In vivo adenosine A(2B) receptor desensitization in guinea-pig airway smooth muscle: implications for asthma.
This study was aimed at characterizing the role of adenosine receptor subtypes in the contractility modulation of guinea-pig airway smooth muscle in normal and pathological settings. In vitro and in vivo experiments were performed by testing selective agonists and antagonists on isolated tracheal smooth muscle preparations and pulmonary inflation pressure, respectively, under normal conditions or following ovalbumin-induced allergic sensitization. In normal and sensitized animals, the adenosine A(2A)/A(2B) receptor agonist, NECA, evoked relaxing responses of isolated tracheal preparations precontracted with histamine, and such an effect was reversed by the adenosine A(2B) antagonist, MRS 1706, in the presence or in the absence of epithelium. The expression of mRNA coding for adenosine A(2B) receptors was demonstrated in tracheal specimens. In vitro desensitization with 100 microM NECA markedly reduced the relaxing effect of the agonist. In vivo NECA or adenosine administration to normal animals inhibited histamine-mediated bronchoconstriction, while these inhibitory effects no longer occurred in sensitized guinea-pigs. Adenosine plasma levels were significantly higher in sensitized than normal animals. In conclusion, our data demonstrate that: (i) adenosine A(2B) receptors are responsible for the relaxing effects of adenosine on guinea-pig airways; (ii) these receptors can undergo rapid adaptive changes that may affect airway smooth muscle responsiveness to adenosine; (iii) ovalbumin-induced sensitization promotes a reversible inactivation of adenosine A(2B) receptors which can be ascribed to homologous desensitization. These findings can be relevant to better understand adenosine functions in airways as well as mechanisms of action of asthma therapies targeting the adenosine system.
Breschi
Maria Cristina
MC
Department of Psychiatry, Neurobiology, Pharmacology and Biotechnology, University of Pisa, Via Bonanno 6, I-56126, Pisa, Italy. breschi@farm.unipi.it
Blandizzi
Corrado
C
Fogli
Stefano
S
Martinelli
Cinzia
C
Adinolfi
Barbara
B
Calderone
Vincenzo
V
Camici
Marcella
M
Martinotti
Enrica
E
Nieri
Paola
P
D000241:Adenosine / Q000097:blood; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D001993:Bronchodilator Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006632:Histamine / Q000097:blood; D006967:Hypersensitivity / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D007545:Isoproterenol / Q000494:pharmacology / Q000627:therapeutic use; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use; D043704:Receptor, Adenosine A2B / Q000187:drug effects / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D001993:Bronchodilator Agents; C496145:N-(4-acetylphenyl)-2-(4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)phenoxy)acetamide; D011687:Purines; D043704:Receptor, Adenosine A2B; D019830:Adenosine-5'-(N-ethylcarboxamide); D006632:Histamine; D000241:Adenosine; D007545:Isoproterenol