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

Where Are We Now?

X Jiang; K Chitaley

Disclosures

Int J Impot Res. 2012;24(2):49-60. 

In This Article

Inhibition of Vasoconstriction to Induce Erection

Endogenous Mechanisms

The main driving force for penile erection is NO-mediated signaling. Sexual stimulation or nocturnal tumescence activates neuronal NO synthase-mediated NO release from non-adrenergic non-cholinergic nerve endings[8,124] initiating vasodilation. Subsequently, maintenance of dilation has been proposed to occur through sheer flow-induced endothelial NOS activation.[125] In the smooth muscle cell, NO stimulates soluble guanylate cyclase, activating cGMP-dependent protein kinase for cavernosal relaxation.[126]

NO signaling was originally thought to induce vasodilation by modulation of [Ca2+]i, through events including the inhibition of L-type VGCCs, the activation of Ca2+-dependent K+ channels, the promotion of plasma membrane Ca2+-ATPases and Na+–Ca2+ exchangers activity and the activation of sarco(endo)plasmic reticulum Ca2+-ATPases.[56,127,128] It is now clear that NO signaling can also inhibit Ca2+-sensitizing mechanisms directly resulting in vasorelaxation. cGMP-dependent protein kinase can decrease levels of phosphorylated MLC through telokin-mediated activation of MLC phosphatase,[93] as well as direct inhibition of RhoA through its phosphorylation.[129,130] Recombinant cGMP-dependent protein kinase has been shown to phosphorylate RhoA, destabilizing its membrane binding resulting in NO-mediated inhibit of RhoA/ROCK activity.[129,130] It is tempting to speculate that decreased NO bioavailability leads to an increase in RhoA/ROCK constrictor activity. Elevated ROCK activity may then mediate the increased vasoconstrictor sensitivity seen in various animal models of ED. Endogenously, decreased [Ca2+]i induced by NO may also lead to vasodilation through inactivation of PKC, rapid CPI-17 dephosphorylation as well as MLCK inactivation, resulting in rapid MLC dephosphorylation and relaxation.[131]

Pharmacological Therapies

Blockage of Upstream Signaling (NE, ET-1, ANG-II)NE: The non-selective α-adrenoceptor blocker, phentolamine, can block the effect of NE by competitively binding to the α1-adrenoceptor in the CC, leading to the relaxation of the CSM.[132] In addition to the blockage of α-adrenoceptors, phentolamine may also induce relaxation of cavernous tissue by blocking ET-1 signaling.[133] However, ICI with 5 mg phentolamine only resulted in penile tumescence, but not rigidity in humans.[5] Currently, phentolamine is administered in conjunction with other vasoactive agents, such as papaverine, prostaglandin E1 and vasoactive intestinal polypeptide[5] as ICI therapies, with the advantages of lowering the dosages and therefore the adverse effects of the other agents.[134] The safety and efficacy of oral phentolamine in the treatment of ED have been explored.[135,136] Compared to sildenafil, oral phentolamine has a higher incidence of adverse effects and is less effective in improving penile erection.[136] Selective α1-adrenoceptor antagonists are commonly used to treat lower urinary tract symptoms. Studies showed that they slightly improved erectile function as well.[137,138] An additive effect was observed when the selective α1-adrenoceptor antagonist alfuzosin was used together with sildenafil to treat ED.[139]

ET-1: An ETA receptor antagonist was shown to increase the duration of nerve-stimulated elevations in intracavernosal pressure in rabbits, although the peak pressure values were not altered.[6] Despite the efficacy of the ETA receptor antagonist in animal studies, oral administration of this drug to men with mild-to-moderate ED did not significantly improve erectile function compared to placebo.[6] This disparity in efficacy between lab studies in rabbits and clinical studies was possibly due to important differences between species with regard to the role of ET-1 in erectile function. This is further supported by the findings in rats that ET receptor antagonists do not significantly alter the erectile response, although they inhibit potent contractions to exogenous ET-1.[140] Nevertheless, treatment with ET receptor antagonists for 2 weeks reversed cavernous apoptosis in diabetic rats,[141] indicating that chronic administration of ET receptor antagonists might be beneficial in the protection of erectile tissue.

