title: Dexmedetomidine's inhibitory effects on acetylcholine release from cholinergic nerves in guinea pig trachea: a mechanism that accounts for its clinical benefit during airway irritation.
abstract: Airway instrumentation can evoke upper airway reflexes including bronchoconstriction and cough which can cause serious complications including airway trauma, laryngospasm or bronchospasm which may in turn lead to difficulty with ventilation and hypoxemia. These airway events are mediated in part by irritant-induced neuronal modulation of airway tone and cough responses. We investigated whether the commonly used anesthetic agents dexmedetomidine, lidocaine or remifentanil attenuated neuronal and airway smooth muscle responses in the upper airways of guinea pigs.
  
  
  
  The ability of dexmedetomidine, lidocaine or remifentanil to attenuate direct cholinergic nerve stimulation, C-fiber stimulation or direct smooth muscle contraction were studied using isolated tracheal rings from male guinea pigs under four paradigms; (1) the magnitude of contractile force elicited by cholinergic electrical field stimulation (EFS); (2) the amount of acetylcholine released during cholinergic EFS; (3) the direct airway smooth muscle relaxation of a sustained acetylcholine-induced contraction and (4) the magnitude of C-fiber mediated contraction.
  
  
  
  Dexmedetomidine (1-100 μM) and lidocaine (1 mM) attenuated cholinergic 30Hz EFS-induced tracheal ring contraction while remifentanil (10 μM) had no effect. Dexmedetomidine at 10 μM (p = 0.0047) and 100 μM (p = 0.01) reduced cholinergic EFS-induced acetylcholine release while lidocaine (10 μM-1 mM) and remifentanil (0.1-10 μM) did not. Tracheal ring muscle force induced by the exogenous addition of the contractile agonist acetylcholine or by a prototypical C-fiber analogue of capsaicin were also attenuated by 100 μM dexmedetomidine (p = 0.0061 and p = 0.01, respectively). The actual tracheal tissue concentrations of dexmedetomidine achieved (0.54-26 nM) following buffer application of 1-100 μM of dexmedetomidine were within the range of clinically achieved plasma concentrations (12 nM).
  
  
  
  The α2 adrenoceptor agonist dexmedetomidine reduced cholinergic EFS-induced contractions and acetylcholine release consistent with the presence of inhibitory α2 adrenoceptors on the prejunctional side of the postganglionic cholinergic nerve-smooth muscle junction. Dexmedetomidine also attenuated both exogenous acetylcholine-induced contraction and C-fiber mediated contraction, suggesting a direct airway smooth muscle effect and an underlying mechanism for cough suppression, respectively.
authors.affiliation: Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, 630 West 168th Street, P&S Box 46, New York, NY, 10032, USA. mm2545@cumc.columbia.edu.
authors.forename: Maya
authors.identifier: 0000-0002-3109-632X
authors.initials: M
authors.lastname: Mikami
authors.affiliation: Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, 630 West 168th Street, P&S Box 46, New York, NY, 10032, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Cell Biology, College of Physicians and Surgeons of Columbia University, New York, NY, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kim
authors.affiliation: Department of Pathology and Cell Biology, College of Physicians and Surgeons of Columbia University, New York, NY, USA.
authors.forename: Tilla S
authors.initials: TS
authors.lastname: Worgall
authors.affiliation: Department of Anesthesiology, Intensive Care and Pain Therapy, Kliniken Essen-Mitte, Essen, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Groeben
authors.affiliation: Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, 630 West 168th Street, P&S Box 46, New York, NY, 10032, USA.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Emala
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000777:Anesthetics / Q000494:pharmacology; D000818:Animals; D059329:Cholinergic Neurons / Q000187:drug effects* / Q000378:metabolism*; D020927:Dexmedetomidine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology; D000077208:Remifentanil; D014132:Trachea / Q000187:drug effects / Q000294:innervation*
chemical_list: D000777:Anesthetics; D010880:Piperidines; D020927:Dexmedetomidine; D008012:Lidocaine; D000109:Acetylcholine; D000077208:Remifentanil
keywords: Airway Management; Anesthetic Agents; Bronchodilation; Muscle Relaxation; Smooth Muscle; α2 adrenoceptor agonist