The Involvement of Oxidation-Sensitive Mechanisms in the Pathophysiology of Renovascular Hypertension

Abstract

P16 The mechanisms responsible for the maintenance of chronic renovascular hypertension (RVH) remain undefined. Excess systemic or local generation of angiotensin II (AII) may lead to enhanced release of reactive oxygen radical species, vasoconstrictor activity, and parenchymal injury. To examine the potential involvement of oxidation-sensitive mechanisms, blood samples were collected from 7 RVH pigs with unilateral renal artery stenosis (achieved by a local-irritant stent) 5 and 10 weeks after induction of RVH, and from 7 normal pigs. Shock-frozen renal cortical tissue was analyzed post mortem. At 5 weeks after induction of RVH, plasma renin activity (PRA) was elevated in RVH pigs and correlated with an increase in MAP of 27±11% (r=0.85). PGF2 alpha isoprostanes, markers of oxidative status and potent vasoconstrictors, were also increased compared to normal (157±21 vs. 99±16 pg/mL, p<0.05), and correlated with the concurrent increase in PRA (r=0.99) and MAP (r=0.84). By 10 weeks, MAP was still elevated (150±13 mmHg), but PRA returned to baseline, and they no longer correlated. Isoprostanes tended to further increase (to 187±29 pg/mL, p=0.07 compared to 5 weeks) and still correlated directly with the change in MAP from baseline (r=0.75). Plasma thiobarbituric acid-reactive substances, markers of increased oxidation, were also elevated (3.9±0.5 vs. 2.1±0.2 nmol/mL, p=0.005). In tissue of both kidneys, endogenous intracellular radical scavengers (glutathione peroxidase, catalase, CuZn- and Mn- superoxide dismutase) were significantly decreased (all p<0.001 compared to normal pigs), as well as natural antioxidants (alpha-tocopherol and ascorbate, p<0.03 compared to normal). This study demonstrates, for the first time, that in the early phase of RVH an increase in PRA and MAP is associated with increased plasma oxidation. When systemic PRA later declines, isoprostanes remain elevated, possibly due to local activation and/or slow responses to AII, and may potentially mediate sustenance of MAP. Moreover, oxidation-sensitive mechanisms may conceivably play a role in progression of ischemic and hypertensive renal tissue injury observed in RVH.