Department of Anesthesiology and Operative Intensive Care Medicine, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitätsmedizin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
Department of Anesthesiology and Intensive Care Medicine, University of Leipzig, Leipzig, Germany.
J Physiol. 2019 Feb;597(4):1045-1058. doi: 10.1113/JP275894. Epub 2018 May 31.
Carbonic anhydrase (CA) inhibitors such as acetazolamide inhibit hypoxic pulmonary vasoconstriction (HPV) in humans and other mammals, but the mechanism of this action remains unknown. It has been postulated that carbonic anhydrase may act as a nitrous anhydrase in vivo to generate nitric oxide (NO) from nitrite and that this formation is increased in the presence of acetazolamide. Acetazolamide reduces HPV in pigs without evidence of any NO generation, whereas nebulized sodium nitrite reduces HPV by NO formation; however; combined infusion of acetazolamide with sodium nitrite inhalation did not further increase exhaled NO concentration over inhaled nitrite alone in pigs exposed to alveolar hypoxia. We conclude that acetazolamide does not function as either a nitrous anhydrase or a nitrite reductase in the lungs of pigs, and probably other mammals, to explain its vasodilating actions in the pulmonary or systemic circulations.
The carbonic anhydrase (CA) inhibitors acetazolamide and its structurally similar analogue methazolamide prevent or reduce hypoxic pulmonary vasoconstriction (HPV) in dogs and humans in vivo, by a mechanism unrelated to CA inhibition. In rodent blood and isolated blood vessels, it has been reported that inhibition of CA leads to increased generation of nitric oxide (NO) from nitrite and vascular relaxation in vitro. We tested the physiological relevance of augmented NO generation by CA from nitrite with acetazolamide in anaesthetized pigs during alveolar hypoxia in vivo. We found that acetazolamide prevents HPV in anaesthetized pigs, as in other mammalian species. A single nebulization of sodium nitrite reduces HPV, but this action wanes in the succeeding 3 h of hypoxia as nitrite is metabolized and excreted. Pulmonary artery pressure reduction and NO formation as measured by exhaled gas concentration from inhaled sodium nitrite were not increased by acetazolamide during alveolar hypoxia. Thus, our data argue against a physiological role of carbonic anhydrase as a nitrous anhydrase or nitrite reductase as a mechanism for its inhibition of HPV in the lung and blood in vivo.
碳酸酐酶（CA）抑制剂，如乙酰唑胺，抑制人类和其他哺乳动物的低氧性肺血管收缩（HPV），但其作用机制尚不清楚。有人推测，碳酸酐酶在体内可能作为亚硝基水解酶，将亚硝酸盐转化为一氧化氮（NO），而在乙酰唑胺存在的情况下，这种转化会增加。乙酰唑胺可降低猪的 HPV，但没有证据表明有任何 NO 生成，而雾化吸入亚硝酸钠可通过形成 NO 降低 HPV；然而，在暴露于肺泡低氧的猪中，联合输注乙酰唑胺和吸入亚硝酸钠并没有进一步增加吸入的亚硝酸钠单独吸入时呼出的 NO 浓度。我们的结论是，乙酰唑胺在猪的肺部，可能在其他哺乳动物的肺部，不起作为亚硝基水解酶或亚硝酸盐还原酶的作用，无法解释其在肺或全身循环中的血管扩张作用。
碳酸酐酶（CA）抑制剂乙酰唑胺及其结构类似物甲唑胺通过与 CA 抑制无关的机制，预防或减少体内狗和人类的低氧性肺血管收缩（HPV）。在啮齿动物的血液和分离的血管中，据报道，CA 的抑制导致从亚硝酸盐产生的一氧化氮（NO）增加和体外血管松弛。我们在体内肺泡低氧的情况下，在麻醉猪中测试了 CA 从亚硝酸盐产生的 NO 增加的生理相关性。我们发现，乙酰唑胺在麻醉猪中可预防 HPV，与其他哺乳动物物种一样。单次雾化吸入亚硝酸钠可降低 HPV，但在随后的 3 小时低氧中，由于亚硝酸盐被代谢和排泄，其作用减弱。在肺泡低氧期间，肺动脉压降低和通过吸入的亚硝酸钠测量的呼气气体浓度的 NO 形成并未因乙酰唑胺而增加。因此，我们的数据反对 CA 作为生理上的亚硝基水解酶或亚硝酸盐还原酶的作用机制，以解释其在体内肺和血液中对 HPV 的抑制作用。
