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

Abstract

Aim To investigate the possible beneficial effect of mirabegron [a selective β₃-adrenoceptor (AR) agonist] treatment on erectile dysfunction (ED) in streptozotocin-induced diabetic rats.

Methods Sprague-Dawley rats (n=20) were divided into two groups: control group and streptozotocin-induced diabetic group. In vivo erectile responses were evaluated after intracavernosal injection of mirabegron (0.4 mg/kg) in rats. The relaxation responses to electrical field stimulation (EFS, 10 Hz), sodium nitroprusside (SNP, 10 nM) and sildenafil (1 μM) of corpus cavernosum (CC) strips were examined after the incubation with mirabegron (10 μM). β₃-ARs expression and localization were determined by Western blot and immunohistochemical analyses in CC tissue.

Results In vivo erectile responses of diabetic rats [intracavernasal pressure (ICP) / mean arterial pressure, 0.17±0.01] were decreased, which were restored after administration of mirabegron (0.75±0.01, P<0.001). The basal ICP (7.1±0.6 mmHg) in diabetic rats was markedly increased after mirabegron (36.1 ±5.4 mmHg, P<0.01). Mirabegron caused markedly relaxation in diabetic rat CC after phenylephrine precontraction. The relaxation responses to EFS and sildenafil were reduced in diabetic CC, which were increased in the presence of mirabegron. Mirabegron enhanced SNP-induced relaxation response in both groups. The expression and immunoreactivity of β₃-ARs localized to CC smooth muscle were observed in control and diabetic rats.

Conclusions This is the first study to show that intracavernosal administration of mirabegron improved erectile function and neurogenic relaxation of CC in diabetic rats. These results may be supported by further studies using combinations of mirabegron and phosphodiesterase type 5 (PDE5) inhibitors for the treatment of diabetic ED, especially in patients who do not respond to PDE5 inhibitor therapy.

Key words

corpus cavernosum - erectile dysfunction - intracavernosal pressure - mirabegron - diabetes.

