The effects of calcium channel blockers on isoproterenol induced cyclic adenosine 3',5'-monophosphate generation in intact human lymphocytes.
We have investigated the effects of clinically available calcium channel blockers (nifedipine, verapamil and diltiazem) on isoproterenol stimulated cyclic adenosine 3',5'-monophosphate (cyclic AMP) generation in intact human lymphocytes. After preincubation of various calcium antagonists with intact lymphocytes at 37 degrees C for 15 minutes, 10 microM nifedipine or verapamil partially inhibited isoproterenol induced cyclic AMP generation in the presence of cyclic AMP phosphodiesterase inhibitor (3-isobutyl-1-methylxanthine) while they alone had no effect on cyclic AMP level at a concentration of up to 100 microM. In contrast, 10 nM-1.0 microM nifedipine, verapamil or diltiazem potentiated cyclic AMP generation induced by isoproterenol in a dose dependent manner. Similar results were observed in the time course studies of cyclic AMP generation. These effects are somewhat similar to the effect of phenothiazine, a calmodulin inhibitor, which, at 10 microM (close to IC50), also potentiated the effects of isoproterenol. In contrast, lanthanum chloride (LaCl3), an extracellular inorganic calcium antagonist, at 1.0 mM, inhibited isoproterenol induced cyclic AMP generation. The biochemical mechanisms underlying these potentiating effects are unknown. It may be partly related to the effect of calcium channel blockers (at least for nifedipine) on preventing beta 2 adrenergic receptor desensitization. This may provide a potential mechanism for the synergistic effect between calcium channel blockers and beta 2 adrenoceptor agonists on bronchial dilatation.
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D000242:Cyclic AMP / Q000097:blood*; D004110:Diltiazem / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology*; D007700:Kinetics; D007811:Lanthanum / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology; D010640:Phenothiazines / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D010640:Phenothiazines; C028521:lanthanum chloride; D007811:Lanthanum; D014700:Verapamil; D000242:Cyclic AMP; D004110:Diltiazem; C031637:phenothiazine; D009543:Nifedipine; D007545:Isoproterenol; D015056:1-Methyl-3-isobutylxanthine