Biomedical subjects
W Mitzner
Publications and source records attributed to W Mitzner.
Effect of bronchial smooth muscle contraction on lung compliance.
Lung compliance is generally considered to represent a blend of surface and tissue forces, and changes in compliance in vivo are commonly used to indicate changes in surface forces. There are, however, theoretical arguments that would allow contraction of airway smooth muscle to affect substantially the elasticity of the lung. In the present study we evaluated the role of conducting airway contraction on lung compliance in vivo by infusing methacholine (MCh) at a constant rate into the bronchial circulation. With a steady-state MCh infusion of 2.4 micrograms/min into the bronchial perfusate (perfusate concentration = 0.7 microM), there was an approximate doubling of lung resistance and a 50% fall in dynamic compliance. There were also significant decreases in chord compliance measured from the quasi-static pressure-volume curves and in total lung capacity and residual volume. When the same infusion rate was administered into the pulmonary artery, no changes in lung mechanics were observed. These results indicate that the conducting airways may have a major role in regulating lung elasticity. This linkage between airway contraction and lung compliance may account for the common observation that pharmacological challenges given to the lung usually result in similar changes in lung compliance and airway conductance. Our results also suggest the possibility that the lung tissue resistance, which dominates the measurement of lung resistance in many species, might in fact reflect the physical properties of conducting airways.
Quantitative evaluation of pulmonary stretch receptor activity during high-frequency ventilation.
The purpose of this study was to determine the neural output of pulmonary stretch receptors (PSRs) in response to conditions that, in previous studies (J. Appl. Physiol. 65: 179-186, 1988 and Respir. Physiol. 80: 307-322, 1990), produced apnea in anesthetized cats. These conditions included changes in airway pressure (Paw; 2 or 6 cmH2O), stroke or tidal volume (1-4 ml/kg), frequency [conventional mechanical ventilation (CMV) vs. high-frequency ventilation (HFV) at 10, 15, and 20 Hz], and levels of inspired CO2 (0, 2, and 5%). These data were needed to assess properly the specific contribution of the PSRs to the apnea found with certain combinations of the above variables. Each PSR was subjected to HFV over a range of mechanical and chemical settings, and its activity was recorded. PSRs exhibited continuous activity associated with pump stroke in 11 of 12 fibers tested. PSRs fired more rapidly when mean Paw was 6 cmH2O [45.3 +/- 0.8 (SE) impulses/s] than when it was 2 cmH2O (31.7 +/- 0.9 impulses/s, P = 0.0001). At both pressures, PSR activity increased as the volume of inflation, or tidal volume, was increased from 1 to 4 ml/kg. At Paw of 2 cmH2O, the number of impulses per second for HFV was not different from that for CMV (averaged over the respiratory cycle), under conditions previously demonstrated as apneogenic for both modes of ventilation. Therefore the absolute amount of information being sent to the brain stem processing centers via PSRs during HFV did not differ from that during CMV. Thus any PSR contribution to HFV-induced apnea must have been the result of changes in the pattern of the signal or the central nervous system's processing of it rather than an increase in the amount of inhibitory afferent signal.
Effects of left atrial pressure on the pulmonary vascular response to hypoxic ventilation.
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Antagonists of EDRF attenuate acetylcholine-induced vasodilation in isolated hamster lungs.
