Effects of endothelin-1 on airway and parenchymal mechanics in guinea-pigs

Abstract

The contributions of the airways and the parenchyma to the overall lung mechanical response to endothelin-1 (ET-1) have not been systematically studied. In this investigation, the ET-1 induced changes on lung mechanics in guinea-pigs were separated into airway and parenchymal components.Pulmonary impedance (ZL) data were collected between 0.5 and 21 Hz in six anaesthetized, paralysed, open-chest animals by introducing small-amplitude pseudorandom oscillations into the trachea through a wave tube. ZL was calculated before and following intravenous boluses of ET-1, with doses doubled from 0.125±2 mg . kg of body weight -1 . A model containing an airway resistance (Raw) and inertance (Iaw) and tissue damping (G) and elastance (H) was fitted to the ZL spectra in each condition. Parenchymal hysteresis (g) was calculated as G/H.After each dose, ET-1 induced significant increases in Raw (at peak response meanSEM: 424129%), G (40080%), H (9522%) and g (15633%), whereas Iaw decreased following the two highest doses (-29177%).These data suggest that the parenchymal constriction was accompanied by inhomogeneous constriction of the peripheral airways. Eur Respir J 1999; 13: 767±774. Endothelin-1 (ET-1) was originally described as a potent smooth muscle constrictor derived from vascular endothelial cells [1]. Numerous subsequent studies on the synthesis of ET-1 in nonvascular cell types, such as airway epithelial cells, type II pneumocytes and alveolar macrophages [2± 4], have indicated the physiological and pathophysiological importance of this peptide in the lung. It is also known that ET-1 exerts a constrictor effect on both the vascular and the bronchial smooth muscles [5±11] However, the overall effect of ET-1 on lung mechanics has not been completely characterized.Previous studies revealed dose-dependent increases in the peak pulmonary inflation pressure (PIP) [7,9,10], or elevations in the total lung resistance (RL) with a concurrent decrease in the dynamic lung compliance (Cdyn) following the i.v. injection of ET-1 into guinea-pigs [5,6,8,11]. The measurement of these global lung mechanical parameters, however, does not allow a separate estimation of the changes in the mechanical properties of the airways and parenchyma. Recent studies partitioning the lung responses to various constrictor agents into airway and parenchymal components established the importance of the elevated tissue resistance (Rti) accompanying bronchoconstriction [12±20]. The only study on separation of the airway and parenchymal responses to ET-1 was reported by NAGASE et al. [16], who measured local alveolar pressures (PA) through one or two alveolar capsules in guinea-pigs. It has been demonstrated, however, that PA exhibits a significant heterogeneity during constriction, which makes separations based on the measurement of PA highly accidental [12,21]. Further, recent studies involving a modelbased evaluation of lung impedance (ZL) revealed that the parameters of a model of pulmonary mechanics estimated from low-frequency ZL spectra ...

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