Nitrite infusion in humans and nonhuman primates - Endocrine effects, pharmacokinetics, and tolerance formation
Nitrite infusion in humans and nonhuman primates - Endocrine effects, pharmacokinetics, and tolerance formation
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DOI：
10.1161/circulationaha.107.712133
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发表时间：
2007-10-16
期刊：
影响因子：
37.8
通讯作者：
Gladwin, Mark T.
中科院分区：
文献类型：
--
作者：
Dejam, Andre;Hunter, Christian J.;Gladwin, Mark T.
背景-最近发现亚硝酸盐是一种接近生理浓度的内在血管舒张剂和信号分子，这提高了亚硝酸盐参与缺氧血管舒张和硝化甘油生物活性的可能性，并介导地中海饮食中硝酸盐的心血管保护作用。然而，效价、动力学、作用机制和可能诱导耐受性的重要问题仍未得到解答。方法和结果-在本研究中，我们在20名正常人类志愿者和非人灵长类动物中使用亚硝酸盐注射方案进行了生化、生理学和药理学研究，以回答这些问题，我们特别测试了3种生物激活机制：通过黄嘌呤氧化还原酶还原为一氧化氮，非酶歧化和脱氧血红蛋白还原。我们发现(1)亚硝酸盐在接近生理浓度时是一种相对有效和快速的血管扩张剂；(2)亚硝酸盐作为一氧化氮的内分泌储存库，在对肢首次灌注时产生远端血管舒张；(3)亚硝酸盐通过与血红蛋白和血管内还原剂（即抗坏血酸）的血管内反应还原为一氧化氮；(4)用氧嘌呤醇抑制黄嘌呤o氧化还原酶不能抑制亚硝酸盐依赖性血管扩张，但能增强血管扩张；(5)亚硝酸盐不像有机硝酸盐那样诱导耐受性。结论-我们提出亚硝酸盐作为血管功能和内分泌一氧化氮稳态的生理调节剂，并建议它是有机硝酸盐的活性代谢物，可用于治疗绕过酶耐受。
Background - The recent discovery that nitrite is an intrinsic vasodilator and signaling molecule at near-physiological concentrations has raised the possibility that nitrite contributes to hypoxic vasodilation and to the bioactivity of nitroglycerin and mediates the cardiovascular protective effects of nitrate in the Mediterranean diet. However, important questions of potency, kinetics, rnechanism of action, and possible induction of tolerance remain unanswered.Methods and Results - In the present study, we performed biochemical, physiological, and pharmacological studies using nitrite infusion protocols in 20 normal human volunteers and in nonhuman primates to answer these questions, and we specifically tested 3 proposed mechanisms of bioactivation: reduction to nitric oxide by xanthine oxidoreductase, nonenzymatic disproportionation, and reduction by deoxyhemoglobin. We found that (1) nitrite is a relatively potent and fast vasodilator at near-physiological concentrations; (2) nitrite functions as an endocrine reservoir of nitric oxide, producing remote vasodilation during first-pass perfusion of the opposite limb; (3) nitrite is reduced to nitric oxide by intravascular reactions with hemoglobin and with intravascular reductants (ie, ascorbate); (4) inhibition of xanthine o xidoreductase with oxypurinol does not inhibit nitrite-dependent vasodilation but potentiates it; and (5) nitrite does not induce tolerance as observed with the organic nitrates.Conclusions - We propose that nitrite functions as a physiological regulator of vascular function and endocrine nitric oxide homeostasis and suggest that it is an active metabolite of the organic nitrates that can be used therapeutically to bypass enzymatic tolerance.