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

Contractile Signaling and ED

Diabetic ED

Several lines of evidence showed that diabetic ED is associated with an imbalance towards enhanced penile vasoconstriction, resulting from changes in contractile signaling of the CSM at multiple levels. The concentration of penile NE was found to be increased in diabetic rats,[110] and elevated plasma level of ET-1 has been shown in diabetic patients.[111,112] Chang et al.[5] found that the expression of ETA receptors was significantly upregulated in the CC of diabetic rabbits and rats.[84] Sullivan et al.[26] reported a significant increase in ETB receptor binding sites in cavernous tissue of diabetic rabbits. As the downstream signaling of both NE and ET, RhoA/ROCK axis was found to be upregulated in diabetic animals as well. The expression of ROCK1, but not ROCK2, was significantly increased in penile tissues from different diabetic animal models,[4,83,84] indicating that ROCK1 is involved in diabetic ED. Furthermore, Angulo et al.[101] demonstrated that diabetes causes hypercontractility of human cavernous tissue by a mechanism involving overactivity of PKC.

Hypertension-related ED

Similar to diabetic ED, hypertension-related ED may be related to augmented contractile signaling in the CC as well. Deoxycorticosterone acetate-salt-induced hypertensive animals showed increased cavernous contractile responses to both ET-1 and the α-adrenergic receptor agonist phenylephrine.[113,114] As to the downstream signaling, although protein expression levels of ROCK in the CC of deoxycorticosterone acetate-treated animals were similar to those of control animals, the phosphorylated form of myosin phosphatase regulatory subunit, a downstream effector of ROCK, was increased in cavernous tissue from deoxycorticosterone acetate animals.[114] In the spontaneously hypertensive rat, Wilkes et al.[115] found that hypertension-related ED is associated with elevated penile RhoA levels and that inhibition of ROCK activity with Y-27632 was beneficial in attenuating the decline in erectile function. In another study, ROCK2 protein was found to be elevated in spontaneous hypertensive rats.[81] However, Behr-Roussel et al.[116] found both a reduced cavernous contractile response to phenylepherine and an impaired endothelium-dependent relaxation to acetylcholine in spontaneous hypertensive rats. The authors proposed that the pathophysiology of ED in hypertension is the result of an increase in cyclooxygenase-dependent constrictor tone, although a defect of endothelial or neuronal NO production and/or bioavailability cannot be excluded.

Aging-related ED

Aging is closely related to ED, and interestingly, despite an increased contractile response in the CC,[117] aged animals showed decreased (rather than increased) penile concentration of NE[110] and expression of L-type VGCC and ryanodine receptors.[118] It is possible that aging mainly impairs the relaxation signaling, resulting in 'unmasking' of the contractile signaling. However, Jin et al.[119] reported that though the expression of total RhoA remains unchanged, membrane-bound RhoA and phosphorylated myosin phosphatase regulatory subunit in the CC of aged rats are increased, indicating that enhanced RhoA and ROCK activity may play a role. Treatment with an Ang-II receptor antagonist[120] and the ROCK inhibitor Y-27632[121] also improve erectile function in aged animals, indicating that elevated contractile tone may be involved in aging-related ED.

ED Caused by Cavernous Nerve Injury

Cavernous nerve injury is another common cause of ED. Following cavernous nerve injury, animals show penile fibrosis, that is, decreased smooth muscle and increased collagen content.[122] Gratzke et al.[82] reported that bilateral cavernous nerve injury causes increased RhoA and ROCK2 protein expression, and increased RhoA GTPase and ROCK activity in rat CC. The penile ROCK1 protein expression is unchanged in these animals. However, Cho et al.[123] found increased ROCK1 expression in the CC of rats following cavernous nerve injury. In accordance with these findings, ICI of Y-27632 causes a significantly greater increase in intracavernosal pressure in nerve-injured rats compared to that in sham-operated rats.[123]

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