Regular articleXanthine oxidase activity in the dexamethasone-induced hypertensive rat
Introduction
Increasing evidence suggests that reactive oxygen species may be involved in the hypertensive syndrome Nakazono et al 1991, Kumar and Das 1993, Grunfeld et al 1995, Suzuki et al 1995a, Saruta 1996, Swei et al 1997, Newaz and Nawal 1998, Schnackenberg et al 1998. Superoxide spontaneously reacts with nitric oxide, an ever-present vasodilator. Thus, the overabundance of superoxide through annihilation of nitric oxide may lead to arteriolar constriction and elevated resistance Grunfeld et al 1995, Vega et al 1995, Tschudi et al 1996, Kerr et al 1999, McIntyre et al 1999.
Among several mechanisms, xanthine oxidase may be a potential source for the enhanced oxidative stress. Xanthine oxidoreductase (XOR) can exist in two different forms, xanthine dehydrogenase (XDH) or xanthine oxidase (XO). XDH normally reduces NAD+, while XO accepts an electron from oxygen. Thus, XO generates superoxide and hydrogen peroxide (Fridovich, 1970; Lacy et al., 1998a). The predominant XDH form can be converted into XO under severe conditions, such as ischemic injury, and thereby cause increased oxidative stress (McCord, 1985).
In normotensive individuals, mean arterial blood pressure was reported to have a positive correlation with XO activity and uric acid concentration (Newaz et al., 1996). Hypertensive patients have higher plasma rates of hydrogen peroxide production than controls, which can be inhibited by addition of allopurinol, an XO inhibitor Lacy et al 1998a, Lacy et al 1998b. Mesenteric XO is increased in the spontaneously hypertensive rat (SHR) compared with its normotensive control, the Wistar Kyoto (WKY) rat (Suzuki et al., 1998).
Furthermore, glucocorticoids are known to participate in blood pressure regulation and in hypertension Saruta 1996, Schimmer and Parker 1996, Walker et al 1996. Adrenalectomy normalizes the blood pressure of the SHR Suzuki et al 1995b, Lim et al 2001. Dexamethasone induces XDH/XO activity and gene expression in bovine epithelial cells (Pfeffer et al., 1994). The superoxide anion, generated by XO, may react with nitric oxide, resulting in increased vasoconstriction as well as production of peroxynitrite. Dexamethasone can also block inducible nitric oxide synthase gene expression at the transcriptional level (Kanno et al., 1994). Thus, dexamethasone can act by way of several pathways to deplete the supply of nitric oxide and thereby lead to enhanced arteriolar vasoconstriction.
In light of this evidence, we hypothesize that an elevated XO activity may be a source for the oxygen free radicals in glucocorticoid-induced hypertension. To examine this hypothesis, the levels of XO activity in cremaster muscle were determined in a glucocorticoid-induced model of hypertension. In addition, the XO inhibitor, allopurinol, was administered in an attempt to determine the effects of XO as a source of reactive oxygen species.
Section snippets
Animals and dexamethasone administration
Male Wistar rats (200–300 g, Charles River Breeding Laboratories, Wilmington, MA) were maintained on a diet of standard rat chow (0.9% NaCl) and water ad libitum. The rats were divided into two age-matched groups. The experimental group was given daily injections of water-soluble dexamethasone (0.5 mg/kg of body weight for 5 days i.m.; Sigma Chemical Co., St. Louis, MO, in Plasma-Lyte, Baxter, McGaw Park, IL; pH = 7.4). This dose is sufficient to elevate blood pressure in the adrenalectomized
Blood pressures
During local and general anesthesia the mean arterial blood pressure (MBP) varied considerably and was therefore examined at several time points during the experiment (Fig. 1A). At all times, the dexamethasone-treated group had significantly elevated MBP compared with controls (P < 0.02). Addition of allopurinol served to significantly reduce the MBP (Fig. 1B). The dexamethasone-treated group had significantly reduced MBPs in the presence of allopurinol, measured in conscious rats under local
Xanthine oxidase in hypertension
In line with the current results, several studies have suggested that XO activity is enhanced in hypertensives Newaz et al 1996, Higuchi et al 1998, Laakso et al 1998, Suzuki et al 1998. The elevation of the XO activity is clearly detectable in a representative skeletal muscle, an organ that makes a major contribution to the elevation of vascular resistance (Zweifach et al., 1981). Furthermore, the current evidence indicates that the XO activity in cremaster muscle is under the control of
Acknowledgements
Supported by NIH Grant HL-10881.
References (59)
Insights into glucocorticoid-associated hypertension
Am. J. Kidney Dis.
(2001)Quantitative aspects of the production of superoxide anion radical by milk xanthine oxidase
J. Biol. Chem.
(1970)- et al.
Increased NAD(P)H oxidase-mediated superoxide production in renovascular hypertension: evidence for an involvement of protein kinase C
Kidney Int.
(1999) - et al.
The role of glucocorticoid activity in the inheritance of hypertension: studies in the rat
J. Steroid Biochem. Mol. Biol.
(1993) - et al.
Allopurinol: discrimination of antioxidant from enzyme inhibitory activities
Free Radic. Biol. Med.
(1996) - et al.
Role of xanthine oxidase in hydrogen peroxide production
Free Radic. Biol. Med.
(1998) - et al.
Effect of alpha-tocopherol on lipid peroxidation and total antioxidant status in spontaneously hypertensive rats
Am. J. Hypertens.
(1998) - et al.
Xanthine oxidoreductase release after descending thoracic aorta occlusion and reperfusion in rabbits
J. Thorac Cardiovasc. Surg.
(1994) - et al.
Glucocorticoid-induced apoptosis in lymphocytes
Biochem. Biophys. Res. Commun.
(2000) - et al.
Dexamethasone worsens nitric oxide inhibition-induced hypertension and renal dysfunction
Am. J. Hypertens.
(2000)