Publication History

Received: 22 August 2018
Received: 20 February 2019

Accepted: 04 March 2019

Article published online:
12 April 2019

• References

• 1 Saigal CS, Wessells H, Pace J. et al. Predictors and prevalence of erectile dysfunction in a racially diverse population. Arch Intern Med 2006; 166: 207-212
• 2 Mazzilli R, Elia J, Delfino M. et al. Prevalence of Diabetes Mellitus (DM) in a population of men affected by Erectile Dysfunction (ED). Clin Ter 2015; 166: e317-e320
• 3 Rastrelli G, Corona G, Mannucci E. et al. Vascular and chronological age in subjects with erectile dysfunction: A cross-sectional study. J Sex Med 2015; 12: 2303-2312
• 4 Jacobson AM, Braffett BH, Cleary PA. et al. The long-term effects of type 1 diabetes treatment and complications on health-related quality of life: A 23-year follow-up of the Diabetes Control and Complications / Epidemiology of Diabetes Interventions and Complications cohort. Diabetes Care 2013; 36: 3131-3138
• 5 Cirino G, Sorrentino R, di Villa Bianca R. et al. Involvement of beta 3-adrenergic receptor activation via cyclic GMP- but not NO-dependent mechanisms in human corpus cavernosum function. Proc Natl Acad Sci USA 2003; 100: 5531-5536
• 6 Gur S, Peak T, Yafi FA. et al. Mirabegron causes relaxation of human and rat corpus cavernosum: Could it be a potential therapy for erectile dysfunction?. BJU Int 2016; 118: 464-474
• 7 Mitidieri E, Tramontano T, Gurgone D. et al. beta3 adrenergic receptor activation relaxes human corpus cavernosum and penile artery through a hydrogen sulfide / cGMP-dependent mechanism. Pharmacol Res 2017; 124: 100-104
• 8 Alexandre EC, Kiguti LR, Calmasini FB. et al. Mirabegron relaxes urethral smooth muscle by a dual mechanism involving beta3 -adrenoceptor activation and alpha1 -adrenoceptor blockade. Br J Pharmacol 2016; 173: 415-428
• 9 Chapple CR, Amarenco G, Lopez Aramburu MA. et al. A proof-of-concept study: Mirabegron, a new therapy for overactive bladder. Neurourol Urodyn 2013; 32: 1116-1122
• 10 Khullar V, Amarenco G, Angulo JC. et al. Efficacy and tolerability of mirabegron, a beta(3)-adrenoceptor agonist, in patients with overactive bladder: Results from a randomised European-Australian phase 3 trial. Eur Urol 2013; 63: 283-295
• 11 Takasu T, Ukai M, Sato S. et al. Effect of (R)-2-(2-aminothiazol-4-yl)-4'-{2-[(2-hydroxy-2-phenylethyl)amino]ethyl} acetanilide (YM178), a novel selective beta3-adrenoceptor agonist, on bladder function. J Pharmacol Exp Ther 2007; 321: 642-647
• 12 Malik M, van Gelderen EM, Lee JH. et al. Proarrhythmic safety of repeat doses of mirabegron in healthy subjects: a randomized, double-blind, placebo-, and active-controlled thorough QT study. Clin Pharmacol Ther 2012; 92: 696-706
• 13 Yilmaz-Oral D, Bayatli N, Gur S. The Beneficial effect of fesoterodine, a competitive muscarinic receptor antagonist on erectile dysfunction in streptozotocin-induced diabetic rats. Urology 2017; 107: 271 e271-271 e277
• 14 Cengiz T, Kaya E, Oral DY. et al. Intracavernous injection of human umbilical cord blood mononuclear cells improves erectile dysfunction in streptozotocin-induced diabetic rats. J Sex Med 2017; 14: 50-58
• 15 Bhadri N, Razdan R, Goswami SK. Nebivolol, a β-blocker abrogates streptozotocin-induced behavioral, biochemical, and neurophysiological deficit by attenuating oxidative-nitrosative stress: a possible target for the prevention of diabetic neuropathy. Naunyn Schmiedebergs Arch Pharmacol. 2018; Feb 391 (2): 207-217
• 16 Oikawa F, Nakahara T, Akanuma K. et al. Protective effects of the beta3-adrenoceptor agonist CL316243 against N-methyl-D-aspartate-induced retinal neurotoxicity. Naunyn Schmiedebergs Arch Pharmacol 2012; 385: 1077-1081
• 17 Zhang R, Kang X, Wang Y. et al. Effects of carvedilol on ventricular remodeling and the expression of beta3-adrenergic receptor in a diabetic rat model subjected myocardial infarction. Int J Cardiol 2016; 222: 178-184
