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Re: Oxidative Stress in Arteriogenic Erectile Dysfunction: Prophylactic Role of Antioxidants
LETTERS TO THE EDITOR be a noninvasive test of diagnostic significance in the evaluation of erectile dysfunction, since it seemingly provides information about the integrity of the corpus cavernosum smooth musculature. It should be indicated that this is not the first study to record the electrical activity of the corpus cavernosum with surface electrodes attached to the penile skin. Stief et al first reported the possibility of recording corpus cavernosum electromyography with the use of surface electrodes placed on the penile skin.1 However, in subsequent studies they did not advocate the surface recording method due to the possibility of the interference of skin potentials.2 Cavernous activity can be recorded spontaneously, which is called corpus cavernosum electromyography.3 It is also possible to record evoked cavernous activity in response to startling stimulus.4 In a recent study we demonstrated that spontaneous and evoked electrical activity can be recorded from penile skin with surface electrodes in men with disrupted smooth musculature following penile prosthesis implantation.5 The electrical activity recorded from the skin represents mostly the sudomotor sweat gland activity of the penile skin, although there may be electrical interference from the underlying corpus cavernosum smooth muscle activity. In this study Shafik et al gave close attention to a possible interference of respiratory movement artifacts but did not address the sudomotor component. Recordings from penile skin electrodes are a composite of the electrical activity from the penile skin and the corpus cavernosum. Pure corpus cavernosum activity is recordable only with needle electrodes. Respectfully, Ugur Yilmaz Department of Urology University of Washington Seattle, Washington 98195 and Ahmet Soylu Department of Urology Inonu University Medical Faculty Malatya, Turkey 1. Stief, C. G., Thon, W. F., Djamilian, M., Allhoff, E. P. and Jonas, U.: Transcutaneous registration of cavernous smooth muscle electrical activity: noninvasive diagnosis of neurogenic autonomic impotence. J Urol, 147: 47, 1992 2. Stief, C. G., Höppner, C., Sauerwein, D. and Jonas, U.: Single potential analysis of cavernous electrical activity in spinal cord injury patients. J Urol, 151: 367, 1994 3. Sasso, F., Stief, C. G., Gulino, G., Alcini, E., Junemann, K. P., Gerstenberg, T. et al: Progress in corpus cavernosum electromyography (CC-EMG)-third international workshop on corpus cavernosum electromyography (CC-EMG). Int J Impot Res, 9: 43, 1997 4. Yilmaz, U., Soylu, A., Özcan, C., Kutlu, R. and Günes, A.: Evoked cavernous activity. J Urol, 167: 188, 2002 5. Soylu, A., Yilmaz, U., Ozcan, C., Sarier, M. and Baydinc, C.: Role of penile electrodermal activity in the evaluation of autonomic innervation of corpus cavernosum. Int J Impot Res, 16: 535, 2004
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Re: Oxidative Stress in Arteriogenic Erectile Dysfunction: Prophylactic Role of Antioxidants K. M. Azadzoi, R. N. Schulman, M. Aviram and M. B. Siroky J Urol, 174: 386 –393, 2005 To the Editor. We read with interest the article by Azadzoi et al, who demonstrated that pomegranate juice improved erectile dysfunction and decreased fibrosis in an animal model of erectile dysfunction by virtue of its antioxidant properties. We would like to add some comments on other findings that may be of interest. We and others have also suggested that oxidative stress, in particular the overproduction of superoxide (O2䡠⫺) may be central to the etiology of vasculogenic erectile dysfunction (VED).1-7 O2䡠⫺ reacts with nitric oxide (NO) to form reactive nitrogen species, effectively reducing NO bioavailability, a key determinant of erection.1,2 Furthermore, the principal risk factors for VED (hypercholesterolemia, diabetes mellitus and cigarette smoking, and possibly hyperhomocysteinemia) are all associated with increased intracavernous expression/activity of reduced nicotinamide adenine dinucleotide phosphate oxidase (NADPH), an enzyme that generates O2䡠⫺.3-8 More recently, we demonstrated that thromboxane A2 (TXA2) is a potent up-regulator of NADPH oxidase and O2䡠⫺ formation in cavernous vascular smooth muscle cells.9 Azadzoi et al also reported that there was increased formation of 8-isoprostane F2␣ (8-ISOP) in their model. We also found that 8-ISOP is a potent stimulator of O2䡠⫺ formation and of NADPH oxidase expression, and that, in turn, O2䡠⫺ derived from NADPH oxidase promotes the formation of 8-ISOP and TXA2.10 Since 8-ISOP activates the TXA2 receptor, these data indicate that these 2 prostanoids would augment intracavernous oxidative stress. Interestingly, iloprost, a prostacyclin (PGI2) analogue, inhibits the expression of NAPDH oxidase elicited by TXA2 and 8-ISOP.10 In turn, PGI2 formation is diminished by O2䡠⫺,10 altering the balance of TXA2/ 8-ISOP relative to PGI2, which would further auto-augment intracavernous oxidative stress by further up-regulation of NADPH