1 Responses of human bronchial strip preparations to contractile and relaxant agonists were measured in preparations from non-diseased and from asthmatic lung obtained 3-15 h post-mortem. 2 The potencies of carbachol and histamine were approximately two times less in asthmatic than in non-diseased bronchi. This was statistically significant for carbachol (P < 0.05), but not for histamine (P > 0.05). These results clearly indicate that the bronchial hyperreactivity to airway spasmogens observed in asthma is exclusively an in vivo phenomenon not involving increasing sensitivity of bronchial smooth muscle. 3 The potencies of the ,-adrenoceptor agonists isoprenaline, fenoterol and terbutaline were significantly reduced by 4-5 fold in asthmatic bronchi compared with non-diseased airways. In contrast, theophylline was equipotent in the two populations of airway preparations. Thus, it appears that severe asthma is associated with decreased bronchial smooth muscle P2-adrenoceptor function.

The autoradiographic distribution and density of beta-adrenoceptors in human non-diseased and asthmatic bronchi were investigated using [125I]iodocyanopindolol (I-CYP). Analysis of the effects of the beta-adrenoceptor antagonists on I-CYP binding demonstrated that betaxolol (20 nM, beta 1-selective) had no significant effect on specific grain density in either nonasthmatic or asthmatic human bronchus, whereas ICI-118551 (20 nM, beta 2-selective) inhibited I-CYP binding by 85 +/- 9% and 89 +/- 3%, respectively. Thus, homogeneous populations of beta 2-adrenoceptors existed in bronchi from both sources. Large populations of beta-adrenoceptors were localized to the bronchial epithelium, submucosal glands, and airway smooth muscle. Asthmatic bronchial tissue featured epithelial damage with exfoliated cells associated with luminal mucus plugs. A thickened basement membrane and airway smooth muscle hyperplasia were also evident. High levels of specific I-CYP binding were also detected over asthmatic bronchial smooth muscle, as assessed by autoradiography and quantitation of specific grain densities. Isoproterenol and fenoterol were 10- and 13-fold less potent, respectively, in bronchi from asthmatic lung than in those from nonasthmatic lung. However, this attenuated responsiveness to beta-adrenoceptor agonists was not caused by reduced beta-adrenoceptor density in asthmatic airways. A defect may exist in the coupling between beta-adrenoceptors and postreceptor mechanisms in severely asthmatic lung.

In the 1980s, studies in the vascular field revealed that the endothelium was not simply a metabolic and physical barrier, but liberated substances that could modulate the function of underlying vascular smooth muscle. Investigators in the respiratory field also found that the airway epithelium was more than a physical barrier to airborne insults. The epithelium is composed of at least eight different cell types that have a range of functions, including ciliary motility and mucous secretion, and contain enzymes for liberating arachidonic acid metabolites and peptides. The epithelium also contains degradative enzymes for a number of peptides and biological amines. It was also recognized that the epithelium released substances that, like their vascular counterparts, could regulate the function of a number of cell types, including nerves and airway smooth muscle. These studies document the importance the epithelium plays in the regulation of human airway smooth muscle.

1 The binding of the P-adrenoceptor radioligand [1251-iodocyanopindolol (I-CYP) antagonists ((± )-propranolol > ICI-1 18551 > atenolol), indicating a predominance of P2-adrenoceptors. Further analysis showed that displacement data for the p1-selective antagonist atenolol and the P2-,selective antagonist ICI-1 18551 were fitted best to a 2 binding site model and that both PI-and Radrenoceptors were present in pig lung in the ratio 28:72 respectively. 4 Autoradiographic grains were localized over tissue and were most dense over alveolar walls > vascular endothelium > vascular smooth muscle > bronchial smooth muscle = bronchial epithelium. Atenolol (10-5M) caused a 31% reduction in specific grain density over alveolar wall tissue, while a 10 fold lower concentration of ICI-l 18551 (10-6M) caused a 50% decrease. These results are consistent with binding data in pig lung parenchyma demonstrating a mixed population of P-adrenoceptors with a predominance of the P2 subtype.5 Approximately 95% of the parenchymal P-adrenoceptors were associated with the alveolar wall as a mixed population of the PI and P2 subtypes in the ratio 30:70 respectively. A greater proportion of the P-adrenoceptors associated with bronchial and vascular smooth muscle seemed to be ofthe 2 subtype. 6 It is possible that the previously described relaxant responses of the pig lung parenchyma strip to Pagonists, mediated via P2-adrenoceptors, resulted from the sum of reactivities in airway and vascular smooth muscle together with relaxation of alveolar interstitial cells.

CYP, 50pM) to fi-adrenoceptors was detected in these airways. Furthermore, very low levels of autoradiographic grains representing specific H-PZ binding were found in all airway structures in human non-diseased or asthmatic lung parenchyma. 4 Consistent with these data, the a-adrenoceptor agonist phenylephrine failed to induce significant increases in tone in bronchi isolated from either non-diseased or asthmatic human lung. Results indicate that asthma does not involve significant increases in airway a1-adrenoceptor function.