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)
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001381:Azepines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002132:Calcium Radioisotopes; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003000:Clonidine / Q000494:pharmacology; D007083:Iliac Artery / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008729:Methoxamine / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular; D011724:Pyridazines / Q000494:pharmacology*; D011817:Rabbits; D014665:Vasodilator Agents / Q000494:pharmacology*
D000316:Adrenergic alpha-Agonists; D001381:Azepines; D002132:Calcium Radioisotopes; D002316:Cardiotonic Agents; D011724:Pyridazines; D014665:Vasodilator Agents; C024763:talipexole; C052228:MCI 154; D008729:Methoxamine; D003000:Clonidine; D002118:Calcium