Xanthine oxidase activity associated with arterial blood pressure in spontaneously hypertensive rats (microcirculationyxanthine dehydrogenaseyendotheliumytungsten) (1998)

Recent evidence in vivo indicates that spon- taneously hypertensive rats (SHR) exhibit an increase in oxyradical production in and around microvascular endothe- lium. This study is aimed to examine whether xanthine oxidase plays a role in overproduction of oxidants and thereby may contribute to hypertensive states as a consequence of the increasing microvascular tone. The xanthine oxidase activity in SHR was inhibited by dietary supplement of tungsten (0.7 gykg) that depletes molybdenum as a cofactor for the enzyme activity as well as by administration of (2)BOF4272 ((2)-8- (3-methoxy-4-phenylsulfinylphenyl)pyrazolo(1,5-a)-1,3,5- triazine-4-monohydrate), a synthetic inhibitor of the enzyme. The characteristic elevation of mean arterial pressure in SHR was normalized by the tungsten diet, whereas Wistar Koto (WKY) rats displayed no significant alteration in the pres- sure. Multifunctional intravital videomicroscopy in mesentery microvessels with hydroethidine, an oxidant-sensitive f luoro- probe, showed that SHR endothelium exhibited overproduc- tion of oxyradicals that coincided with the elevated arteriolar tone as compared with WKY rats. The tungsten diet signifi- cantly repressed these changes toward the levels observed in WKY rats. The activity of oxyradical-producing form of xanthine oxidase in the mesenteric tissue of SHR was '3-fold greater than that of WKY rats, and pretreatment with the tungsten diet eliminated detectable levels of the enzyme activity. The inhibitory effects of the tungsten diet on the increasing blood pressure and arteriolar tone in SHR were also reproducible by administration of (2)BOF4272. These results suggest that xanthine oxidase accounts for a putative source of oxyradical generation that is associated with an increasing arteriolar tone in this form of hypertension. The progressive elevation of arterial blood pressure in the spontaneously hypertensive rat (SHR) is associated with an upward displacement in vascular resistance, which is especially striking in the small arterial or arteriolar segments of the microcirculation. Previous investigations focused on the mi- crocirculation of hypertensives have reported morphological changes in the wall of arterioles (1) as well as changes in the overall makeup of the arteriolar network (2-4), which could account for the elevation in peripheral resistance. An above- normal level of arteriolar tone can be demonstrated in the microcirculation of SHR down to the smallest precapillary ramifications of the terminal arterioles in different tissues (5-8). Several hypothesis have been advanced to account for the high blood pressure in SHR. Among the factors that have been proposed to account for the increase in arteriolar resistance are smooth muscle medial hypertrophy (9), vessel rarefaction (2), an elevation of tone in resistance arteries (10), an in- creased sympathetic activity (11), differences in catecholamine transmitter disposition and sensitivity of smooth muscle cells (12, 13), and differences in central vascular regulation (14). We previously reported that the level of microvascular oxidative stress in SHR was significantly above that displayed in its Wistar Kyoto (WKY) normotensive control strain. The en- hanced level in SHR showed a linear correlation with the increase in arteriolar tone (15). Superfusion of a synthetic xanthine oxidase (XO) inhibitor ((2)BOF4272, (2)-8-(3-