Search

Salmeterol and formoterol, two new long-acting beta 2-agonists were equipotent (values of negative log molar concentration eliciting half-maximal effect [pD2] 9.2 +/- 0.03 and 8.9 +/- 0.03, respectively) in relaxing maximally contracted guinea pig tracheal spirals (histamine, 100 microM). Both agonists were 10 times more potent than L-isoproterenol and fenoterol and 100 times more potent than albuterol. L-Isoproterenol and fenoterol induced90% relaxation (percentage of maximal aminophylline relaxation). Formoterol and albuterol were equally efficacious. Formoterol was more efficacious (86 +/- 5%) than salmeterol (62 +/- 3%) or soterenol (59 +/- 3%). In minimally contracted tissues (10 microM histamine), agonist potencies increased 10-fold and relaxation was complete. In [125I]iodocyanopindolol-labeled bronchial membranes, formoterol and salmeterol induced high-affinity states of the beta 2-receptor (pKh 9.6 +/- 0.4 and 10.4 +/- 0.7, respectively), the former inducing a higher percentage (57 +/- 6 versus 28 +/- 4, p0.05). Only low-affinity binding (pKI) was observed when guanine nucleotide was present. pD2 values were similar to pKh values and relative efficacies significantly correlated with percentage of pKI sites. Formoterol and salmeterol were highly selective for the beta 2 versus beta 1-subtype (pKI values were 8.2 +/- 0.09 and 6.25 +/- 0.06 and 8.3 +/- 0.04 and 5.7 +/- 0.04, respectively). Albuterol (5.83 +/- 0.06 and 4.71 +/- 0.16) and fenoterol (6.33 +/- 0.07 and 5.67 +/- 0.05) were less selective. These results can explain the potencies and efficacies of salmeterol and formoterol in humans.

Muco-ciliary transport is only effective because of the coordination of the ciliary beats (metachronous) and the harmony between mucus and cilia. The tip of the cilia is in contact with a jellyform layer of mucus propelled to the oropharynx. This jellyform layer has a complex rheological behaviour: it flows like a liquid and shapes like solid elastic. When the rheological properties of bronchial secretion are abnormal, mucociliary transport becomes inefficient. However, the most fluid secretions are not necessarily best transported, because the elasticity and viscosity to guarantee efficient muco-ciliary transport can only vary within defined limits. The mechanism regulating the ciliary beats is poorly understood; the bronchial secretions conduct impulses through the autonomic nervous system as well as mediators such as histamine and the metabolites of arachidonic acid. Mucociliary function may be studied either, directly through mucociliary transport or through mucociliary clearance. A fall in mucociliary activity can be produced by a primary ciliary disorder, by bronchial disease or the consequences of respiratory infection. General anaesthetics and Atropine slow mucociliary transport but Ipratropium bromide does not; Theophylline and sympathomimetics speed it up. The expectorants are mucolytics (proteolytic enzymes, N-acetyl-cysteine), there are agents to correct hydration anomalies of the bronchial secretion (water, hypertonic sodium chloride) iodides, antifibrins by substitution, anti-inflammatory agents and mucoregulatory agents (S-carboxymethylcysteine, bromhexine). The efficacy of the greater part of these expectorants has not been established in vivo by controlled therapeutic trials.