Effects of a new positive inotropic agent with a vasodilatory action, 5-methyl-6-(4-pyridyl)-2H-1,4-thiazin-3(4H)-one (ZSY-27), on agonists-induced contractions in the isolated rabbit thoracic aorta.
The mechanism of the vasodilatory effect of 5-methyl-6-(4-pyridyl)-2H-1,4-thiazin-3(4H)-one (ZSY-27), a non-catecholamine and non-glycoside positive inotropic agent with a vasodilatory action, was investigated using helically-cut strips of the rabbit thoracic aorta. The contractile responses of the thoracic aorta to phenylephrine and prostaglandin F2 alpha were antagonized noncompetitively in a concentration-dependent manner by ZSY-27 (1 x 10(-4) - 1 x 10(-3) M). Furthermore, precontractions induced by high K (34.5 mM K) and by phenylephrine (1 x 10(-6) M) were relaxed in a concentration-dependent manner by ZSY-27 (1 x 10(-6) - 1 x 10(-3) M). These relaxant effects were not affected by a decrease in extracellular Ca or by pretreatment with methylene blue, an inhibitor of guanylate cyclase, but were significantly potentiated by pretreatment with forskolin, a direct stimulator of adenylate cyclase. Moreover, the amount of Ca stored in smooth muscle cells was estimated from the amplitude of the phasic contractions induced by phenylephrine in Ca-deprived medium. The first phasic contraction induced by phenylephrine was inhibited by pretreatment with ZSY-27. After ZSY-27 was washed out with a Ca-deprived solution, the second phasic contraction induced by phenylephrine occurred manifestly, but not in preparations untreated with ZSY-27. It is concluded that ZSY-27 caused a nonspecific relaxation of arterial smooth muscle contractility mainly by acting on some processes distal to adenosine 3',5'-monophosphate (cAMP) production by adenylate cyclase; probably inhibition of cAMP-phosphodiesterases.
Yoshioka
K
K
Department of Chemical Pharmacology, Toho University School of Pharmaceutical Sciences, Japan.
Takayanagi
I
I
Hisayama
T
T
Furukawa
A
A
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D002118:Calcium / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D015237:Dinoprost / Q000037:antagonists & inhibitors; D004347:Drug Interactions; D066298:In Vitro Techniques; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D010656:Phenylephrine / Q000037:antagonists & inhibitors; D011188:Potassium / Q000037:antagonists & inhibitors; D011817:Rabbits; D013843:Thiazines / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology
D002316:Cardiotonic Agents; D013843:Thiazines; D014665:Vasodilator Agents; D005576:Colforsin; D010656:Phenylephrine; C050142:ZSY 27; D015237:Dinoprost; D014700:Verapamil; D011188:Potassium; D002118:Calcium; D008751:Methylene Blue