Highly potent beta-2 sympathomimetics convert to less potent partial agonists as relaxants of guinea pig tracheae maximally contracted by carbachol. Comparison of relaxation with receptor binding and adenylate cyclase stimulation.

Beta-adrenergic agonists are among to the most potent dilators of airway smooth muscle available and act as functional antagonists of a variety of contractile stimuli. In order to elucidate their loss of relaxant potency in dependence on antagonistic stimuli tracheal relaxation by the beta-2 sympathomimetics (+/-)-salbutamol (+/-)-fenoterol, and (+/-)-formoterol was compared to (-)-isoprenaline in guinea pig tracheae partially and maximally precontracted by carbachol. In partially precontracted tracheae, salbutamol, fenoterol and formoterol exerted maximum relaxation with low EC50 of 20, 5.6 and 0.29 nmol/l, respectively. In maximally precontracted tracheae, however, salbutamol, fenoterol and formoterol were only partial agonists for relaxation with different intrinsic activities (0.62, 0.62 and 0.77, respectively) and increased EC50 (120, 50 and 3.6 nmol/l, respectively). A reduction of relaxant potency by increased muscarinic stimuli was also observed for beta-1 adrenoceptors stimulated by (-)-noradrenaline after blockade of beta-2 adrenoceptors. In order to investigate if the reduced relaxant potency of beta-2 sympathomimetics was caused by a reduced spare receptor capacity or a reduced intrinsic activity for stimulation of adenylate cyclase (AC), we performed experiments in membranes from lung and tracheal cells. In radioligand binding, beta-2 sympathomimetics recognized the high-affinity state (57%) of the beta-2 adrenoceptor with a lower effectiveness than (-)-isoprenaline, which exhibited a 100-fold higher affinity for high over low-affinity states. Dissociation constants for the low-affinity state matched EC50 for AC stimulation. Intrinsic activities (%) for AC stimulation were significantly lower for salbutamol (67%), fenoterol (67%) and formoterol (89%) than for (-)-isoprenaline (100%), indicating that the reduced relaxation potency of the beta-2 sympathomimetics of maximally precontracted tracheae is caused by a reduced intrinsic activity for AC stimulation. It might be speculated that formoterol could improve drug therapy of asthma due to its high binding affinity and its high intrinsic activity for relaxation.