Pro-VGF-derived peptides induce penile erection in male rats: Involvement of paraventricular nitric oxide

The effect of four peptides derived from the C-terminal portion of rat pro-VGF(556-617) (VGF(556-576), VGF(588-617), VGF(599-617), and VGF(588-597)), on penile erection and nitric oxide production in the paraventricular nucleus of the hypothalamus was studied in male rats after injecting into this hypothalamic nucleus. VGF(588-617) (0.5, 1 and 2 microg), VGF(599-617) (0.5, 2 and 5 microg) and, to a lower extent, VGF(588-597) (2 and 5 microg) induced penile erection episodes when injected into the paraventricular nucleus and concomitantly increased paraventricular nitric oxide production, while VGF(556-576) (5 microg) was ineffective. VGF(588-617)-induced nitric oxide production was reduced by N(G)-nitro-l-arginine methylester (l-NAME) (20 microg), a nitric oxide synthase inhibitor, which also reduced penile erection when injected in the paraventricular nucleus 15 min before the VGF peptide. The oxytocin receptor antagonist d(CH(2))(5)Tyr(Me)-Orn(8)-vasotocin (1 microg) also effectively reduced VGF(588-617)-induced penile erection when given into the lateral ventricles, but not when injected into the paraventricular nucleus. In both experimental conditions, d(CH(2))(5)Tyr(Me)-Orn(8)-vasotocin was unable to influence nitric oxide production in the paraventricular nucleus. The present results confirm that C-terminal pro-VGF-derived peptides induce penile erection when injected into the paraventricular nucleus and show that this effect is mediated by an increased nitric oxide production in this hypothalamic nucleus. Apparently, this causes the activation of paraventricular oxytocinergic neurons projecting to extra-hypothalamic brain areas and mediating penile erection, as found with dopamine agonists, oxytocin, excitatory amino acids and hexarelin analogue peptides.