Recent studies have demonstrated that vasoconstriction in the erectile vasculature of the penis is mediated in part by RhoA/Rho-kinase signaling. However, this constrictor activity must be overcome to permit the vasodilation essential for erection. We hypothesize that the primary action of nitric oxide and other agents that cause penile erection is inhibition of the RhoA/Rho-kinase pathway, thereby allowing vasodilation and erection. This hypothesis, as well as experiments using hypogonadal and hypertensive animal models, are discussed in terms of the potential clinical value of Rho-kinase inhibitors for the treatment of erectile dysfunction.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
References and Recommended Reading
Andersson KE: Pharmacology of erectile function and dysfunction. Urol Clin North Am 2001, 28:233–247.
Andersson KE: Pharmacology of penile erection. Pharmacol Rev 2001, 53:417–450. An extremely throrough and very well-documented review of the pathways and agents that regulate the erectile response.
Andersson KE: Neurophysiology/pharmacology of erection. Int J Impot Res 2001, 13(Suppl 5):S8-S17.
Naylor AM: Endogenous neurotransmitters mediating penile erection. Br J Urol 1998, 81:424–431.
Kim NN, Goldstein I, Moreland RB, Traish AM: Alphaadrenergic receptor blockade by phentolamine increases the efficacy of vasodilators in penile corpus cavernosum. Int J Impot Res 2000, 12(Suppl 1):S26-S36.
Andersson KE, Hedlund P, Alm P: Sympathetic pathways and adrenergic innervation of the penis. Int J Impot Res 2000, 12(Suppl 1):S5–12.
Traish A, Kim NN, Moreland RB, Goldstein I: Role of alpha adrenergic receptors in erectile function. Int J Impot Res 2000, 12(Suppl 1):S48-S63.
Mills T, Pollock DM, Lewis RW, et al.: Endothelin-1 induced vasoconstriction is inhibited during erection in rats. Am J Physiol Regul Integr Comp Physiol 2001, 281:R476-R483.
Dai Y, Pollock DM, Lewis RW, et al.: Receptor-specific influence of endothelin-1 in the erectile response of the rat. Am J Physiol Regul Integr Comp Physiol 2000, 279:R25-R30.
Jong MY, Kang TM, Lee S: The effects of nitric oxide on the endothelin-1-induced intracellular calcium increases in smooth muscle cells of human corpus cavernosum [abstract]. Paper presented at the 7th Biennial Asia-Pacific Meeting on Impotence. Tokyo, Japan. October 26–30, 1999.
Giraldi A, Serels S, Autieri M, et al.: Endothelin-1 as a putative modulator of gene expression and cellular physiology in cultured human corporal smooth muscle cells. J Urol 1998, 160:1856–1862.
Rossi P, Menchini Fabris F, Fiorini I, et al.: Comparison between plasma concentrations of testosterone nitric oxide and endothelin-1 in penile and brachial venous blood: preliminary results in men with psychogenic impotence. Biomed Pharmacother 1998, 52:308–310.
Redmond EM, Cahill PA, Hodges R, et al.: Regulation of endothelin receptors by nitric oxide in cultured rat vascular smooth muscle cells. J Cell Physiol 1996, 166:469–479.
Pollock DM, Tasker AS: Endothelin receptors and receptor antagonists. In Endothelin Receptors and Signaling Mechanisms. Edited by Pollock DM, Highsmith RF. Berlin: Springer-Verlag; 1998:3–15.
Somlyo AP, Wu X, Walker LA, Somlyo AV: Pharmacomechanical coupling: the role of calcium, G-proteins, kinases and phosphatases. Rev Physiol Biochem Pharmacol 1999, 134:201–234.
Somlyo AP, Somlyo AV: Signal transduction by G-proteins rho-kinase and protein phosphatase to smooth muscle and non-muscle myosin II. J Physiol 2000, 522:177–185. An excellent overall review that demonstrates the importance of the RhoA/ Rho-kinase calcium sensitization pathway in smooth muscle physiology.
DeFeo T, Morgan K: Calcium-force relationships as detected with aequorin in two different vascular smooth muscles of the ferret. J Physiol 1985, 369:269–292.
Stief CG, Noack T, Andersson KE: Signal transduction in cavernous smooth muscle. World J Urol 1997, 15:27–31.
Burnett AL: The role of nitric oxide in the physiology of erection. Biol Reprod 1995, 52:485–489.
Tamura M, Kagawa S, Tsuruo Y, et al.: Localization of NADPH diaphorase and vasoactive intestinal polypeptide-containing neurons in the efferent pathway to the rat corpus cavernosum. Eur Urol 1997, 32:100–104.
McMahon CG: A pilot study of the role of intracavernous injection of vasoactive intestinal peptide (VIP) and phentolamine mesylate in the treatment of erectile dysfunction. Int J Impot Res 1996, 8:233–236.
Champion HC, Wang R, Santiago JA, et al.: Comparison of responses to adrenomedullin and calcitonin generelated peptide in the feline erection model. J Androl 1997, 18:513–521.
Truss MC, Becker AJ, Thon WF, et al.: Intracavernous calcitonin gene-related peptide plus prostaglandin E1: possible alternative to penile implants in selected patients. Eur Urol 1994, 26:40–45.
