CYCLIC-GMP POTENTIATION BY WIN-58237, A NOVEL CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE INHIBITOR

The objectives of this study were to determine the potency and selecti vity of the structurally novel cyclic nucleotide phosphodiesterase (PD E) inhibitor, WIN 58237 6-(4-pyridyl)pyrazolo[3,4-d]pyrimidin-4-(5H)-o ne}, 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 K-i 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 5823 7 is a functional cGMP PDE inhibitor at submicromolar concentrations a s evident by potentiation of both sodium nitroprusside- and atrial nat riuretic factor-mediated vasorelaxation of contracted, endothelial-den uded rat aortic rings. Moreover, WIN 58237 possesses vasorelaxant acti vity 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.) decrea ses mean arterial pressure in conscious spontaneously hypertensive rat s with an associated increase in vascular (aortic) cGMP content in viv o. Both the decrease in mean arterial blood pressure and increase in a ortic cGMP content are attenuated by the nitric oxide synthase inhibit or, N-omega-nitro-l-arginine. However, WIN 58237 may possess an additi onal depressor mechanism of action. WIN 58237 restores vasorelaxation responsiveness to nitroglycerin in vitro and in vivo in models of vasc ular tolerance. These data show that WIN 58237 is a potent, competitiv e inhibitor of cGMP PDE, and that it possesses cGMP PDE inhibitory act ivity in vascular smooth muscle in vitro and in vivo.