Long‐term oral treatment with BAY 41‐2272 ameliorates impaired corpus cavernosum relaxations in a nitric oxide‐deficient rat model
Authors: Claudino Mário A. , da Silva Fabio H. , Mónica Fabíola Z. T. , Rojas‐Moscoso Julio A. , De Nucci Gilberto , Antunes Edson 
Published: October 2010

Study Type – Therapy (case control)  Level of Evidence 3bWhat’s known on the subject? and What does the study add?Erectile dysfunction is defined as the persistent inability to achieve and/or maintain an erection sufficient for satisfactory sexual performance. Nitric oxide (NO) is the main transmitter released from nitrergic nerves and endothelial cells involved in the erectile erection. NO activates the soluble guanylyl cyclase (sGC) in cavernosal smooth muscle to generate cyclic GMP (cGMP) that in turn promotes relaxation and penile erection. Erectile dysfunction genesis can be attributed to a variety of factors such as stress, ageing, drugs, and certain pathological conditions including arterial hypertension, atherosclerosis, dyslipidemia and diabetes mellitus. Inhibitors of phosphodiesterase‐5 (PDE5) like sildenafil (viagraTM), vardenafil (levitraTM) and tadalafil (cialisTM) remain the main oral therapy for erectile dysfunction. These compounds inhibit the cGMP hydrolysis thereby preserving cGMP thus causing an enhancement of corporeal smooth muscle relaxation.The existence of a new NO‐independent regulatory site on sGC has been described. BAY 41‐2272 is a novel compound that generates significant amounts of cGMP by stimulating the sGC in the absence of NO. Compound BAY 41‐2272 also synergize with endogenous NO producing higher cGMP‐dependent cell responses. Using a model of chronic NO deficiency in rats to produce erectile dysfunction, we show that long‐term oral treatment of with BAY 41‐2272 prevents the erectile dysfunction in the NO‐deficient rats. Therefore, this compound may have great therapeutic potential to erectile dysfunction treatment.OBJECTIVE• To investigate the potential beneficial effects of 4‐week oral treatment with 5‐cyclopropyl‐2‐[1‐(2‐fluoro‐benzyl)‐1Hpyrazolo[3,4‐b]pyridin‐3‐yl]‐pyrimidin‐4‐ylamine (BAY 41‐2272), a nitric oxide (NO)‐independent soluble guanylate cyclase activator, on impaired rat corpus cavernosum relaxations in NO‐deficient rats.MATERIAL AND METHODS• Male Wistar rats were divided into four groups: Control, N (G)‐nitro‐L‐ arginine methyl ester (L‐NAME; 20 mg/rat/day), BAY 41‐2272 (20 mg/kg/day) and L‐NAME + BAY 41‐2272.• Rats were treated with L‐NAME concomitantly with BAY 41‐2272 for 4 weeks.• Concentration–response curves to acetylcholine (ACh) and sodium nitroprusside (SNP), along with the nitrergic relaxations (1–32 Hz) were obtained in rat corpus cavernosum (RaCC).• The RaCC contractile responses to the α1‐adrenoceptor agonist phenylephrine (PE) were obtained.RESULTS• Acetylcholine (0.01–1000 µmol/L) produced concentration‐dependent relaxing responses in RaCC that were significantly enhanced (P < 0.05) in BAY 41‐2272‐treated rats.• The ACh‐induced relaxations were largely reduced in L‐NAME‐treated rats, and co‐treatment with BAY 41‐2272 failed to significantly modify these impaired relaxations.• The SNP‐induced relaxations were modified neither by L‐NAME nor by co‐treatment with BAY 41‐2272.• The nitrergic relaxations were significantly amplified in BAY 41‐2272‐treated rats (at 16 and 32 Hz). A significant reduction in the nitrergic relaxations was observed in L‐NAME‐treated rats, an effect largely restored by co‐treatment with BAY 41‐2272.• The contractile RaCC responses produced by PE (0.001–100 µmol/L) were significantly higher (P < 0.05) in L‐NAME‐treated rats, and co‐treatment of L‐NAME with BAY 41‐2272 nearly restored these enhanced contractile responses.CONCLUSION• Four‐week therapy with BAY 41‐2272 prevents the impaired corpus cavernosum relaxations of rats treated chronically with L‐NAME, indicating that accumulation of cyclic guanosine monophosphate into erectile tissue counteracts the NO deficiency.