Role of cyclic GMP in inhibitory effects of CD-349 in isolated blood vessels.
1. We investigated the effects of CD-349, a dihydropyridine derivative with nitrate ester, on contractile responses induced by high K+, norepinephrine (NE) and Ca2+ in isolated rabbit aorta. 2. CD-349 (10(-9)-10(-5) M) and nifedipine (10(-9)-10(-5) M) equally inhibited the 64 mM KCl-induced contraction of the aortic strips in a concentration-dependent manner. 8-Br-cyclic GMP (10(-3) M) did not inhibit the KCl-induced contraction of the aortic strips. 3. CD-349 (10(-8)-10(-5) M) and 8-Br-cyclic GMP (10(-6)-10(-3) M) inhibited the 10(-6) M NE-induced contraction of the aortic strips in a concentration-dependent manner. However, nifedipine had no effect on the NE-induced contraction in rabbit aorta. 4. The inhibitory effects of CD-349 on NE-induced contraction were antagonized by treatment with methylene blue and oxyhemoglobin, while they were augmented by treatment with zaprinast. 5. CD-349 (10(-8)-10(-5) M) and 8-Br-cyclic GMP (10(-5)-10(-4) M) inhibited the NE-induced phasic contraction and Ca(2+)-induced contraction of the aortic strips preincubated with NE in Ca(2+)-free medium. However, nifedipine (10(-5) M) had little or no effect on both NE-induced phasic contraction and Ca(2+)-induced contraction of the aortic strips preincubated with NE in Ca(2+)-free medium. 6. CD-349 (10(-7)-10(-5) M) increased the levels of cyclic GMP in rabbit aorta. 7. These results indicate that CD-349 has a hybrid property deriving from Ca(2+)-antagonist and cyclic GMP increasing agents.
Research Center, Taisho Pharmaceutical Co. Ltd., Saitama, Japan.
N
N
Miyata
H
H
Yamaura
K
K
Tsuchida
S
S
Otomo
E
E
Miyajima
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism / Q000502:physiology*; D004095:Dihydropyridines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011188:Potassium / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011817:Rabbits
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D015124:8-Bromo Cyclic Adenosine Monophosphate; C054179:CD 349; D006152:Cyclic GMP; D009543:Nifedipine; D011188:Potassium; D002118:Calcium; D009638:Norepinephrine