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The Promise of Inhibition of Smooth Muscle Tone As a Treatment for Erectile Dysfunction: Where Are We Now?

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The Promise of Inhibition of Smooth Muscle Tone As a Treatment for Erectile Dysfunction: Where Are We Now? International Journal of Impotence Research (2012) 24, 49–60 & 2012 Macmillan Publishers Limited All rights reserved 0955-9930/12 www.nature.com/ijir REVIEW The promise of inhibition of smooth muscle tone as a treatment for erectile dysfunction: where are we now? X Jiang and K Chitaley Department of Urology, University of Washington, Seattle, WA, USA 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. International Journal of Impotence Research (2012) 24, 49–60; doi:10.1038/ijir.2011.49; published online 6 October 2011 Keywords: contraction; erectile dysfunction; RhoA/Rho kinase; smooth muscle Introduction (NO)-mediated pathways), may be a bene- ficial strategy for the treatment of ED.5–7 Erectile dysfunction (ED) affects 30 million men In this review, we will outline the major smooth in the United States1 and is associated with muscle signaling pathways involved in penile co-morbidities ranging from prostatectomy to dia- vasoconstriction and discuss the potential for betes and increased age. Penile erection is a inhibition of these pathways as a treatment option dynamic process requiring dilation of feeder arter- for organic ED. A focus will be on the promise ioles and cavernosal sinusoids allowing for in- and limitations of pharmacological therapy based on creased inflow of blood. It is important to current progress in the development of RhoA/ remember, however, that the vast majority of the Rho-kinase (ROCK) antagonists. time, these arterioles and sinusoids are maintained in the collapsed/contracted state, severely restrict- ing penile blood flow.2 The maintenance of penile Contractile signaling flaccidity through vasomotor tone is an active process involving complex signaling mechanisms. The vast majority of time, the penis is maintained in Heightened smooth muscle contraction is present in the flaccid state through active contraction of penile 3,4 some models of ED, and various studies have arterioles. The release of norepinephrine (NE) from suggested that pharmacological inhibition of sympathetic nerve terminals activates arteriolar and smooth muscle contraction, as opposed to active cavernosal a-adrenergic receptors.2,8,9 Subsequent 2 þ 2 þ induction of dilation (such as through nitric oxide increases in intracellular Ca concentration ([Ca ]i) result in the activation of myosin light-chain kinase (MLCK) and phosphorylation of myosin light chain (MLC), enabling actin–myosin cross-bridge cycling. In addition to the Ca2 þ -dependent contractile Correspondence: Dr K Chitaley, Department of Urology, 2 þ University of Washington, Box 358050, 815 Mercer Street, mechanism, Ca -sensitizing pathways, such as Room 319, Seattle, WA 98109, USA. ROCK- and protein kinase C (PKC)-mediated signal- E-mail: [email protected] ing, can promote contraction through the inhibition Received 28 March 2011; revised 13 July 2011; accepted of MLC phosphatase or the direct stimulation of 17 August 2011; published online 6 October 2011 MLC phosphorylation.10,11 Both Ca2 þ -dependent Inhibition of smooth muscle tone as a treatment for ED X Jiang and K Chitaley 50 and Ca2 þ -sensitizing signaling can be activated by arteries showed that Ca2 þ influx and release from NE or other agonists, including endothelin-1 (ET-1), the intracellular Ca2 þ store may also be involved in serotonin (5-HT) and angiotensin-II (Ang-II).4,10,12–15 5-HT-induced contraction.15 Ang-II. Being an important component of the Upstream signaling: NE, ET-1, 5-HT and Ang-II renin–Ang system, Ang-II is converted from Ang-I NE. It is generally accepted that penile detumes- by Ang-converting enzyme (ACE) predominately in cence and flaccidity are achieved mainly by constant the lung. Ang-II binds to Ang receptors on the sympathetic input.2 Both cavernous smooth muscle membranes of smooth muscle cells and other (CSM) and the smooth muscle of the penile arteries cell types, causing contraction via both Ca2 þ and veins are rich in sympathetic innervation. Upon -dependent30 and Ca2 þ -sensitizing31 mechanisms, activation, the sympathetic nerve terminals release similar to the other agonists. Becker et al.32,33 NE, which binds to and stimulates a-adreno- reported that Ang-II levels were 30% higher in the ceptors on the smooth muscle