Airway Receptor Distribution

There is very limited information about longitudinal distribution of receptors in humans. Barnes and coworkers (67) have studied receptor distribution in ferrets. The results indicated that beta-adrenergic receptors were present in high density throughout the airways, with highest density in the bronchioles. Alpha receptors were sparse in large airways, but numerous in small bronchioles, whereas cholinergic receptors were numerous in bronchial smooth muscle, sparse in proximal bronchioles, and almost absent from distal bronchioles. This study has been frequently cited. 

At least three subtypes of muscarinic receptors have been found in human lung, M1-M3 (68). Mak and Barnes (69) found that in human lung and lung from guinea pigs, muscarinic receptors have a different distribution from that reported in the ferret. Airway smooth musele was distributed with Mj-receptor subtype, and there was a more peripheral distribution of reeeptors than was expeeted from the studies on ferret. 

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The human histamine Hi-receptor is a 487 amino acid protein that is widely distributed within the body. Histamine potently stimulates smooth muscle contraction via Hi-receptors in blood vessels, airways and in the gastrointestinal tract. In vascular endothelial cells, Hi-receptor activation increases vascular permeability and the synthesis and release of prostacyclin, plateletactivating factor, Von Willebrand factor and nitric oxide thus causing inflammation and the characteristic wheal response observed in the skin. Circulating histamine in the bloodstream (from, e.g. exposure to antigens or allergens) can, via the Hi-receptor, release sufficient nitric oxide from endothelial cells to cause a profound vasodilatation and drop in blood pressure (septic and anaphylactic shock). Activation of... 

Beta receptors are also unevenly distributed with P2-receptors the more common subtype on the effector tissues. Beta-two receptors tend to be inhibitory for example, P2-receptor stimulation causes relaxation of vascular smooth muscle and airway smooth muscle, resulting in vasodilation and bronchodilation, respectively. Beta-two receptors have a significantly greater affinity for epinephrine than for norepinephrine. Furthermore, terminations of sympathetic pathways are not found near these receptors, so P2-receptors are stimulated only indirectly by circulating epinephrine instead of by direct sympathetic nervous activity. 

Dixon AK, Gubitz AK, Sirinathsinghji DJ, Richardson PJ, Freeman TC (1996) Tissue distribution of adenosine receptor mRNAs in the rat. Br J Pharmacol 118(6) 1461—1468 Douillet CD, Robinson WP 3rd, Zarzaur BL, Lazarowski ER, Boucher RC, Rich PB (2005) Mechanical ventilation alters airway nucleotides and purinoceptors in lung and extrapulmonary organs. Am J Respir Cell Mol Biol 32(l) 52-58... 

Adcock et al. (1993) reported increased levels of Nkl receptor mRNA in airway tissue obtained from asthmatic subjects compared to normal subjects. However, these authors did not evaluate the cellular distribution of receptor protein. In contrast, Bai et al. (1994) reported no difference between levels of Nkl receptor mRNA in lung tissue from non-asthmatic subjects and that in lung tissue from asthmatic patients these investigators did find that the level of Nk2 receptor mRNA was increased in the asthmatic individuals. The medications used for the treatment of asthma may explain this discrepancy Adcock et al. (1993) have shown that treatment with glucocorticoids decreases Nkl receptor expression in asthmatic airways. 

These drugs exert their effects on airway function by mediation of P -receptors located on the surface of the smooth muscle and other tissues of the airways. Pj-and Pj-receptors are, however, distributed throughout the body. Stimulation of these receptors are considered to be responsible for side effects, such as tachycardia, arrhythmias, prolongation of the Q-Tc interval, tremor, and decrease in serum potassium, and become generally apparent when higher than conventional doses are inhaled (32-34). The relationship between increase in FEV, and the inhaled dose of a Pj-agonist is not linear but consists of a steep part followed by a plateau (34). 

In experiments in ferret lungs, Barnes et al. showed that 3-receptors were located near airway smooth muscle and their numbers increased in the smaller airways. They also found that a large number of these receptors was present in the alveoli (22). In other experiments, they found an increase in both a- and P-receptors in peripheral airways and a decrease in cholinergic receptors (23). These investigators have also shown that a similar distribution pattern for P-receptors is found in the human lung (Table 6) (24). 

Based on the distribution of Pj receptors, the optimal target appears to be the smaller airways in patients with asthma. 

Based on the distribution of Mj receptors, inhaled muscarinics and antimuscarinics should be targeted to the larger central airways of patients with asthma. 

Many specific mediator receptors are involved in asthma but they are so abundant that specific antagonists for these receptors have little effect, with an exception for cysteinyl leukotriene-1 (cys-LTj) receptors which are distributed predominantly on airway smooth muscle and (to a lesser extent) on macrophages. Their numbers are small, however, and this may explain why antileukotrienes like montelukast and zafirlukast, which prevent predominantly leukotriene-induced bronchoconstriction, are less effective than P2-agonists. 

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