Nifedipine, diltiazem, bepridil and verapamil uptakes into cardiac and smooth muscles

Vogel et al. (1979; J. Pharmacol. Exp. Ther. 210, 378) reported that one calcium antagonist, bepridil, exerted an effect internally as well as its effect on blocking Ca2+ entry in cardiac muscle. Therefore, the uptakes of tritiated nifedipine, diltiazem, bepridil, and verapamil by cat ileal smooth muscle, chick embryonic ventricular muscle, and rabbit papillary muscle were investigated. It was found that the uptakes of verapamil and bepridil by the muscles were much higher than those of nifedipine and diltiazem. The uptake of bepridil was substantially greater than that of verapamil; thus, the order of uptake was: bepridil greater than verapamil much greater than nifedipine greater than diltiazem. The cardiac muscles accumulated at least 2-fold greater amount of calcium antagonists than the smooth muscle. The amount of a given calcium antagonist accumulated by a muscle was not a function of the ability of that calcium antagonist to inhibit Ca2+ uptake into the muscle, since nifedipine and diltiazem were more potent in depressing Ca2+ uptake, but had the smallest uptakes. The calcium antagonists were more effective in depressing Ca2+ uptake into smooth muscle than into cardiac muscle. Calculation indicates that internal drug concentration at steady state for both cardiac and smooth muscles was either equal to (diltiazem) or much higher than the drug concentration in the medium (bepridil and verapamil). It is concluded that bepridil and verapamil enter and accumulate in the muscle cells, whereas nifedipine and diltiazem permeate more slowly into the muscles. The ability of all four drugs to enter the muscle cells confers the possibility that these calcium antagonists may exert secondary actions on internal sites of the muscle, such as the sarcoplasmic reticulum.