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Antagonism of Rho-kinase stimulates rat penile erection via a nitric oxide-independent pathway

Abstract

Relaxation of the smooth muscle cells in the cavernosal arterioles and sinuses results in increased blood flow into the penis, raising corpus cavernosum pressure to culminate in penile erection1. Nitric oxide, released from non-adrenergic/non-cholinergic nerves, is considered the principle stimulator of cavernosal smooth muscle relaxation2,3,4, however, the inhibition of vasoconstrictors (that is, norepinephrine and endothelin-1, refs. 59) cannot be ignored as a potential regulator of penile erection. The calcium-sensitizing ρ-A/Rho-kinase pathway may play a synergistic role in cavernosal vasoconstriction to maintain penile flaccidity. Rho-kinase is known to inhibit myosin light chain phosphatase10,11,12, and to directly phosphorylate myosin light-chain (in solution), altogether resulting in a net increase in activated myosin and the promotion of cellular contraction10,11,13,14,15,16. Although Rho-kinase protein and mRNA have been detected in cavernosal tissue17, the role of Rho-kinase in the regulation of cavernosal tone is unknown. Using pharmacologic antagonism (Y-27632, ref. 13, 18), we examined the role of Rho-kinase in cavernosal tone, based on the hypothesis that antagonism of Rho-kinase results in increased corpus cavernosum pressure, initiating the erectile response independently of nitric oxide. Our finding, that Rho-kinase antagonism stimulates rat penile erection independently of nitric oxide, introduces a potential alternate avenue for the treatment of erectile dysfunction.

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Figure 1: In vivo effect of Y-27632 on CCP/MAP in the presence and absence of ganglionic nerve stimulation.
Figure 2: Effect of NOS inhibition on Y-27632-induced potentiation of ganglionic-stimulated CCP/MAP (5 volt stimulation).
Figure 3: In vitro effect of Y-27632 on isolated rat cavernosal tissue.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (NIH HL18575), American Heart Association (AHA 9960075V, Southeast Affiliate), and American Health Assistance Foundation (AHAF H2000011). K.C. is the recipient of support from a NIH training grant for Systems and Integrative Physiology (2-T32-GM0832211). Y-27632 was a gift from Welfide Corporation. We thank A. Dorrance for her assistance with western-blot analysis.

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Correspondence to Kanchan Chitaley.

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Chitaley, K., Wingard, C., Clinton Webb, R. et al. Antagonism of Rho-kinase stimulates rat penile erection via a nitric oxide-independent pathway. Nat Med 7, 119–122 (2001). https://doi.org/10.1038/83258

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