Ang-II: ACE inhibitors and Ang-II receptor blockers are widely used antihypertensive drugs. Since blockage of the Ang-II pathway results in smooth muscle relaxation, these agents might be beneficial in the treatment of ED. Animal studies showed that Ang-II receptor antagonists improved penile function in aged animals or animals with dyslipidemia.[120,142] Another study showed that the ACE inhibitor captopril corrected both the blood pressure and erectile response of hypertensive rats to control levels.[143] Several small clinical studies have also suggested that treatment with Ang-II receptor blockers or ACE inhibitors are associated with improved erectile function and sexual performance in patients with hypertension and diabetes mellitus.[144–146] However, a recent double-blind, randomized study, involving 1549 patients, failed to reveal any significant effect of an Ang-II receptor blockers or an ACE inhibitor on ED.[147]

Blockage of the Accumulation of [Ca2+]i Given that [Ca2+]i plays a central role in mediating CSM contraction, drugs that inhibit the increase in [Ca2+]i may be potentially effective in the treatment of ED. This is supported by the findings that calcium channel blockers (CCBs) significantly relaxed rabbit[48] and human[148,149] CSM contracted by α-adrenergic agonists in vitro. However, ICI of CCBs in dogs was less effective and had more side effects compared to papaverine.[150] The results of clinical trials with oral CCBs in the treatment of ED are disappointing. CCBs exert either no effect or a negative effect on erectile function.[151,152] The safety and efficacy of ICI of CCBs have also been studied.[153,154] Although the side effect of ICI of CCBs was comparable to other agents, CCBs may not be as effective as blockade of α-adrenoceptors.[148,153,154]

Blockage of Ca2+-sensitizing Pathway (Mainly RhoA/ROCK) Ten years ago, the inhibition of ROCK by ICI of Y-27632 was found to induce an erectile response in rats.[7] This effect did not require activation of NO-mediated signaling, thus introducing a potential target pathway for the treatment of ED, with potential extended benefit in cases where NO bioavailability was attenuated and thus phosphodiesterase type 5 (PDE5) inhibitors were less efficacious. At this point, ROCK inhibitors are being developed and tested for a wide range of potential uses. In Japan, the ROCK inhibitor fasudil has been used to treat vasospasm following subarachnoid hemorrhage[155] and pulmonary hypertension.[156] One animal study showed that chronic administration of oral fasudil prevented the development of ED and pelvic atherosclerosis.[157] Another study using diabetic rat models demonstrated that fasudil restores erectile function by suppressing corporal apoptosis caused by diabetes.[74] These promising results from animal studies indicate the possibilities of administration of ROCK inhibitors either acutely to induce erection or chronically to prevent or reverse ED. To date, the effect of ROCK inhibitors in the treatment of ED in humans has not been reported. In the era of oral therapy for ED, ICI therapy becomes less attractive. However, one potential problem with systemic administration of ROCK inhibitors is whether it would cause profound extra-cavernosous effects, such as hypotension. Further, the two ROCK isoforms share ~90% homology in their kinase domains.[158] This has made it quite challenging to develop isoform-selective inhibitors for clinical use. A recent compound, SLx2119 (Surface Logix), is unique in its specificity for only ROCK2.[159]

A summary of the outcomes of both animal and human studies on the pharmacological targets modulating CSM contraction for the treatment of ED is shown in Table 1 . The most significant advances during the past decade are listed as follows:

  • α-Adrenoceptor antagonists have an additive effect when administered together with other ED medications.

  • Chronic administration of ET receptor antagonists is beneficial in the protection of erectile tissue in rats. However, data in humans are lacking.

  • Chronic administration of ROCK inhibitors prevents ED or restores erectile function in animals. However, clinical studies are needed.

Conclusions

This review outlines contractile signaling pathways, which play a role in the maintenance of penile flaccidity. The potential for therapeutic intervention at the level of smooth muscle contraction, bypassing the need for intact NO-dependent signaling, is especially appealing for the treatment of ED associated with co-morbidities such as diabetes or prostatectomy, where NO signaling may be impaired. However, more than 10 years after the discovery of potent contractile signaling pathways in the cavernosum, we remain far from such targeted therapeutics. The most promise for therapeutic intervention has been found with the inhibitor of ROCK signaling. The availability of the ROCK inhibitor fasudil in Japan for the treatment of other conditions makes clinical studies of its efficacy and safety in the treatment of ED possible. Furthermore, isoform-selective ROCK inhibitors may be indicated in the treatment of ED with different etiologies with a reduced systemic side effect, although various obstacles, such as isoform homology and lack of tissue specificity, have hindered their development. Other potential targets in both Ca2+-dependent and Ca2+-sensitizing signaling pathways may be explored for benefits in the treatment of ED. Combined blockages of multiple targets in these pathways may enhance the efficacy in promoting penile erection. Development of these targeted therapeutics, which may benefit even cohorts refractory to PDE5 inhibition, are certainly promising and warranted.

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