To evaluate the role of endothelium-dependent relaxing factor (EDRF) in acetylcholine- (ACh) induced vasodilation in the intact pulmonary circulation, we examined the effects of atropine and three EDRF antagonists that have been shown to be effective in vitro: nitro-L-arginine (NOARG), hemoglobin (Hb), and methylene blue (MB). We studied ACh-induced dilation after preconstriction with angiotensin II and prostaglandin F2 alpha (PGF2 alpha) in hamster lungs perfused with Krebs solution containing Ficoll (4 g/dl) and indomethacin (10 microM). In the constricted lungs with no blockers, infusion of ACh (1 microM) decreased the constriction by 67%, and this effect was completely abolished by atropine pretreatment (1 microM). Treatment of hamster lungs with each of the three EDRF blockers, NOARG (30 microM), Hb (10 microM), and MB (250 microM), augmented the pressor responses to angiotensin II and PGF2 alpha. However, NOARG and MB inhibited the ACh-induced dilation by 49 and 60%, respectively, without affecting vasodilatory responses to isoproterenol, an agent that relaxes vascular smooth muscle independent of EDRF synthesis. In contrast, Hb significantly inhibited both ACh- and isoproterenol-induced vasodilations. Because all these EDRF antagonists attenuated ACh-induced vasodilation in intact hamster lungs, we conclude that EDRF plays a role in this response. Nonselective inhibitory effects of Hb in hamster lungs, however, suggest that mechanisms other than inhibition of EDRF by this agent are also involved.
On the purported discovery of the bronchial circulation by Leonardo da Vinci.
Among modern physiologists and anatomists, there has been a nearly universal acceptance that Leonardo da Vinci was the first to identify the anatomy of the bronchial circulation. However, because of certain ambiguities in both his anatomic drawing that was supposed to have shown this circulation and the accompanying descriptive text, we questioned whether he really could have been the first to discover this small but important vasculature. To address this question, we set out to repeat Leonardo's dissections in the ox. We reasoned that perhaps the normally tiny bronchial vessels would be considerably more noticeable in this very large species. Our dissections, however, failed to provide any evidence that Leonardo's drawing was that of the bronchial circulation. Furthermore we observed a set of distinct small pulmonary veins to the left upper and right middle lobes that Leonardo, given his lack of understanding of the function of the lung and its circulation, could have easily mistaken for a separate circulation. We thus conclude that Leonardo da Vinci did not describe the anatomy of the bronchial circulation. We believe that the first person to clearly and unequivocally describe the anatomy of this circulation was the Dutch Professor of Anatomy and Botany, Frederich Ruysch.
Pulmonary vascular reactivity and hemodynamic changes in elastase-induced emphysema in hamsters.
Changes in pulmonary hemodynamics and vascular reactivity in emphysematous hamsters were studied in an isolated lung preparation perfused at constant flow with blood and 3% dextran. Hamsters were treated with intratracheal porcine pancreatic elastase at 70 days of age, and experimental studies were conducted at 1, 3, and 8 mo after treatment. Baseline pulmonary arterial pressure in elastase-treated lungs was increased compared with saline-treated control lungs 1 mo after treatment, but this increase did not progress at 3 and 8 mo. Increases in pulmonary arterial pressure in elastase-treated lungs were temporally correlated with the morphological development of emphysema and right ventricular hypertrophy; both of these were evident at 1 mo after treatment and showed little change thereafter. Pressor responses to hypoxia and angiotensin II were not different between elastase-treated and control lungs at 1 and 3 mo. At 8 mo, however, pressor responses in emphysematous lungs to 0% O2 (but not to angiotensin II) were significantly increased. This was the result of a lack of the normal age-related fall in the hypoxic pressor response. Our results suggest that the right ventricular hypertrophy found in these emphysematous animals results from a chronically increased pulmonary vascular resistance. Furthermore, increases in pulmonary vascular resistance in the early development of emphysema are likely a result of the loss of vascular beds and supporting connective tissue.
Design and calibration of a high-frequency oscillatory ventilator.
High-frequency ventilation (HFV) is a modality of mechanical ventilation which presents difficult technical demands to the clinical or laboratory investigator. The essential features of an ideal HFV system are described, including wide frequency range, control of tidal volume and mean airway pressure, minimal dead space, and high effective internal impedance. The design and performance of a high-frequency oscillatory ventilation system is described which approaches these requirements. The ventilator utilizes a linear motor regulated by a closed loop controller and driving a novel frictionless double-diaphragm piston pump. Finally, the ventilator performance is tested using the impedance model of Venegas [1].
Assessment of pulmonary airway reactivity with high-resolution CT.
