title: The sGC activator BAY 60-2770 has potent erectile activity in the rat.
abstract: Nitric oxide (NO) is the principal mediator of penile erection, and soluble guanylate cyclase (sGC) is the receptor for NO. In pathophysiological conditions when sGC is inactivated and not responsive to NO or sGC stimulators a new class of agents called sGC activators increase the activity of NO-insensitive sGC and produce erection. The aim of this study was to investigate erectile responses to BAY 60-2770, a sGC activator, under physiological and pathophysiological conditions. In the present study increases in intracavernosal pressure (ICP) in response to intracavernosal (ic) injections of BAY 60-2770 were investigated under baseline conditions, when sGC was inhibited by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), when nitric oxide synthase (NOS) was inhibited by N-nitro-L-arginine methyl ester (L-NAME), and after cavernosal nerve crush injury. Under baseline conditions ic injections of BAY 60-2770 increase ICP, ICP/mean arterial pressure (MAP), and area under the ICP curve (AUC) and produce small decreases in MAP at the highest doses studied. BAY 60-2770 was very potent in its ability to induce erection and responses to BAY 60-2770 were enhanced by ODQ which attenuates erectile responses to sodium nitroprusside (SNP), diethylamine NONOate (DEA/NO), and cavernosal nerve stimulation. Responses to BAY 60-2770 were not altered by L-NAME or cavernosal nerve crush injury. These data indicate that BAY 60-2770 has potent erectile activity that is enhanced by ODQ and show that responses to BAY 60-2770 are not attenuated by NOS inhibition or cavernosal nerve injury. These results suggest that BAY 60-2770 would be effective in the treatment of erectile dysfunction when NO bioavailability is reduced, after pelvic nerve injury, and when sGC is oxidized.
authors.affiliation: Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA.
authors.forename: George F
authors.initials: GF
authors.lastname: Lasker
authors.forename: Edward A
authors.initials: EA
authors.lastname: Pankey
authors.forename: Terrence J
authors.initials: TJ
authors.lastname: Frink
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Zeitzer
authors.forename: Korey A
authors.initials: KA
authors.lastname: Walter
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Kadowitz
mesh_terms: D000818:Animals; D001565:Benzoates / Q000008:administration & dosage / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase; D006834:Hydrazines / Q000494:pharmacology; D006845:Hydrocarbons, Fluorinated / Q000008:administration & dosage / Q000494:pharmacology*; D007267:Injections; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009409:Nerve Crush; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009599:Nitroprusside / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010410:Penile Erection / Q000187:drug effects*; D010413:Penis / Q000294:innervation; D010525:Peripheral Nerves / Q000502:physiology / Q000601:surgery; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists; D000071756:Soluble Guanylyl Cyclase
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; C528797:4-(((4-carboxybutyl) (2- (5-fluoro-2-((4'-(trifluoromethyl) biphenyl-4-yl)methoxy)phenyl)ethyl) amino)methyl)benzoic acid; D001565:Benzoates; D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D006834:Hydrazines; D006845:Hydrocarbons, Fluorinated; D010069:Oxadiazoles; D011810:Quinoxalines; D018160:Receptors, Cytoplasmic and Nuclear; D009599:Nitroprusside; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D019331:NG-Nitroarginine Methyl Ester
keywords: erectile dysfunction; impaired cavernosal nerve function; oxidative stress