Abstract
BackgroundThe effectiveness of strategies for treatment of the altered static lung volume and against the development of bronchial hyperreactivity (BHR) following a left ventricular dysfunction (LVD) induced by myocardial ischaemia was investigated in a rat model of sustained postcapillary pulmonary hypertension.MethodsAirway resistance (Raw) was identified from the respiratory system input impedance (Zrs) in four groups of rats. End-expiratory lung volume (EELV) was determined plethysmographically, and Zrs was measured under baseline conditions and following iv infusions of 2, 6 or 18 μg/kg/min methacholine. Sham surgery was performed in the rats in Group C, while the left interventricular coronary artery was ligated and Zrs and its changes following identical methacholine challenges were reassessed in the same rats 8 weeks later, during which no treatment was applied (Group I), or the animals were treated daily with a combination of an angiotensin enzyme converter inhibitor and a diuretic (enalapril and furosemide, Group IE), or a calcium channel blocker (diltiazem, Group ID). The equivalent dose of methacholine causing a 100% increase in Raw (ED50) was determined in each group. Diastolic pulmonary arterial pressure (PapD) was assessed by introducing a catheter into the pulmonary artery.ResultsThe sustained presence of a LVD increased PapD in all groups of rats, with variable but significant elevations in Groups I (p = 0.004), ID (p = 0.013) and IE (p = 0.006). A LVD for 8 weeks induced no changes in baseline Raw but elevated the EELV independently of the treatments. In Group I, BHR consistently developed following the LVD, with a significant decrease in ED50 from 10.0 ± 2.5 to 6.9 ± 2.5 μg/kg/min (p = 0.006). The BHR was completely abolished in both Groups ID and IE, with no changes in ED50 (9.5 ± 3.6 vs. 10.7 ± 4.7, p = 0.33 and 10.6 ± 2.1 vs. 9.8 ± 3.5 μg/kg/min p = 0.56, respectively).ConclusionsThese findings suggest that a LVD following coronary ischaemia consistently induces BHR. The more consistent efficacy of both treatment strategies in preventing BHR than in treating the adverse pulmonary vascular consequences suggests the benefit of both calcium channel blockade and ACE inhibition to counteract the airway susceptibility following a LVD.
Highlights
The effectiveness of strategies for treatment of the altered static lung volume and against the development of bronchial hyperreactivity (BHR) following a left ventricular dysfunction (LVD) induced by myocardial ischaemia was investigated in a rat model of sustained postcapillary pulmonary hypertension
The results of previous clinical and experimental studies clearly established that a left ventricular dysfunction (LVD) leads to a lung function impairment manifested in airflow limitation and compromised lung compliance [1,2]
Measurements of end-expiratory lung volume (EELV) After the anaesthesia with chloral hydrate and the surgical preparations, the measurements of EELV were performed in all groups by using a body plethysmograph, as detailed earlier [12]
Summary
Animal preparations The experimental protocol was approved by the Experimental Ethics Committee of the University of Geneva (No 09-45) and the Animal Welfare Committee of the Canton of Geneva (No 1051/3542/3). Measurements of end-expiratory lung volume (EELV) After the anaesthesia with chloral hydrate and the surgical preparations, the measurements of EELV were performed in all groups by using a body plethysmograph, as detailed earlier [12]. To separate the airway and tissue mechanics, a model containing a frequency-independent resistance (Raw) and inertance (Iaw) in series with a constant-phase tissue model [16] including tissue damping (G) and elastance (H) was fitted to the Zrs spectra by minimizing the differences between the measured and modelled impedance values: Zrs 1⁄4 Raw þ jωIaw þ ðG−jHÞ=ωα where j is the imaginary unit, ω is the angular frequency (2πf ) andα =2/π arctan(H/G). The equivalent dose causing a 50% increase in Raw (ED50) was calculated in each rat by linear interpolation Following these measurements, pulmonary arterial pressure was measured as described below. Because of the technical demands of this manoeuvre for successful introduction of the miniature catheter in rats, this measurement proved technically acceptable only in subgroups of the main study groups, involving 7, 6, 7 and 10 rats in Groups C, I, ID and IE, respectively
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