Mirabegron causes relaxation of human and rat corpus cavernosum: could it be a potential therapy for erectile dysfunction?

Abstract

ObjectiveTo examine the effects of mirabegron, a selective b 3 -adrenoceptor agonist that has recently been approved for the treatment of overactive bladder (OAB), on erectile function. Stimulation of b 3 -adrenoceptors localised in cavernosal smooth muscle cells may play a physiological role in mediating penile erection, and offer a beneficial pharmacological action for patients who have OAB and erectile dysfunction (ED). Materials and MethodsCorpus cavernosal (CC) specimens were obtained from patients with ED and Peyronie's disease undergoing penile prosthesis implantation. Erectile responses were also evaluated in vivo after intracavernosal injection (ICI) of mirabegron in anaesthetised rats. Mirabegron-elicited relaxation responses (10 -8 -10-3 M) on phenylephrine-induced contraction were seen in human CC (HCC) and rat CC strips in isolated organbath studies. The effects of inhibitors, namely L-NAME [N G -nitro-L-arginine methyl ester, a competitive inhibitor of nitric oxide synthase (NOS), 100 lM], ODQ [1H-(1,2,4) oxadiazolo (4,3-a) quinoxalin-1-one, a soluble guanylyl cyclase (sGC) inhibitor, 30lM], methylene blue (a NOS and sGC inhibitor, 20lM), SR59230A (b 3 -adrenoceptor blocker, 1 lM), and fasudil [Rho-associated protein kinase (ROCK) inhibitor, 0.1 lM], on mirabegron-induced relaxation responses were evaluated. Responses to mirabegron were compared with responses to isoprenaline and nebivolol. Immunohistochemistry was used to localise b 3 -adrenoceptors and ROCK in CC smooth muscle cells. In vivo rat data were expressed as intracavernosal pressure (ICP)/mean arterial pressure, and total ICP. ResultsMirabegron resulted in a relaxation of phenylephrineevoked CC contractions in a concentration-dependent manner and SR59230A antagonised the mirabegron-induced relaxations in HCC and rat CC. Other inhibitors, L-NAME, ODQ, and methylene blue, did not affect the mirabegroninduced relaxation responses. Mirabegron relaxation responses at concentrations (0.1-10 lM) were enhanced by fasudil (ROCK inhibitor) in rat but not in HCC strips. KCl-induced contractions in HCC 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 with vehicle administration. Immunohistochemistry data showed b 3 -adrenoceptors localised in the smooth muscle cells of the HCC and rat CC. ConclusionsMirabegron markedly relaxed isolated CC strips by activating b 3 -adrenoceptors independently of the NO-cGMP pathway. There is also evidence of the existence of a close functional link between b 3 -adrenoceptors and the RhoA/ROCK pathway. These results may support further clinical studies using combinations of mirabegron with ROCK and phosphodiesterase type 5 inhibitors (PDE5i) for the treatment of ED, especially in patients who do not respond to PDE5i therapy.

Mirabegron, A Selective β3-Adrenoceptor Agonist Causes an Improvement in Erectile Dysfunction in Diabetic Rats

“…In addition, a marked alteration in basal ICP was observed in diabetic rats after intracavernosal injection of mirabegron. However, our previous data showed that intracavernosal injection of mirabegron (doses of 0.1-1 mg/kg) had a minor effect on in vivo erectile response [6]. Interestingly, mirabegron did not increase ICP basal levels in healthy rats.…”

“…The CN was stimulated (2.5, 5 and 7.5 V, 15 Hz, 30-second pulse width) with a square pulse stimulator (Grass Instruments, Quincy, MA) and, ICP and MAP were continuously measured. The measurements were repeated after intracavernosal administration of mirabegron (dose of 0.4 mg/kg) in the diabetic group [6,13]. All injections of mirabegron solution (10 − 2 M) were administered in a total volume of 300 µL, and a washout period of 15-30 min was observed between injections.…”

“…The large majority of β 3 -adrenergic receptors (β 3 -ARs) are localized in human corpus cavernosum (HCC) smooth muscle cells [5,6]. In the previous study, we have demonstrated that β 3 -AR is present in human and rat CC and its activation leads to penile erection by cyclic guanosine monophosphate (cGMP) / nitric oxide (NO)independent relaxation involving the Rho-kinase pathway [6]. On the other hand, the activation of β 3 -AR causes relaxation of HCC isolated strips in cGMP-dependent and NO-independent manner [5,7].…”

“…We recently demonstrated that mirabegron markedly relaxed isolated CC strips via activating β 3 -AR in the physiologic condition in human and rat CC independently of the NO-cGMP pathway [6]. However, it remains unknown that mirabegron exerts favourable effects on erectile function under conditions of diabetes.…”

Combination drug therapy against OAB normalizes micturition parameters and increases the release of nitric oxide during chemically induced cystitis

“…Saline Treatment * While studies on the relaxatory effects of mirabegron in human and rat corpus cavernosum or human and rabbit prostate could not show any mechanistic involvement of NO, 23,24 others have suggested that NO is part of the relaxatory mechanism of mirabegron in the bladder. 11 The current study shows that combination treatment causes release of NO in the urinary bladder.…”