OBJECTIVE - To examine the effects of mirabegron, a selective β3-AR agonist that has recently been approved for the treatment of overactive bladder, in rat and human erectile tissues with a focus on elucidating the mechanism of such an action.
Stimulation of β3-adregenic receptors (ARs) localized in cavernosal smooth muscle cells may play a physiological role in mediating penile erection, and offer a beneficial pharmacologic action for the patient who has overactive bladder and erectile dysfunction (ED).
MATERIALS AND METHODS - Corpus cavernosal (CC) specimens were obtained from patients with ED and Peyronie's disease undergoing penile prosthesis implantation. Erectile responses were also evaluated in vivo following intracavernosal injection (ICI) of mirabegron in anesthetized rats. Mirabegron-elicited relaxation responses (10(-8) -10(-3) M) on phenylephrine (Phe)-induced contraction were observed in human and rat CC strips in isolated organ bath studies. The effects of inhibitors namely L-NAME [N(G)-nitro-L-arginine methyl ester (a competitive inhibitor of NO synthase), 100μM), ODQ [1H-(1,2,4) oxadiazolo(4,3-α) quinoxalin-1-one (a nitric oxide-sensitive guanylyl cyclase (GC) inhibitor, 30μM), methylene blue (a NOS and GC inhibitör, 20μM), SR59230A (β3-AR blocker, 1 μM), and fasudil (Rho-kinase (ROCK) inhibitor, 0.1 μM)] on mirabegron-induced relaxation responses were evaluated. Responses to mirabegron were compared with responses to isoprenaline and nebivolol. Immunohistochemistry was used to localize β3-AR and ROCK in CC smooth muscle cells. In vivo rat data were expressed as intracavernosal pressure (ICP)/mean arterial pressure and total ICP.
RESULTS - Mirabegron resulted in a relaxation of Phe-evoked CC contractions in a concentration-dependent manner and SR59230A antagonized mirabegron-induced relaxations in human and rat CC. Other inhibitors, L-NAME, ODQ, and methylene blue, did not affect the mirabegron-induced relaxation responses. Mirabegron relaxation responses at concentrations (between 0.1 and 10μM) were enhanced by fasudil (ROCK inhibitor) in rat but not in human CC strips. KCl-induced contractions in human and rat CC were partially inhibited by mirabegron. In vivo ICI of mirabegron (doses of 0.1 - 1 mg/kg) had a minor effect on ICP when compared to vehicle administration. Immunohistochemistry data showed β3-ARs localization into the smooth muscle cells of human and rat CC.
CONCLUSIONS - Mirabegron markedly relaxed isolated CC strips by activating β3-ARs independently of the NO-cGMP pathway. There is also evidence of the existence of a close functional link between β3-ARs and the RhoA/ROCKpathway. These results may support further clinical studies using combinations of mirabegron with ROCK and phosphodiesterase-5 inhibitors (PDE5i) for the treatment of ED, especially in patients who do not respond to PDE5i therapy. This article is protected by copyright. All rights reserved.
BJU international. 2016 Apr 28 [Epub ahead of print]
Serap Gur, Taylor Peak, Faysal A Yafi, Philip J Kadowitz, Suresh C Sikka, Wayne J G Hellstrom
Department of Pharmacology, School of Pharmacy, Ankara University, Turkey., Departments of Urology, Tulane University Health Sciences Center, New Orleans, LA, USA., Departments of Urology, Tulane University Health Sciences Center, New Orleans, LA, USA., Departments of Pharmacology, Tulane University Health Sciences Center, New Orleans, LA, USA., Departments of Urology, Tulane University Health Sciences Center, New Orleans, LA, USA., Departments of Urology, Tulane University Health Sciences Center, New Orleans, LA, USA.