EP 60761 and EP 50885, two hexarelin analogues, induce penile erection in rats

Abstract

The effect of hexarelin and four related peptide analogues, EP 40904, EP 40737, EP 50885 and EP 60761, injected into the paraventricular nucleus of the hypothalamus of male rats in doses between 2 and 2000 ng on spontaneous penile erection was studied. Of these peptides, EP 60761 and EP 50885, but not hexarelin, EP 40904 or EP 40737, increased dose-dependently the number of spontaneous penile erections. EP 60761 was active already at the dose of 20 ng, which induced the sexual response in 70% of the treated rats. The maximal response was induced by 200 ng of the peptide. EP 50885 was less potent than EP 60761, with 1000 ng being the minimal effective dose and 2000 ng as the dose required to induce the maximal response. At the doses used, both peptides also increased slightly the number of spontaneous yawning episodes. EP 60761- and EP 50885-induced penile erection was prevented by the oxytocin receptor antagonist [d(CH 2) 5Tyr(Me) 2-Orn 8]vasotocin (0.1–1 μg) given intracerebroventricularly (i.c.v.), but not into the paraventricular nucleus (0.1–1μg), by the competitive nitric oxide (NO) inhibitor N G-nitro-L-arginine methyl ester ( l-NAME) given either into the paraventricular nucleus (10–20 μg) or i.c.v. (75–150 μg), by the N-type Ca 2+ channel blocker ω-conotoxin-GVIA (2–5 ng) or by the opiate morphine (1–10 μg), but not by the dopamine receptor antagonist ( Z)-4-[3-[2-(trifluoromethyl)-9 H-thioxanthen-9-ylidene]propyl]-1-piperazine-ethanol ( cis-flupenthixol) (10 μg) or by the N-methyl- d-aspartic acid (NMDA) receptor antagonist (5 R,10 S)-(+)-5-methyl-10,11-dihydro-5 H-dibenzo[ a, d]cyclohepten-5,10-imine ((+)-MK-801) (1 μg), all given into the paraventricular nucleus before either peptide. The present results show that EP 60761 and EP 50885 induced penile erection by increasing central oxytocin transmission, possibly by activating NO synthase in the cell bodies of oxytocinergic neurons located in the paraventricular nucleus that control penile erection.