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 (β-aminoethyl ether) N, N, N', N'-tetraacetic acid (EGTA) 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-27 (10-5-10-3M). The IC50 values for ZSY-27 on cAMP-and cGMP-PDE activity were 2.1×10-4 and 8.8×10-4M, respectively. Furthermore, ZSY-27 antagonized competitively cAMP-PDE (Ki=1.9×10-4M). On the other hand, ZSY-27 exhibited a mixed-type inhibitory pattern, with reduction of both maximum velocity and affinity for the substrate of the cGMP-PDE, with a Ki value of 1.0×10-3M. Spontaneous myogenic tone of rabbit thoracic aorta was significantly attenuated from 1 min after addition of ZSY-27 (3×10-4M). 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 cAMPPDE activity is intimately involved in the mechanism of vasorelaxation produced by ZSY-27.