Djamilian M, Stief CG, Kuczyk M, Jonas U: Followup results of a combination of calcitonin gene-related peptide and prostaglandin E1 in the treatment of erectile dysfunction. J Urol 1993, 149:1296–1298.
Sauzeau V, Le Jeune H, Cario-Toumaniantz C, et al.: Cyclic GMP-dependent protein kinase signaling pathway inhibits RhoA-induced Ca2+ sensitization of contraction in vascular smooth muscle. J Biol Chem 2000, 275:21722–21729.
Sanez De Tejada I: Molecular mechanisms for the regulation of penile smooth muscle. Int J Impot Res 2002, 14(Suppl 1):S6-S10.
Suh JK, Mun KH, Cho CK, et al.: Effect of vasoactive intestinal peptide and acetylcholine on penile erection in the rat in vivo. Int J Impot Res 1995, 7:111–118.
Bivalacqua TJ, Champion HC, Rajasekaran MA, et al.: Potentiation of erectile response and cAMP accumulation by combination of prostaglandin E1 and rolipram, a selective inhibitor of the type 4 phosphodiesterase (PDE 4). J Urol 1999, 162:1848–1855.
Burnett AL, Nelson RJ, Calvin DC, et al.: Nitric oxidedependent penile erection in mice lacking neuronal nitric oxide synthase. Mol Med 1996, 2:288–296.
Goldstein I, Lue TF, Padma-Nathan H, et al.: Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. New Engl J Med 1998, 338:1397–1404.
Mills TM, Chitaley K, Wingard CJ, et al.: Effect of Rho-kinase inhibition on vasoconstriction in the penile circulation. J Appl Physiol 2001, 91:1269–1273.
Chitaley K, Webb RC, Mills TM: RhoA/Rho-kinase: a novel player in the regulation of penile erection. Int J Impot Res 2001, 13:67–72.
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 2001, 7:119–122. The first demonstration of the importance of the RhoA/Rho-kinase pathway in the erectile response of the mammalian penis. These studies showed that both RhoA and Rho-kinase proteins are present in rat erectile tissue. Furthermore, through the use of NOS inhibitors and guanylate cyclase, the experiments showed that inhibition of Rho-kinase leading to erection did not activate NO/cGMPdependent vasorelaxation.
Rees RW, Ziessen T, Ralph DJ, et al.: Human and rabbit cavernosal smooth muscle cells express Rho-kinase. Int J Impot Res 2002, 14:1–7.
Rees RW, Ralph DJ, Royle M, et al.: Y-27632, an inhibitor of Rho-kinase antagonizes noradrenergic contractions in the rabbit and human penile corpus cavernosum. Br J Pharmacol 2001, 133:455–458.
Wingard C, Lewis R, Mills T: Erection and NO override the vasoconstrictor effect of alpha adrenergic stimulation in the rat penile vasculature. Int J Impot Res 2001, 13(Suppl 5):212–220.
Reilly CM, Stopper VS, Mills TM: Androgens modulate the alpha-adrenergic responsiveness of vascular smooth muscle in the corpus cavernosum. J Androl 1997, 18:26–31.
Chitaley K, Webb RC: Nitric oxide induces dilation of rat aorta via inhibition of Rho-kinase signaling. Hypertension 2002, 39:438–442.
Mills TM, Chitaley K, Lewis RW, Webb RC: Nitric oxide inhibits RhoA/Rho-kinase signaling to cause erection. Eur J Pharmacol 2002, 439:173–174. These studies support the hypothesis that an important action of NO leading to erection is the inhibition of the RhoA/Rho-kinase pathway.
Chitaley K, Webb RC, Mills TM: The ups and downs of Rho-kinase and penile erection: upstream regulators and downstream substrates of Rho-kinase and their potential role in the erectile response. Int J Impot Res 2002, In press.
Mills TM, Chitaley K, Lewis R: Vasoconstrictors in erectile physiology. Int J Impot Res 2001, 13(Suppl 5):S1-S5.
Chitaley K, Webb RC, Dorrance AM, Mills TM: Decreased penile erection in DOCA-salt and stroke prone-spontaneously hypertensive rats. Int J Impot Res 2001, 13(Suppl 5):S16-S20.
Dai Y, Lewis RW, Stopper VS, Mills TM: Effects of castration and testosterone replacement on veno-occlusion during penile erection in the rat. Asian J Androl 1999, 1:53–59.
Mills TM, Lewis RW: The role of androgens in the erectile response: a 1999 perspective. Mol Urol 1999, 3:75–80.
Mills TM, Dai Y, Stopper VS, Lewis RW: Androgenic maintenance of the erectile response in the rat. Steroids 1998, 64:605–609.
Uehata M, Ishizaki T, Sagoh H, et al.: Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature 1997, 389:990–994.
About this article
Cite this article
Mills, T.M. Vasoconstriction and vasodilation in erectile physiology. Curr Urol Rep 3, 477–483 (2002). https://doi.org/10.1007/s11934-002-0101-9
- Mean Arterial Pressure
- Erectile Dysfunction
- Vasoactive Intestinal Peptide
- Penile Erection