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abstract

abstract

029

A novel dopamine reuptake inhibitor, IPED2015 induces spontaneous erections through activation of dopamine receptors in rats

Comerma-Steffensen, S1; Kun, A2; Munro, G3; Peters, D4; Simonsen, U2

1: Department of Biomedicine, Aarhus University, Denmark and Initiator PharmaA/S, Aarhus, Denmark; 2: Department of Biomedicine, Aarhus University, Denmark; 3: Department of Clinical Medicine, Danish Headache Center, Glostrup, Denmark; 4: DanPET AB, Sweden.

Objective(s). Erectile dysfunction where current drugs are insufficient is frequent and new approaches are required to optimize the treatment. The present study investigated whether a newly developed monoamine transport inhibitor, IPED2015 with preference for the dopamine transporter improve erectile function.

Material and Method(s). In male Wistar rats increases in intracavernosal pressure (ICP) and mean arterial pressure (MAP) were measured and the ratio ICP/MAP used as a measure of erectile function. It was investigated whether IPED2015 induced erections and whether IPED2015 facilitate suboptimal increases erectile function by electrical stimulation of the cavernosal nerve. Mechanical cutting of the cavernosal nerve and dopamine receptor antagonists were applied to further investigate the mechanism underlying the effects of IPED2015 on erectile function. Microdialysis and locomotor studies were performed in mice.

Results. In contrast to vehicle and the 5-hydroxytryptamine reuptake inhibitor, fluoxetine, infusion of IPED2015 (0.1 and 1 mg/kg) increased the number and the duration of spontaneous erections. Section of the proximal cavernosal nerve markedly reduced IPED2015-induced erections. In contrast to the dopamine D1 receptor antagonist, SCH 23390 hydrochloride, the dopamine D2 receptor antagonist, clozapine, decreased magnitude (with 60%) and frequency (with 86%) of IPED2015-induced rises in ICP/MAP. Preinfusion of the phosphodiesterase type 5 (PDE5) inhibitor, sildenafil enhanced the magnitude and duration of rises in intracavernosal pressure induced by IPED2015 (0.1 mg/kg). Suboptimal stimulation of the cavernous nerve induced reproducible increases in ICP/MAP that were unchanged in the presence of IPED2015 and IPED2015 plus clozapine. The microdialysis studies showed IPED2015 (10 mg/kg) increased dopamine in cortex and less in striatum compared to noradrenaline and 5-hydroxytrypamine. In locomotor studies 3 mg/kg IPED2015 had no effect, while 10 and 30 mg/kg after 60 min increased distance travelled.

Conclusions and Implications. IPED2015 induces erections in anaesthetized rats by a central mechanism involving inhibition of dopamine reuptake followed by activation of dopamine D2 receptors. IPED2015 induced erections were enhanced by a PDE5 inhibitor. Thus, IPED2015 may act via both central and peripheral mechanisms to initiate erection. Moreover, the erectile inducer effect in low doses with inactivity of these doses in locomotor studies show a benign adverse effect profile of IPED2015.

Disclosure:

Work supported by industry: yes, by Initiator Pharma (industry funding only - investigator initiated and executed study). The presenter or any of the authors act as a consultant, employee (part time or full time) or shareholder of an industry.

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