COMP-4, a nutraceutical combination consisting of ginger rhizome, muira puama, Paullinia cupana, and l-citrulline, enhances intracellular nitric oxide (NO) production by the corporal smooth muscle cells (CSMC). This study aims to determine if the previously shown beneficial effect of COMP-4 on the histology and function of the aging penis is associated with an antioxidative effect from endogenously produced NO. Ten-month-old male rats were treated daily for 2 months with COMP-4 or vehicle at which time the corpora and penile dorsal artery (PDA) were evaluated by immunohistochemistry for (a) apoptosis (b) proliferative cell nuclear antigen, (c) heme oxygenase-1 (HO-1), (d) myeloperoxidase (MPO), and (e) nitrotyrosine (NT). CSMC were cultured and incubated with COMP-4 in order to determine intracellular oxidative stress via the GSH/GSSG ratio. In both the corpora and PDA, daily treatment with COMP-4 resulted in an increase in both smooth muscle cell proliferation and HO-1 expression as well as a decrease in MPO. There was no change in either apoptosis or NT expression. In the CSMC cell culture, treatment with COMP-4 increased the intracellular GSH/GSSG ratio. COMP-4 appears to have an antioxidant effect on the aging vascular smooth muscle cells both in the corpora and peripheral vasculature.
Subscribe to Journal
Get full journal access for 1 year
only $55.50 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol. 1994;151:54–61.
Rajfer J, Rosciszewski A, Mehringer M. Prevalence of corporeal venous leakage in impotent men. J Urol. 1988;140:69–71.
Junemann KP, Persson-Junemann C, Lue TF, Tanagho EA, Alken P. Neurophysiological aspects of penile erection: the role of the sympathetic nervous system. Br J Urol. 1989;64:84–92.
Nehra A, Goldstein I, Pabby A, Nugent M, Huang YH, de las Morenas A, et al. Mechanisms of venous leakage: a prospective clinicopathological correlation of corporeal function and structure. J Urol. 1996;156:1320–9.
Jevtich MJ, Khawand NY, Vidic B. Clinical significance of ultrastructural findings in the corpora cavernosa of normal and impotent men. J Urol. 1990;143:289–93.
Ferrini MG, Gonzalez-Cadavid NF, Rajfer J. Aging related erectile dysfunction-potential mechanism to halt or delay its onset. Transl Androl Urol. 2017;6:20–7.
Ferrini MG, Davila HH, Valente EG, Gonzalez-Cadavid NF, Rajfer J. Aging-related induction of inducible nitric oxide synthase is vasculo-protective to the arterial media. Cardiovasc Res. 2004;61:796–805.
Gonzalez-Cadavid NF, Rajfer J. The pleiotropic effects of inducible nitric oxide synthase (iNOS) on the physiology and pathology of penile erection. Curr Pharm Des. 2005;11:4041–6.
Gonzalez-Cadavid NF. Mechanisms of penile fibrosis. J Sex Med. 2009;6 (Suppl 3):S353–62.
Ferrini MG, Kovanecz I, Sanchez S, Umeh C, Rajfer J, Gonzalez-Cadavid NF. Fibrosis and loss of smooth muscle in the corpora cavernosa precede corporal veno-occlusive dysfunction (CVOD) induced by experimental cavernosal nerve damage in the rat. J Sex Med. 2009;6:415–28.
Ferrini MG, Davila HH, Kovanecz I, Sanchez SP, Gonzalez-Cadavid NF, Rajfer J. Vardenafil prevents fibrosis and loss of corporal smooth muscle that occurs after bilateral cavernosal nerve resection in the rat. Urology. 2006;68:429–35.
Ferrini MG, Garcia E, Abraham A, Artaza JN, Nguyen S, Rajfer J. Effect of ginger, Paullinia cupana, muira puama and L-citrulline, singly or in combination, on modulation of the inducible nitric oxide- NO-cGMP pathway in rat penile smooth muscle cells. Nitric Oxide. 2018;76:81–6.
Ferrini MG, Hlaing SM, Chan A, Artaza JN. Treatment with a combination of ginger, L-citrulline, muira puama and Paullinia cupana can reverse the progression of corporal smooth muscle loss, fibrosis and veno-occlusive dysfunction in the aging rat. Andrology. 2015;4:132.
Nguyen S, Rajfer J, Shaheen M. Safety and efficacy of daily Revactin((R)) in men with erectile dysfunction: a 3-month pilot study. Transl Androl Urol. 2018;7:266–73.
Buttery LD, Springall DR, Chester AH, Evans TJ, Standfield EN, Parums DV, et al. Inducible nitric oxide synthase is present within human atherosclerotic lesions and promotes the formation and activity of peroxynitrite. Lab Investig. 1996;75:77–85.
Ferrini MG, Kovanecz I, Sanchez S, Vernet D, Davila HH, Rajfer J, et al. Long-term continuous treatment with sildenafil ameliorates aging-related erectile dysfunction and the underlying corporal fibrosis in the rat. Biol Reprod. 2007;76:915–23.
Nicholls SJ, Hazen SL. Myeloperoxidase and cardiovascular disease. Arterioscler Thromb Vasc Biol. 2005;25:1102–11.
Choi AM, Alam J. Heme oxygenase-1: function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury. Am J Respir Cell Mol Biol. 1996;15:9–19.
Jin YC, Gam SC, Jung JH, Hyun JS, Chang KC, Hyun JS. Expression and activity of heme oxygenase-1 in artificially induced low-flow priapism in rat penile tissues. J Sex Med. 2008;5:1876–82.
Joza N, Susin SA, Daugas E, Stanford WL, Cho SK, Li CY, et al. Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death. Nature. 2001;410:549–54.
This study was funded by NIH-National Institute on Minority Health and Health Disparities (NIH/NIMHD) 5U54MD007598-06 (MGF) and a Urology Resident Training Grant from the UCLA Department of Urology (SN). Certain aspects of the study were also supported in part by the National Institute of Neurological Disorders and Stroke and the National Institute of General Medicine NINDS/NIGMS SC1NS064611 (MGF).
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Nguyen, S., Castellanos, K.A., Abraham, A. et al. Reduction of oxidative stress markers in the corpora cavernosa and media of penile dorsal artery in middle-aged rats treated with COMP-4. Int J Impot Res (2020). https://doi.org/10.1038/s41443-020-0233-9