Cyclic GMP potentiation by WIN 58237, a novel cyclic nucleotide phosphodiesterase inhibitor.

P J Silver, R L Dundore, D C Bode, L de Garavilla, R A Buchholz, G van Aller, L T Hamel, E Bacon, B Singh, G Y Lesher

Department of Pharmacology, Sterling Winthrop Pharmaceuticals Research Division, Collegeville, Pennsylvania.

The Journal of pharmacology and experimental therapeutics 1994 Dec

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The objectives of this study were to determine the potency and selectivity of the structurally novel cyclic nucleotide phosphodiesterase (PDE) inhibitor, WIN 58237 (1-cyclopentyl-3-methyl-6-(4- pyridyl)pyrazolo[3,4-d]pyrimidin-4-(5H)-one), and to determine if this compound possesses cyclic GMP (cGMP) PDE inhibitory activity in vitro and in vivo. WIN 58237 is a competitive inhibitor of cGMP PDE V from canine aorta, with a Ki value of 170 nM. It is a relatively less potent inhibitor of calmodulin-sensitive PDE I and cGMP-inhibitable cyclic AMP PDE III; but does inhibit cyclic AMP PDE IV with an IC50 value of approximately 300 nM. In vitro, WIN 58237 is a functional cGMP PDE inhibitor at submicromolar concentrations as evident by potentiation of both sodium nitroprusside- and atrial natriuretic factor-mediated vasorelaxation of contracted, endothelial-denuded rat aortic rings. Moreover, WIN 58237 possesses vasorelaxant activity in the presence of an intact endothelium or nitric oxide. Similar results are evident in vivo, as WIN 58237 (0.3-3.0 mg/kg i.v.) decreases mean arterial pressure in conscious spontaneously hypertensive rats with an associated increase in vascular (aortic) cGMP content in vivo. Both the decrease in mean arterial blood pressure and increase in aortic cGMP content are attenuated by the nitric oxide synthase inhibitor, N omega-nitro-l-arginine. However, WIN 58237 may possess an additional depressor mechanism of action. WIN 58237 restores vasorelaxation responsiveness to nitroglycerin in vitro and in vivo in models of vascular tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

Citation

P J Silver, R L Dundore, D C Bode, L de Garavilla, R A Buchholz, G van Aller, L T Hamel, E Bacon, B Singh, G Y Lesher. Cyclic GMP potentiation by WIN 58237, a novel cyclic nucleotide phosphodiesterase inhibitor. The Journal of pharmacology and experimental therapeutics. 1994 Dec;271(3):1143-9