XANTHINE-OXIDASE ACTIVITY ASSOCIATED WITH ARTERIAL BLOOD-PRESSURE IN SPONTANEOUSLY HYPERTENSIVE RATS

Recent evidence in vivo indicates that spontaneously hypertensive rats (SHR) exhibit an increase in oxyradical production in and around micr ovascular endothelium. This study is aimed to examine whether xanthine oxidase plays a role in overproduction of oxidants and thereby may co ntribute to hypertensive states as a consequence of the increasing mic rovascular tone. The xanthine oxidase activity in SBR was inhibited by dietary supplement of tungsten (0.7 g/kg) that depletes molybdenum as a cofactor for the enzyme activity as well as by administration of (- )BOF4272 [(-)-8-(3-methoxy-4-phenylsulfinylphenyl)pyrazolo pyrazolo(1, 5-alpha)-1,3,5-triazine-4-monohydrate], a synthetic inhibitor of the e nzyme. The characteristic elevation of mean arterial pressure in SHR w as normalized by the tungsten diet, whereas Wistar Koto (WKY) rats dis played no significant alteration in the pressure. Multifunctional intr avital videomicroscopy in mesentery microvessels with hydroethidine, a n oxidant-sensitive fluoroprobe, showed that SHR endothelium exhibited overproduction of oxyradicals that coincided with the elevated arteri olar tone as compared with WKY rats. The tungsten diet significantly r epressed these changes toward the levels observed in WKY rats. The act ivity of oxyradical-producing form of xanthine oxidase in the mesenter ic tissue of SHR was approximate to 3-fold greater than that of WKY ra ts, and pretreatment with the tungsten diet eliminated detectable leve ls of the enzyme activity, The inhibitory effects of the tungsten diet on the increasing blood pressure and arteriolar tone in SBR were also reproducible by administration of (-)BOF4272. These results suggest t hat xanthine oxidase accounts for a putative source of oxyradical gene ration that is associated with an increasing arteriolar tone in this f orm of hypertension.