CALCIUM-CHANNEL MODULATION - ABILITY TO INHIBIT OR PROMOTE CALCIUM INFLUX RESIDES IN THE SAME DIHYDROPYRIDINE MOLECULE

  • 1 January 1984
    • journal article
    • research article
    • Vol. 6  (6) , 1170-1176
Abstract
BAY K 8644, a dihydropyridine of the nifedipine type, increases coronary resistance and enhances myocardial contractility, in contrast to the well-known vasodilating and negative inotropic effects of the classical Ca2+ channel blockers. In the isolated perfused guinea pig heart at high concentrations (> 3 .mu.M), however, the coronary constricting and positive inotropic effects of BAY K 8644 progressively reverse until the drug has a negative inotropic effect and decreases coronary resistance, thus mimicking the effects of the classical Ca2+ antagonists. Ca2+ antagonists like nifedipine, nitrendipine and nicardipine exert a small but definite positive inotropic effect at low concentrations, indicating a Ca2+ agonistic action at those concentrations. To explain the pharmacological effects of BAY K 8644 and the Ca2+ channel blockers of the dihydropyridine type, a model is proposed that suggests the existence of 2 dihydropyridine binding sites per channel. According to this model, it depends on the chemical structure of the respective dihydropyridine whether, after occupation of the 1st site, which increases the Ca2+ influx through the channel, the occupation of the 2nd site is unimpaired, turning the channel to one with low Ca2+ permeabiilty, or whether occupation of the 2nd site is hindered, leaving the channel in the high conductance state.