title: Modulation of adenosine-induced responses in the guinea-pig trachea during long-term caffeine treatment: possible role of epithelium.
abstract: The responses to adenosine were studied on isolated, methacholine-precontracted tracheal strips of guinea pigs in the course of long-term caffeine or solvent treatment. Guinea pigs were fed caffeine for 10 weeks (average serum caffeine concentration: 39.1 +/- 3.9 microM). In epithelium-intact tracheal preparations (EITPs), sensititization to adenosine-induced relaxation (AIR) developed. It attained a maximum in week 1 of caffeine treatment, and then its level diminished and disappeared completely by weeks 4 - 6. In epithelium-denuded tracheal preparations (EDTPs), an increase in the sensitivity to adenosine was observed from week 1 to week 10 (a 4 - 6-fold reduction in EC50). Use of a coaxial bioassay system confirmed the role of epithelium in this process. The enhancement of the AIR of the EITPs was not modified by inhibitors of cyclooxygenase and lipoxygenase. Following depletion of the neuropeptides by acute capsaicin pretreatment, the AIR of the EITPs was strongly enhanced after caffeine treatment for 6 weeks. In chronically caffeine-treated EITPs, the inhibition of neutral endopeptidase led to dramatic reduction of the AIR. On the basis of the results by inhibiting nitric oxide synthase, it can be supposed that nitric oxide released from EITPs of long-lasting caffeine-treated animals operated as a constrictor agent. Our results show that chronic caffeine treatment gives rise to an initial sensitization to adenosine of the EITPs, this being followed by the development of a specific adaptive process in the epithelial cells, which counterbalances the increased tracheal sensitivity to adenosine.
authors.affiliation: Department of Pulmonology, University of Debrecen, Medical and Health Science Center, PO Box 12, Debrecen H-4012, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Brugós
authors.forename: Rudolf
authors.initials: R
authors.lastname: Gesztelyi
authors.forename: Judit
authors.initials: J
authors.lastname: Zsuga
authors.forename: Agnes
authors.initials: A
authors.lastname: Cseppento
authors.forename: Ilona
authors.initials: I
authors.lastname: Benko
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Galajda
authors.forename: György
authors.initials: G
authors.lastname: Deák
authors.forename: Sándor
authors.initials: S
authors.lastname: Sipka
authors.forename: Tamás
authors.initials: T
authors.lastname: Roszer
authors.forename: Péter
authors.initials: P
authors.lastname: Kovács
authors.forename: Mária
authors.initials: M
authors.lastname: Szilasi
authors.forename: István
authors.initials: I
authors.lastname: Edes
authors.forename: András József
authors.initials: AJ
authors.lastname: Szentmiklósi
mesh_terms: D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002110:Caffeine / Q000097:blood / Q000494:pharmacology*; D002211:Capsaicin / Q000494:pharmacology; D004205:Cromolyn Sodium / Q000494:pharmacology; D004848:Epithelium / Q000502:physiology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009569:Nitric Oxide / Q000502:physiology; D019335:Nitroarginine / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects* / Q000502:physiology
chemical_list: D019335:Nitroarginine; D009569:Nitric Oxide; D002110:Caffeine; D000241:Adenosine; D004205:Cromolyn Sodium; D002211:Capsaicin