Program

PO2-4-23

A role for the Rho-kinase pathway in mediating smooth muscle tone of the porcine prostate and corpus cavernosum

[Speaker] Donna J Sellers:1
[Co-author] Amelia Jack:1, Russ Chess-Williams:1
1:Centre for Urology Research, Faculty of Health Sciences and Medicine, Bond University, Australia

Background
Benign prostatic hyperplasia and erectile dysfunction are associated conditions, found commonly in ageing men. Current pharmacotherapies can be limited by sexual and non-sexual adverse effects, and around 40% of patients with erectile dysfunction do not respond to the main pharmacotherapy, phosphodiesterase-5 inhibitors, which are also contraindicated in patients with diabetes and cardiovascular disease. Since smooth muscle relaxation is a desired outcome of treatment for both conditions, the RhoA/Rho-kinase pathway has been under investigation to better understand the mechanisms involved in calcium sensitisation and smooth muscle tone, and to potentially establish this pathway as a novel target for treatment. The aim of this study was to investigate the role of the RhoA/Rho-kinase signalling pathway in mediating smooth muscle tone in porcine prostate and corpus cavernosum.

Methods
Strips of porcine prostate and corpus cavernosum were mounted in gassed Krebs-bicarbonate solution at 37%deg;C and α1-adrenoceptor mediated contractile responses to phenylephrine were obtained in the absence and presence of the Rho-kinase inhibitors Y-27632, fasudil and GSK-269962.

Results
Phenylephrine evoked concentration-dependent contractile responses in porcine prostate and corpus cavernosum. In prostate, mean maximum contractions were inhibited in the presence of Y-27632 (10μM) (67.9±7.8% inhibition, p<0.0001, n=8) and fasudil (30μM) (49.6±8.5, p<0.001, n=9). Similarly, in corpus cavernosum maximum contractions to phenylephrine were inhibited by Y-27632 (68.2±6.1%, p<0.0001, n=9) and fasudil (52.7±5.2%, p<0.0001, n=9). The more potent Rho-kinase inhibitor GSK-269962 (100nM) also decreased maximum contractions to phenylephrine in prostate and cavernosum (by 22.8±11.2% (p=0.09) and 29.3±6.5% (p<0.001), n=8-9 respectively). Inhibition of contractions by GSK-269962 was significantly less than with Y-27632 and fasudil in both tissues (p<0.01).

Conclusion
The present study confirms that the RhoA/Rho-kinase signalling pathway plays a role in mediating smooth muscle tone in both porcine prostate and corpus cavernosum. The effects of the Rho-kinase inhibitors were similar in both tissues. The greater inhibitory effects observed with Y-27632 and fasudil versus GSK-269962 may be due to additional non-selective actions on other kinases involved in smooth muscle tone. Further elucidation of the precise role of the RhoA/Rho-kinase pathway may provide an alternative target for development of new treatments for erectile dysfunction and benign prostatic hyperplasia.


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