Cardiac and vascular effects of NZ-105, a novel dihydropyridine derivative, in vitro.
The cardiovascular selectivity of NZ-105, a novel dihydropyridine derivative, was studied in vitro in comparison with nicardipine and other calcium antagonists. NZ-105 and nicardipine (10(-9), 10(-8) M) decreased the spontaneous contraction rate of the isolated guinea-pig right atrium. On the other hand, NZ-105, even at concentrations as high as 10(-6) M, slightly diminished the contractile force of the electrically driven left atrium, while nicardipine strongly and dose-dependently decreased the contractile force at a concentration of 10(-7) M by 39.9% and at 10(-6) M by 72.1%. NZ-105, nicardipine and diltiazem, at concentrations below 10(-6) M, caused no or only a slight depression of isoproterenol-induced increases in the contractile force of the driven left atrium. In left atrium partially depolarized with high K+ (22 mM) in the presence of 10(-6) M of isoproterenol, NZ-105 (10(-8)-10(-6) M), nicardipine (10(-9)-10(-7) M) and diltiazem (10(-7), 10(-6) M) produced both a concentration-related displacement of the concentration-response curves for CaCl2 to the right and a depression of the maximum response to CaCl2. In various rabbit blood vessels depolarized with high K+ (100 mM) (coronary, superior mesenteric, renal and femoral arteries and saphenous vein). NZ-105 (3 x 10(-10)-10(-8) M) caused a non-parallel depression of the concentration-response curves for CaCl2-induced contractions. The calcium-antagonizing effect of NZ-105 was strongest in the basilar artery. NZ-105 displaced the [3H]-nitrendipine binding to rabbit cardiac and aortic membranes in a manner similar to nicardipine and nifedipine. The Ki values of these compounds, with respect to cardiac membranes, were several times larger than in the case of aortic membranes. The Ki value of NZ-105, but not of nicardipine, grew smaller as the preincubation period with the drug increased. These findings indicate that NZ-105 possesses selective calcium-antagonizing properties in vascular smooth muscle, especially in the basilar artery, when compared with cardiac muscle. The negative chronotropic action of NZ-105 was more potent than its inotropic action. On the basis of these pharmacological properties, NZ-105 is considered to be a useful drug for the treatment of cardiovascular disorders.
Masuda
Y
Y
Shiraoka Research Station of Biological Science, Nissan Chemical Industries, Ltd., Saitama, Japan.
Iwama
T
T
Yamashita
T
T
Sakai
T
T
Hibi
M
M
Tanaka
S
S
Shigenobu
K
K
Kasuya
Y
Y
D000818:Animals; D000959:Antihypertensive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels; D004095:Dihydropyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D004558:Electric Stimulation; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D009596:Nitrophenols; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits; D011978:Receptors, Nicotinic / Q000187:drug effects
D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; D009596:Nitrophenols; D009943:Organophosphorus Compounds; D011978:Receptors, Nicotinic; C066425:efonidipine