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Discussion & Conclusion



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Mechanisms of Oxygen Free Radical Formation in Experimental Forms of Hypertension

Contact Person: Geert W. Schmid-Schönbein (gwss@bioeng.ucsd.edu)

Discussion and Conclusion

Recently, we obtained evidence for a significant oxidative stress in circulating leukocytes as well as in the microvascular wall of spontaneously hypertensive rats (SHR) and Dahl hypertensive rats (Shen et al., 1995, Circulating leukocyte counts, activation, and degranulation in Dahl hypertensive rats. Circ Res 76:276-83; Shen , et al., 1995, Properties of circulating leukocytes in spontaneously hypertensive rats. Biochem. Cell Biol. 73:491-500). We subsequently targeted the enzyme xanthine oxidase as a potential source of excess oxygen free radical production. Xanthine oxidase exists in endothelial cells and is believed to be responsible for reperfusion injury since it is capable of producing both superoxide and hydrogen peroxide.

The present observation that chronic tungsten diet lowers systemic blood pressure lead us to hypothesize that XO-mediated superoxide generation contributes to the mechanisms for the increasing arteriolar tone in SHR. The results indicate that there is a greater oxyradical-producing form of XO in vessels of SHR than in those from WKY rats. Both forms of hypertension (SHR and DAHL rats) exhibit this abnormality.

Overproduction of oxygen radicals in and around endothelial cells may cause pathologic responses of microvascular tone through a variety of mechanisms: Among such mechanisms, cancellation of endothelial cell-derived nitric oxide (NO) by superoxide anions is likely to be an event responsible for the increasing arteriolar tone in SHR. Reduced TNBT in the form of formazan deposits were seen along the vessel walls of both arterioles and venules and the development of hypertension was associated with enhanced staining, suggesting a greater production of superoxide radicals by endothelial cells. High salt + tungsten treatment of Dahl-S rats was associated with a reduction of staining level in both arterioles and venules. However, a significantly greater staining level was still seen in tungsten treated Dahl-S venules when compared to low salt treated Dahl-S venules.

Administration of xanthine oxidase inhibitors has been shown to significantly attenuate elevated microvascular oxidative changes and decrease the blood pressure of SHR rats, with no effect on WKY rats. We have also found a similar pressure reduction with a more specific xanthine oxidase inhibitor (BOF 4272, Otsuka, Japan) (Suzuki, et al. Xanthine oxidase activity associated with blood pressure in spontaneously hypertensive rats. Proc. Nat. Acad. Sci. USA, 95: 4754-4759, 1998). In addition, this hypotensive effect was eliminated by treatment of SHR with L-NAME, indicating that reduction of blood pressures was mediated by the nitric oxide synthesis pathway. Thus, xanthine oxidase may regulate nitric oxide in vascular endothelial cells. Uric acid, a by-product of xanthine oxidase, was also found to be increased in essential hypertensive patients and identified as a strong predictor of developing hypertension (Selby et al., 1990, Precursors of essential hypertension: pulmonary function, heart rate, uric acid, serum cholesterol, and other serum chemistries. Am J Epidemiol 131:1017-27.). In addition, mean arterial pressure positively correlated with uric acid and xanthine oxidase activity (Newaz et al., 1996, Uric acid, xanthine oxidase and other risk factors of hypertension in normotensive subjects. Clin Exp Hypertens 18:1035-50). Thus, the rise in blood pressure in humans was accompanied by a rise in uric acid level and a rise in xanthine oxidase activity.

Use of a chronic 0.07% sodium tungstate diet to inhibit xanthine oxidase activity has been used in rats, rabbits and mice. Tungsten is a competitive antagonist for molybdenum and is incorporated in place of molybdenum at the active redox site, resulting in decreased molybdenum content and decreased xanthine oxidase activity of tissues. It has been shown that tungsten treated rats do not differ from control rats in any observable physical criteria such as body weight, liver and lung weight, liver and lung protein content and succinate-cytochrome c reductase, a mitochondrial enzyme system not dependent on molybdenum (Johnson et al., 1974, Molecular basis of the biological function of molybdenum. Effect of tungsten on xanthine oxidase and sulfite oxidase in the rat. J Biol Chem 249:859-66.). Tungsten treated endothelial cells lack xanthine oxidase and are unable to generate superoxide. It should be noted that other molybdenum containing enzyme systems, such as sulfite oxidase, can also be inhibited by tungsten. The body weight of the high salt + tungsten treated Dahl rats did not differ from high salt treated rats indicating that the tungsten treatment had no toxic effects. Xanthine oxidase inhibitors allopurinol and oxypurinol may be more specific for xanthine oxidase activity, but may also have an antioxidant capacity and scavenge highly reactive hydroxyl radicals directly. In acute situations we have not found a significant effect on blood pressure which may be due to a lack of these two compounds to enter the endothelial cells.

CONCLUSION Tungsten treatment of Dahl-S rats or SHR was associated with decreased XO+XD and XO activity, as well as decreased in vivo superoxide generation. The evidence that tungsten treatment was also associated with decreased blood pressure suggests that xanthine oxidase derived oxygen free radicals may be involved in the pathogenesis of hypertension. The resulting free radical production may constitute a key mechanisms that leads to organ injury and lesion formation in the hypertensives.

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Swei, A.; Suzuki, H.; Parks, D.A.; Delano, F.A.; Schmid-Schönbein, G.W.; (1998). Mechanisms of Oxygen Free Radical Formation in Experimental Forms of Hypertension. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Invited Symposium. Available at URL http://www.mcmaster.ca/inabis98/
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