title: Calcium antagonistic effects and the in vitro duration of actions of KW-3049, a new 1,4-dihydropyridine derivative, in isolated canine coronary arteries.
abstract: The newly-developed 1,4-dihydropyridine derivative KW-3049 was investigated for calcium antagonistic effects in isolated canine coronary arteries. KW-3049 relaxed the arteries contracted by KCI-depolarization with an IC50 of 7.4 x 10(-9) M, while the IC50 of nifedipine, verapamil and diltiazem were 9.1 x 10(-9) M, 1.7 x 10(-7) M and 3.1 x 10(-7) M, respectively. Comparison with negative inotropic activities examined in electrically-driven canine papillary muscles indicated that KW-3049 was more selective for vasorelaxing versus negative inotropic activities than nifedipine, verapamil and diltiazem. KW-3049 inhibited 45Ca-uptake induced by depolarization without affecting 45Ca-uptake in polarized arteries. Inhibitory effects of KW-3049 at 10(-9) and 10(-8) M on depolarization-induced contractions of arteries exhibited no recovery for up to 4 hr after washout of the tissues, whereas those of nifedipine, nitrendipine, verapamil and diltiazem at vasoinhibitory concentrations disappeared within 1 to 4 hr after washout. The uptake and efflux of [3H]compounds of KW-3049, nitrendipine, verapamil and diltiazem were examined. The uptake of compound after 2 hr of incubation was the highest for nitrendipine. The efflux rate of KW-3049 was 1/10 or less than those of the other compounds examined. In summary, the present results in isolated coronary arteries demonstrate that KW-3049 is a potent, vasculoselective calcium antagonist whose effects persist long even after washout of tissues presumably due to its slow dissociation rate from arteries.
authors.affiliation: Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Karasawa
authors.forename: K
authors.initials: K
authors.lastname: Kubo
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000494:pharmacology*; D002132:Calcium Radioisotopes; D003331:Coronary Vessels / Q000187:drug effects; D004285:Dogs; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014665:Vasodilator Agents
chemical_list: D002121:Calcium Channel Blockers; D002132:Calcium Radioisotopes; D014665:Vasodilator Agents; C050883:benidipine hydrochloride; D009543:Nifedipine