Effects of CD-349 and 8-BrcGMP on isoproterenol-induced relaxation in rabbit aorta precontracted with endothelin-1.
We investigated the effects of CD-349, a dihydropyridine derivative, on isoproterenol (Iso)-induced relaxation in rabbit aorta precontracted with endothelin-1 (ET-1). The Iso (10(-8)-10(-5) M)-induced relaxation responses in rabbit aorta precontracted with 1-2 x 10(-7) M ET-1 were augmented by pretreatment with CD-349 (10(-9)-10(-5) M) in a concentration-dependent manner. The effects of CD-349 on Iso-induced relaxation of the aortic strips precontracted with ET-1 were inhibited by treatment with methylene blue (10(-5) M) and oxyhemoglobin (10(-5) M), whereas they were augmented by treatment with N omega-nitro-L-arginine (10(-4) M). The Iso-induced relaxation responses were also augmented by pretreatment with 8-Br-guanosine 3',5'-cyclic monophosphate (cGMP) (3 x 10(-6)-3 x 10(-4) M) in a concentration-dependent manner. However, nifedipine (10(-5) M) and nicardipine (10(-5) M) had no effect on Iso-induced relaxation responses of the aortic strips precontracted with 10(-7) M ET-1. CD-349 also augmented forskolin (10(-8)-10(-5) M)-induced relaxation responses of rabbit aorta in a concentration-dependent manner. CD-349 (10(-7)-10(-5) M) increased the levels of cGMP but not of adenosine 3',5'-cyclic monophosphate (cAMP) in a concentration-dependent manner in rabbit aorta without endothelium. Both CD-349 (10(-5) M) and 8-BrcGMP (3 x 10(-5) M) augmented the Iso-induced elevations of cAMP in rabbit aorta without endothelium. These results indicate that CD-349 and 8-BrcGMP can augment Iso-induced relaxation responses by enhancing the accumulation of cAMP.
Miyata
N
N
Research Center, Taisho Pharmaceutical, Saitama, Japan.
Yamaura
H
H
Tsuchida
K
K
Otomo
S
S
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004095:Dihydropyridines / Q000494:pharmacology*; D004357:Drug Synergism; D016232:Endothelins / Q000494:pharmacology; D007545:Isoproterenol / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D011817:Rabbits; D014661:Vasoconstriction / Q000187:drug effects*; D014664:Vasodilation
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D016232:Endothelins; C016276:8-bromocyclic GMP; C054179:CD 349; D000242:Cyclic AMP; D006152:Cyclic GMP; D007545:Isoproterenol