Relationship between cyclic nucleotide levels and 5-methyl-6-(4-pyridyl)-2H-1,4-thiazin-3(4H)-one (ZSY-27), a new positive inotropic agent with a vasodilatory action, -induced relaxation of rabbit thoracic aorta.

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Abstract
The aim of this investigation was to substantiate the hypothesis that the vasorelaxant effects of 5-methyl-6-(4-pyridyl)-2H-1,4-thiazin-3(4H)-one (ZSY-27) are mediated by accumulation of intracellular cyclic nucleotides as a consequence of inhibition of cyclic nucleotide phosphodiesterase activity. Both activities of adenosine 3'',5''-monophosphate-phosphodiesterase (cAMP-PDE) in the presence of ethylene glycol-bis(.beta.-aminoethyl ether)N,N,N'',N''-tetraacetic acid (EDTA) and guanosine 3'',5''-monophosphate-phosphodiesterase (cGMP-PDE) in the presence of calcium-calmodulin from rabbit thoracic aorta were inhibited in a concentration-dependent manner by ZSY-37 (10-5-10-3 M). The IC50 values for ZSY-27 on cAMP- and cGMP-PDE activity were 2.1 .times. 10-4 and 8.8 .times. 10-4 M, respectively. Furthermore, ZSY-27 antagonized competitively cAMP-PDE (Ki = 1.9 .times. 10-4 M). On the other hand, ZSY-27 exhibited a mixed-type inhibitory pattern, with reduction on both maximum velocity and affinity for the substrate of the cGMP-PDE, with a Ki value of 1.0 .times. 10-3 M. Spontaneous myogenic tone of rabbit thoracic aorta was significantly attenuated from 1 min after addition of ZSY-27(3 .times. 10-4 M). Contents of cAMP and cGMP were significantly increased from 1 and 3 min after addition of ZSY-27, respectively. Temporally, relaxant effects of ZSY-27 were associated with increases of cAMP content, but not with that of cGMP content. Furthermore, the relaxant effect of ZSY-27 on the phenylephrine-induced contraction was not affected by the pretreatment with nitroprusside. These results support the hypothesis that elevation of cAMP level via inhibition of cAMP-PDE activity is intimately involved in the mechanism of vasorelaxation produced by ZSY-27.