Letter: Antioxidant Activities and Oxidative Stress Byproducts in Human Hypertension
To the Editor:
We note with interest the study by Redon et al1 on antioxidant activities and oxidative stress byproducts in human hypertension. The authors have reported an increase in oxidative stress and a reduction in the activity of antioxidant mechanisms in hypertensive subjects which appeared to be independent of the blood pressure levels. Although oxidative stress is known to occur in hypertension, direct cause-and-effect relationships have not been clearly delineated. Several factors inherent to hypertensive status such as enhanced activity of angiotensin II, hyperinsulinemia, and increased NAD(P)H oxidase activity have been implicated in inducing altered oxidative state in hypertension. Oxidative stress has been seen to promote the entry of Ca2+ into vascular myocytes, stimulating neointimal hyperplasia and vasoconstriction.2 Although no relationship between oxidative stress and blood pressure values was observed by Redon et al,1 such a relationship cannot be excluded. In fact, we have observed a significant negative correlation between diastolic blood pressure and several endogenous antioxidants in hypertensive patients. We found a negative correlation between glutathione-S-transferase (GST; r=−0.52), glutathione peroxidase (GPx; r=−0.46), ascorbic acid (r=−0.40), and non-protein thiols (r=−0.482). The levels of GST, GPx, ascorbic acid, and non-protein thiols were observed to be significantly low in hypertensives as compared with normotensives. We also observed a significant decrease in plasma ferric-reducing antioxidant power (FRAP) in hypertensives as compared to normotensive controls, which also showed a negative correlation (r=−0.52) with diastolic pressure. FRAP is a direct indicator of antioxidant status and measures endogenous reduction of Fe+3 to Fe+2. A low FRAP activity would lead to increased Fe+3, which is a potent pro-oxidant and would result in increased oxidative stress. The increased oxidative stress observed in hypertensive patients could lead to endothelial dysfunction by increasing intracellular Ca levels. Antioxidants such as probucol and ascorbic acid have been shown to improve endothelium-dependent relaxation, suggesting the role of reactive oxygen species (ROS) in endothelial dysfunction. Redon et al1 have also proposed that ROS products released from peripheral mononuclear cells may also contribute to endothelial dysfunction and organ damage present in hypertensive subjects. We have observed significantly lower nitric oxide levels in hypertensive patients. There was, however, no correlation between severity of disease, organ damage, and plasma nitric oxide levels. Patients on antihypertensive therapy (Ca channel blockers or ACE inhibitors) showed a significant increase in nitric oxide levels, but their antioxidant levels remained lower as compared with normotensives. Thus, there appear to be other factors contributing to oxidative stress, which need to be further investigated.
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Khullar et al1 commented in their study that hypertensive subjects had a reduced activity in plasma of the antioxidant systems, glutathione-S-transferase, glutathione peroxidase, ascorbic acid, non-protein thiols, and the plasma ferric-reducing antioxidant power as compared with normotensive controls. Furthermore, a lower nitric oxide activity was also present in hypertensive subjects compared with the normotensive control group. These data correspond to the findings of our group measuring the activity of other antioxidant enzymes, SOD, catalase, and glutathione peroxidase2 in plasma and in mononuclear cells. How the results of Khulla et al differ from our own data are in the finding of a significant negative correlation between the antioxidant activity and the diastolic blood pressure, a correlation that was not present in our own data. The authors, however, did not provide information about the number of subjects analyzed, selection criteria, or characteristics of the study population, making it difficult to discuss more in depth what the explanation for the different results could be. In our study, patients were analyzed out of antihypertensive treatment, and 85% of them were previously untreated. Furthermore, blood pressure was assessed using 24-hour ambulatory BP monitoring, a more accurate estimate of BP. More detailed information is required to find out whether differences in the selection criteria and/or characteristics of the hypertensive subjects analyzed would be able to explain the discrepancies.
Another commentary addressed by the authors is that the antihypertensive treatment produced a significant increase in nitric oxide levels, but the antioxidant levels remained lower as compared with normotensive subjects. The authors did not explain whether antihypertensive treatment had induced an increase in antioxidant mechanisms even when they did not achieve the values observed in normotensive subjects. In our experience, antihypertensive treatment reduces oxidative stress parameters and increases the activity of the antioxidant enzymes, in both plasma and mononuclear cells. A complete normalization of these values was observed after 1 year of treatment.
The relationship among the production of reactive oxygen species and their control, BP values, and hypertension-induced organ damage is a complex phenomenon. More studies are necessary to understand further the significance of oxidative stress in hypertension.
Khullar M, Relan V, Sherawat BS. Antioxidant activities and oxidative stress byproducts in human hypertension.Hypertension. 2003;in press.
Redon J, Oliva MR, Tormos C, Giner V, Chaves J, Iradi A, Saez GT. Antioxidant activities and oxidative stress byproducts in human hypertension. Hypertension. 2003; 41: 1096–1101.