H. Suzuki et al., XANTHINE-OXIDASE ACTIVITY ASSOCIATED WITH ARTERIAL BLOOD-PRESSURE IN SPONTANEOUSLY HYPERTENSIVE RATS, Proceedings of the National Academy of Sciences of the United Statesof America, 95(8), 1998, pp. 4754-4759
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.