Actions of bronchodilator drugs, glucocorticoid, and their combinations on airways in rats and guinea pigs.

Abstract

The principal aim of the present investigation was to examine in detail individual and combined actions on airways of four antiasthmatic drugs with different mechanisms of action. They were theophylline (THEO), the beta 2-adrenoceptor agonist terbutaline (TER), the antimuscarinic ipratropium bromide (IPRA), and the glucocorticoid betamethasone (BM). The respiratory measurements (intratracheal pressure in rats and lung resistance and dynamic lung compliance in guinea pigs) were performed in anaesthetized, mechanically ventilated animals. Mild, moderate, and submaximal obstruction of mainly large or small airways were induced by a cumulative administration of either methacholine (MeCh) or leukotriene D4 (LTD4), both i.v. The antiasthmatic drugs were given acutely i.v., but THEO and BM also as intraperitoneal pretreatments. Moreover, actions of the antiasthmatic drugs were studied ex vivo on lung beta-adrenoceptors in rats and guinea pigs. 3H-dihydroalprenolol was used as a ligand in the beta-receptor binding assay. A detailed evaluation of the lung resistance and dynamic lung compliance responses to MeCh and LTD4 suggested that MeCh induced obstruction in more proximal airways than LTD4. THEO attenuated both airway challenges, being about 2-4 times more efficient on LTD4 than on MeCh. TER inhibited both MeCh- and LTD4-induced airway obstruction about equally, whereas IPRA was effective on the MeCh-induced obstruction only. In most cases, treatment with THEO+TER or THEO+IPRA attenuated the MeCh-induced mild or moderate obstruction of large airways additively, and the submaximal airway response to MeCh synergistically. The relatively good effect of THEO on small airway obstruction caused by MeCh was not augmented by TER or IPRA. In contrast to these results, combination of subefficient doses of THEO and TER, but not of THEO and IPRA, resulted in an antagonistic interaction on the MeCh challenge in rats and guinea pigs. The combined action of THEO+TER was at its best additive on large and small airways obstruction caused by LTD4. Addition of IPRA to THEO treatment did not modify the effects on LTD4 challenge. Neither TER nor IPRA enhanced the cardiovascular effects of THEO in rats or guinea pigs. THEO administration to rats and guinea pigs resulted in plasma concentrations (7.5-32 micrograms/ml) that were roughly comparable to clinically relevant values. The respective lung tissue concentrations were 53-81% of the plasma values. In rats, but not in guinea pigs, combined treatment with THEO+TER increased the THEO concentration in lung tissue.(ABSTRACT TRUNCATED AT 400 WORDS)