The Promise of Inhibition of Smooth Muscle Tone as a Treatment for Erectile Dysfunction

Where Are We Now?

X Jiang; K Chitaley


Int J Impot Res. 2012;24(2):49-60. 

In This Article

Abstract and Introduction


Ten years ago, the inhibition of Rho kinase by intracavernosal injection of Y-27632 was found to induce an erectile response. This effect did not require activation of nitric oxide-mediated signaling, introducing a novel target pathway for the treatment of erectile dysfunction (ED), with potential added benefit in cases where nitric oxide bioavailability is attenuated (and thus phosphodiesterase type 5 (PDE5) inhibitors are less efficacious). Rho-kinase antagonists are currently being developed and tested for a wide range of potential uses. The inhibition of this calcium-sensitizing pathway results in blood vessel relaxation. It is also possible that blockade of additional smooth muscle contractile signaling mechanisms may have the same effect. In this review, we conducted an extensive search of pertinent literature using PUBMED. We have outlined the various pathways involved in the maintenance of penile smooth muscle tone and discussed the current potential benefit for the pharmacological inhibition of these targets for the treatment of ED.


Erectile dysfunction (ED) affects 30 million men in the United States[1] and is associated with co-morbidities ranging from prostatectomy to diabetes and increased age. Penile erection is a dynamic process requiring dilation of feeder arterioles and cavernosal sinusoids allowing for increased inflow of blood. It is important to remember, however, that the vast majority of the time, these arterioles and sinusoids are maintained in the collapsed/contracted state, severely restricting penile blood flow.[2] The maintenance of penile flaccidity through vasomotor tone is an active process involving complex signaling mechanisms. Heightened smooth muscle contraction is present in some models of ED,[3,4] and various studies have suggested that pharmacological inhibition of smooth muscle contraction, as opposed to active induction of dilation (such as through nitric oxide (NO)-mediated pathways), may be a beneficial strategy for the treatment of ED.[5–7]

In this review, we will outline the major smooth muscle signaling pathways involved in penile vasoconstriction and discuss the potential for inhibition of these pathways as a treatment option for organic ED. A focus will be on the promise and limitations of pharmacological therapy based on current progress in the development of RhoA/Rho-kinase (ROCK) antagonists.