Formoterol, fenoterol, and salbutamol as partial agonists for relaxation of maximally contracted guinea pig tracheae: comparison of relaxation with receptor binding.

In severe asthma attacks beta 2-sympathomimetics lose part of their therapeutic efficiency. To elucidate this loss of efficiency in an experimental model we compared the relaxant potency of salbutamol (SAL), fenoterol (FEN), formoterol (FOR), and (-)-isoprenaline (ISO) in guinea pig tracheae partially and maximally precontracted by 0.1 and 60 mumol/L carbachol, respectively. In partially precontracted tracheae the beta 2-sympathomimetics exerted maximum relaxation in comparison with ISO and low EC50S (nmol/L) for relaxation (SAL, 20; FEN, 5.6; FOR, 0.28; and ISO, 2.5). In maximally precontracted tracheae, however, the beta 2-sympathomimetics were only partial agonists for relaxation with reduced intrinsic activities (%) in comparison to ISO (SAL, 59%; FEN, 61%; FOR, 76%) and significantly increased EC50S (nmol/L) for relaxation (SAL, 130; FEN, 57; FOR, 3.0; ISO, 37). To investigate if the high relaxant potency of FOR is correlated with a higher binding affinity and/or a higher intrinsic activity for adenylate cyclase stimulation than for FEN and SAL, we performed experiments in receptor membranes from guinea pig lung. Binding competition of SAL, FEN, and FOR with [3H]ICI 118,551 for lung beta 2-adrenoceptors yielded dissociation constants (KD) of 320 (SAL), 120 (FEN), and 7.6 (FOR) nmol/L, which exhibited the same ranking as EC50S for relaxation. Concentrations of SAL, FEN, and FOR equivalent to 100 KD of the respective dissociation constants stimulated beta 2-adrenoceptor-coupled adenylate cyclase with different intrinsic activities (%) incomparison to ISO (SAL, 61%; FEN, 63%; FOR, 89%) matching intrinsic activities for relaxation. From these experiments it may be concluded that FOR might improve drug therapy of severe asthma not only due to its long mode of action discovered in clinical studies but also due to its high intrinsic activity and receptor affinity.