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Methacholine-induced bronchoconstriction in rats: effects of intravenous vs. aerosol delivery
F Peták1, Z Hantos, A Adamicza
1Institute for Child Health Research, Perth, Australia.
Abstract:
To determine the predominant site of action of methacholine (MCh) on lung mechanics, two groups of open-chest Sprague-Dawley rats were studied. Five rats were measured during intravenous infusion of MCh (i.v. group), with doubling of concentrations from 1 to 16 micrograms.kg-1.min-1. Seven rats were measured after aerosol administration of MCh with doses doubled from 1 to 16 mg/ml (ae group). Pulmonary input impedance (ZL) between 0.5 and 21 Hz was determined by using a wave-tube technique. A model containing airway resistance (Raw) and inertance (Iaw) and parenchymal damping (G) and elastance (H) was fitted to the ZL spectra. In the iv group, MCh induced dose-dependent increases in Raw [peak response 270 +/- 9 (SE) % of the control level; P < 0.05] and in G (340 +/- 150%; P < 0.05), with no increase in Iaw (30 +/- 59%) or H (111 +/- 9%). In the ae group, the dose-dependent increases in Raw (191 +/- 14%; P < 0.05) and G (385 +/- 35%; P < 0.05) were associated with a significant increase in H (202 +/- 8%; P < 0.05). Measurements with different resident gases [air vs. neon-oxygen mixture, as suggested (K.R. Lutchen, Z. Hantos, F. Peták, A. Adamicza, and B. Suki J. Appl. Physiol. 80: 1841-1849, 1996)] in the control and constricted states in another group of rats suggested that the entire increase seen in G during the i.v. challenge was due to ventilation inhomogeneity, whereas the ae challenge might also have involved real tissue contractions via selective stimulation of the muscarinic receptors.
Insights
Methacholine (MCh) administered intravenously primarily affects airway resistance and ventilation inhomogeneity. Aerosolized MCh, however, impacts airway resistance, inhomogeneity, and lung tissue elastance, suggesting distinct mechanisms of action.
Area of Science:
- Respiratory Physiology
- Pulmonary Mechanics
- Pharmacology
Background:
- Methacholine (MCh) is a bronchoconstrictor used to assess airway hyperresponsiveness.
- Understanding the site of MCh action (airways vs. lung parenchyma) is crucial for interpreting lung mechanics studies.
- Previous studies have not definitively distinguished the predominant site of MCh's effects on lung mechanics.
Purpose of the Study:
- To determine the predominant site of action of methacholine (MCh) on lung mechanics.
- To differentiate the effects of intravenous (i.v.) vs. aerosol (ae) MCh administration on airway and parenchymal function.
- To investigate the contribution of airway resistance, inertance, parenchymal damping, and elastance to MCh-induced changes in lung mechanics.
Main Methods:
- Open-chest Sprague-Dawley rats were studied using two groups: intravenous MCh infusion and aerosol MCh administration.
- Pulmonary input impedance (ZL) was measured using a wave-tube technique across a frequency range of 0.5–21 Hz.
- A physical model incorporating airway resistance (Raw), airway inertance (Iaw), parenchymal damping (G), and parenchymal elastance (H) was fitted to the ZL spectra.
Main Results:
- Intravenous MCh significantly increased airway resistance (Raw) and parenchymal damping (G), but not airway inertance (Iaw) or elastance (H).
- Aerosolized MCh significantly increased Raw, G, and also parenchymal elastance (H).
- Gas measurements suggested that i.v. MCh's effect on G was primarily due to ventilation inhomogeneity, while ae MCh may also involve direct tissue effects.
Conclusions:
- Intravenous methacholine predominantly acts on airways, leading to increased resistance and ventilation inhomogeneity.
- Aerosolized methacholine affects both airways and lung parenchyma, causing increased resistance, inhomogeneity, and tissue elastance.
- The route of MCh administration significantly influences its site of action and the resulting changes in lung mechanics.