Y-20487

• Published in: Japanese Journal of Pharmacology 1990, Vol.52 (suppl-1.1), p.278-278
• Main Authors: Masayoshi Uehata, Yohji Miura, Osafumi Shimada, Kiyoteru Ikegami
• Format: Article
• Language: Japanese
• ISSN: 0021-5198

Inhibitory effects of Y-20487, a new inodilator, on subtypes of cyclic nucleotide phosphodiesterase (PDE) were examined, in relation to its positive inotropic action. In cytosolic PDE subtypes (PDEI, II. III) of the canine left ventricular muscle, Y-20487 selectively inhibited the PDEIII (cAMP-specific, Ca^++ /calmodulin-independent form)(IC_50 =29μM). However, the potency was less than milrinone (IC_50 =9μM), whereas the positive inotropic action of Y-20487 was more potent. So, we investigated membrane bound PDE activity in sarcoplasmic reticulum vesicles (SR-PDE). SR-PDE showed the same substrate specificity and Ca^++ /calmodulin-independency as cytosolic PDEIII, but it was strongly inhibited hy cGMP (IC_50 =0.23μM), although PDEIII was cGMP-insensitive (IC_50 =320μM). Y-20487 strongly inhibited the SR-PDE (IC_50 =0.13μM) and was found to he more potent than milrinone (IC_50 =1.6μM). Then, a positive correlation was observed between the inhibitory activities of several cardiotonic agents on SR-PDE and the positive inotropic activities in the dog. Similar results were obtained with rabbit left ventricular muscle. These results demonstrate that the selective inhibition of SR-PDE by Y-20487 may contribute to its positive inotropic action, together with the enhancement of myofibrillar Ca^++ sensitivity, as reported in the accompanying paper.