Combined actions of bronchodilators in guinea-pigs depend on the severity of cholinergic airway obstruction

Abstract

The effects of theophylline (THEO), given alone and in combination with terbutaline (TER) or ipratropium bromide (IPRA), were investigated on the dose-related methacholine (MeCh)-induced bronchoconstriction in anaesthetized guinea-pigs. MeCh increased lung resistance (R L) relatively more than it decreased dynamic lung compliance (C DYN), which indicates obstruction of mainly large airways. THEO counteracted MeCh effects on C DYN more than those on R L, in comparison with the effects of TER or IPRA. Combined treatment with THEO + TER or THEO + IPRA usually antagonized the MeCh-induced rise in R L more than did the individual drugs, but the decrease in C DYN was not prevented more than by THEO alone. The actions of the bronchodilator combinations on R L depended on the degree of airway obstruction, being additive on mild or moderate states and synergistic on the most severe bronchoconstriction. Subtherapeutic doses of TER antagonized rather than enhanced the effects of THEO on R L. These results suggest that THEO has a more peripheral apparent site of action than TER or IPRA. A sufficient dose of a β 2-agonist seems decisive in order to produce an enhanced bronchodilator effect with THEO on large airways.