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.
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 (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(-3) M). The IC50 values for ZSY-27 on cAMP- and cGMP-PDE activity were 2.1 x 10(-4) and 8.8 x 10(-4) M, respectively. Furthermore, ZSY-27 antagonized competitively cAMP-PDE (Ki = 1.9 x 10(-4) M). 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 x 10(-3) M. Spontaneous myogenic tone of rabbit thoracic aorta was significantly attenuated from 1 min after addition of ZSY-27 (3 x 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Yoshioka
K
K
Department of Chemical Pharmacology, Toho University School of Pharmaceutical Sciences, Chiba, Japan.
Takayanagi
I
I
Hisayama
T
T
D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D009712:Nucleotides, Cyclic / Q000378:metabolism*; D010656:Phenylephrine / Q000037:antagonists & inhibitors; D011817:Rabbits; D013843:Thiazines / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D002316:Cardiotonic Agents; D009712:Nucleotides, Cyclic; D013843:Thiazines; D014665:Vasodilator Agents; D009599:Nitroprusside; D010656:Phenylephrine; C050142:ZSY 27; D000242:Cyclic AMP; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D006152:Cyclic GMP