Oximes Induce Erection and Are Resistant to Oxidative Stress

Abstract

Introduction Because of their nitric oxide (NO)-donating capacities, oxime derivatives have shown to offer some therapeutic perspective for the treatment of erectile dysfunction (ED) as well as cardiovascular diseases. However, to date the in vivo effect of these oximes on erectile function remains unknown. In many disease states oxidative stress occurs, impairing NO-mediated relaxations. Hence the influence of oxidative stress on oxime-induced effects is also of interest. Aims This study aimed to evaluate the in vivo effect of formaldoxime (FAL) and formamidoxime (FAM) on blood pressure and intracavernosal pressure (ICP); and to examine the role of soluble guanylyl cyclase (sGC) and the influence of oxidative stress on the FAL and FAM responses. Methods Blood pressure and ICP were monitored in vivo after resp. intravenous or intracavernosal injection of FAL and FAM. Moreover isometric tension was measured in vitro on isolated mice corpora cavernosa (CC), thoracic aorta, and femoral artery in organ baths. The role of sGC was investigated using transgenic mice lacking the alpha 1 subunit of sGC. Main Outcome Measures Mean arterial pressure (MAP) and ICP were measured after FAL/FAM injection. In vitro relaxation of CC strips was evaluated in response to addition of FAL/FAM. Results In vivo both FAL and FAM elicit a dose-dependent lowering of blood pressure (maximal ΔMAP: 33.66 ± 4.07 mm Hg [FAL] and 20.43 ± 2.06 mm Hg [FAM] ) as well as an increase of ICP (maximal increase of ICP/MAP: 70.29 ± 2.88% [FAL] and 52.91 ± 8.61% [FAM] ). The FAL/FAM effect is significantly lower in knockout vs. wild-type mice. Oxidative stress has an inhibitory effect on corporal NO-mediated relaxations induced by electrical field stimulation, acetylcholine, and sodium nitroprusside whereas the responses to 8-(4-chlorophenylthio)-guanosine 3′,5′-cyclic monophosphate sodium salt, FAL and FAM were not influenced. Conclusions Oximes induce erection which is mediated by sGC. The oxime-induced relaxations are resistant to oxidative stress, which increases their therapeutic potential for the treatment of ED.

Erectile Function and Sexual Behavior: A Review of the Role of Nitric Oxide in the Central Nervous System

“…As recalled above, many other NO donors have been synthesized and a few also tested in in vivo and in in vitro experiments in penile tissues, such as 3-morpholino-sydnonimine hydrochloride (SIN-1) or z-1-[N-(3-ammoniopropyl)-N-(n-propyl)amino]diazen-1-ium-1,2-diolate (PAPA/NONOate), but to our knowledge, not tested at the central level for their effect on penile erection. This is true also for new NO donors under development for the treatment of erectile dysfunction [ 138 , 139 ]. Intriguingly, some of these are also light-controllable, e.g., when administered in the cavernous corpora, they can be activated by light to release NO that becomes immediately available for the activation of guanylate cyclase, thereby increasing cGMP that induces the cavernous corpora relaxation and penile erection [ 140 ].…”

“…As recalled above, this may be due to the fact that NO is a potent vasorelaxing modulator present in all vascular tissues, and this may cause severe complications (e.g., marked hypotension). Whether this picture is going to change with the use of the new NO donors under development cited above ( Section 2.2.1 and Section 2.2.2 ) [ 138 , 139 , 140 ] is still unknown.…”

Oximes: Novel Therapeutics with Anticancer and Anti-Inflammatory Potential

“…For example, NO-donating NSAIDs, which are safer than their NSAID counterparts, inhibit the growth of colon cancer cells with greater potency than traditional NSAIDs [ 202 ]. Due to their NO-donating capacities, some oxime derivatives have also been shown to offer therapeutic potential for the treatment of erectile dysfunction, as well as cardiovascular diseases [ 203 , 204 ]. Likewise, a number of oxime derivatives have been shown to exhibit antithrombogenic, hypotensive, and cardiotonic activity [ 198 , 205 , 206 ].…”