Airway hyperresponsiveness to adenosine induced by lipopolysaccharide in Brown Norway rats.
We have explored the effects of bacterial endotoxin (lipopolysaccharide; LPS) on the response of the airways of Brown Norway (BN) rats to adenosine. Comparisons have been drawn with the effects on responses to methacholine and 5-hydroxytryptamine. In vehicle-challenged animals, adenosine, given i.v. was only a weak bronchoconstrictor. In contrast, 1 h following intratracheal administration of LPS, 0.3 mg kg-1, bronchoconstrictor responses to adenosine were markedly and selectively enhanced. At this time point, there were no significant changes in leukocyte numbers, eosinophil peroxidase and myeloperoxidase activities or protein concentrations in bronchoalveolar lavage (BAL) fluid. Twenty-four hours after challenge, the sensitivity of the airways to both adenosine and methacholine was reduced relative to the earlier time point and there were substantial increases in each marker of inflammation in BAL fluid. The bronchoconstrictor response to adenosine was blocked selectively by methysergide, disodium cromoglycate and the broad-spectrum adenosine receptor antagonist, 8-SPT, but not by DPCPX or ZM 243185, selective antagonists for the A1 and A2A receptors, respectively. Thus, the response to adenosine augmented following LPS is mast cell mediated and involves a receptor which can be blocked by 8-SPT but not by selective A1 or A2A receptor antagonists. It thus bears similarity to the augmented response to adenosine induced by allergen challenge in actively sensitized BN rats. Exposure to LPS could be a factor along with allergen in determining the increased sensitivity of the airways of asthmatics to adenosine.
Tigani
B
B
Research Department, Novartis Pharma AG, CH-4002 Basel, Switzerland.
Hannon
J P
JP
Rondeau
C
C
Mazzoni
L
L
Fozard
J R
JR
D000241:Adenosine / Q000008:administration & dosage / Q000494:pharmacology* / Q000502:physiology; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology; D015415:Biomarkers / Q000032:analysis; D001794:Blood Pressure / Q000187:drug effects; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000503:physiopathology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D016084:Bronchoconstriction / Q000187:drug effects; D004205:Cromolyn Sodium / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006339:Heart Rate / Q000187:drug effects; D007249:Inflammation / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D008407:Mast Cells / Q000378:metabolism; D016210:Methacholine Chloride / Q000008:administration & dosage / Q000494:pharmacology; D008784:Methysergide / Q000494:pharmacology; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D012701:Serotonin / Q000008:administration & dosage / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D018927:Anti-Asthmatic Agents; D015415:Biomarkers; D008070:Lipopolysaccharides; D058915:Purinergic P1 Receptor Antagonists; D014662:Vasoconstrictor Agents; D016210:Methacholine Chloride; D012701:Serotonin; D000241:Adenosine; D004205:Cromolyn Sodium; D008784:Methysergide