AMP-activated protein kinase and hypoxic pulmonary vasoconstriction

Eur J Pharmacol. 2008 Oct 24;595(1-3):39-43. doi: 10.1016/j.ejphar.2008.07.035. Epub 2008 Jul 30.

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 rat 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 microM). Most importantly, pre-incubation of intrapulmonary arteries with compound C (40 microM) inhibited phase II, but not phase I, of hypoxic pulmonary vasoconstriction. Likewise, compound C (40 microM) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases
  • Acetyl-CoA Carboxylase / metabolism
  • Aminoimidazole Carboxamide / analogs & derivatives
  • Aminoimidazole Carboxamide / pharmacology
  • Animals
  • Calcium / metabolism
  • Dinoprost / metabolism
  • Hypoxia / enzymology*
  • Hypoxia / physiopathology
  • Male
  • Multienzyme Complexes / antagonists & inhibitors*
  • Multienzyme Complexes / metabolism
  • Phosphorylation
  • Potassium / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / metabolism
  • Pulmonary Artery / drug effects*
  • Pulmonary Artery / enzymology
  • Pyrazoles / pharmacology*
  • Pyrimidines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Ribonucleotides / pharmacology
  • Signal Transduction / drug effects
  • Vasoconstriction / drug effects*

Substances

  • Multienzyme Complexes
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • Ribonucleotides
  • dorsomorphin
  • Aminoimidazole Carboxamide
  • Dinoprost
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • Acetyl-CoA Carboxylase
  • AICA ribonucleotide
  • Potassium
  • Calcium