Inhibition of phosphodiesterase type 5 (PDE5) is an effective therapy to treat male erectile dysfunction (MED) via enhancement of nitric oxide (NO)-mediated vasorelaxation (Boolell, 1996). In addition to NO, the central and peripheral nervous systems, which control erectogenic activity, contain a number of peptides (Andersson, 2001). Many of these peptides are metabolised by neutral endopeptidase EC3.4.24.11 (NEP; Duggan, 1995, Turner, 1997). The aim of this study was to investigate the role of NEP in the control of medial pre-optic area (mPOA)-stimulated erection in the anaesthetised rat. Moreover, the potential for increased erectogenic effects during concomitant inhibition of NEP/PDE5 was investigated.

Experiments were in compliance with UK legislation and subject to local ethical review. Experiments were carried out in male rats (Sprague Dawley, CD, 280-350g) under anaesthesia without recovery (urethane 0.5ml.100g^-1 i.p. of a 25% w.v^-1). A concentric bipolar electrode was inserted in the mPOA using stereotaxic techniques (Bregma -0.5mm lateral, -0.6mm posterior and -8.9mm from the skull surface). Intracavernosal pressure (ICP) was recorded as an index of erectile function. Mean arterial blood pressure (MAP) was also recorded. Increases in ICP were elicited by electrical stimulation of the mPOA (7V, 33Hz, 2mS duration for 30s every 10 minutes for 60min). Following three consistent baseline responses, rats were dosed i.v. with either vehicle, NEP inhibitor (NEPi; (R)-2-({1-[(5-ethyl-1,3,4-thiadiazol-2-yl)carbamoyl]cyclopentyl}methyl) valeric acid), PDE5 inhibitor (PDE5i; 3-ethyl-5-{5-[(4-ethylpiperazino)sulphonyl]-2-propoxyphenyl}-2-(2-pyridylmethyl)-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimid-in-7-one) or concomitant administration of NEPi and PDE5i were studied. Responses to mPOA stimulation were measured as ICP area-under-curve AUC for 30 seconds during stimulation (AUC_0-30) and for 30 seconds after stimulation (AUC_30-60) and expressed as a percentage increase over basal. Data were analyzed using ANOVA and subsequent pairwise comparison of means.

PDE5i (3mg.kg^-1 i.v.; n=4) increased AUC_30-60(55±19%; P<0.05) by 10 minutes post dose versus vehicle treated controls. There was no effect on AUC_0-30 (1±16%). NEPi (1mg.kg^-1 i.v., n=4) had no effect on AUC_0-30 or AUC_30-60. Co-administration of PDE5i and NEPi (3mg.kg^-1 and 1mg.kg^-1 i.v. respectively, n=4) was associated with significantly increased AUC_0-30 (75±41%; P<0.05) and AUC_30-60 (126±43%; P<0.05) by 10 minutes post dose versus vehicle controls. The effect on AUC_30-60 was significantly greater than that obtained with the PDE5 inhibitor alone (P<0.05).

This study demonstrates that an inhibitor of PDE5, but not a NEP inhibitor, enhances penile erection following electrical stimulation of the mPOA. Concomitant inhibition of PDE5 and NEP acts synergistically to increase erectile function in the anaesthetised rat. Approaches that enhance NO and peptidergic mechanisms may represent useful rapid onset MED therapies of the future.

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