p38 mitogen-activated protein kinase mediates the sustained phase of hypoxic pulmonary vasoconstriction and plays a role in phase I vasodilation.
Hypoxic pulmonary vasoconstriction (HPV) and pulmonary hypertension present common and formidable clinical problems for thoracic, transplant, and trauma surgeons. We hypothesized that acute hypoxia causes pulmonary artery (PA) contraction and that p38 mitogen-activated protein (MAP) kinase is a key mediator in that process. To test this hypothesis, we measured isometric force displacement in isolated rat pulmonary artery rings during hypoxia in the presence and absence of the selective p38 MAP kinase inhibitor SB-20358, and stimulator anisomycin. In separate experiments, we measured the functional effects in isolated rat pulmonary artery rings of inhibiting p38 MAP kinase during normoxic conditions. p38 MAP kinase inhibition significantly attenuated the delayed, but not early, contractile phase of HPV. Additionally, stimulation of p38 MAP kinase significantly decreased the phase I vasodilation of HPV. Under normoxia conditions, there was no statistically significant difference in isometric force displacement between control and p38 MAPK inhibitor-treated pulmonary artery rings. We conclude that p38 MAP kinase may be a key mediator in the pathogenesis of HPV and that further understanding may lead to new therapies for HPV associated with acute lung injury.
Department of Surgery, Section of Cardiothoracic Surgery, Indiana University Medical Center, Indianapolis, Indiana, USA.
Eric D
ED
Morrell
Ben M
BM
Tsai
Meijing
M
Wang
Paul R
PR
Crisostomo
Daniel R
DR
Meldrum
D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000860:Hypoxia / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology; D007537:Isometric Contraction; D008171:Lung Diseases / Q000209:etiology / Q000517:prevention & control; D008297:Male; D010656:Phenylephrine / Q000008:administration & dosage; D011651:Pulmonary Artery / Q000503:physiopathology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000502:physiology*; D014664:Vasodilation / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D010656:Phenylephrine; D000841:Anisomycin; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580