Karmelo M. Lulich

THE CAT LUNG STRIP AS AN in vitro PREPARATION OF PERIPHERAL AIRWAYS: A COMPARISON OF β‐ADRENOCEPTOR AGONISTS, AUTACOIDS AND ANAPHYLACTIC CHALLENGE ON THE LUNG STRIP AND TRACHEA

1 A new in vitro preparation, the isolated lung strip of the cat, is described for investigating the direct effect of drugs on the smooth muscle of the peripheral airways of the lung. The preparation comprises a thin strip of lung parenchyma which can be mounted in a conventional organ bath for isometric tension recording. Its pharmacological responses have been characterized and compared with the isolated tracheal preparation of the cat. 2 The lung strip exhibited an intrinsic tone which was relaxed by catecholamines, aminophylline and flufenamate. It was contracted strongly by histamine, prostaglandin F2α, acetylcholine, compound 48/80, potassium depolarizing solution and alternating current field stimulation. In contrast, the cat trachea was unresponsive to histamine and prostaglandin F2α and did not exhibit an intrinsic tone. 3 (–)‐Isoprenaline and (–)‐adrenaline were much more potent in relaxing the lung strip than the trachea. The potency order of relaxation responses to isoprenaline, adrenaline and (±)‐noradrenaline in the lung strip was isoprenaline > adrenaline > noradrenaline but in the trachea was isoprenaline > noradrenaline > adrenaline. 4 β2‐Adrenoceptor selective agonists salbutamol and terbutaline were more potent in the lung strip than the trachea, suggesting β2‐adrenoceptors predominated in the lung strip. Propranolol was equipotent in inhibiting isoprenaline relexations of the lung strip and trachea, whereas practolol was much less effective in inhibiting lung strip than trachea, further supporting a predominance of β2‐adrenoceptors in lung strip and β‐adrenoceptors in trachea. 5 Strong Schultz‐Dale type contractions were elicited in both lung strips and trachea by Ascaris lumbricoides antigen in actively sensitized cats. The initial phase of the contractile response of the lung strip following challenge was shown to be due to histamine release and was absent in the trachea. The delayed phase of the contraction which took several minutes to develop in both the mepyramine‐treated lung strip and trachea was not due to prostaglandins E1, F2α or bradykinin, the probable mediator being slow reacting substance of anaphylaxis (SRS‐A). 6 It is concluded that the isolated lung strip of the cat is useful as an in vitro model for investigating the effect of drugs on the smooth muscle of the peripheral airways of the lungs.

Adverse Reactions to β 2 -Agonist Bronchodilators

Summaryβ2-Agonists are safe and effective bronchodilator drugs. Their major adverse effects of skeletal muscle tremor, tachycardia and various metabolic effects are mediated by β-adrenoceptor stimulation and are reversible. Skeletal muscle tremor is the most frequent dose-limiting side effect. It may be reduced by commencing treatment with a low dose and if it persists another β2-agonist may be tried. Other side effects such as cardiac arrhythmias and reduction in PaO2 are a serious potential problem in some susceptible asthmatics. However, they are infrequent or of a mild degree and are generally outweighed by the good control of asthma produced by β2-agonists.Side effects from β2-agonist therapy can be minimised by use of the inhaled route which selectively delivers the drug to the airways. Furthermore, selective tolerance develops to their side effects. The dose of a β2-agonist should be assessed on the basis of therapeutic effect and the level of tolerance to its side effects. Recommended doses of β2-agonists used for long term therapy do not cause clinically significant desensitisation of airway β-adrenoceptors, although this may become a relevant problem in patients who are regularly receiving very high doses.Intravenous β2-agonists have a place in the treatment of severe asthma not responding to nebuliser therapy. In this life-threatening situation with severe airflow obstruction, monitoring of heart rate, PaO2, plasma potassium and the electrocardiogram should be mandatory and supplemental oxygen given so that serious adverse effects are prevented.

Adrenoceptors in airway smooth muscle

This review examines the roles and functional significance of alpha and beta-adrenoceptor subtypes in airway smooth muscle, with emphasis on human airway function and the influence of asthma. Specifically, we have examined the distribution of beta-adrenoceptors in lung and the influence of age, the epithelium, respiratory viruses and inflammation associated with asthma on airway smooth muscle beta-adrenoceptor function. Sites of action, beta 2-selectivity, efficacy and tolerance are also examined in relation to the use of beta 2-agonists in man. In addition, alpha-adrenoceptor function in airway smooth muscle has been reviewed, with some emphasis on comparing observations made in airway smooth muscle with those in animal models.

AN in vitro STUDY OF VARIOUS DRUGS ON CENTRAL AND PERIPHERAL AIRWAYS OF THE RAT: A COMPARISON WITH HUMAN AIRWAYS

1 The effect of histamine and other drugs on the central and peripheral airways of the rat was studied by applying them directly to isolated tracheal and lung strip preparations. These effects were then compared with those observed on human isolated bronchial muscle preparations. 2 Acetylcholine and 5‐hydroxytryptamine (5‐HT) both contracted the lung strip and trachea of the rat, and both were more potent on the trachea than the lung strip. 3 Histamine and prostaglandins E2 (PGE2) or F2γ (PGF2γ) produced no effect on either the lung strip or trachea of the rat. 4 On the human isolated bronchial preparation, in contrast to the rat airways, both histamine and PGF2γ produced marked concentration‐dependent contractions and 5‐HT either produced no response or a slight relaxation. 5 In view of these results, the use of anaphylactic bronchoconstriction in the rat as a model for the study of asthma in man is questioned.

Bronchial α-adrenoceptor function in asthma

Abstract The role played by bronchial α-adrenoceptors in the production of reversible airway obstruction in asthma remains controversial. The question has not been resolved by evaluations of the bronchoconstricting effect of α-agonists or of the clinical efficacy of α-antagonists in asthma sufferers. Clearly, an in-vitro study of α-adrenoceptor function in human asthmatic bronchi was required. Roy Goldie and colleagues have completed such a study and conclude that bronchial α-adrenoceptor function was insignificant in both non-diseased and asthmatic airways. Their data support the contention that there is no definite clinical indication for the use of α-blockers in asthma.

Experimental testing of Mackay's model for functional antagonism in the isolated costo-uterus of the rat

1 Several key predictions of a recently developed model for functional antagonism (Mackay, 1981) were experimentally tested using the rat isolated costo‐uterine preparation. 2 In the presence of the functional antagonist fenoterol (Fen), the functional affinity constants (KAF) for carbachol and oxotremorine (Oxo) were respectively 9.9 and 3.4 fold greater than their corresponding affinity constants (KA). According to Mackays model for functional antagonism, the higher KAF/KA ratio for carbachol indicates that this cholinoceptor agonist has a greater efficacy than Oxo. This was confirmed by using conventional pharmacological methods. 3 As predicted from the model of functional antagonism, the plot of KAF/KA ‐ 1 against the fraction of cholinoceptors not irreversibly blocked by phenoxybenzamine (Pbz) was linear for both carbachol and Oxo and the lines of best fit crossed the axes at a point not significantly different from the origin. 4 The value of 4.6 for the relative efficacy of carbachol to Oxo estimated from functional antagonism studies was comparable to the value of 5.6 calculated using the method of irreversible antagonism proposed by Furchgott (1966).