The evaluation of airway reactivity plays a central role in the diagnosis of bronchial hyperreactivity and asthma. The authors used high-resolution computed tomography (HRCT) to assess airway reactivity and compared the results with simultaneously performed measurements of airway pressure (Paw). Ten anesthetized and ventilated dogs were studied in a control state, after saline aerosol application, and after histamine aerosol challenge. In each condition, Paw was determined and HRCT was performed at functional residual capacity. On the HRCT scans, the cross-sectional areas of airway lumina were measured by using a computer edging process. After histamine challenge, HRCT demonstrated a decrease in airway areas of 43% +/- 2% (mean +/- standard error) from baseline (control) and Paw increased 99% +/- 18%. Surprisingly, saline aerosol challenge also resulted in a significant decrease in airway areas (26% +/- 3%) from control, while Paw measurements did not change significantly. Airway reactivity varied between dogs and within dogs. The authors conclude that HRCT can depict the site and degree of airway reactions and thus represents a new tool to assess airway reactivity in vivo.
Use of collateral airways to assess airway reactivity.
We investigated the correlation between collateral airway reactivity and other indexes of lung reactivity in response to aerosol and intravenous (iv) challenges. In four anesthetized mongrel dogs, we measured the peripheral airway resistance (Rp) to gas flow out of a wedged lung segment in different lobes on multiple occasions. We obtained dose-response curves of peripheral airways challenged with iv histamine or aerosols through the bronchoscope. During the same iv bolus challenge, whole lung airway pressure (Paw) responses to histamine were also measured. On separate occasions, changes in lung resistance (RL) were measured after the whole lung was challenged with a histamine aerosol. Reactivity was assessed from the dose-response curves for Rp and RL as the PD50 (dose required to produce a 50% increase); for changes in Paw we calculated the PD15 (dose required to produce a 15% increase over baseline). Results for Rp showed considerably more variability among different lobes in a given animal with the aerosol challenge through the bronchoscope than with the iv challenge. With aerosol challenge there were no significant differences in the mean PD50 for Rp among any of the animals. However, with the iv challenge two of the dogs showed significant differences from the others in reactivity assessed with Rp (P less than 0.01). Moreover, the differences found in the peripheral airways with iv challenge reflected differences found in whole lung reactivity assessed with either iv challenge (Paw vs. Rp, r2 = 0.96) or whole lung aerosol challenge (RL vs. Rp, r2 = 0.84). We conclude that the measurement of the collateral resistance response to iv challenge may provide a sensitive method for assessing airway reactivity.
Measurement of airway wall blood flow in sheep by laser-Doppler flowmetry: interpretation and problems.
We have used laser-Doppler flowmetry (LDF), a technique that detects movement of erythrocytes, to measure tracheal and bronchial wall blood flow in anesthetized open-chest sheep. LDF derives continuous measurements noninvasively, although fiber-optic bronchoscopy is necessary to introduce the LDF probe into the airways. The response of the LDF flow signals at four regions of the airway walls to varying bronchial arterial flow rates was examined in both live and dead sheep by cannulation and subsequent perfusion of the common bronchial artery at different flow rates by use of a roller pump. In the live sheep, variations in bronchial arterial blood flow resulted in variations in LDF signals in the principal bronchus and in lobar and segmental bronchi but not in the trachea. In the dead sheep, variations in bronchial arterial blood flow resulted in variations in LDF signals in all four regions. Within regions, the average response of the LDF signals to varying bronchial blood flow rates was approximately linear in both live and dead sheep, but considerable site-to-site variation in response was observed. In the live sheep, significant LDF signals were observed when the bronchial arterial flow was set to zero and when the bronchial artery was perfused with dextran solution, which would in theory be expected to produce no LDF signal. A small LDF signal was also detected under zero flow conditions in the dead sheep. These observations suggest that the LDF technique, in addition to detecting blood flow from the bronchial artery also detects background noise and/or collateral circulation.(ABSTRACT TRUNCATED AT 250 WORDS)
Interaction between CO2 concentration and flow rate on peripheral airway resistance.
