Carbonic anhydrase is not a relevant nitrite reductase or nitrous anhydrase in the lung

Abstract

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.

Carbonic anhydrase II does not regulate nitrite‐dependent nitric oxide formation and vasodilation

“…Our findings demonstrate that CAII is not the enzyme responsible for the bio‐activation of nitrite in the circulation. This is in agreement with other reports that CAII did not contribute to NO formation from nitrite reduction (Andring et al, ; Liu et al, ; Pickerodt et al, ). Further studies should explore other potential nitrite reductases which may have physiological significance in blood flow regulation.…”

“…The role of CAII in nitrite‐dependent NO production and vascular responses is controversial with conflicting published reports (Aamand et al, 2009a; Andring et al, 2018; Hanff et al, 2016; Pickerodt et al, 2018). Previous investigations utilized a combination of NO chemiluminescence, NO specific microelectrode, stable‐isotope MS, and vascular myography to investigate the role of mammalian CAII catalysing the conversion of nitrite to NO.…”

“…Haemoglobin (Basu et al, 2007), nitrophorin (He & Knipp, 2009), and the zinc‐containing carbonic anhydrase (CA) II (Aamand et al, 2009b) have been reported to exhibit nitrite anhydrase activities. However, the role of CAII in nitrite‐dependent NO formation remains controversial as a number of studies have been unable to detect changes in measured NO formation from nitrite with red blood cells (Liu et al, 2015) and in vivo after treatment with CA inhibitors (Andring et al, 2018; Pickerodt et al, 2018; Zinke, Hanff, Böhmer, Supuran, & Tsikas, 2016).…”

Nitrous anhydrase activity of carbonic anhydrase II: cysteine is required for nitric oxide (NO) dependent phosphorylation of VASP in human platelets

“…There are contradictory reports in the literature regarding the above mentioned newest CA II activities and even a disputation of a physiological role of CA II in the bioactivation of nitrite [11][12][13][14] . Here, we provide new experimental data in support of the nitrous anhydrase activity of CA II.…”

Overview: pulmonary vascular function in health and disease

“…A study by Pickerodt and colleagues (Pickerodt et al . ) demonstrates that while carbonic anhydrase can act as a nitrite reductase in vascular cells, exhaled nitric oxide levels were not altered by carbonic anhydrase during alveolar hypoxia, indicating that this is not the mechanism by which it inhibits HPV. With respect to chronic exposure to hypoxia, residence at high altitude is one of the most common causes of long‐term reduced alveolar oxygen levels.…”