• 18 Moniotte S, Kobzik L, Feron O. et al. Upregulation of beta(3)-adrenoceptors and altered contractile response to inotropic amines in human failing myocardium. Circulation 2001; 103: 1649-1655
• 19 Cheng HJ, Zhang ZS, Onishi K. et al. Upregulation of functional beta(3)-adrenergic receptor in the failing canine myocardium. Circ Res 2001; 89: 599-606
• 20 Sawada N, Nomiya M, Hood B. et al. Protective effect of a beta3-adrenoceptor agonist on bladder function in a rat model of chronic bladder ischemia. Eur Urol 2013; 64: 664-671
• 21 Gillespie JI, Palea S, Guilloteau V. et al. Modulation of non-voiding activity by the muscarinergic antagonist tolterodine and the beta(3)-adrenoceptor agonist mirabegron in conscious rats with partial outflow obstruction. BJU Int 2012; 110: E132-E142
• 22 Chapple CR, Kaplan SA, Mitcheson D. et al. Randomized double-blind, active-controlled phase 3 study to assess 12-month safety and efficacy of mirabegron, a beta(3)-adrenoceptor agonist, in overactive bladder. Eur Urol 2013; 63: 296-305
• 23 Rossello X, Pinero A, Fernandez-Jimenez R. et al. Mirabegron, a Clinically Approved beta3 Adrenergic Receptor Agonist, Does Not Reduce Infarct Size in a Swine Model of Reperfused Myocardial Infarction. J Cardiovasc Transl Res 2018; 11: 310-318
• 24 Shimamoto S, Ijiri D, Kawaguchi M. et al. beta1- and beta2-adrenergic receptor stimulation differ in their effects on PGC-1alpha and atrogin-1 / MAFbx gene expression in chick skeletal muscle. Comp Biochem Physiol A Mol Integr Physiol 2017; 211: 1-6
• 25 Garcia-Alvarez A, Pereda D, Garcia-Lunar I. et al. Beta-3 adrenergic agonists reduce pulmonary vascular resistance and improve right ventricular performance in a porcine model of chronic pulmonary hypertension. Basic Res Cardiol 2016; 111: 49
• 26 Deeks ED. Mirabegron: A review in overactive bladder syndrome. Drugs 2018; 78: 833-844
• 27 Yilmaz D, Bayatli N, Un O. et al. The effect of intracavernosal avanafil, a newer phosphodiesterase-5 inhibitor, on neonatal type 2 diabetic rats with erectile dysfunction. Urology 2014; 83: 508 e507-508 e512
• 28 Zhang XH, Filippi S, Morelli A. et al. Testosterone restores diabetes-induced erectile dysfunction and sildenafil responsiveness in two distinct animal models of chemical diabetes. J Sex Med 2006; 3: 253-264 discussion 264-255, author reply 265-256
• 29 Calmasini FB, Candido TZ, Alexandre EC. et al. The beta-3 adrenoceptor agonist, mirabegron relaxes isolated prostate from human and rabbit: New therapeutic indication?. Prostate 2015; 75: 440-447
• 30 Eric A, Andreasen LLR. Myrbetriq (mirabegron) Extended Release Tablets Company: Astellas Pharma Global. Development, Inc. In April 25 2012
• 31 Gur S, Kadowitz PJ, Hellstrom WJ. A protein tyrosine kinase inhibitor, imatinib mesylate (Gleevec), improves erectile and vascular function secondary to a reduction of hyperglycemia in diabetic rats. J Sex Med 2010; 7: 3341-3350
• 32 Rosen RC, Kostis JB. Overview of phosphodiesterase 5 inhibition in erectile dysfunction. Am J Cardiol 2003; 92: 9M-18M
• 33 Martinez-Salamanca JI, La Fuente JM, Cardoso J. et al. Nebivolol potentiates the efficacy of PDE5 inhibitors to relax corpus cavernosum and penile arteries from diabetic patients by enhancing the NO / cGMP pathway. J Sex Med 2014; 11: 1182-1192
• 34 Angulo J, Wright HM, Cuevas P. et al. Nebivolol dilates human penile arteries and reverses erectile dysfunction in diabetic rats through enhancement of nitric oxide signaling. J Sex Med 2010; 7: 2681-2697
• 35 Michel-Reher MB, Michel MC. Agonist-induced desensitization of human beta3-adrenoceptors expressed in human embryonic kidney cells. Naunyn Schmiedebergs Arch Pharmacol 2013; 386: 843-851
• 36 Avogaro A, Albiero M, Menegazzo L. et al. Endothelial dysfunction in diabetes: The role of reparatory mechanisms. Diabetes Care 2011; 34 (Suppl. 02) S285-S290
• 37 Bundgaard H, Axelsson A, Hartvig Thomsen J. et al. The first-in-man randomized trial of a beta3 adrenoceptor agonist in chronic heart failure: the BEAT-HF trial. Eur J Heart Fail 2017; 19: 566-575