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.