Calcium antagonistic drugs. Mechanism of action.

Calcium antagonists represent a new class of drugs, which were suggested to act by a selective inhibition of Ca2+ influx through cell membranes. We studied the mechanism of action of three calcium antagonists, diltiazem, nifedipine, and verapamil, by investigating the effect on 45Ca uptake and efflux in rat heart and aorta and in rabbit vessels. The uptake of La3+-resistant 45Ca was not decreased by nifedipine or verapamil either in the heart or in the vessels and was increased by diltiazem in rabbit vessels. The efflux of 45Ca from the mesenteric vein of rabbit, originating presumably from intracellular and membrane-boudn fractions, was enhanced by nifedipine. These effects were observed with drug concentrations inhibiting contractions in isolated atria and the spontaneous and norepinephrine-, potassium-, or barium-induced contractions in the portal vein of rats. Thus, our results suggest that calcium antagonistic drugs act by other mechanisms than the inhibition of transmembranous Ca flux, probably on the release and binding of Ca2+ in intracellular pools. The relatively greater inhibition of norepinephrine- than K+-induced contractions in vessels by the calcium antagonistic drugs and the abolition of the inotropic effect of norepinephrine in rat atrium exposed to 0-Ca Krebs solution for a short period are other effects suggesting an intracellular action for these drugs.