membrane.16,17 The cavernous blood than that in the systemic blood, activation of a-adrenoceptors triggers a series of indicating that Ang-II is produced locally in the CC. intracellular signaling pathways involving both This is further supported by the findings that ACE Ca2 þ -dependent12,13 and Ca2 þ -sensitizing mecha- is expressed in the endothelial cells of canine CC.34 nisms,10,11 to induce contraction. The dynamic changes in Ang-II levels in the caver- nous blood during different penile states32,33 suggest ET-1. ET-1, a member of the ET family of peptides, that Ang II plays a physiological role in regulating penile tone. In organ-bath studies, Ang-II evoked dose- is among the strongest vasoconstrictors known. ET-1 33 35 is produced primarily in the endothelium and plays dependent contraction of human and rabbit CC an important role in vascular homeostasis.18 In the strips. In vivo studies demonstrated that intracaverno- corpus cavernosum (CC), ET-1 elicits slow-develop- sal injection (ICI) of Ang-II terminated spontaneous ing but strong, long-lasting contractions.19 Smooth erections, whereas an Ang II receptor blocker, losartan, increased the intracavernosal pressure, in a dose- muscle cells including CSM cells express two 36 19 dependent manner, in anesthetized dogs. subtypes of ET-1 receptors: ETA and ETB. The binding of ET-1 to ETA increases vasocontraction, whereas the binding of ET-1 to ETB leads 19–21 to vasorelaxation via the release of NO. In the Intracellular signaling CC, ET expression is dominant over ET , and 2 þ 2 þ A B Ca -dependent pathways. Regulation of [Ca ]i: therefore, ET-1 mainly induces CSM contrac- 2 þ It has been widely accepted that elevated [Ca ]i is tion.22,23 Similar to NE, ET-1-induced CSM contrac- 2 þ 13,24 critical for maintaining smooth muscle in a con- tion is mediated by an increase in both [Ca ]i 37,38 2 þ 2 þ 4 tracted state. The increase in [Ca ]i could be a and Ca sensitization. Evidence indicates that result of: (1) increased Ca2 þ release from the changes in the ET-1 pathway are involved in the 4 intracellular store-sarcoplasmic reticulum (SR); pathophysiology of ED. Chang et al. found that the (2) increased Ca2 þ influx, mainly through the expression of ETA receptors was significantly upre- L-type voltage-gated Ca2 þ channels (VGCCs); and/ gulated in the CSM of diabetic rabbits. Sullivan 2 þ 39 25 or (3) inhibited Ca removal. et al. reported a significant decrease in ETB Ca2 þ release from the SR—There are two types of receptor binding sites in cavernosal tissue from Ca2 þ channels in the SR membrane: inositol hypercholesterolemic rabbits, and a significant in- 40,41 trisphosphate (IP3) and ryanodine receptors. crease in ETB receptor binding sites in cavernous 26 The binding of agonists (NE and others) to their tissue of diabetic rabbits. receptors on the cell membranes activates phospho- lipase C, which leads to the production of IP3 and 5-HT. 5-HT is a monoamine neurotransmitter that diacylglycerol. IP3 then binds to IP3 receptors on the has a variety of functions in the central nervous SR membrane and triggers the release of Ca2 þ . system as well as peripheral tissues. In the CC, 5-HT These Ca2 þ transients activate Ca2 þ -dependent released from the serotonergic nerve fibers has a ClÀ channels and depolarize the membrane, and in physiological role in the maintenance of penile turn, open the VGCCs.42,43 The opening of ryano- flaccidity and the initiation of detumescence.14,27 dine receptors is Ca2 þ -dependent, through the Several studies showed that 5-HT induced contrac- process of Ca2 þ -induced Ca2 þ release, resulting 2 þ 44 2 þ tion of isolated penile tissue, which could be in a further increase in [Ca ]i. The role of Ca blocked by 5-HT receptor antagonists.14,27–29 release through ryanodine receptors seems to be Further, pre-incubation with ROCK inhibitor more complicated: whereas evidence shows that Y-27632 attenuated maximum contraction induced they function similarly as the IP3-mediated by 5-HT of penile tissue, indicating that RhoA/ Ca2 þ release (that is, mediating contraction),45 ROCK pathway is a mediator of 5-HT-induced other studies indicate that they may activate contraction.14 Evidence from human pulmonary Ca2 þ -dependent K þ channels, which in turn causes International Journal of Impotence Research Inhibition of smooth muscle tone as a treatment for ED X Jiang and K Chitaley 51 2+ - hyperpolarization of smooth muscle cells leading Agonists Ca Cl 46 to relaxation.
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