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)