Differential effects of inhaled methacholine on circumferential wall and vascular smooth muscle of third-generation airways in awake sheep

Abstract

Evolution and natural selection ensure that specific mechanisms exist for selective airway absorption of inhaled atmospheric molecules. Indeed, nebulized cholinoceptor agonists used in asthma-challenge tests may or may not enter the systemic circulation. We examined the hypothesis that inhaled cholinoceptor agonists have selective access. Six sheep were instrumented under general anesthesia (propofol 5 mg/kg iv, 2-3% isoflurane–oxygen), each with pulsed-Doppler blood flow transducers mounted on the single bronchial artery and sonomicrometer probes mounted on the intrapulmonary third-generation lingula lobe bronchus. Continuous measurements were made of bronchial blood flow (Qbr), Qbr conductance (Cbr), bronchial hemicircumference (CIRCbr), and bronchial wall thickness (WALL THbr) in recovered, standing, awake sheep. Methacholine (MCh; 0.125–2.0 μg/kg iv), at the highest dose, caused a 233% rise in Qbr ( P < 0.05) and a 286% rise in Cbr ( P < 0.05). CIRCbr fell to 90% ( P < 0.05); WALL THbr did not change. In contrast, nebulized MCh (1–32 mg/ml), inhaled through a mask at the highest dose, caused a rise in ventilation and a rise in Qbr proportional to aortic pressure without change in Cbr. CIRCbr fell to 91% ( P < 0.01), and WALL THbr did not change. Thus inhaled MCh has access to cholinoceptors of bronchial circumferential smooth muscle to cause airway lumen narrowing but effectively not to those of the systemic bronchovascular circulation. It is speculated that the mechanism is selective neuroparacrine inhibition of muscarinic acetylcholine receptors (M3 bronchovascular cholinoceptors) by prostanoids released by intense MCh activation of epithelial and mucosal cells lining the airway.