1. The aim of this study was to compare the ability of four different bronchodilators (atrial natriuretic peptide, salbutamol, sodium nitroprusside and isosorbide dinitrate) to reverse and also to protect against contractions evoked by the spasmogens endothelin-1 and methacholine in human isolated bronchial rings. 2. Contractions evoked by either endothelin-1 or methacholine were reversed by atrial natriuretic peptide (10 −9 −10 −6 mol/l), salbutamol (10 −9 −10 −5 mol/l), sodium nitroprusside (10 −9 −10 −5 mol/l) and isosorbide dinitrate (10 −7 −10 −4 mol/l). 3. Sodium nitroprusside produced a significantly ( P < 0.05 for data points) greater mean maximal inhibition of endothelin-1-induced tone than methacholine-induced tone; however, the other dilators were equally effective at reversing either endothelin-1- or methacholine-induced contractions. Comparing sodium nitroprusside and salbutamol, sodium nitroprusside was significantly ( P < 0.05 for data set) less effective than salbutamol at reversing either endothelin-1- or methacholine-induced contractions. 4. To compare the ability of these bronchodilator substances to protect against spasmogen challenge, cumulative concentration—response curves to either endothelin-1 (10 −10 −3 × 10 −7 mol/l) or methacholine (10 −9 −3 × 10 −4 mol/l) were constructed in the presence and absence of each bronchodilator. Atrial natriuretic peptide, at a concentration of 10 −6 mol/l, significantly attenuated contractions evoked by methacholine. In contrast, contractions evoked by endothelin-1 were enhanced by atrial natriuretic peptide at concentrations of 3 × 10 −7 and 10 −6 mol/l. Preincubation of salbutamol at a concentration of 10 −6 mol/l significantly attenuated methacholine-induced contractions, but responses to endothelin-1 were not altered by preincubation of salbutamol at concentrations of 3 × 10 −7 , 10 −6 and 3 × 10 −6 mol/l. Sodium nitroprusside (10 −6 mol/l) and isosorbide dinitrate (3 × 10 −5 mol/l) did not alter responses evoked by subsequent addition of either endothelin-1 or methacholine. At a concentration of 10 −4 mol/l, however, isosorbide dinitrate significantly attenuated endothelin-1-evoked contractions. 5. These results show that drugs which reverse agonist-induced tone in isolated bronchial rings may not necessarily protect against subsequent challenge with this agonist. This suggests that the pharmacology of relaxation may be dissimilar to that of protection.

1. We have previously shown that atrial natriuretic peptide causes bronchodilatation and reduces bronchial reactivity when administered intravenously or by inhalation to asthmatic patients. We wished to determine the direct effect of exogenously applied atrial natriuretic peptide on isolated airway and the role of proteases important in atrial natriuretic peptide degradation in other organ systems. 2. The ability of atrial natriuretic peptide (α-human atrial natriuretic peptide 28-amino acid) to relax precontracted tissues and to protect against methacholine-induced contraction was studied in human and bovine tissue. The role of neutral endopeptidase-24.11 and other proteases in regulating the effect of atrial natriuretic peptide on bronchial smooth muscle was also examined by studying the influence of phosphoramidon, a protease inhibitor, whose actions include the inhibition of neutral endopeptidase-24.11, and the protease inhibitors leupeptin, aprotinin and soybean trypsin inhibitor on the airway response to atrial natriuretic peptide. 3. In human and bovine tissue atrial natriuretic peptide (10 −6 mol/l) caused a slight relaxation of methacholine-contracted tissue [mean (SEM) percentage inhibition of contraction of 13.2 (3.02)% and 9.41 (2.63)% respectively] and evoked a signficant rightward shift of the cumulative concentration–-response curve to methacholine [p D 2 5.15 (0.23) and 4.85 (0.1) compared with control values of 6.14 (0.1) and 5.85 (0.16), respectively]. 4. Phosphoramidon potentiated atrial natriuretic peptide-induced relaxation of methacholine-induced tone and the ability of atrial natriuretic peptide to protect against methacholine-induced contraction. The combination of leupeptine, aprotinin and soybean trypsin inhibitor did not significantly alter the bronchial response to atrial natriuretic peptide in either human or bovine tissues. 5. We conclude that in human and bovine tissue, atrial natriuretic peptide confers protection against methacholine-induced contraction and can relax induced tone and that inhibition of phosphoramidon-sensitive protease increases these effects of atrial natriuretic peptide on airway smooth muscle.

