Compounds with dual action on cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) may be a treatment option for erectile dysfunction, as they not only promote penile erection but also prevent the upregulation of phosphodiesterase-5. In this study, we examined the possible relaxant effect and mechanism of 17-nor-subincanadine E (SEC, 0.2-200 mmol l 21 ), a plant-derived alkaloid, in rabbit corpus cavernosum (RbCC) strips that had been precontracted by exposure to phenylephrine (10 mmol l 21 ) or a high concentration of K 1 (60 mmol l 21 ) in vitro. In addition to SEC's effect on cAMP and cGMP levels, electrical field stimulation (EFS) in phenylephrine-precontracted RbCC and calcium chloride (1-100 mmol l 21 ) evoked responses in depolarized RbCC were analysed. SEC relaxed the phenylephrine-precontracted RbCCs in a concentration-dependent manner. Atropine, guanethidine and N-v-nitro-L-arginine methyl ester (L-NAME) did not have any effect on the relaxation of RBCCs. When 1H-1,2,4 oxadiazole[4,3-a] quinoxalin-1-one (ODQ) was added, it effectively blocked the relaxant response of SEC. Although SEC enhanced the maximal relaxation produced by sodium nitroprusside (SNP) and forskolin in phenylephrine-precontracted cavernosal smooth muscle, it caused a decrease in the maximal contractile response induced by calcium chloride in depolarized RbCCs. The relaxant effect of SEC was paralleled by an increase in the tissue levels of the cyclic nucleotides cAMP and cGMP. We conclude that SEC promotes the relaxation of RbCC, possibly favouring cAMP and cGMP accumulation and calcium blockade. This novel mechanism could be useful for patients who do not benefit from phosphodiesterase inhibitors and for those with endothelial and nitrergic dysfunction, such as patients with diabetes, hypertension and dyslipidaemias. Asian Journal of Andrology (2011) 13, 747-753; doi:10.1038/aja.2011.41; published online 18 July 2011Keywords: 17-nor-subincanadine E; cyclic nucleotides; electrical field stimulation; nitric oxide; rabbit corpus cavernosum; smooth muscle relaxation INTRODUCTIONThe erect penis has always been a symbol of power, virility and fertility. Erectile dysfunction (ED) is the consistent inability to achieve and maintain an erection sufficient for satisfactory sexual activity. This condition is a complex neurovascular disorder that affects 52% of men aged 40-70 years and causes considerable distress, unhappiness and relationship problems for these men. 1,2 Penile erection occurs as a function of trabecular smooth muscle relaxation and a subsequent increase in blood flow to lacunar spaces, which results in engorgement of the penis and restriction of venous drainage. Basically, the process is mediated by nitric oxide (NO) release from cavernosal nerve varicosities and endothelial cells, and this release activates intracellular guanylate cyclase to produce cGMP. 3 Recently, the selective phosphodiesterase 5 (PDE5) inhibitors sildenafil, tadalafil and vardenafil were shown to enhance the proerectile effect ...