Vasorelaxing and receptor binding properties of NZ-105, a novel dihydropyridine derivative, in isolated rabbit aorta.
The vasorelaxing and dihydropyridine receptor binding properties of NZ-105, a new dihydropyridine derivative, were studied using isolated rabbit aorta, and compared with those of nicardipine, nifedipine and diltiazem. NZ-105 (3 x 10(-10)-3 x 10(-9) M), nicardipine (3 x 10(-10), 10(-9) M), and diltiazem (3 x 10(-7), 10(-6) M) selectively relaxed aortic strips precontracted with high-K+ solution (50 mM) with little effect on strips precontracted with phenylephrine (10(-5) M) or clonidine (10(-6) M). The relaxation produced by NZ-105 was of very slow onset, and no recovery was observed after a 2 hr washout with high-K+ or normal bathing solution. NZ-105 (3 x 10(-10)-3 x 10(-9) M) caused a non-parallel depression of the concentration-response curve for the CaCl2-induced contraction in high-K(+)-depolarized rabbit aorta, whereas nicardipine (10(-10), 3 x 10(-10) M), nifedipine (10(-9), 3 x 10(-9) M) and diltiazem (10(-7), 3 x 10(-7) M) all produced a concentration-related rightward displacement of the curve. The depression induced by NZ-105, but not by nicardipine, became greater as the period of preincubation with the drug was prolonged. NZ-105, nicardipine and diltiazem, at the very high concentration of 10(-6) M, caused a slight and noncompetitive inhibition of the concentration-response curves for norepinephrine, prostaglandin F2 alpha, angiotensin II and 5-hydroxytryptamine. NZ-105 displaced 3H-nitrendipine binding to rabbit aortic membranes in a manner similar to that of nicardipine and nifedipine, and this was also incubation time-dependent. These results indicate that NZ-105 possesses selective calcium antagonist properties, with respect to the rabbit isolated vascular smooth muscle, which are of very slow onset and long-lasting. The slow onset of the vasorelaxation may be due to a slow association rate to dihydropyridine receptors. These pharmacological properties of NZ-105 may, at least in part, be responsible for the slow onset and long duration of its antihypertensive action in vivo.
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
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001011:Aorta; D002118:Calcium / Q000494:pharmacology; D015220:Calcium Channels; D003000:Clonidine / Q000494:pharmacology; D004095:Dihydropyridines / Q000378:metabolism / Q000494:pharmacology*; D004110:Diltiazem / Q000494:pharmacology; D015237:Dinoprost / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009529:Nicardipine / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D009596:Nitrophenols; D009638:Norepinephrine / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000378:metabolism / Q000494:pharmacology*; D010656:Phenylephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011817:Rabbits; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*
D000959:Antihypertensive Agents; D015220:Calcium Channels; D004095:Dihydropyridines; D009596:Nitrophenols; D009943:Organophosphorus Compounds; D011978:Receptors, Nicotinic; D000804:Angiotensin II; D010656:Phenylephrine; D012701:Serotonin; C066425:efonidipine; D011189:Potassium Chloride; D015237:Dinoprost; D009529:Nicardipine; D004110:Diltiazem; D009543:Nifedipine; D003000:Clonidine; D002118:Calcium; D009638:Norepinephrine