1. We describe a method for supporting pieces of human bronchi in Ussing chambers, for radiolabelling the contents of the secretory cells with 35 S, and for collecting radiolabeled macromolecules secreted on to the luminal aspect of the tissue. This method has previously been used to study airway secretions in animals [R. J. Phipps, J. A. Nadel & B. Davis, American Review of Respiratory Disease , (1980) 121 , 359–365]. Evidence is given that the radiolabelled molecules are secretory glycoproteins, probably mucus glycoproteins. 2. Phenylephrine, an α-adrenoceptor agonist, increased the rate at which the bronchi secreted radiolabeled glycoproteins. Thymoxamine, an α-adrenoceptor antagonist, blocked this effect but propranolol, a β-adrenoceptor antagonist, did not. 3. Dobutamine, a β 1 -adrenoceptor agonist, increased the rate of secretion of radiolabeled glycoproteins. Propranolol blocked this but thymoxamine did not. 4. Salbutamol, a β 2 -adrenoceptor agonist, also increased the rate of secretion of radiolabeled glycoproteins. Propranolol blocked this effect. 5. We conclude that both α and β-adrenoceptor agonists increase the rate of glycoprotein secretion in human bronchi in vitro and that this almost certainly means that they increase the rate of mucus secretion.

1. Nine normal subjects inhaled increasing concentrations of histamine aerosol from an aerosol generator attached to a breath-actuated dosimeter. The responses were monitored by measuring specific airways-conductance in a body plethysmograph, and the results were expressed as cumulative log dose-response curves. On separate days, histamine challenges were repeated after intravenous injections of sodium chloride solution (placebo), or an H 1 -receptor antagonist chlorpheniramine, or an H 2 -receptor antagonist cimetidine, or H 1 - and H 2 -receptor antagonists together. The anticholinergic activity of chlorpheniramine was estimated by comparing the effect of chlorpheniramine and atropine on methacholine challenge. 2. In all subjects the response to histamine was reproducible. Analysis of the variance showed that placebo did not alter the histamine dose-response curve significantly. In contrast, chlorpheniramine produced a large shift in the histamine dose-response curve to the right and cimetidine produced a significant shift of this curve to the right only at the highest dose of histamine. A combination of cimetidine and chlorpheniramine produced a shift not significantly different from that seen with chlorpheniramine alone. Chlorpheniramine showed no significant anticholinergic activity in this study. 3. In the normal subjects histamine-induced bronchoconstriction appeared to be mediated predominantly by the H 1 -receptors. The H 2 -receptor contributed very little to this bronchoconstriction.

1. The bronchial response to α-adrenoreceptor stimulation has been investigated in normal and asthmatic subjects with a specific α-receptor agonist, methoxamine hydrochloride, after atropine and β-adrenergic blockade. 2. No significant changes in forced expiratory volume in 1 s (FEV 1·0 ) were seen in normal subjects. 3. Methoxamine inhalation caused mild symptomatic wheezing and significant falls in FEV 1·0 in asthmatic subjects. No change in FEV 1·0 occurred after inhalation of distilled water as control. 4. It therefore appears that methoxamine causes bronchoconstriction in asthmatic subjects through its α-adrenergic-stimulating properties, since we were not able to detect any β-receptor-blocking activity of methoxamine on the airways.