oxidase. Azadzoi et al also propose that hypoxia may be a key component of VED. We found that hypoxia up-regulates the expression of NADPH oxidase and increases the endogenous formation of superoxide, partly through NADPH oxidase activity in cavernous and arterial vascular smooth muscle cells.11,12 In support of the proposal that NADPH oxidase is central to intracavernous and pudendal arterial oxidative stress, we demonstrated that sildenafil is a potent inhibitor of NADPH oxidase in isolated cavernous cells,8 and ex vivo in cavernous tissue from the hypercholesterolemic rabbit6 and in the pulmonary artery.13,14 This effect is mediated by the augmentation of the cyclic guanosine monophosphate-protein kinase G axis, which then down-regulates NADPH oxidase expression, thereby reducing O2䡠⫺ formation.15 This action would augment the levels of NO, thereby enhancing erectile function. The NO donating version of sildenafil (NCX 911) proved to be more potent than sildenafil citrate.14
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LETTERS TO THE EDITOR
The study by Azadzoi et al indicates that antioxidants may represent a potential strategy to treat VED, a view with which we wholeheartedly agree. One relevant finding was that O2䡠⫺ itself up-regulates NADPH oxidase expression, thereby promoting further O2䡠⫺ formation.16 It may be that antioxidants exert an inhibitory effect on this pathway, which, in turn, may explain the beneficial effects of antioxidants on erectile dysfunction reported by Azadzoi et al. Further studies are required to determine whether this is the case. Respectfully, Jamie Y. Jeremy Robert A. Jones Anthony J. Koupparis Matthew Hotston Gianni D. Angelini Raj Persad and Nilima Shukla Departments of Cardiac Surgery and Urology Bristol Royal Infirmary University of Bristol Bristol, United Kingdom 1. Jeremy, J. Y., Angelini, G. D., Khan, M., ., Mikhailidis, D. P., Morgan, R. J.., Thompson, C. S. et al: Platelets, oxidant stress and erectile dysfunction: an hypothesis. Cardiovasc Res, 46: 50, 2000 2. Jones, R. W. A., Rees, R. W., Minhas, S., Ralph, D., Persad, R. A. and Jeremy, J. Y.: Oxygen free radicals and the penis. Expert Opin Pharmacother, 3: 889, 2002 3. Khan, M. A., Thompson, C. S., Jeremy, J. Y., Mumtaz, F. H., Mikhailidis, P. and Morgan, R. J.: The effect of superoxide dismutase on nitric oxide-mediated and electrical field-stimulated diabetic rabbit cavernosal smooth muscle relaxation. BJU Int, 87: 98, 2001 4. Koupparis, A. J., Jeremy, J. Y., Persad, R., Angelini, G. D. and Shukla, N.: Smoking and erectile dysfunction: the role of NADPH oxidase. BJU Int, 94: 257, 2004
5. Jones, R. W., Jeremy, J. Y., Koupparis, A., Persad, R. and Shukla, N.: Cavernosal dysfunction in a rabbit model of hyperhomocysteinaemia. BJU Int, 95: 125, 2005 6. Shukla, N., Jones, R., Persad, R., Angelini, G. D. and Jeremy, J. Y.: Effect of sildenafil citrate and a nitric oxide donating sildenafil derivative, NCX 911, on cavernosal relaxation and superoxide formation in hypercholesterolaemic rabbits. Eur J Pharmacol, 517: 224, 2005 7. Khan, M. A., Thompson, C. S., Emsley, A. M., Mumtaz, F. H., MikhailididMikhailidis, D. P., Angelini, G. D. et al: The interaction of homocysteine and copper markedly inhibits the relaxation of rabbit corpus cavernosum: new risk factors for angiopathic erectile dysfunction? BJU Int, 84: 720, 1999 8. Jones, R. W. A., Shukla, N., Angelini, G. D., Gingell, J. C., Persad, R. A. and Jeremy, J. Y.: Streptozotocin-induced diabetes increases superoxide production in rat corpus cavernosum, in vitro. BJU Int, suppl., 90: 23, abstract P010, 2002 9. Koupparis, A. J., Jeremy, J. Y., Muzaffar, S., Persad, R. and Shukla, N.: Sildenafil inhibits the formation of superoxide and the expression of gp47NAD[P]H oxidase induced by the thromboxane A2 mimetic, U46619, in corpus cavernosal smooth muscle cells. BJU Int, 96: 423, 2005 10. Muzaffar, S., Shukla, N., Lobo, C., Angelini, G. D. and Jeremy, J. Y.: Iloprost inhibits superoxide formation and gp91phox expression induced by the thromboxane A2 analogue U46619, 8-isoprostane F2alpha, prostaglandin F2alpha, cytokines and endotoxin in the pig pulmonary artery. Br J Pharmacol, 141: 488, 2004 11. Koupparis, A. J., Jeremy, J. Y., Muzaffar, S., Angelini, G. D. and Shukla, N.: Unpublished data 12. Muzaffar, S., Shukla, N., Angelini, G. D. and Jeremy, J. Y.: Acute hypoxia simultaneously induces the expression of gp91phox and endothelial nitric oxide synthase in the porcine pulmonary artery. Thorax, 60: 305, 2005 13. Jeremy, J. Y., Koupparis, A., Muzaffar, S., Persad, R., Angelini, G. and Shukla, N.: Is the therapeutic action of sildenafil mediated partly through the inhibition of superoxide formation? BJU Int, 95: 930, 2005 14. Muzaffar, S., Shukla, N., Angelini, G. D. and Jeremy, J. Y.: Sildenafil citrate and sildenafil nitrate are potent inhibitors of superoxide formation and gp91phox expression in porcine pulmonary artery endothelial cells. Br J Pharmacol, 141: 488, 2005
ERRATUM FRAGMENT DETECTION DURING NEPHROLITHOTOMY Volume 175, Number 1, Page 166: The first author of the Editorial Comment is Michael C. Ost.
