The vasoinhibitory action of FR 46171, a new pyridine alcohol antianginal agent, on isolated rabbit vascular smooth muscles.
The vasoinhibitory effect of FR 46171, a new pyridine alcohol derivative, on contractile responses to alpha-adrenoceptor agonists was examined in isolated rabbit aorta. FR 46171 (10(-8)-10(-5) M) inhibited the maximum contractile response to clonidine (CL) in a concentration-dependent manner, but it only inhibited the responses to low concentrations of norepinephrine (NE) and methoxamine (MO). In the aorta pretreated with phenoxybenzamine, however, FR 46171 at 10(-5) M inhibited the residual maximum response to NE and MO. FR 46171 at 10(-5) M only inhibited the response to KCl (20 mM). FR 46171 at 10(-6) and 10(-5) M also moderately inhibited the response to added Ca2+ in a Ca2+-free medium in K+-depolarized preparations. Nifedipine at 10(-6) M, by contrast, nearly abolished the responses to potassium or added Ca2+. In a Ca2+-free medium with EGTA, an addition of NE (10(-5) M), MO (10(-5) M), or CL (10(-5) M) induced a phasic contraction. The inhibitory effect of FR 46171 (10(-8)-10(-5) M) was much greater on the response to CL than that to NE or MO. In a Ca2+-free medium with low EGTA and nifedipine (10(-6) M) in the presence of an alpha-adrenoceptor agonist (NE, MO, or CL), an addition of Ca2+ (2 mM) induced a tonic contraction. FR 46171 (10(-9)-10(-5) M) inhibited the Ca2+ response, which is activated by the agonists, in a concentration-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)
Shibata
S
S
Department of Pharmacology, School of Medicine, University of Hawaii, Honolulu 96822.
Satake
N
N
Kurahashi
K
K
Ohtsuka
M
M
D000787:Angina Pectoris / Q000188:drug therapy*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology; D003505:Cyclodextrins / Q000494:pharmacology*; D003912:Dextrins / Q000494:pharmacology*; D004533:Egtazic Acid / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008729:Methoxamine / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009543:Nifedipine / Q000494:pharmacology; D005996:Nitroglycerin / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D010643:Phenoxybenzamine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits; D013213:Starch / Q000494:pharmacology*; D047392:beta-Cyclodextrins
D003505:Cyclodextrins; D003912:Dextrins; C056576:FR 46171; D011725:Pyridines; D047392:beta-Cyclodextrins; D010643:Phenoxybenzamine; D004533:Egtazic Acid; D011189:Potassium Chloride; D013213:Starch; D005996:Nitroglycerin; D008729:Methoxamine; D009543:Nifedipine; D003000:Clonidine; D009638:Norepinephrine