EP 60761-and EP 50885-induced penile erection: structure-activity studies and comparison with apomorphine, oxytocin and N-methyl-D-aspartic acid

The effect of 10 peptides structurally related to the growth hormone (GH) r eleasing peptide hexarelin, injected into the paraventricular nucleus of th e hypothalamus (PVN), on penile erection was studied in male rats. Six out of the 10 peptides tested induced penile erection in a dose-dependent manne r. Among them, the most potent were EP 80661, EP 60761 and EP 91072, which were active at doses of 20-200 ng. The potency of these peptides in inducin g penile erection is comparable to that of apomorphine, oxytocin and N-meth yl-D-aspartic acid similarly injected into the PVN. Other peptides found ac tive were EP 50885, EP 90101 and EP 91071, which induced penile erection at doses of zoo - 2000 ng. In contrast, EP 51322, EP 70555, EP 51216 and EP 9 1073 were inactive, as were hexarelin, EP 40904 and EP 40737 in a previous study. The majority of EP peptides found active when injected into the PVN induced penile erection, although to a lesser extent, also when given syste mically (endovenously). The proerectile effect of EP peptides was prevented by the oxytocin receptor antagonist [d(CH2)(5) Tyr(Me)(2)-Orn(8)]-vasotoci n given into the lateral ventricles but not into the PVN, by the nitric oxi de (NO) synthase inhibitor N-G-nitro-l-arginine methyl ester given either i nto the lateral ventricles or into the PVN, by the N-type Ca2+ channel bloc ker omega -conotoxin GVIA and by morphine, but not by the dopamine receptor antagonist cis-flupenthixol or by the N-methyl-D-aspartic acid receptor an tagonist dizolcipine, given into the PVN. As the structure - activity relat ionship of EP peptides for proerectile activity is different from those of other biological actions of these compounds, ie for GH release and eating b ehaviour, the present results suggest that EP peptides induce penile erecti on by acting on specific hypothalamic receptor sites that activate paravent ricular oxytocinergic neurons projecting to extrahypothalamic brain areas t hat mediate this sexual function by a mechanism similar to that of dopamine receptor agonists, oxytocin and N-methyl-D-aspartic acid.