Differential effects of inhaled methacholine on circumferential wall and vascular smooth muscle of third-generation airways in awake sheep.
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 (Q(br)), Q(br) conductance (C(br)), bronchial hemicircumference (CIRC(br)), and bronchial wall thickness (WALL TH(br)) in recovered, standing, awake sheep. Methacholine (MCh; 0.125-2.0 μg/kg iv), at the highest dose, caused a 233% rise in Q(br) (P < 0.05) and a 286% rise in C(br) (P < 0.05). CIRC(br) fell to 90% (P < 0.05); WALL TH(br) 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 Q(br) proportional to aortic pressure without change in C(br). CIRC(br) fell to 91% (P < 0.01), and WALL TH(br) 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.
Discipline of Human Physiology, School of Biomedical Sciences & Pharmacy, Faculty of Health, The University of Newcastle, Callaghan, 2308 NSW, Australia.
Damian
D
McLeod
Gibbe
G
Parsons
Robert
R
Gunther
Anthony
A
Quail
David
D
Cottee
Saxon
S
White
D000280:Administration, Inhalation; D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects / Q000502:physiology; D001980:Bronchi / Q000098:blood supply / Q000187:drug effects* / Q000502:physiology; D001981:Bronchial Arteries / Q000187:drug effects* / Q000502:physiology; D018679:Cholinergic Agonists / Q000008:administration & dosage; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology; D005260:Female; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D009241:Ipratropium / Q000494:pharmacology; D016210:Methacholine Chloride / Q000008:administration & dosage*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology; D011950:Receptors, Cholinergic / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D012119:Respiration / Q000187:drug effects; D020545:Respiratory Mucosa / Q000098:blood supply / Q000187:drug effects / Q000502:physiology; D012756:Sheep; D014851:Wakefulness / Q000187:drug effects* / Q000502:physiology
D018679:Cholinergic Agonists; D011950:Receptors, Cholinergic; D016210:Methacholine Chloride; D009241:Ipratropium