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

The effect of hexarelin and four related peptide analogues, EP 40904, EP 40 737, EP 50885 and EP 60761, injected into the paraventricular nucleus of th e hypothalamus of male rats in doses between 2 and 2000 ng on spontaneous p enile erection was studied. Of these peptides, EP 60761 and EP 50885, but n ot hexarelin, EP 40904 or EP 40737, increased dose-dependently the number o f 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 ma ximal response was induced by 200 ng of the peptide. EP 50885 was less pote nt than EP 60761, with 1000 ng being the minimal effective dose and 1000 ng as the dose required to induce the maximal response. At the doses used, bo th peptides also increased slightly the number of spontaneous yawning episo des. EP 60761- and EP 50885-induced penile erection was prevented by the ox ytocin receptor antagonist [d(CH2)(5)Tyr(Me)(2)-Orn(8)]vasotocin (0.1-1 mu g) given intracerebroventricularly (i.c.v.), but not into the paraventricul ar nucleus (0.1-1 mu g), by the competitive nitric oxide (NO) inhibitor N-G -nitro-L-arginine methyl ester (L-NAME) given either into the paraventricul ar nucleus (10-20 mu g) or i.c.v. (75-150 mu g), by the N-type Ca2+ channel blocker omega-conotoxin-GVIA (2-5 ng) or by the opiate morphine (1-10 mu g ), but not by the dopamine receptor antagonist (Z)-4-[3-[2-(trifluoromethyl )-9H-thioxanthen-9-ylidine]propyl]-1-piperazine-ethanol (cis-flupenthixol) (10 mu g) or by the N-methyl-D-aspartic acid (NMDA) receptor antagonist (5R ,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ((+) -MK-801) (1 mu g), all given into the paraventricular nucleus before either peptide. The present results show that EP 60761 and EP 50885 induced penil e erection by increasing central oxytocin transmission, possibly by activat ing NO synthase in the cell bodies of oxytocinergic neurons located in the paraventricular nucleus that control penile erection. (C) 2000 Elsevier Sci ence B.V. All rights reserved.