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This Article Full Text Full Text (PDF) All Versions of this Article: 290/3/L526    most recent 00340.2005v2 00340.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Allen, I. C. Articles by Koller, B. H. Search for Related Content PubMed PubMed Citation Articles by Allen, I. C. Articles by Koller, B. H.

Thromboxane A₂ induces airway constriction through an M₃ muscarinic acetylcholine receptor-dependent mechanism

¹Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; ²Center For Human Genomics, Wake Forest University Health Science Center, Winston-Salem, North Carolina; ³Division of Nephrology, Duke University Medical Center, Durham, North Carolina; and ⁴Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland

Submitted 3 August 2005 ; accepted in final form 20 October 2005

Thromboxane A₂ (TXA₂) is a potent lipid mediator released by platelets and inflammatory cells and is capable of inducing vasoconstriction and bronchoconstriction. In the airways, it has been postulated that TXA₂ causes airway constriction by direct activation of thromboxane prostanoid (TP) receptors on airway smooth muscle cells. Here we demonstrate that although TXA₂ can mediate a dramatic increase in airway smooth muscle constriction and lung resistance, this response is largely dependent on vagal innervation of the airways and is highly sensitive to muscarinic acetylcholine receptor (mAChR) antagonists. Further analyses employing pharmacological and genetic strategies demonstrate that TP-dependent changes in lung resistance and airway smooth muscle tension require expression of the M₃ mAChR subtype. These results raise the possibility that some of the beneficial actions of anticholinergic agents used in the treatment of asthma and chronic obstructive pulmonary disease result from limiting physiological changes mediated through the TP receptor. Furthermore, these findings demonstrate a unique pathway for TP regulation of homeostatic mechanisms in the airway and suggest a paradigm for the role of TXA₂ in other organ systems.

nerve; prostanoid; bronchoconstriction; asthma; vagus

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