, 2009). Therefore, the authors proposed that two of these genes (ednrb and sparc), which were found over-expressed in cavernosal tissue, were involved in priapism. mTOR inhibitor Ednrb gene directly activates the NO/cGMP pathway responsible for cavernosal

relaxation and consequently erection. Sparc gene is involved in many biological processes, such as vascular function, and could modulate cavernosal relaxation. Conversely, sod1 gene (superoxide dismutase 1) was suggested to be under-expressed after PnTx2-6 exposure, and this would have a negative effect in cavernosal cells, however this result was not confirmed by real time-PCR (Villanova et al., 2009). Functional experiments on cavernosal Selleck Gemcitabine strips using the pharmacological inhibitor ω-conotoxin GVIA (1 uM) and knockout mice (nNOS−/−, eNOS−/−) suggested that the relaxation promoted by PnTx2-6 depends on N-type Ca2+ channels in nitrergic nerve endings, which are the main source of NO release during erection (Nunes et al., 2010, 2012c). Furthermore, the same study showed that cavernosal relaxation improvement by PnTx2-6 does not depend on PDE-5 inhibition. In addition, it was shown that PnTx2-6 potentiates the CC relaxation by sildenafil, what suggests a different site to this toxin (Nunes et al., 2012b). This and other results suggest a local effect of PnTx2-6 (Fig. 2), although a central action for this toxin influencing the penile

erection could not be excluded. It is worth of note that the erection

with a purified toxin from P. nigriventer was firstly observed when PnTx2-6 was injected intracerebrally in mice (Dr. Carlos Diniz – personal for communication). In addition, mice injected intraperitoneally with this toxin showed an increase in c-fos activation in the paraventricular hypothalamus and in the nucleus of the stria terminalis, which are indirect markers for neuronal activity ( Troncone et al., 2011). These areas of the brain have been implicated in penile erection but are also related to stress. Although the crude venom has been shown to be able to cross the blood–brain barrier ( Le Sueur et al., 2003, 2004) it is not clear whether PnTx2-6 is able to do so. Thus, these data are not sufficient to support the involvement of the central nervous system in the pro-erectile action of PnTx2-6. Recent in vivo and in vitro studies showed that PnTx2-6 toxin improves cavernosal relaxation in different models of ED. In hypertensive patients, ED is a general complaint ( Javaroni and Neves, 2012), and these conditions seem to be connected ( Nunes et al., 2012a, Nunes and Webb, 2012). In DOCA– salt (deoxycorticosterone-acetate) rats, mineralocorticoide-induced hypertensive animals, which are well known models for hypertension and ED ( Chitaley et al., 2001), subcutaneous injection of PnTx2-6 toxin reversed severe ED.