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This Article Full Text Full Text (PDF) All Versions of this Article: 105/1/187    most recent 01048.2007v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted 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 Google Scholar Articles by Reynolds, S. M. Articles by Page, C. P. PubMed PubMed Citation Articles by Reynolds, S. M. Articles by Page, C. P.

Adenosine induces a cholinergic tracheal reflex contraction in guinea pigs in vivo via an adenosine A₁ receptor-dependent mechanism

¹Pharmaceutical Science Research Division, The Sackler Institute of Pulmonary Pharmacology, School of Biomedical and Health Science, King's College London, and ²Wolfson Centre for Age-Related Research, School of Biomedical and Health Science, King's College London, London, United Kingdom

Submitted 1 October 2007 ; accepted in final form 10 April 2008

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 A₁ receptor agonist N⁶-cyclopentyladenosine (CPA) induced a cholinergic reflex, causing tracheal smooth muscle contraction that was significantly inhibited by the adenosine A₁ receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 100 µg/kg) (P < 0.05) in anesthetized animals. Furthermore, the adenosine A₂ agonist 2-p-(2-carboxyethyl) phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS-21680) induced a small reflex, whereas the A₃ selective agonist N⁶-(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 H₁ receptor antagonist pyrilamine (1 mg/kg) or the cyclooxygenase inhibitor meclofenamic acid (3 mg/kg), respectively. In conclusion, activation of pulmonary adenosine A₁ receptors can stimulate cholinergic reflexes, and these reflexes are increased in allergic guinea pigs.

N⁶-cyclopentyladenosine; cholinergic reflex; adenosine 5'-monophosphate; capsaicin; passively sensitized