Potentiation of reflex erectile responses in the anaesthetized rat by the selective melanocortin receptor 4 agonist MB243.
OBJECTIVE
To assess the potentiation of erectile responses induced by electrical stimulation (ES) of the dorsal penile nerve (DPN) in the urethane-anaesthetized rat by the selective melanocortin receptor 4 agonist MB243.


METHODS
Intracavernosal and blood pressures (ICP and BP, respectively) were monitored in urethane-anaesthetized rats after complete spinal cord transection at the thoracic level. Erectile responses were induced by ES of the DPN (train of square wave pulses of 1 ms and 6 V for 20 s at 1, 2 and 5 Hz) after i.v. injection of either saline or MB243, 3 mg/kg, in two groups of six rats. The maximal and mean ICP, and the area under the curve (AUC) of the ICP response, corrected for the corresponding BP, were measured and used as an index of erectile function (ICPmax/BP, ICPmean/BP and AUC/BP, respectively).


RESULTS
MB243 increased the number of spontaneous erections between the injection and the first ES when compared with the vehicle group, but this difference was not statistically significant. ES of the DPN induced frequency-dependent erectile responses, the mean (sem) ICPmean/BP was 0.26 (0.02), 0.34 (0.04) and 0.39 (0.05) after administration of saline (vehicle) at 1, 2 and 5 Hz, respectively. All the variables, except the ICPmax/BP at 5 Hz, were significantly increased in the group injected with MB243 when compared with the vehicle group (P < 0.05 for ICPmax/BP and ICPmean/BP; P < 0.01 for AUC/BP). The AUC/BP showed the greatest increases of (+79%, +60% and +44% at 1, 2 and 5 Hz, respectively) in the group injected with MB243 compared with the vehicle group.


CONCLUSIONS
Erectile responses induced by ES of the DPN in spinalized, urethane-anaesthetized rat are suitable for evaluating the proerectile facilitator activity of selective peripherally restricted melanocortin receptor 4 agonists. This model represents a valuable alternative to the classically used cavernous/pelvic nerve stimulated model.
Allard
Julien
J
Pfizer Global Research and Development, Sandwich, Kent, UK. Julien.allard@pfizer.com
Reynolds
David S
DS
Edmunds
Nicholas J
NJ
D018686:Anesthetics, Intravenous / Q000008:administration & dosage; D000818:Animals; D004558:Electric Stimulation; D008297:Male; D010410:Penile Erection / Q000187:drug effects* / Q000502:physiology; D010413:Penis / Q000294:innervation* / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists*; D012018:Reflex / Q000187:drug effects / Q000502:physiology; D014520:Urethane / Q000008:administration & dosage
C500023:(2S)-N-((1R)-2-(4-cyclohexyl-4-(((1,1-dimethylethyl)amino)carbonyl)-1-piperidinyl)-1-((4-fluorophenyl)methyl)-2-oxoethyl)-4-methyl-2-piperazinecarboxamide; D018686:Anesthetics, Intravenous; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D010880:Piperidines; D044105:Receptor, Melanocortin, Type 4; D014520:Urethane