Understanding and targeting the Rho kinase pathway in erectile dysfunction

Sopko, Nikolai A.; Hannan, Johanna L.; Bivalacqua, Trinity J.

doi:10.1038/nrurol.2014.278

Cited by 74 publications

(63 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The roles of (ROCK) signaling in maintaining a flaccid penile state and inhibition of RhoA-ROCK signalling in potentiating smooth-muscle relaxation in an NO-independent manner have been well demonstrated in earlier reports [36]. In our present study, the inhibitory effect of ROCK-inhibitor fasudil (100 lM) on mirabegron-induced relaxation was greater in rat CC than HCC.…”

supporting

confidence: 83%

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

et al. 2016

View full text Add to dashboard Cite

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.

show abstract

supporting

confidence: 83%

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

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Among these NO-independent targets is the ROCK pathway 59 , which contributes to tonic smooth muscle cell contraction via calcium sensitization (FIG. 3a).…”

Section: Mechanisms/pathophysiologymentioning

confidence: 99%

Erectile dysfunction

Yafi

Jenkins

Albersen

et al. 2016

Nat Rev Dis Primers

602

500

View full text Add to dashboard Cite

Erectile dysfunction is a multidimensional but common male sexual dysfunction that involves an alteration in any of the components of the erectile response, including organic, relational and psychological. Roles for nonendocrine (neurogenic, vasculogenic and iatrogenic) and endocrine pathways have been proposed. Owing to its strong association with metabolic syndrome and cardiovascular disease, cardiac assessment may be warranted in men with symptoms of erectile dysfunction. Minimally invasive interventions to relieve the symptoms of erectile dysfunction include lifestyle modifications, oral drugs, injected vasodilator agents and vacuum erection devices. Surgical therapies are reserved for the subset of patients who have contraindications to these nonsurgical interventions, those who experience adverse effects from (or are refractory to) medical therapy and those who also have penile fibrosis or penile vascular insufficiency. Erectile dysfunction can have deleterious effects on a man’s quality of life; most patients have symptoms of depression and anxiety related to sexual performance. These symptoms, in turn, affect his partner’s sexual experience and the couple’s quality of life. This Primer highlights numerous aspects of erectile dysfunction, summarizes new treatment targets and ongoing preclinical studies that evaluate new pharmacotherapies, and covers the topic of regenerative medicine, which represents the future of sexual medicine.

show abstract

“…Certain etiologies like diabetes, however, are difficult to treat with current modalities. Thus new molecular targets are in urgent need [25]. Researchers have demonstrated the importance of the RhoA/ROCK signaling pathway in maintaining a flaccid state of the penile, and inhibition of the signaling potentiates smooth muscle relaxation in an NO-independent manner [26].…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

MicroRNA-141 Inhibits the Proliferation of Penile Cavernous Smooth Muscle Cells Associated with Down-Regulation of the Rhoa/Rho Kinase Signaling Pathway

Zhang¹,

Jia²,

Ji³

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: The role of the RhoA/Rho kinase signaling pathway in diabetes mellitus-induced erectile dysfunction has been partially understood. Methods: In the present study, we explored the changes of the RhoA/Rho associated kinase (ROCK) signaling pathway in diabetic erectile dysfunction in vivo and the effects of microRNA-141 on the RhoA/ROCK signaling pathway in vitro. Results: The mRNA and protein expressions of RhoA and ROCK2 were significantly increased while the expression of microRNA-141 was decreased in the penile cavernous smooth muscle cells of rats with diabetic erectile dysfunction. Moreover, increased expression of microRNA-141, decreased expressions of RhoA and ROCK2 (mRNA and protein), accelerated cell proliferation rate and reduced cell apoptosis were found in the microRNA-141 mimics group and the siRNA-Rho group. The microRNA-141 expression in the microRNA-141 inhibitors + siRNA-Rho group was significantly decreased. microRNA-141 specifically bound to Rho-3’-UTR and down-regulated the expression of Rho gene at the post transcriptional level. Conclusion: Decreased expression of miR-141 is associated with up-regulation of RhoA and ROCK2 in the RhoA/ROCK signaling pathway in rats with diabetic erectile dysfunction. miR-141 inhibits the growth of penile cavernous smooth muscle cells associated with down-regulation of the RhoA/ROCK signaling pathway in vitro.

show abstract

Understanding and targeting the Rho kinase pathway in erectile dysfunction

Cited by 74 publications

References 66 publications

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

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

Erectile dysfunction

MicroRNA-141 Inhibits the Proliferation of Penile Cavernous Smooth Muscle Cells Associated with Down-Regulation of the Rhoa/Rho Kinase Signaling Pathway

Contact Info

Product

Resources

About