Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan
Correspondence to Akira Nishiyama, MD, PhD, Department of Pharmacology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kagawa 761-0794, Japan. Tel: +81 87 891 2125; fax: +81 87 891 2126; e-mail: firstname.lastname@example.org
Inappropriate augmentation of reactive oxygen species (ROS) production reduces the bioavailability of antioxidant defenses [1,2] and plays a pivotal role in the pathophysiology of hypertension and renal injury [3–5]. Experimental studies have indicated that enhanced ROS production is involved in vascular remodeling and endothelium dysfunction during the development of hypertension . Earlier clinical studies have also suggested a strong association between lower antioxidant levels and cardiovascular risks .
To date, much effort has been directed toward the benefits of antioxidant therapy. Clinical studies, including the Cambridge Heart Antioxidant Study  and the Antioxidant Supplementation in Atherosclerosis Prevention Study , have shown the beneficial effects of antioxidant therapy for cardiovascular events. Large epidemiological studies have also reported that dietary intake of antioxidants inversely correlates with hypertension [9,10]. Similarly, treatment with ascorbic acid significantly improved SBP and DBP in mild-to-moderate hypertensive patients . In experimental models of hypertension, vitamin C alone or in combination with vitamin E increased the synthesis of nitric oxide and reduced blood pressure [12,13]. Furthermore, an antioxidant rich diet was shown to relieve hypertension and reduces renal immune cell infiltration . By contrast, many clinical trials failed to demonstrate any beneficial effects of antioxidant therapy on blood pressure [15–17] and cardiovascular events [18–20]. For example, the Heart Protection Study Collaborative Group studied high-risk individuals and showed that although antioxidant vitamin supplementation substantially increased blood vitamin concentrations, it did not produce any significant reductions in the incidence of any type of cardiovascular disease .
In this issue of Journal of Hypertension, the article ‘Superoxide dismutase mimetic, tempol, aggravates renal injury in advanced-stage stroke-prone spontaneously hypertensive rats’ by Sugama et al. shows that antioxidant therapy with a superoxide mimetic, tempol, did not reduce blood pressure in salt-loaded old stroke prone spontaneously hypertensive rats (SHRSP). The authors also showed that although tempol effectively reduced oxidative stress in the kidney, it actually exacerbated the progression of proteinuria and histological damage, such as glomerulosclerosis and interstitial fibrosis. These data suggest that alternative pathways that are ROS-independent are involved in the pathogenesis of the advanced stage of hypertension and renal injury in SHRSP. It is also possible that oxidative stress is merely a consequence of the activation of these alternative pathways. However, Park et al. had performed similar experiments in SHRSP and shown that long-term treatment with tempol from early stages of hypertension did attenuate the progression of hypertension through the prevention of vascular remodeling, and that this was associated with decreased vascular superoxide production and increased plasma antioxidant levels.
Thus, the question arises as to why antioxidant therapies show such conflicting results in clinical and experimental studies . Importantly, it is clear from the clinical studies that dose differences do not seem to be responsible for such discrepant results . One possible explanation for the discrepancy in these studies is the different stage of hypertension and renal injury. In both clinical and experimental studies, beneficial effects of antioxidants were mostly found when interventions were started at an early stage. For example, Park et al. administered tempol from an early age and showed an attenuation in the development of hypertension in SHRSP, whereas Sugama et al. failed to observe a blood pressure-lowering effect of tempol if treatment started at an advanced hypertensive stage. Inatomi et al. have also shown that in patients with mild cardioembolic stroke, treatment with an antioxidant, edaravone, resulted in early functional improvement, but these effects were not observed in late stages.
The finding that antioxidant therapies have no beneficial effects on advanced hypertension, as well as cardiovascular and renal diseases, suggest a potential involvement of systems other than ROS. Consistent with this idea, in their current article Sugama et al. showed that treatment with an angiotensin II receptor blocker (ARB), candesartan, effectively decreased blood pressure and attenuated renal injury in advanced-stage SHRSP. Furthermore, although both tempol and candesartan reduced ROS in the kidney, only tempol did not improve hypertension and renal injury. These data suggest that in advanced-stage SHRSP, the renin–angiotensin system plays an important role in the pathogenesis of hypertension and renal injury through ROS-independent mechanisms. By contrast, previous studies in SHRSP showed that long-term treatment with an ARB from an early stage attenuates the progression of hypertension and renal injury, which are accompanied by reductions in ROS production . Taken together, these data suggest that the pharmacological mechanisms responsible for the beneficial effects of ARBs may be different between early and advanced stages in SHRSP.
