tolybenzo)-5-(3-Methylbut-2-Enyloxy) Phenol-1, 5- Benzothiazepines and Its Derivatives as Anti Cancer Agents

“…1, 5-Benzothiazepines having a heterocyclic group at the different position of the ring have been found to be of psychopharmacological use. Various other useful properties [9][10][11][12][13][14][15][16][17][18][19][20] have been shown by 1, 5-Benzothiazepines and different compounds having heterocyclic function have been synthesized. The biodynamic nature of 1, 5-benzothiazepine derivatives led to the current synthesis of 1,5-benzothiazepines having various substituents at positions 2, 4 and 8, which may prove to be medicinally potent.…”

Piperidine Mediated Synthesis of Hetero Chalcones and -Substituted-2, 5-dihydro-2-(2-furanyl)-4-(2-thienyl)-1,5-benzothiazepines as Antibacterial Agents

“…1, 5-Benzothiazepines having heterocyclic group at different position of ring have been found to be of psychopharmacological use. Various other useful properties [9][10][11][12][13][14][15][16][17][18][19][20] has been shown by 1, 5-benzothiazepines and different compounds having heterocyclic function have been synthesized.…”