Actions of theophylline, terbutaline, and ipratropium bromide alone and in combinations on the methacholine induced bronchoconstriction in rats

Rats under pentobarbitone anaesthesia, pancuronium relaxation and artificial ventilation with constant volume, were given methacholine (MeCh) 4, 6, and 9 micrograms intravenously at 2 min. intervals; the rise in intratracheal pressure indicated bronchoconstriction. The heights of peak responses (PIPR), response areas (RA), and blood pressure and heart rate were recorded, and theophylline (THEO) concentrations in plasma and lung tissue were measured. THEO (5, 10, or 20 mg/kg intravenously) proved a weak bronchodilator agent with pronounced effects on circulation. Terbutaline (TER) (10, 20, or 40 microgram/kg intravenously) shifted dose dependently the airways MeCh dose-response curves to the right, with minor stimulation of the heart. THEO 5+TER 20, and THEO 20+TER 20 enhanced the bronchodilator action of each other in an additive manner. Ipratropium bromide (IPRA) (5 micrograms/kg intravenously) eliminated MeCh bronchoconstriction without any inhibition of MeCh bradycardia and with partial inhibition of MeCh hypotonia. THEO 20+IPRA 0.5 provided a supra-additive bronchodilation. Injection of TER 20 promoted the penetration of THEO into the lungs thus increasing THEO concentrations in the lung tissue. The present results suggest that in this animal model combinations of low doses of THEO with TER/IPRA provide enhanced bronchodilation but reduced cardiovascular effects, in comparison with single therapy. Further, a pharmacokinetic interaction between THEO and a beta 2-agonist was evident within certain doses.