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The mode of vasoinhibitory action of a pyridazone derivative mci 154 a new cardiotonic agent on contractile responses induced by alpha adrenoceptor agonists and calcium 45 in isolated vascular smooth muscles

, : The mode of vasoinhibitory action of a pyridazone derivative mci 154 a new cardiotonic agent on contractile responses induced by alpha adrenoceptor agonists and calcium 45 in isolated vascular smooth muscles. European Journal of Pharmacology 145(2): 113-122

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 .times. 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. Conversely, it inhibited Ca2+ influx induced by 3 .times. 10-7 M clonidine by 68.3%. These results suggest that in rabbit aorta, the inhibitory action of MCI on responses to an .alpha.2-adrenoceptor agonist is much greater than that on responses to an .alpha.1-adrenoceptor agonists primarily as a result of the greater receptor reserve for the latter in this tissue. In addition, an inhibition of voltage-dependent Ca2+ influx by MCI in aorta was not noted. Furthermore, the results demonstrated that MCI interferes with contractile responses due to both intracellular Ca2+ mobilization and Ca2+ translocation through receptor-activated, nifedipine-insensitive Ca2+ channels.

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