Temporal dynamics of acute isovolume bronchoconstriction in the rat JASON H. T. BATES, THOMAS F. SCHUESSLER, CARRIE DOLMAN, AND DAVID H. EIDELMAN Meakins-Christie Laboratories and Department of Biomedical Engineering, McGill University, Montreal, Quebec, Canada H2X 2P2 Bates, Jason H. T., Thomas F. Schuessler, Carrie Dolman, and David H. Eidelman. Temporal dynamics of acute isovolume bronchoconstriction in the rat. J. Appl. Physiol. 82(1): 55–62, 1997.—The time course of lung imped- ance changes after intravenous injection of bronchial agonist have produced significant insights into the mechanisms of bronchoconstriction in the dog (J. H. T. Bates, A.-M. Lauzon, G. S. Dechman, G. N. Maksym, and T. F. Shuessler. J. Appl. Physiol. 76: 616–626, 1994). We studied the time course of acute induced bronchoconstriction in five anesthetized para- lyzed open-chest rats injected intravenously with a bolus of methacholine. For the 16 s immediately after injection, we held the lung volume constant while applying small-ampli- tude flow oscillations at 1.48, 5.45, and 19.69 Hz simulta- neously, which provided us with continuous estimates of lung resistance (RL) and elastance (EL) at each frequency. This procedure was repeated at initial lung inflation pressures of 0.2, 0.4, and 0.6 kPa. Both RL and EL increased progressively after methacholine administration; however, the rate of change of EL increased dramatically as frequency was increased, whereas RL remained relatively independent of frequency. We interpret these findings in terms of a three-compartment model of the rat lung, featuring two parallel alveolar compart- ments feeding into a central airway compartment. Model simulations support the notions that both central airway shunting and regional ventilation inhomogeneity developed to a significant degree in our constricted rats. We also found that the rates of increase in both RL and EL were greatly enhanced as the initial lung inflation pressure was reduced, in accord with the notion that parenchymal tethering is an important mechanism limiting the extent to which airways can narrow when their smooth muscle is stimulated to contract. lung impedance; frequency dependence of resistance and elastance; parenchymal tethering; central airway shunting; ventilation inhomogeneity PREVIOUS STUDIES from our laboratory (2, 3, 11) have shown that a great deal of important physiological information is embodied in the time course of broncho- constriction during the first minute or so after intrave- nous agonist injection in dogs. In particular, when bronchoconstriction is tracked by applying small- amplitude flow oscillations to the airway opening at fixed lung volume, we have shown that effects of peripheral lung stiffening, central airway constriction, and development of regional ventilation inhomogeneity can all be inferred in a quantitative fashion. Further- more, most of these effects are exquisitely sensitive to lung volume, with the rate of reaction increasing dramatically as volume is reduced (2). We have extended this line of investigation to the rat, which has become a popular model for the study of obstructive lung disease in recent years because of its low cost and ready availability in a number of pure- bred strains. Recently, Lutchen et al. (13) measured transfer impedance in rats between 0.234 and 12 Hz and found evidence of significant parallel inhomogene- ities in the lung after bronchoconstriction. We therefore expected that the time course of acute bronchoconstric- tion in the rat should produce similar insights to those we found previously in the dog (2). In the present study, we measured lung mechanics in open-chest rats by using a computer-controlled small-animal ventilator (SAV) (22) consisting of a piston driven in a cylinder by a linear motor under computer control. We used this device to monitor the evolution of pulmonary imped- ance at constant lung volume after an intravenous bolus of methacholine (MCh). We also determined how variations in initial lung inflation pressure affected this evolution. METHODS Experimental procedures. We studied five adult Brown- Norway rats (weight 290–360 g). The rats were anesthetized with an intraperitoneal bolus of pentobarbital sodium (8.5 mg) and tracheostomized, and the trachea was cannulated with a 14-gauge metal needle. The cannula was connected to the SAV. The rats were then paralyzed: two with an intraperi- toneal bolus of pancuronium bromide (8.5 μg) and three with an intraperitoneal bolus of succinylcholine (0.1 mg). The chest was opened widely by midline sternotomy, and a venous line was established for the administration of saline and MCh. Regular mechanical ventilation was performed with the SAV as follows. During inspiration, the piston of the SAV moved forward in a half-sinusoidal fashion, thereby pushing air directly into the lungs of the rat. During expiration, the main valve of the SAV was closed and the cylinder-refill valve was opened so that the cylinder could refill with air as the piston moved back to its starting position. At the same time the expiratory valve, connected to the tracheal cannula via a ‘‘Y’’ piece, was opened to allow the animal to expire passively through a water trap adjusted to maintain a certain positive end-expiratory pressure (PEEP). Tidal volume was 2.5–3.0 ml, and breathing frequency was 100 breaths/min. The animals were allowed to expire passively to functional residual capacity as determined by PEEP. Flow oscillations into the lungs were then produced by the piston of the SAV for a period of 16 s. A control experiment was performed at each PEEP level by injecting a 0.08-ml bolus of saline intrave- nously at the start of the 16-s oscillation period. Each control experiment was followed by a bronchoconstriction experi- ment at the same PEEP, in which a bolus of MCh (0.08 mg in 0.08 ml) was administered intravenously at the start of the 16-s oscillation period. During data collection, the piston position and the pressure inside the cylinder were recorded at 1,024 Hz after they were passed through six-pole Bessel low-pass filters with cutoff at 200 Hz. This high sampling rate 0161-7567/97 $5.00 Copyright r 1997 the American Physiological Society 55 Downloaded from journals.physiology.org/journal/jappl (107.023.116.065) on May 4, 2021.