Is antioxidant therapy effective for advanced hypertension and renal injury?

Abstract

nappropriate augmentation of reactive oxygen species(ROS) production reduces the bioavailability of anti-oxidant defenses [1,2] and plays a pivotal role in thepathophysiology of hypertension and renal injury [3–5].Experimental studies have indicated that enhanced ROSproduction is involved in vascular remodeling and endo-thelium dysfunction during the development of hyperten-sion [6]. Earlier clinical studies have also suggested a strongassociation between lower antioxidant levels and cardio-vascular risks [7].To date, much effort has been directed toward thebenefits of antioxidant therapy. Clinical studies, includingthe Cambridge Heart Antioxidant Study [8] and the Anti-oxidant Supplementation in Atherosclerosis PreventionStudy [9], have shown the beneficial effects of antioxidanttherapy for cardiovascular events. Large epidemiologicalstudies have also reported that dietary intake of anti-oxidants inverselycorrelateswithhypertension[9,10].Simi-larly, treatment with ascorbic acid significantly improvedSBP and DBP in mild-to-moderate hypertensive patients[11]. In experimental models of hypertension, vitamin Calone or in combination with vitamin E increased thesynthesis of nitric oxide and reduced blood pressure[12,13]. Furthermore, an antioxidant rich diet was shownto relieve hypertension and reduces renal immune cellinfiltration [14]. By contrast, many clinical trials failed todemonstrate any beneficial effects of antioxidant therapyon blood pressure [15–17] and cardiovascular events[18–20]. For example, the Heart Protection Study Collabo-rative Group studied high-risk individuals and showed thatalthoughantioxidantvitaminsupplementationsubstantiallyincreased blood vitamin concentrations, it did not produceany significant reductions in the incidence of any type ofcardiovascular disease [19].In this issue of Journal of Hypertension, the article‘Superoxide dismutase mimetic, tempol, aggravates renalinjury in advanced-stage stroke-prone spontaneouslyhypertensive rats’ by Sugama et al. [21] shows that anti-oxidanttherapywithasuperoxidemimetic,tempol,didnotreduce blood pressure in salt-loaded old stroke pronespontaneously hypertensive rats (SHRSP). The authors alsoshowed that although tempol effectively reduced oxidativestress in the kidney, it actually exacerbated the progressionof proteinuria and histological damage, such as glomerulo-sclerosis and interstitial fibrosis. These data suggestthat alternative pathways that are ROS-independent areinvolved in the pathogenesis of the advanced stage ofhypertension and renal injury in SHRSP. It is also possiblethat oxidative stress is merely a consequence of the acti-vation of these alternative pathways. However, Park et al.[22] had performed similar experiments in SHRSP andshown that long-term treatment with tempol from earlystages of hypertension did attenuate the progression ofhypertension through the prevention of vascular remodel-ing, and that this was associated with decreased vascularsuperoxide production and increased plasma antioxidantlevels.Thus, thequestion arisesastowhyantioxidanttherapiesshow such conflicting results in clinical and experimentalstudies [23]. Importantly, it is clear from the clinical studiesthatdosedifferencesdonotseemtoberesponsibleforsuchdiscrepant results [23]. One possible explanation for thediscrepancy in these studies is the different stage of hyper-tension and renal injury. In both clinical and experimentalstudies,beneficialeffectsofantioxidantsweremostlyfoundwhen interventions were started at an early stage. Forexample, Park et al. [22] administered tempol from an earlyage and showed an attenuation in the development ofhypertension in SHRSP, whereas Sugama et al. [21] failedto observe a blood pressure-lowering effect of tempolif treatment started at an advanced hypertensive stage.Inatomi et al. [24] have also shown that in patients withmild cardioembolic stroke, treatment with an antioxidant,edaravone, resulted in early functional improvement, butthese effects were not observed in late stages.Thefindingthatantioxidanttherapieshavenobeneficialeffects on advanced hypertension, as well as cardiovas-cular and renal diseases, suggest a potentialinvolvement of