In the present study, we investigated the interaction between CO2 concentration and rate of delivered flow on peripheral airway resistance (Rp) in the intact canine lung. Dogs were anesthetized, intubated, paralyzed, and mechanically ventilated with room air to maintain end-tidal CO2 between 4.8 and 5.2%. Using a wedged bronchoscope technique, we measured Rp at functional residual capacity. The relationship between CO2 concentration and Rp was measured at flow rates of 100 and 400 ml/min with 5, 3, 2, 1, and 0% CO2 in air. Measurements were made at the end of a 3-min exposure to each gas. At low flow rates (100 ml/min) responses to hypocapnia were small, whereas at high flow rates (400 ml/min) responses were large. The PC50 (defined as the CO2 concentration required to produce a 50% increase in Rp above baseline Rp established on 5% CO2) at 400 ml/min (1.73%) was significantly larger than that at 100 ml/min (0.38%). We also directly measured the relationship between Rp and flow rate with 5% CO2 (normocapnia) or 1% CO2 (hypocapnia) delivered into the wedged segment. Increases in normocapnic flow caused small but significant decreases in Rp. In contrast, increases in hypocapnic flow from 100 to 400 ml/min caused a 108% increase in Rp. Thus the response to hypocapnia is augmented by increasing flow rate. This interaction can be explained by a simple model that considers the effect of local ventilation-perfusion ratio and gas mixing on the local CO2 concentration at the site of peripheral airway contraction.
Role of the epithelium in airway smooth muscle responses to relaxant agonists.
We studied the role of the guinea pig tracheal epithelium in modulating tracheal smooth muscle responses to the relaxant agonists albuterol, sodium nitroprusside, and theophylline. We used an in vitro preparation that allowed separation of the fluids bathing the luminal (internal) and serosal (external) surfaces of the trachea, and bronchodilators were administered to either surface of carbachol-contracted tracheae. All three drugs produced dose-dependent relaxation. However, albuterol and nitroprusside were less potent (concentration that produced half-maximal effect increased by 100- and 32-fold, respectively) when given to the epithelial side with the epithelium intact compared with the epithelium denuded or compared with serosal administration with the epithelium intact. These differences were not observed for theophylline, where smooth muscle responses were independent of either the side of stimulation or of the presence or absence of the epithelium. Direct measurements of the diffusion of theophylline across the tracheal wall in the presence or absence of epithelium showed that after 5 h of incubation with a fixed luminal concentration of theophylline, only 1.7% had diffused across the tracheal wall with the epithelium intact. This increased to only approximately 3.3% when the epithelium was denuded. These results suggest that the epithelial is a relatively weak barrier for lipophilic agents but has a major role as a diffusion barrier to hydrophilic substances.
In vivo measurements of airway reactivity using high-resolution computed tomography.
Changes in airway resistance are reported to account for only a portion of changes in total lung resistance. The fraction of total lung resistance caused by airway resistance is difficult to quantify in vivo. High-resolution computed tomography (HRCT) has potential application for directly measuring changes in airway size in vivo. In the present investigation, we studied five anesthetized mongrel dogs using HRCT to locate and measure changes in airway area after aerosol histamine challenge in the absence and presence of deep inspiration. We also related changes in total lung resistance to changes in airway area. We found that in all dogs after histamine aerosol challenge, airway area decreased (range, 23 +/- 7 to 67 +/- 5%, mean +/- SEM), and total lung resistance increased (range, 191 to 378%). After deep inspiration (equal to three times tidal volume), four of the five dogs showed further significant decreases in airway area (range, 13 +/- 6 to 71 +/- 8%), whereas all five dogs showed decreases in RL (range, 3 to 35%). The fact that preconstricted airways constricted further after deep inspiration while the measured RL decreased suggests that RL may not always be a reliable indicator of changes in the size of conducting airways larger than 1 mm.
Mechanism of thiopental-induced constriction of guinea pig trachea.
