New 1,4-dihydropyridines with vasoconstrictor action through activation of Ca++-channels.
We found four new phenylcarbamoyl-substituted 1,4-dihydropyridines which produced vasoconstrictor and vasopressor effects and we further investigated the mode of vasoconstrictor action of one of the derivatives, 2-(2-pyridil)ethyl-4-(2-chlorophenyl)-2,6-dimethyl-5-phenylcarbamo yl-1, 4-dihydropyridine-3-carboxylate (YC-170). In anesthetized dogs. YC-170 (0.1-3 mg/kg i.v.) produced dose-dependent increases in blood pressure, total peripheral resistance and maximum dLVP/dt with slight reductions of heart rate and aortic blood flow. Intracoronary injection of YC-170 (10-1000 micrograms) produced not only a decrease in coronary blood flow but also an immediate reversal of the coronary vasodilation induced by nicardipine (3 micrograms). YC-170 (0.1-3 mg/kg i.v.) also produced a dose-dependent and reversible vasopressor effect in both anesthetized and pithed rats. The vasopressor response to YC-170 in pithed rats was not attenuated by either hexamethonium, prazosin, yohimbine, ketanserin or reserpine but was antagonized by either nicardipine, nifedipine, verapamil or diltiazem. In isolated rabbit aorta, YC-170 (3 X 10(-6) to 3 X 10(-5) M) induced a dose-dependent and reversible contraction which was not affected by either phentolamine, prazosin, mepyramine, ketanserin or atropine but removed by either nicardipine, verapamil or a Ca++-free medium. YC-170 (1 X 10(-6) to 3 X 10(-5) M) displaced [3H]nitrendipine binding to the canine cardiac membrane in an apparently competitive manner with a Ki value of 1.7 X 10(-6) M. The results suggest that the new phenylcarbamoyl-substituted dihydropyridines, including YC-170, exert a direct vasoconstrictor effect, which appears to be associated with an influx of Ca++ through Ca++ channels.
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects*; D008297:Male; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009568:Nitrendipine / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D007473:Ion Channels; D014662:Vasoconstrictor Agents; C046721:YC 170; D009568:Nitrendipine; D009543:Nifedipine; D002118:Calcium