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Re: Oxidative Stress in Arteriogenic Erectile Dysfunction: Prophylactic Role of Antioxidants K. M. Azadzoi, R. N. Schulman, M. Aviram and M. B. Siroky J Urol, 174: 386 –393, 2005 To the Editor. We read with interest the article by Azadzoi et al, who demonstrated that pomegranate juice improved erectile dysfunction and decreased fibrosis in an animal model of erectile dysfunction by virtue of its antioxidant properties. We would like to add some comments on other findings that may be of interest. We and others have also suggested that oxidative stress, in particular the overproduction of superoxide (O2䡠⫺) may be central to the etiology of vasculogenic erectile dysfunction (VED).1-7 O2䡠⫺ reacts with nitric oxide (NO) to form reactive nitrogen species, effectively reducing NO bioavailability, a key determinant of erection.1,2 Furthermore, the principal risk factors for VED (hypercholesterolemia, diabetes mellitus and cigarette smoking, and possibly hyperhomocysteinemia) are all associated with increased intracavernous expression/activity of reduced nicotinamide adenine dinucleotide phosphate oxidase (NADPH), an enzyme that generates O2䡠⫺.3-8 More recently, we demonstrated that thromboxane A2 (TXA2) is a potent up-regulator of NADPH oxidase and O2䡠⫺ formation in cavernous vascular smooth muscle cells.9 Azadzoi et al also reported that there was increased formation of 8-isoprostane F2␣ (8-ISOP) in their model. We also found that 8-ISOP is a potent stimulator of O2䡠⫺ formation and of NADPH oxidase expression, and that, in turn, O2䡠⫺ derived from NADPH oxidase promotes the formation of 8-ISOP and TXA2.10 Since 8-ISOP activates the TXA2 receptor, these data indicate that these 2 prostanoids would augment intracavernous oxidative stress. Interestingly, iloprost, a prostacyclin (PGI2) analogue, inhibits the expression of NAPDH oxidase elicited by TXA2 and 8-ISOP.10 In turn, PGI2 formation is diminished by O2䡠⫺,10 altering the balance of TXA2/ 8-ISOP relative to PGI2, which would further auto-augment intracavernous oxidative stress by further up-regulation of NADPH oxidase. Azadzoi et al also propose that hypoxia may be a key component of VED. We found that hypoxia up-regulates the expression of NADPH oxidase and increases the endogenous formation of superoxide, partly through NADPH oxidase activity in cavernous and arterial vascular smooth muscle cells.11,12 In support of the proposal that NADPH oxidase is central to intracavernous and pudendal arterial oxidative stress, we demonstrated that sildenafil is a potent inhibitor of NADPH oxidase in isolated cavernous cells,8 and ex vivo in cavernous tissue from the hypercholesterolemic rabbit6 and in the pulmonary artery.13,14 This effect is mediated by the augmentation of the cyclic guanosine monophosphate-protein kinase G axis, which then down-regulates NADPH oxidase expression, thereby reducing O2䡠⫺ formation.15 This action would augment the levels of NO, thereby enhancing erectile function. The NO donating version of sildenafil (NCX 911) proved to be more potent than sildenafil citrate.14
1176
LETTERS TO THE EDITOR
