Differentiation of functional adrenoceptors in human and guinea pig airways

Abstract

The nature of the beta-adrenoceptor population(s) mediating direct smooth muscle relaxation, inhibition of antigen-induced histamine release and inhibition of antigen-induced (leukotriene-mediated) smooth muscle contraction of human and guinea pig central and peripheral airways was investigated. Preferential blockade by beta 1- and beta 2-selective antagonists of the relaxation induced by beta 1- and beta 2-selective agonists, respectively, revealed the guinea pig tracheal smooth muscle relaxation to be mediated by both beta 1- and beta 2-adrenoceptors. Using a highly beta 2-selective antagonist, the NE-induced relaxation was split up biphasically into a beta 1- and a beta 2-component. In contrast, no such differential blockade was observed with the relaxation of the guinea pig lung parenchyma strip, neither with the human tracheal, main bronchus and respiratory bronchiolus smooth muscle, which are all mediated by homogeneous beta 2-adrenoceptor populations. Only in the guinea pig trachea did neuronal and extraneuronal uptake inhibitors produce pronounced left shifts of the NE- and ISO-induced relaxation curves, respectively, suggesting a causal relationship between noradrenergic innervation and the presence of the beta 1-adrenoceptor subpopulation in the airways. Using the same techniques, it was established that inhibition of antigen-induced histamine release from guinea pig lung and tracheal mast cells is mediated by homogeneous beta 2-adrenoceptor populations as well. In contrast to catecholamines, non-catecholamine beta-agonists such as fenoterol, clenbuterol and zinterol had a substantially higher apparent affinity for the inhibition of the anaphylactic (leukotriene-mediated) guinea pig tracheal contraction than for the inhibition of histamine release; the same was true for lung tissue, though the difference was less pronounced. With some non-catecholamine beta-agonists considerable selectivity both in central and peripheral airway preparations was observed for the inhibition of anaphylactic contraction as compared with smooth muscle relaxation.