title: Mechanism of erectogenic effect of the selective phosphodiesterase type 5 inhibitor, DA-8159.
abstract: DA-8159, a new Phosphodiesterase (PDE) 5 inhibitor, has exhibited potent erectogenic potential in a penile erection test in rats and anesthetized dogs. In this study, we investigated the mechanism of its erectogenic activity by measuring the activity of DA-8159 against a various PDE isozymes and assessing cGMP and cAMP formation in a rabbit corpus cavernosum in vitro. DA-8159 inhibited the PDE 5 activity in rabbit and human platelets, which the IC50 was 5.84 +/- 1.70 nM and 8.25 +/- 2.90 nM, respectively. The IC50 of DA-8159 on PDE 1, PDE 2, PDE 3 and PDE 6 were 870+/- 57.4 nM, 101 +/- 15 microM, 52.0 +/- 3.53 microM and 53.3 +/- 2.47 nM, respectively. This suggests that DA-8159 is a potent, highly selective, competitive inhibitor of PDE 5-catalyzed cGMP hydrolysis. The rates of cGMP hydrolysis catalyzed by human platelets-derived PDE 5 as a function of the cGMP concentration (5-100 nM) and two-fixed DA-8159 concentration (11.3 and 18.8 nM) were investigated in order to characterize the mode of PDE 5 inhibition by DA-8159. DA-8159 increased the apparent Km value for cGMP hydrolysis but had no effect on the apparent Vmax, indicating a competitive mode of inhibition. DA-8159 increased the cGMP concentrations in the rabbit corpus cavernosum dose dependently. In the presence of sodium nitroprusside (SNP), DA-8159 significantly stimulated the accumulation of cGMP when compared to the control level. This indicated that the enhancement of a penile erection by DA-8159 involved the relaxation of the cavernosal smooth muscle by NO-stimulated cGMP accumulation. In conclusion, DA-8159 is a selective inhibitor of PDE 5-catalyzed cGMP hydrolysis and the enhancement of a penile erection by DA-8159 is mediated by the relaxation of the cavernosal smooth muscle by the NO-stimulated cGMP accumulation.
authors.affiliation: Research Laboratories, Dong-A Pharm. Co. Ltd. 47-5, Sanggal, Kiheung, Yongin, Kyunggi 449-900, Korea.
authors.forename: Hyounmie
authors.initials: H
authors.lastname: Doh
authors.forename: Chang Yell
authors.initials: CY
authors.lastname: Shin
authors.forename: Miwon
authors.initials: M
authors.lastname: Son
authors.forename: Jun Il
authors.initials: JI
authors.lastname: Ko
authors.forename: Moohi
authors.initials: M
authors.lastname: Yoo
authors.forename: Soon Hoe
authors.initials: SH
authors.lastname: Kim
authors.forename: Won Bae
authors.initials: WB
authors.lastname: Kim
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D002417:Cattle; D006152:Cyclic GMP / Q000037:antagonists & inhibitors / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000201:enzymology; D010410:Penile Erection / Q000187:drug effects* / Q000502:physiology; D010413:Penis / Q000187:drug effects* / Q000201:enzymology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011743:Pyrimidines; D011817:Rabbits; D011892:Rana catesbeiana; D013449:Sulfonamides; D000096926:Benzenesulfonamides
chemical_list: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D006152:Cyclic GMP; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases; D011743:Pyrimidines; D013449:Sulfonamides; C517381:PDE5A protein, human; C419664:udenafil; D000096926:Benzenesulfonamides