The study by Azadzoi et al indicates that antioxidants may represent a potential strategy to treat VED, a view with which we wholeheartedly agree. One relevant finding was that O2䡠⫺ itself up-regulates NADPH oxidase expression, thereby promoting further O2䡠⫺ formation.16 It may be that antioxidants exert an inhibitory effect on this pathway, which, in turn, may explain the beneficial effects of antioxidants on erectile dysfunction reported by Azadzoi et al. Further studies are required to determine whether this is the case. Respectfully, Jamie Y. Jeremy Robert A. Jones Anthony J. Koupparis Matthew Hotston Gianni D. Angelini Raj Persad and Nilima Shukla Departments of Cardiac Surgery and Urology Bristol Royal Infirmary University of Bristol Bristol, United Kingdom 1. Jeremy, J. Y., Angelini, G. D., Khan, M., ., Mikhailidis, D. P., Morgan, R. J.., Thompson, C. S. et al: Platelets, oxidant stress and erectile dysfunction: an hypothesis. Cardiovasc Res, 46: 50, 2000 2. Jones, R. W. A., Rees, R. W., Minhas, S., Ralph, D., Persad, R. A. and Jeremy, J. Y.: Oxygen free radicals and the penis. Expert Opin Pharmacother, 3: 889, 2002 3. Khan, M. A., Thompson, C. S., Jeremy, J. Y., Mumtaz, F. H., Mikhailidis, P. and Morgan, R. J.: The effect of superoxide dismutase on nitric oxide-mediated and electrical field-stimulated diabetic rabbit cavernosal smooth muscle relaxation. BJU Int, 87: 98, 2001 4. Koupparis, A. J., Jeremy, J. Y., Persad, R., Angelini, G. D. and Shukla, N.: Smoking and erectile dysfunction: the role of NADPH oxidase. BJU Int, 94: 257, 2004
5. Jones, R. W., Jeremy, J. Y., Koupparis, A., Persad, R. and Shukla, N.: Cavernosal dysfunction in a rabbit model of hyperhomocysteinaemia. BJU Int, 95: 125, 2005 6. Shukla, N., Jones, R., Persad, R., Angelini, G. D. and Jeremy, J. Y.: Effect of sildenafil citrate and a nitric oxide donating sildenafil derivative, NCX 911, on cavernosal relaxation and superoxide formation in hypercholesterolaemic rabbits. Eur J Pharmacol, 517: 224, 2005 7. Khan, M. A., Thompson, C. S., Emsley, A. M., Mumtaz, F. H., MikhailididMikhailidis, D. P., Angelini, G. D. et al: The interaction of homocysteine and copper markedly inhibits the relaxation of rabbit corpus cavernosum: new risk factors for angiopathic erectile dysfunction? BJU Int, 84: 720, 1999 8. Jones, R. W. A., Shukla, N., Angelini, G. D., Gingell, J. C., Persad, R. A. and Jeremy, J. Y.: Streptozotocin-induced diabetes increases superoxide production in rat corpus cavernosum, in vitro. BJU Int, suppl., 90: 23, abstract P010, 2002 9. Koupparis, A. J., Jeremy, J. Y., Muzaffar, S., Persad, R. and Shukla, N.: Sildenafil inhibits the formation of superoxide and the expression of gp47NAD[P]H oxidase induced by the thromboxane A2 mimetic, U46619, in corpus cavernosal smooth muscle cells. BJU Int, 96: 423, 2005 10. Muzaffar, S., Shukla, N., Lobo, C., Angelini, G. D. and Jeremy, J. Y.: Iloprost inhibits superoxide formation and gp91phox expression induced by the thromboxane A2 analogue U46619, 8-isoprostane F2alpha, prostaglandin F2alpha, cytokines and endotoxin in the pig pulmonary artery. Br J Pharmacol, 141: 488, 2004 11. Koupparis, A. J., Jeremy, J. Y., Muzaffar, S., Angelini, G. D. and Shukla, N.: Unpublished data 12. Muzaffar, S., Shukla, N., Angelini, G. D. and Jeremy, J. Y.: Acute hypoxia simultaneously induces the expression of gp91phox and endothelial nitric oxide synthase in the porcine pulmonary artery. Thorax, 60: 305, 2005 13. Jeremy, J. Y., Koupparis, A., Muzaffar, S., Persad, R., Angelini, G. and Shukla, N.: Is the therapeutic action of sildenafil mediated partly through the inhibition of superoxide formation? BJU Int, 95: 930, 2005 14. Muzaffar, S., Shukla, N., Angelini, G. D. and Jeremy, J. Y.: Sildenafil citrate and sildenafil nitrate are potent inhibitors of superoxide formation and gp91phox expression in porcine pulmonary artery endothelial cells. Br J Pharmacol, 141: 488, 2005
ERRATUM FRAGMENT DETECTION DURING NEPHROLITHOTOMY Volume 175, Number 1, Page 166: The first author of the Editorial Comment is Michael C. Ost.