The protective effects of intravenous theophylline and enprofylline against histamine- and adenosine 5'-monophosphate-provoked bronchoconstriction: implications for the mechanisms of action of xanthine derivatives in asthma.
The contribution of adenosine antagonism to the anti-bronchoconstrictor effect of xanthines was examined in 7 atopic asthmatic subjects. On separate occasions the effect of intravenous infusions of theophylline, enprofylline and saline placebo was observed on bronchoconstriction provoked by increasing inhaled concentrations of histamine and adenosine 5'-monophosphate (AMP). Airway calibre was followed as the maximum expiratory flow at 70% below total lung capacity (Vmax30) and FEV1. Both active drugs produced a similar 6-8% increase in FEV1 and 28-41% increase in Vmax30 at steady state plasma concentrations of theophylline 11 mg/ml and enprofylline 3 mg/ml respectively. During the placebo infusion histamine and AMP caused dose-related reductions in both indices of airway calibre, with AMP being approximately 10 times less potent than histamine in molar terms. Theophylline and enprofylline produced similar protection against histamine induced reductions in FEV1 and Vmax30. Whereas enprofylline afforded a similar degree of protection against the airway effect of AMP and histamine, theophylline produced significantly greater protection against AMP whether airway calibre was assessed as Vmax30 or FEV1. The differential effects of theophylline and enprofylline against AMP, but not histamine or baseline airway calibre suggest that adenosine antagonism has little role to play in the acute bronchodilator actions of xanthines.
Clarke
H
H
Immunopharmacology Group, Southampton General Hospital, UK.
Cushley
M J
MJ
Persson
C G
CG
Holgate
S T
ST
D000328:Adult; D000485:Allergens; D001249:Asthma / Q000503:physiopathology*; D016084:Bronchoconstriction / Q000187:drug effects*; D001993:Bronchodilator Agents / Q000494:pharmacology*; D000242:Cyclic AMP / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D005260:Female; D005541:Forced Expiratory Volume; D006339:Heart Rate / Q000187:drug effects; D006633:Histamine Antagonists / Q000494:pharmacology*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D012882:Skin Tests; D013806:Theophylline / Q000008:administration & dosage / Q000494:pharmacology*; D014970:Xanthines / Q000009:adverse effects / Q000494:pharmacology*
D000485:Allergens; D001993:Bronchodilator Agents; D006633:Histamine Antagonists; D014970:Xanthines; D013806:Theophylline; C034347:enprofylline; D000242:Cyclic AMP