Activation of calcium channels by novel 1,4-dihydropyridines. A new mechanism for positive inotropics or smooth muscle stimulants.
The effects of the novel, 1,4-dihydropyridine derivative methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl) -pyridine-5-carboxylate (Bay k 8644) are reported. In contrast to the nifedipine-like dihydropyridines, which have calcium antagonistic actions. Bay k 8644 has positive inotropic and vasoconstrictor effects. The effects and mechanism of action of Bay k 8644 have been examined in the anaesthetised dog, on the isolated perfused guinea-pig heart, and on the isolated rabbit aortic strip. In these preparations Bay k 8644 is active in the same dose range as nifedipine, but has effects diametrically opposite to those of nifedipine. There is a competitive antagonism between Bay k 8644 and nifedipine, whereas verapamil and diltiazem produce only a functional, non-competitive inhibition of the effects of Bay k 8644. We conclude that a specific dihydropyridine receptor exists, which may bind both nifedipine and Bay k 8644. In contrast to nifedipine Bay k 8644 stimulates the calcium influx into the cell.
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002316:Cardiotonic Agents; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects*; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects*; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011817:Rabbits; D013045:Species Specificity; D013268:Stimulation, Chemical
D002316:Cardiotonic Agents; D007473:Ion Channels; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D009543:Nifedipine; D011188:Potassium; D002118:Calcium