AMP-activated protein kinase and hypoxic pulmonary vasoconstriction

Tom P. Robertson, Kirsteen J. W. Mustard, Tristan H. Lewis, Jill H. Clark, Christopher N. Wyatt, Elisa A. Blanco, Chris Peers, D. Grahame Hardie, A. Mark Evans

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    Abstract

    Hypoxic pulmonary vasoconstriction is a vital homeostatic mechanism that aids ventilation-perfusion matching in the lung, for which the underlying mechanism(s) remains controversial. However, our most recent investigations strongly suggest that hypoxic pulmonary vasoconstriction is precipitated, at least in part, by the inhibition of mitochondrial oxidative phosphorylation by hypoxia, an increase in the AMP/ATP ratio and consequent activation of AMP-activated protein kinase (AMPK). Unfortunately, these studies lacked the definitive proof that can only be provided by selectively blocking AMPK-dependent signalling cascades. The aim of the present study was. therefore, to determine the effects of the AMPK inhibitor compound C upon: (1) phosphorylation in response to hypoxia of a classical AMPK substrate, acetyl CoA carboxylase, in rat pulmonary arterial smooth muscle and (2) hypoxic pulmonary vasoconstriction in isolated intrapulmonary arteries. Acetyl CoA carboxylase phosphorylation was increased approximately 3 fold in the presence of hypoxia (pO(2) = 16-21 mm Hg, 1 h) and 5-aminoimidazole-4-carboxamide riboside (AICAR; 1 mM; 4 h) and in a manner that was significantly attenuated by the AMPK antagonist compound C (40 mu M). Most importantly, pre-incubation of intrapulmonary arteries with compound C (40 mu M) inhibited phase II, but not phase I, of hypoxic pulmonary vasoconstriction. Likewise, compound C (40 mu M) inhibited constriction by AICAR (1 mM). The results of the present study are consistent with the activation of AMPK being a key event in the initiation of the contractile response of pulmonary arteries to acute hypoxia. (C) 2008 Elsevier B.V. All rights reserved.

    Original languageEnglish
    Pages (from-to)39-43
    Number of pages5
    JournalEuropean Journal of Pharmacology
    Volume595
    Issue number1-3
    DOIs
    Publication statusPublished - 24 Oct 2008

    Keywords

    • AMP-activated protein kinase
    • hypoxic pulmonary vasoconstriction
    • compound C
    • AICAR
    • MITOCHONDRIAL OXIDATIVE-PHOSPHORYLATION
    • COUPLE INHIBITION
    • O-2-SENSING CELLS
    • RAT LUNG
    • LKB1
    • METFORMIN
    • CALCIUM
    • MUSCLE
    • ARTERY
    • CHEMORECEPTORS

    Cite this

    Robertson, T. P., Mustard, K. J. W., Lewis, T. H., Clark, J. H., Wyatt, C. N., Blanco, E. A., Peers, C., Hardie, D. G., & Evans, A. M. (2008). AMP-activated protein kinase and hypoxic pulmonary vasoconstriction. European Journal of Pharmacology, 595(1-3), 39-43. https://doi.org/10.1016/j.ejphar.2008.07.035