A major role for carbon monoxide as an endogenous hyperpolarizing factor in the gastrointestinal tract

Gianrico Farrugia, Sha Lei, Xue Lin, Steven M. Miller, Karl A. Nath, Christopher D. Ferris, Michael Levitt, Joseph H. Szurszewski

Research output: Contribution to journalArticlepeer-review

85 Scopus citations


Carbon monoxide (CO) is proposed as a physiological messenger. CO activates cGMP and has a direct effect on potassium channels. Both actions of CO lead to hyperpolarization of a cell's resting membrane potential, suggesting that CO may function as a hyperpolarizing factor, although direct evidence is still lacking. Here we take advantage of the known membrane potential gradient that exists in the muscle layers of the gastrointestinal tract to determine whether CO is an endogenous hyperpolarizing factor. We find that heme oxygenase-2-null mice have depolarized smooth muscle cells and that the membrane potential gradient in the gut is abolished. Exogenous CO hyperpolarizes the membrane potential. Regions of the canine gastrointestinal tract that are more hyperpolarized generate more CO and have higher heme oxygenase activity than more depolarized regions. Our results suggest that CO is a critical hyperpolarizing factor required for the maintenance of intestinal smooth muscle membrane potential and gradient.

Original languageEnglish (US)
Pages (from-to)8567-8570
Number of pages4
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number14
StatePublished - Jul 8 2003
Externally publishedYes

Bibliographical note

Funding Information:
We thank the Fermilab staff and the technical staffs of the participating institutions for their vital contributions. This work was supported by the U.S. Department of Energy and National Science Foundation; the Italian Istituto Nazionale di Fisica Nucleare; the Ministry of Education, Science and Culture of Japan; the Natural Sciences and Engineering Research Council of Canada; the National Science Council of the Republic of China; the A. P. Sloan Foundation; the Max Kade Foundation; and the Ministry of Education, Science and Research of the Federal State Nordrhein-Westfalen of Germany.


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