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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Involvement of the Neurokinin-2 Receptor in Airway Smooth Muscle Stretch-Activated Contractions Assessed in Perfused Intact Bovine Bronchial Segments

Firestone Institute for Respiratory Health, Father Sean O'Sullivan Research Centre, and Department of Medicine, McMaster University, St. Joseph's Hospital, Hamilton, Ontario, Canada

The airway response to deep inspirations (DIs) in asthmatics has been shown to be ineffective in producing bronchodilation and can even cause bronchoconstriction. However, the manner by which a DI is able to cause bronchoconstriction remains ambiguous. We sought to investigate the pathway involved in this stretch-activated contraction and whether this contraction is intrinsic to airway smooth muscle (ASM). In brief, intact bovine bronchial segments were dissected, and side branches were ligated and then mounted horizontally in an organ bath. Intraluminal pressure was measured under isovolumic conditions. Instantaneously opening and then closing the tap on a column of fluid 5 to 30 cm high evoked a sudden increase in intraluminal pressure (equivalent to the height of the column of fluid) followed by a stress relaxation response of the ASM. When tissues were stimulated with carbachol (10^-8 M) or serotonin (10^-7 M) for 10 min, and the consequent agonist-evoked pressure response was dissipated manually, the response to the same transmural stretch was accompanied by a slowly developing and prolonged increase in intraluminal pressure. This stretch-activated response was significantly diminished by the stretch-activated cation channel blocker gadolinium (10^-3 M), the L-type Ca²⁺ channel blockers nifedipine (2 x 10^-6 M), diltiazem (10^-5 M), and verapamil (10^-5 M), the sensory neurotoxin capsaicin (10^-5 M), and the neurokinin (NK)₂ receptor antagonists MEN 10376 ([Tyr^I,D-Trp^6,8,9,Lys¹⁰]-NKA(4–10)) (10^-5 M) and SR48968 (N-[(2S)-4-(4-acetamido-4-phenylpiperidin-1-yl)-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamide) (3 x 10^-6 M). These results show the ability of isolated airways to exhibit stretch-activated contractions and suggest a role for stretch-activated cation channels, sensory afferent neurons, the neurotransmitter NKA, and L-type Ca²⁺ channels in these isolated airway responses.

Address correspondence to: Dr. Luke Jeffrey Janssen, Firestone Institute for Respiratory Health, St. Joseph's Hospital, Room L-314, 50 Charlton Avenue East, Hamilton, ON, Canada L8N 4A6. E-mail: janssenl{at}mcmaster.ca