The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 12 No.
1 • February 2009
Superoxide Radicals, NO, and cGMP:
Links Between Erectile Dysfunction and Cardiovascular Disease
There is a known correlation between erectile dysfunction and the risk of cardiovascular disease. For example, in a recent paper researchers commented “[t]he importance of PDE5 [phosphodiesterase 5, which is inhibited by Viagra, Cialis, and certain other ED therapies] in the aetiology of vasculopathies [endothelial dysfunction] is exemplified by the proven and postulated therapeutic use of sildenafil [Viagra] and other PDE5 inhibitors to treat an array of cardiovascular diseases and syndromes. These include erectile dysfunction, pulmonary hypertension, angina pectoris, myocardial infarction, ischaemia reperfusion injury, vein graft disease and heart failure. In turn, the overproduction of O2- [superoxide radicals] and an upregulation of NOX [NADPH oxidase, which generates superoxide radicals] have been demonstrated in these clinical conditions.” See, for example, in which daily treatment with sildenafil reversed endothelial dysfunction and oxidative stress in an animal model of insulin resistance.
As discussed in this paper and others, NADPH oxidase is a major source of superoxide radicals, which interact with nitric oxide (NO), destroying the vasodilative properties of NO and producing a potent oxidant, peroxynitrite. As explained by the researchers, “[t]he biological actions of NO are mediated principally by the activation of GC [guanyl cyclase], which generates cGMP [cyclic guanosine monophosphate]. In turn, cGMP activates PKG [protein kinase G] which then phosphorylates other proteins that elicit vasculoprotection. The biological effects of the NO-PKG system are reduced by type 5 PDEs (PDE5) [type 5 phosphodiesterase], which hydrolyze cGMP to inactive GMP. In this way, the type 5 PDEs are able to reduce the ability of NO to dilate blood vessels by inactivating cGMP. The ability of drugs like Viagra to restore erectile function is due to their anti-PDE5 activity. Their cardiovascular protection is, as is clear from the above, also due to inhibition of PDE5, leading to protection of the NO-cGMP system pathway that supports normal endothelial function.
As an examination of the metabolic pathway leading to erectile dysfunction shows, however, there are more ways to improve erections than to directly decrease PDE5 activity. For example, increasing SOD (superoxide dismutase) activity directly decreases the presence of superoxide radicals by scavenging them. This helps prevent the induction of PDE5 by the superoxide radicals, as well as protecting NO from destruction by superoxide radicals. In this particular paper, scientists found they could inhibit the upregulation of type 5 phosphodiesterase in human vascular smooth muscle cells with either iloprist, a prostacyclin mimetic drug, or NONOate, an NO donor drug. (These drugs were chosen on the basis that prostacyclin and NO inhibited NOX expression and activity as reported in a separate paper.)
Some recently identified natural products that also inhibit PDE5 are found in Ginkgo biloba and red grapes. There are, in addition, many natural products that improve endothelial dysfunction that, theoretically, could be expected at an appropriate dose to improve erectile function. See, for example, papers on L-arginine, strawberry extract, EGCG, and cocoa. The flavonoid quercetin* has been shown to downregulate NADPH oxidase in spontaneously hypertensive rats. Quercetin and catechin were shown to synergistically enhance platelet nitric oxide by inhibiting protein kinase C-dependent NADPH oxidase activation in vitro. Other papers on NADPH oxidase identify it as having a causative role in erectile dysfunction and as a therapeutic target for cardiovascular diseases, in support of the discussion above.
1. Muzaffar et al. Superoxide from NADPH oxidase upregulates type 5 phosphodiesterase in human vascular smooth muscle cells: inhibition with iloprost and NONOate,” Br J Pharmacol 155:847-56 (2008).
2. Liming Jin et al. NADPH oxidase activation: a mechanism of hypertension-associated erectile dysfunction. J Sex Med 5:544-551 (2008).
3. Behr-Roussel et al. Daily treatment with Sildenafil reverses endothelial dysfunction and oxidative stress in an animal model of insulin resistance. Eur Urol 53:1272-81 (2008).
4. Dell’Agli et al. Inhibition of cGMP-phosphodiesterase-5 by biflavones of Ginkgo biloba. Planta Med 72:468-70 (2006).
5. Dell’Agli et al. In vitro inhibition of human cGMP-specific phosphodiesterase-5 by polyphenols from red grapes. J Agric Food Chem 53:1960-5 (2005).
6. Bai et al. Increase in fasting vascular endothelial function after short-term oral L-arginine is effective when baseline flow- mediated dilation is low: a meta-analysis of randomized controlled trials. Am J Clin Nutr 89:77-84 (2009).
7. Edirisinghe et al. Strawberry extract caused endothelium-dependent relaxation through the activation of PI3 kinase/Akt,” J Agric Food Chem 56:9383-9390 (2008)
8. Kim et al. Epigallocatechin gallate, a green tea polyphenol, mediates NO-dependent vasodilation using signaling pathways in vascular endothelium requiring reactive oxygen species and Fyn. J Biol Chem 282(18):13736-45 (2007).
9. Schroeter et al. (-)-epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans. Proc Natl Acad Sci USA 103(4):1024-9 (2006).
10. Steffen et al. (-)-epicatechin elevates nitric oxide in endothelial cells via inhibition of NADPH oxidase. Biochem Biophys Res Commun 359:828-33 (2007).
11. Sanchez et al. Quercetin downregulates NADPH oxidase, increases eNOS activity and prevents endothelial dysfunction in spontaneously hypertensive rats. J Hypertens 24:75-84 (2006).
11b. Pignatelli et al. Polyphenols enhance platelet nitric oxide by inhuibiting protein kinase C-dependent NADPH oxidase activation: effect on platelet recruitment. FASEB J 20:1082-9 (2006).
12. Cai et al. The vascular NAD(P)H oxidases as therapeutic targets in cardiovascular diseases. Trends Pharmacol Sci 24(9): 471-8 (2003).
13. Liming Jin, Arthur L. Burnett. NADPH oxidase: recent evidence for its role in erectile dysfunction. Asian J Androl 10:6-13 (2008).