IN-VITRO STUDIES ON THE INTERACTIONS OF BETA(2)-ADRENOCEPTOR AGONISTS, METHYLXANTHINES, CA2-CHANNEL BLOCKERS, K+-CHANNEL OPENERS AND OTHER AIRWAY SMOOTH-MUSCLE RELAXANTS IN ISOLATED GUINEA-PIG TRACHEA()

Pharmacodynamic interactions in vitro between different types of airwa y smooth muscle relaxants were systematically and quantitatively evalu ated by using a new methodological technique. Relaxant concentration-e ffect curves for terbutaline, theophylline, cromakalim, sodium nitropr usside and isradipine were obtained in isolated guinea-pig trachea con tracted by histamine (1 mu M) The effects of three different fixed con centrations of each airway smooth muscle relaxant were initially attai ned and concentration-effect curves for combinations with increasing c oncentrations of tither one of the other relaxants were produced. Base d on pharmacodynamic parameters obtained by non-linear regression anal ysis of experimental data for the relaxants alone theoretical concentr ation-effect curves for predicted additive interaction were constructe d by using the isobolic method. Synergistic (over-additive) interactio n was defined as existing when data points and derived pharmacodynamic parameters obtained with combinations of the relaxants showed statist ically significant deviation from the predicted additive interaction c urve and its functional parameters. Significant synergistic interactio n with terbutaline was found for both theophylline (70 or 200 mu M), c romakalim (0.1, 0.3 or 1 mu M), sodium nitroprusside (30 or 100 mu M) and isradipine (1, 3 or 10 mu M). Theophylline showed synergistic inte raction with cromakalim (0.1, 0.3 or 1 mu M), sodium nitroprusside (10 nM) and isradipine (1, 3 or 10 nM). Interactions between cromakalim a nd sodium nitroprusside (10, 30 or 100 nM) were also synergistic, wher eas cromakalim and isradipine (1, 3 or 10 nM) produced only additive i nteraction. Possible mechanisms underlying the interactions are discus sed on basis of existing knowledge with special regards to phosphodies terase isoenzymes, K+ and Ca2+ channels.