title: Acid-induced modulation of airway basal tone and contractility: role of acid-sensing ion channels (ASICs) and TRPV1 receptor.
abstract: The role of extracellular acidosis in inflammatory airway diseases is not well known. One consequence of tissue acidification is the stimulation of sensory nerves via the polymodal H(+)-gated transmembrane channels ASICs and TRPV1 receptor. The present study investigated the effect of acidosis on airway basal tone and responsiveness in the guinea pig. Acidosis (pH 6.8, 10 min, 37 degrees C) significantly decreased the basal tone of tracheal rings (p<0.01 vs. paired control). Moreover, pH fall raised the maximal contraction of tracheal rings to acetylcholine (p<0.05 vs. paired control). The pH-induced relaxation of airway basal tone was inhibited by pretreatments with ASIC1a or ASIC3/ASIC2a inhibitors (0.5 mM ibuprofen, 0.1 mM gadolinium), nitric oxide synthase inhibitor (1 mM L-NAME), and guanylate cyclase inhibitor (1 microM ODQ). In contrast, the pH-induced relaxation of airway basal tone was not modified by epithelium removal or pretreatments with a TRPV1 antagonist (1 microM capsazepine), a combination of NK(1,2,3) receptor antagonists (0.1 microM each), a blocker of voltage-sensitive Na(+) channels (1 microM tetrodotoxin), a cyclooxygenase inhibitor with no activity on ASICs (1 microM indomethacin) or ASIC3 and ASIC3/ASIC2b inhibitors (10 nM diclofenac, 1 microM aspirin). Furthermore, acid-induced hyperresponsiveness to acetylcholine was inhibited by epithelium removal, capsazepine, NK(1,2,3) receptor antagonists, tetrodotoxin, amiloride, ibuprofen and diclofenac. In summary, the initial pH-induced airway relaxation seems to be independent of sensory nerves, suggesting a regulation of airway basal tone mediated by smooth muscle ASICs. Conversely, the pH-induced hyperresponsiveness involves sensory nerves-dependent ASICs and TRPV1, and an unknown epithelial component in response to acidosis.
authors.affiliation: Research Unit UPRES EA220, Université Versailles Saint Quentin, Hôpital Foch, 40 rue Worth, 92150 Suresnes, France. christophe.faisy@wanadoo.fr
authors.forename: Christophe
authors.initials: C
authors.lastname: Faisy
authors.forename: Benjamin
authors.initials: B
authors.lastname: Planquette
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Naline
authors.forename: Paul-André
authors.initials: PA
authors.lastname: Risse
authors.forename: Nelly
authors.initials: N
authors.lastname: Frossard
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Fagon
authors.forename: Charles
authors.initials: C
authors.lastname: Advenier
authors.forename: Philippe
authors.initials: P
authors.lastname: Devillier
mesh_terms: D062565:Acid Sensing Ion Channels; D000138:Acidosis / Q000378:metabolism* / Q000473:pathology; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006168:Guinea Pigs; D006863:Hydrogen-Ion Concentration; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009129:Muscle Tonus / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011042:Poisons / Q000494:pharmacology; D018039:Receptors, Tachykinin; D011984:Sensory Receptor Cells / Q000378:metabolism / Q000473:pathology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology; D014132:Trachea / Q000294:innervation / Q000378:metabolism* / Q000473:pathology
chemical_list: D062565:Acid Sensing Ion Channels; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011042:Poisons; D018039:Receptors, Tachykinin; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D013779:Tetrodotoxin; D000584:Amiloride; C071423:capsazepine; D002211:Capsaicin