Adenosine induces a cholinergic tracheal reflex contraction in guinea pigs in vivo via an adenosine A1 receptor-dependent mechanism.
Adenosine induces dyspnea, cough, and airways obstruction in asthma, a phenomenon that also occurs in various sensitized animal models in which a neuronal involvement has been implicated. Although adenosine has been suggested to activate cholinergic nerves, the precise mechanism has not been established. In the present study, the adenosine A(1) receptor agonist N(6)-cyclopentyladenosine (CPA) induced a cholinergic reflex, causing tracheal smooth muscle contraction that was significantly inhibited by the adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 100 microg/kg) (P < 0.05) in anesthetized animals. Furthermore, the adenosine A(2) agonist 2-p-(2-carboxyethyl) phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS-21680) induced a small reflex, whereas the A(3) selective agonist N(6)-(3-iodobenzyl)-5'-N-methylcarbamoyladenosine (IB-MECA) was without effect. The tracheal reflex induced by CPA was also inhibited by recurrent nerve ligation or muscarinic receptor blockade (P < 0.001), indicating that a cholinergic neuronal mechanism of action accounted for this response. The cholinergic reflex in response to aerosolized CPA was significantly greater in passively sensitized compared with naive guinea pigs (P < 0.01). Chronic capsaicin treatment, which inhibited sensory nerve function, failed to inhibit CPA-induced reflex tracheal contractions in passively sensitized guinea pigs, although the local anesthetic lidocaine inhibited CPA-induced tracheal contractions. The effects of CPA on the reflex response was not dependent on the release of histamine from tissue mast cells or endogenous prostaglandins as shown by the lack of effect of the histamine H(1) receptor antagonist pyrilamine (1 mg/kg) or the cyclooxygenase inhibitor meclofenamic acid (3 mg/kg), respectively. In conclusion, activation of pulmonary adenosine A(1) receptors can stimulate cholinergic reflexes, and these reflexes are increased in allergic guinea pigs.
Reynolds
Sandra M
SM
Pharmaceutical Science Research Division, The Sackler Institute of Pulmonary Pharmacology, School of Biomedical and Health Science, King's College London, London SE1 1UL, UK.
Docherty
Reginald
R
Robbins
Jon
J
Spina
Domenico
D
Page
Clive P
CP
D000241:Adenosine / Q000494:pharmacology*; D058907:Adenosine A1 Receptor Agonists; D000280:Administration, Inhalation; D000403:Airway Resistance / Q000502:physiology; D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin; D002522:Chlorocebus aethiops; D003371:Cough / Q000139:chemically induced / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007823:Laryngeal Nerves / Q000502:physiology; D008026:Ligation; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000294:innervation; D010275:Parasympathetic Nervous System / Q000187:drug effects*; D043682:Receptor, Adenosine A1 / Q000235:genetics / Q000502:physiology*; D012018:Reflex / Q000187:drug effects; D012129:Respiratory Function Tests; D050916:TRPV Cation Channels / Q000235:genetics / Q000502:physiology; D014132:Trachea / Q000187:drug effects*; D014162:Transfection
D058907:Adenosine A1 Receptor Agonists; D043682:Receptor, Adenosine A1; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D000241:Adenosine; D002211:Capsaicin; D002118:Calcium