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A novel reuptake inhibitor, IP2015, induces erection by increasing central dopamine and peripheral nitric oxide release.
- Source :
-
British journal of pharmacology [Br J Pharmacol] 2024 Aug; Vol. 181 (15), pp. 2566-2582. Date of Electronic Publication: 2024 Apr 11. - Publication Year :
- 2024
-
Abstract
- Background and Purpose: An estimated 40% of patients with erectile dysfunction have a poor prognosis for improvement with currently available treatments. The present study investigated whether a newly developed monoamine transport inhibitor, IP2015, improves erectile function.<br />Experimental Approach: We investigated the effects of IP2015 on monoamine uptake and binding, erectile function in rats and diabetic mice and the effect on corpus cavernosum contractility.<br />Key Results: IP2015 inhibited the uptake of 5-HT, noradrenaline and dopamine by human monoamine transporters expressed in cells and in rat brain synaptosomes. Intracavernosal pressure measurement in anaesthetized rats revealed that IP2015 dose-dependently increased the number and the duration of spontaneous erections. Whereas pretreatment with the dopamine D <subscript>2</subscript> -like receptor antagonists, clozapine and (-)-sulpiride, or cutting the cavernosal nerve inhibited IP2015-induced erectile responses, the phosphodiesterase type 5 inhibitor sildenafil further enhanced the IP2015-mediated increase in intracavernosal pressure. IP2015 also increased the number of erections in type 2 diabetic db/db mice. Direct intracavernosal injection of IP2015 increased penile pressure, and in corpus cavernosum strips, IP2015 induced concentration-dependent relaxations. These relaxations were enhanced by sildenafil and blunted by endothelial cell removal, a nitric oxide synthase inhibitor, N <superscript>G</superscript> -nitro-l-arginine and a D <subscript>1</subscript> -like receptor antagonist, SCH23390. Quantitative polymerase chain reaction (qPCR) showed the expression of the dopamine transporter in the rat corpus cavernosum.<br />Conclusion and Implications: Our findings suggest that IP2015 stimulates erectile function by a central mechanism involving dopamine reuptake inhibition and direct NO-mediated relaxation of the erectile tissue. This novel multi-modal mechanism of action could offer a new treatment approach to erectile dysfunction.<br /> (© 2024 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
- Subjects :
- Male
Animals
Rats
Mice
Humans
Mice, Inbred C57BL
Erectile Dysfunction drug therapy
Erectile Dysfunction metabolism
Piperazines pharmacology
Penis drug effects
Penis metabolism
Dose-Response Relationship, Drug
Dopamine metabolism
Nitric Oxide metabolism
Penile Erection drug effects
Rats, Sprague-Dawley
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5381
- Volume :
- 181
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- British journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 38604613
- Full Text :
- https://doi.org/10.1111/bph.16362