|Budget Amount *help
¥2,400,000 (Direct Cost : ¥2,400,000)
Fiscal Year 1995 : ¥600,000 (Direct Cost : ¥600,000)
Fiscal Year 1994 : ¥1,800,000 (Direct Cost : ¥1,800,000)
The distribution of cyclic nucleotide phosphodiesterase (PDE) isoenzymes in human heart, aorta and platelets was investigated. In a cytosolic fraction from human heart, four distinct PDE isoenzymes, namely, PDE1, PDE2, PDE3 and PDE4 were recognized. In the particulate fraction, PDE3, PDE4 and a new isoform of PDE4 (PDE4alpha) were identified. PDE4alpha was inhibited about 10 times more weakly by rolipram and Ro 20-1724 than was PDE4. In human aorta, PDE1, PDE2, PDE3, PDE4 and PDE5 were resolved and no PDE activity was detected in the particulate fraction. Three isoenzymes of PDE,namely, PDE2, PDE3 and PDE5 were identified in extracts of human platelets, and no activities of PDE1 and PDE4 were detected. PDE5 exhibited an organ-specific expression in humans, and the rank order of the levels of PDE5 in human tissues was platelets >> aorta and lung > kidney and PDE5 was not found in the human heart.
New carditonic agents, such as NSP-805 and MS-857, potently and selectively inhibited the activity of PDE3 competitive with respect to cAMP.Pyridazinone derivatives such as NSP-805 inhiubited PDE3 at concentration that were two to four orders of magnitude lower than that required for the inhibition of PDE4, though for the nonpyridazinone derivatives, such as MS-857, the difference was about one order of magnitude. It is now important to estimate the short-and long-term efficacies of these drugs for treatment of congestive heart failure and to clarify the relations between clinical data and the molecular mechanisms of their inotopic effects. E4021 was a potent and highly selective inhibitor of PDE5. E4021 relaxd the prostagrandin F2alpha-induced contraction of human pulmonary artery and inhibited the human platelets aggregation in the combination with SIN-1. These results suggest that PDE5 inhibitor might be useful as a new type of treatment for vasorelaxation and anti-platelets.