Free radical biology & medicine
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Free Radic. Biol. Med. · Jan 2009
Randomized Controlled Trial Comparative Study Clinical Trial20-HETE and F2-isoprostanes in the metabolic syndrome: the effect of weight reduction.
20-Hydroxyeicosatetraenoic acid (20-HETE) is a cytochrome P450 metabolite of arachidonic acid that regulates vascular function and sodium homeostasis. Studies showing an association between 20-HETE excretion, raised BMI, and oxidative stress suggest that 20-HETE may be important in the development of cardiovascular disease in the metabolic syndrome (MetS). We investigated whether 20-HETE and F(2)-isoprostanes (markers of oxidative stress) were altered in the MetS before and after weight reduction. ⋯ In a randomized controlled trial, 42 participants with the MetS were assigned to 16 weeks of weight maintenance or a 12-week weight-loss program followed by 4 weeks weight stabilization. Relative to the weight-maintenance group, a 4-kg loss in weight resulted in a 2-mm Hg fall in blood pressure (BP) but did not alter urinary or plasma 20-HETE or F(2)-isoprostanes. 20-HETE and oxidative stress may be important mediators of cardiovascular disease risk in the MetS. Although a 4% reduction in body weight reduced BP, there were no changes in plasma or urinary 20-HETE or F(2)-isoprostanes.
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Free Radic. Biol. Med. · Jan 2009
Lipophilicity is a critical parameter that dominates the efficacy of metalloporphyrins in blocking the development of morphine antinociceptive tolerance through peroxynitrite-mediated pathways.
Severe pain syndromes reduce the quality of life of patients with inflammatory and neoplastic diseases, partly because reduced analgesic effectiveness with chronic opiate therapy (i.e., tolerance) leads to escalating doses and distressing side effects. Peroxynitrite-mediated nitroxidative stress in the dorsal horn of the spinal cord plays a critical role in the induction and development of antinociceptive tolerance to morphine. This provides a valid pharmacological basis for developing peroxynitrite scavengers as potent adjuncts to opiates in the management of pain. ⋯ Also neither was able to reverse already established morphine tolerance. We have recently shown that the anionic porphyrin Mn(III) tetrakis(4-carboxylatophenyl)porphyrin is selective in removing ONOO(-) over O(2)(-), but at approximately 2 orders of magnitude lower efficacy than MnTE-2-PyP(5+) and MnTnHex-2-PyP(5+), which in turn parallels up to 100-fold lower ability to reverse morphine tolerance. These data (1) support the role of peroxynitrite rather than superoxide as a major mechanism in blocking the development of morphine tolerance and (2) show that lipophilicity is a critical parameter in enhancing the potency of such novel peroxynitrite scavengers.