Generation of nitric oxide from nitrite by carbonic anhydrase: a possible link between metabolic activity and vasodilation

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Standard

Generation of nitric oxide from nitrite by carbonic anhydrase: a possible link between metabolic activity and vasodilation. / Aamand, Rasmus; Dalsgaard, Thomas; Jensen, Frank Bo; Simonsen, Ulf; Roepstorff, Andreas; Fago, Angela.

In: American Journal of Physiology: Heart and Circulatory Physiology, Vol. 297, 2009, p. H2068-H2074.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Harvard

APA

CBE

MLA

Vancouver

Author

Aamand, Rasmus ; Dalsgaard, Thomas ; Jensen, Frank Bo ; Simonsen, Ulf ; Roepstorff, Andreas ; Fago, Angela. / Generation of nitric oxide from nitrite by carbonic anhydrase: a possible link between metabolic activity and vasodilation. In: American Journal of Physiology: Heart and Circulatory Physiology. 2009 ; Vol. 297. pp. H2068-H2074.

Bibtex

@article{e853f8d0e0c511de9e3b000ea68e967b,
title = "Generation of nitric oxide from nitrite by carbonic anhydrase: a possible link between metabolic activity and vasodilation",
abstract = "In catalyzing the reversible hydration of CO2 to bicarbonate and protons, the ubiquitous enzyme carbonic anhydrase (CA) plays a crucial role in CO2 transport, in acid-base balance, and in linking local acidosis to O2 unloading from hemoglobin. Considering the structural similarity between bicarbonate and nitrite, we hypothesized that CA uses nitrite as a substrate to produce the potent vasodilator nitric oxide (NO) to increase local blood flow to metabolically active tissues. Here we show that CA readily reacts with nitrite to generate NO, particularly at low pH, and that the NO produced in the reaction induces vasodilation in aortic rings. This reaction occurs under normoxic and hypoxic conditions and in various tissues at physiological levels of CA and nitrite. Furthermore, two specific inhibitors of the CO2 hydration, dorzolamide and acetazolamide, increase the CA-catalyzed production of vasoactive NO from nitrite. This enhancing effect may explain the known vasodilating effects of these drugs and indicates that CO2 and nitrite bind differently to the enzyme active site. Kinetic analyses show a higher reaction rate at high pH, suggesting that anionic nitrite participates more effectively in catalysis. Taken together, our results reveal a novel nitrous anhydrase enzymatic activity of CA that would function to link the in vivo main end products of energy metabolism (CO2/H+) to the generation of vasoactive NO. The CA-mediated NO production may be important to the correlation between blood flow and metabolic activity in tissues, as occurring for instance in active areas of the brain.",
author = "Rasmus Aamand and Thomas Dalsgaard and Jensen, {Frank Bo} and Ulf Simonsen and Andreas Roepstorff and Angela Fago",
year = "2009",
doi = "10.1152/ajpheart.00525.2009",
language = "English",
volume = "297",
pages = "H2068--H2074",
journal = "American Journal of Physiology: Heart and Circulatory Physiology",
issn = "0363-6135",
publisher = "American Physiological Society",

}

RIS

TY - JOUR

T1 - Generation of nitric oxide from nitrite by carbonic anhydrase: a possible link between metabolic activity and vasodilation

AU - Aamand, Rasmus

AU - Dalsgaard, Thomas

AU - Jensen, Frank Bo

AU - Simonsen, Ulf

AU - Roepstorff, Andreas

AU - Fago, Angela

PY - 2009

Y1 - 2009

N2 - In catalyzing the reversible hydration of CO2 to bicarbonate and protons, the ubiquitous enzyme carbonic anhydrase (CA) plays a crucial role in CO2 transport, in acid-base balance, and in linking local acidosis to O2 unloading from hemoglobin. Considering the structural similarity between bicarbonate and nitrite, we hypothesized that CA uses nitrite as a substrate to produce the potent vasodilator nitric oxide (NO) to increase local blood flow to metabolically active tissues. Here we show that CA readily reacts with nitrite to generate NO, particularly at low pH, and that the NO produced in the reaction induces vasodilation in aortic rings. This reaction occurs under normoxic and hypoxic conditions and in various tissues at physiological levels of CA and nitrite. Furthermore, two specific inhibitors of the CO2 hydration, dorzolamide and acetazolamide, increase the CA-catalyzed production of vasoactive NO from nitrite. This enhancing effect may explain the known vasodilating effects of these drugs and indicates that CO2 and nitrite bind differently to the enzyme active site. Kinetic analyses show a higher reaction rate at high pH, suggesting that anionic nitrite participates more effectively in catalysis. Taken together, our results reveal a novel nitrous anhydrase enzymatic activity of CA that would function to link the in vivo main end products of energy metabolism (CO2/H+) to the generation of vasoactive NO. The CA-mediated NO production may be important to the correlation between blood flow and metabolic activity in tissues, as occurring for instance in active areas of the brain.

AB - In catalyzing the reversible hydration of CO2 to bicarbonate and protons, the ubiquitous enzyme carbonic anhydrase (CA) plays a crucial role in CO2 transport, in acid-base balance, and in linking local acidosis to O2 unloading from hemoglobin. Considering the structural similarity between bicarbonate and nitrite, we hypothesized that CA uses nitrite as a substrate to produce the potent vasodilator nitric oxide (NO) to increase local blood flow to metabolically active tissues. Here we show that CA readily reacts with nitrite to generate NO, particularly at low pH, and that the NO produced in the reaction induces vasodilation in aortic rings. This reaction occurs under normoxic and hypoxic conditions and in various tissues at physiological levels of CA and nitrite. Furthermore, two specific inhibitors of the CO2 hydration, dorzolamide and acetazolamide, increase the CA-catalyzed production of vasoactive NO from nitrite. This enhancing effect may explain the known vasodilating effects of these drugs and indicates that CO2 and nitrite bind differently to the enzyme active site. Kinetic analyses show a higher reaction rate at high pH, suggesting that anionic nitrite participates more effectively in catalysis. Taken together, our results reveal a novel nitrous anhydrase enzymatic activity of CA that would function to link the in vivo main end products of energy metabolism (CO2/H+) to the generation of vasoactive NO. The CA-mediated NO production may be important to the correlation between blood flow and metabolic activity in tissues, as occurring for instance in active areas of the brain.

U2 - 10.1152/ajpheart.00525.2009

DO - 10.1152/ajpheart.00525.2009

M3 - Journal article

VL - 297

SP - H2068-H2074

JO - American Journal of Physiology: Heart and Circulatory Physiology

JF - American Journal of Physiology: Heart and Circulatory Physiology

SN - 0363-6135

ER -