In conclusion, current experimental evidence indicates that early antioxidant treatment can have beneficial effects on the development of hypertension as well as cardiovascular and renal diseases. However, antioxidants become much less effective during advance stages of these diseases. Future studies are needed to better understand the roles of these different pathways in the pathogenesis of these diseases, and which treatments are most effective at each stage.
Conflicts of interest
There are no conflicts of interest.
1. Dhalla NS, Temsah RM, Netticadan T. Role of oxidative stress in cardiovascular diseases. J Hypertens
2. Griendling KK, Sorescu D, Ushio-Fukai M. NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res
3. Bledsoe G, Shen B, Yao Y, Zhang JJ, Chao L, Chao J. Reversal of renal fibrosis, inflammation, and glomerular hypertrophy by kallikrein gene delivery. Hum Gene Ther
4. Chao J, Zhang JJ, Lin KF, Chao L. Human kallikrein gene delivery attenuates hypertension, cardiac hypertrophy, and renal injury in Dahl salt-sensitive rats. Hum Gene Ther
5. Trolliet MR, Rudd MA, Loscalzo J. Oxidative stress and renal dysfunction in salt-sensitive hypertension. Kidney Blood Press Res
6. Schiffrin EL. Reactivity of small blood vessels in hypertension: relation with structural changes. State of the art lecture. Hypertension
7. Harris A, Devaraj S, Jialal I. Oxidative stress, alpha-tocopherol therapy, and atherosclerosis. Curr Atheroscler Rep
8. Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet
9. Salonen RM, Nyyssonen K, Kaikkonen J, Porkkala-Sarataho E, Voutilainen S, Rissanen TH, et al. Six-year effect of combined vitamin C and E supplementation on atherosclerotic progression: the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) Study. Circulation
10. Myint PK, Luben RN, Welch AA, Bingham SA, Wareham NJ, Khaw KT. Plasma vitamin C concentrations predict risk of incident stroke over 10 y in 20 649 participants of the European Prospective Investigation into Cancer Norfolk prospective population study. Am J Clin Nutr
11. Duffy SJ, Gokce N, Holbrook M, Huang A, Frei B, Keaney JRJJr, Vita JA. Treatment of hypertension with ascorbic acid. Lancet
12. Sherman DL, Keaney JF Jr, Biegelsen ES, Duffy SJ, Coffman JD, Vita JA. Pharmacological concentrations of ascorbic acid are required for the beneficial effect on endothelial vasomotor function in hypertension. Hypertension
13. Xu A, Vita JA, Keaney JF Jr. Ascorbic acid and glutathione modulate the biological activity of S-nitrosoglutathione. Hypertension
14. Rodriguez-Iturbe B, Zhan CD, Quiroz Y, Sindhu RK, Vaziri ND. Antioxidant-rich diet relieves hypertension and reduces renal immune infiltration in spontaneously hypertensive rats. Hypertension
15. Hoogwerf BJ, Young JB. The HOPE study. Ramipril lowered cardiovascular risk, but vitamin E did not. Cleve Clin J Med
16. Mann JF, Lonn EM, Yi Q, Gerstein HC, Hoogwerf BJ, Poque J, et al. Effects of vitamin E on cardiovascular outcomes in people with mild-to-moderate renal insufficiency: results of the HOPE study. Kidney Int
17. Palumbo G, Avanzini F, Alli C, Roncaglioni MC, Ronchi E, Cristofari M, et al. Effects of vitamin E on clinic and ambulatory blood pressure in treated hypertensive patients. Collaborative Group of the Primary Prevention Project (PPP): Hypertension study. Am J Hypertens
18. The Alpha-Tocopherol BCCPSGThe effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med
19. Group HPSCMRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet
20. Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med
21. Sugama I, Kohagura K, Yamazato M, Nakamura T, Shinzato T, Ohya Y. Superoxide dismutase mimetic, tempol, aggravates renal injury in advanced-stage stroke-prone spontaneously hypertensive rats. J Hypertens
22. Park JB, Touyz RM, Chen X, Schiffrin EL. Chronic treatment with a superoxide dismutase mimetic prevents vascular remodeling and progression of hypertension in salt-loaded stroke-prone spontaneously hypertensive rats. Am J Hypertens
23. Jialal I, Devaraj S. Antioxidants and atherosclerosis: don’t throw out the baby with the bath water. Circulation
24. Inatomi Y, Takita T, Yonehara T, Fujioka S, Hashimoto Y, Hirano T, Uchino M. Efficacy of edaravone in cardioembolic stroke. Intern Med
25. Nakamura T, Obata J, Kuroyanagi R, Kimura H, Ikeda Y, Takano H, et al. Involvement of angiotensin II in glomerulosclerosis of stroke-prone spontaneously hypertensive rats. Kidney Int Suppl