The mode of vasoinhibitory action of a pyridazione derivative (MCI-154), a new cardiotonic agent, on contractile responses induced by alpha-adrenoceptor agonists and 45Ca influx in isolated vascular smooth muscles.

The vasoinhibitory effects of MCI-154 (MCI), a new pyridazione derivative, on contractile responses to alpha 1- and alpha 2-adrenoceptor agonists were examined in isolated rabbit aorta. MCI (10(-8)-10(-5) M) inhibited the maximum contractile responses to clonidine and BHT-920 (BHT) in a concentration-dependent manner, but only inhibited responses to lower concentrations of methoxamine. In aortas pretreated with phenoxybenzamine however, MCI (10(-5) M) readily inhibited responses to methoxamine. MCI (10(-5) M) had no significant effect on responses to potassium or added Ca2+ in a Ca2+ free, K+-depolarizing medium. In aortas incubated in a Ca2+-free medium with EGTA, the addition of methoxamine (10(-5) M), clonidine (10(-5) M) or BHT (3 X 10(-4) M) induced a phasic contraction. The inhibitory effect of MCI (10(-9)-10(-5) M) on these phasic responses was much greater for clonidine or BHT than for methoxamine. In rabbit iliac artery caffeine (10 mM) induced a rapid phasic contraction in a Ca2+-free medium, which was inhibited by MCI (10(-7)-10(-5) M) in a concentration-dependent manner. In aortas incubated in a Ca2+-free medium with low EGTA and nifedipine (10(-6) M) in the presence of alpha-adrenoceptor agonists (methoxamine, clonidine or BHT), the addition of Ca2+ (2 mM) induced a tonic contraction. MCI (10(-8)-10(-5) M) inhibited these Ca2+-dependent, agonists-mediated responses in a concentration-dependent manner. MCI had no effect on unstimulated La3+ resistant Ca2+ binding or methoxamine-induced Ca2+ influx.(ABSTRACT TRUNCATED AT 250 WORDS)