Pharmacological profile of T-1032, a novel specific phosphodiesterase type 5 inhibitor, in isolated rat aorta and rabbit corpus cavernosum

Abstract This study was designed to examine the pharmacological properties of T-1032 (methyl-2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5-trimethoxyphenyl)-3-isoquinoline carboxylate sulfate), a novel phosphodiesterase type 5 inhibitor, in isolated rat aorta and rabbit corpus cavernosum. T-1032 (3×10 −11 to 3×10 −7 M) caused an endothelium-dependent relaxation in the isolated rat aorta precontracted with phenylephrine, and the relaxation was accompanied by an increase in cGMP but not cAMP levels. The T-1032-induced relaxation was attenuated by N G -nitro- l -arginine methyl ester ( l -NAME) (10 −3 M), a nitric oxide (NO) synthase inhibitor, or 1 H -[1,2,4]oxadiazolo[4,3-α]quinoxalin-1-one (ODQ) (10 −5 M), a guanylyl cyclase inhibitor. T-1032 (10 −9 , 10 −8 M) produced a potentiation of the relaxation induced by sodium nitroprusside, but not of the relaxation induced by isoproterenol. In the isolated rabbit corpus cavernosum precontracted with phenylephrine, the electrical field stimulation-induced relaxation was attenuated by treatment with tetrodotoxin (10 −6 M) as well as l- NAME (10 −4 M). The l- NAME-inhibited relaxation was restored by treatment with l- arginine (5×10 −4 M). T-1032 (10 −9 to 10 −6 M) and sildenafil (10 −9 to 10 −6 M) produced a potentiation of the electrical field stimulation-induced relaxation as well as a decrease in basal tension in a concentration-dependent manner. It was concluded that T-1032 had potentiating effects on the NO/cGMP signaling pathway in isolated tissues, probably through specific blockade of phosphodiesterase type 5. T-1032 would be a useful compound to examine the physiologic functions of phosphodiesterase type 5 in mammalian tissues.