NEUROGENIC CONTROL OF CANINE BRONCHIAL SMOOTH MUSCLE: COMPARISON OF THE NORMAL AND EXPERIMENTALLY-INDUCED HYPERRESPONSIVE STATES

Abstract

<p>Asthma is a disease characterized by airway hyperresponsiveness (AH) to various spasmogens. Ozone-inhalation causes transient AH of human and canine airway smooth muscle (ASM) and has therefore been used as a model of AH. The mechanism(s) underlying ozone-induced or asthma-related AH are not completely understood, but there is a growing body of evidence that there is a causal relationship between airway inflammation and AH.</p> <p>In these studies, the mechanisms regulating canine bronchial smooth muscle (3rd to 5th order) activity were investigated using intracellular microelectrodes (to monitor electrical activity) and muscle baths (to monitor mechanical activity). The effects of ozone-inhalation and inflammatory mediators on regulation of ASM tone were also investigated.</p> <p>Excitation of ASM (membrane depolarization and contraction) was elicited by activation of muscarinic receptors or thromboxane receptors; the former were found to be of the M₃-subtype. The data indicated that pharmacomechanical (rather than electromechanical) coupling was involved.</p> <p>Inhibition of ASM was found to be initiated by activation of β-adrenoceptors; these were found to be predominantly of the β₁-subtype, though there was evidence that some β₂-adrenoceptors were also involved. There was evidence of physiological antagonism between cholinergic receptor-mediated excitation and adrenoceptor-mediated inhibition due to reciprocal effects on adenylate cyclase.</p> <p>Release of acetylcholine from the cholinergic nerve endings was antagonized by activation of muscarinic receptors (M₁-subtype) or adrenoceptors (both β₁- and β₂- subtypes), and potentiated by activation of thromboxane receptors; these receptor populations were presumed to be located on the nerve endings. There was indirect evidence that neurotransmitter-release was also antagonized by a cyclo-oxygenase metabolite of arachidonic acid (presumably PGE₂).</p> <p>Ozone-inhalation significantly enhanced contractions in response to electric stimulation, but did not significantly after those to exogenously-added cholinergic agonist or to KCl. This AH was prevented by indomethacin (cyclo-oxygenase inhibitor) or by L-670,596 (thromoboxane receptor antagonist). It was concluded that the mechanism underlying ozone-induced AH involved decreased prejunctional inhibition (mediated by PGE₂) and/or increased prejunctional excitation (mediated by TxA₂).</p>