COMPARATIVE INHIBITORY EFFECTS OF DIHYDROPYRIDINES ON PLATELET-AGGREGATION, CALCIUM-UPTAKE AND CYCLIC-AMP CONCENTRATION

We studied the in vitro effects of several calcium channel blockers from the dihydropyridine (DHP) family on platelet aggregation and endogenous serotonin secretion, calcium uptake and cyclic AMP (cAMP) concentration using washed rat platelets. We found that, after 1 min incubation, nifedipine (Nif), nitrendipine (Nit) and nisoldipine (Nis) inhibited the thrombin-induced platelet aggregation and serotonin secretion with IC50 of about 140, 5 and 2 mumol/l, respectively. Nis and Nit are thus much more active than Nif. We also found that the thrombin-induced Ca2+ uptake amounted to 2,600 +/- 326 pmol Ca2+/10(9) platelets in control conditions. In the presence of 10 mumol/l of the DHP, this uptake was decreased by 19, 49 or 77%, with Nif, Nit or Nis, respectively. Compound BAY K 8644 (BK) with known agonistic properties on the calcium channel had inhibitory effects on the studied parameters. These compounds were in the order of Nif < BK < Nit < Nis. When added to previously aggregated platelets, Nit caused them to deaggregate. These results seem to be similar to those obtained with cAMP analogues or adenylate cyclase activators. The platelet resting cAMP concentration was therefore measured in the presence of the DHP. A nonsignificant increase was found with 20 mumol/l Nif whereas significant increases of 20 and 68% as compared with controls were obtained with 20 mumol/l Nit and Nis, respectively. Partition studies between platelets and plasma lipoproteins indicated that the effects might be related to the lipophilicity of the compounds. These data suggest that these agents work on platelet activity by multiple effects located intracellularly or at the membrane level. We propose that these effects could work in combination to explain the in vivo potency of these agents in the treatment of cardiovascular disorders.