The authors studied the effects of thiopental on baseline airway tone in intact guinea pig tracheas using a preparation where the epithelial (inside) and serosal (outside) surfaces were isolated. Whole tracheas were excised, cannulated, and mounted in 50-ml tissue baths. The serosal and epithelial surfaces were perfused via separate circuits with Krebs-Henseleit solution. All data were expressed as a percent of constriction produced by 2 X 10(-6) M carbachol (a concentration that elicited a 90 + % of maximal constriction). Thiopental elicited a dose-dependent constriction in all 25 tracheas. Increases in tone were first seen at 10(-5) M (14.3 +/- 1.84%; mean +/- SEM) and reached a peak at 10(-3) M (29 +/- 3.16%; P less than .0001). Responses to thiopental were similar when the epithelium was removed, when thiopental was added to the inner perfusate, and when tracheas were pretreated with 10(-5) M pyrilamine. Constriction was entirely inhibited by pretreatment with indomethacin 10(-5) M. The authors conclude that thiopental, at concentrations in the clinical range, causes a reproducible dose-dependent constriction of guinea pig trachea. This effect is mediated by constrictor prostaglandins.
A genetic approach to the study of lung physiology: understanding biological variability in airway responsiveness.
Genetic techniques are generally applicable to almost any trait or physiological process for which biological variability can be demonstrated. These methods have not commonly been applied to studies on lung pathophysiology, however. The aim of this commentary will be to introduce and discuss the potential application of genetic methods to research on the pathophysiology of asthma. Recent efforts to identify genes that determine airway hyperresponsiveness in the genetically standardized inbred laboratory mouse will be reviewed. These experiments demonstrate how genetic background influences the expression of airway responsiveness to certain environmental stimuli and illustrate the application of selected genetic resources. A discussion follows on how these genetic models may potentially provide insight into asthma and our understanding of the molecular physiology and genetic regulation of airway hyperreactivity to various stimuli.
Influence of the pericardium on ventricular loading during respiration.
The influence of the pericardium on ventricular loading during respiration was studied in 17 acutely instrumented anesthetized dogs. Changes in intrapericardial surface pressures (Ppe) on the ventricles were measured by use of air-filled flat latex balloons during acute changes in ventricular loading with the chest open or during negative intrathoracic pressure (NITP) produced by phrenic nerve stimulation with the chest closed. Ppe always demonstrated a phasic change within a cardiac cycle, with its maximum near end diastole and minimum near end systole, and a waveform similar to ventricular dimensions measured by sonomicrometer crystals. With the chest open we found that 1) inferior vena caval constriction decreased Ppe on both ventricles at end diastole (P less than 0.01), 2) aortic constriction increased Ppe on both ventricles at end systole and end diastole (P less than 0.05), and 3) pulmonary artery constriction increased Ppe on the right ventricle (RV) (P less than 0.01) while decreasing Ppe on the left ventricle (LV) at end diastole (P less than 0.05). Thus regional Ppe over a ventricle is influenced by changes in ventricular loading conditions. During NITP with lung volume either constant or increased, Ppe over the anterolateral LV decreased less than two independent extrapericardial measures of intrathoracic pressure, and this resulted in an increased transpericardial pressure at end systole (P less than 0.05) and end diastole (P less than 0.01). During NITP with increased transpericardial pressure, Ppe over the anterior LV, lateral LV, and RV inflow showed small regional differences, but all decreased less than esophageal pressure (P less than 0.01). These results sugges that the increase in transpericardial pressure during late diastole to early systole, produced by increases in ventricular volume during NITP, could effectively attenuate the increases in ventricular preload and afterload caused by respiration, analogous to a negative feedback loop.
Morphological evidence for alveolar recruitment during inflation at high transpulmonary pressure.
The effect of continuous inflation of lungs at 30 cmH2O transpulmonary pressure (Ptp) on air-space size was assessed by chord length-frequency distribution analysis. Lungs from gerbils were excised, allowed to collapse freely, and inflated to 30 cmH2O Ptp in a humidified chamber kept at 37 degrees C. When the lungs appeared fully inflated with no observable pleural surface atelectasis, the left lung was occluded while the right was maintained at 30 cmH2O for 10 min longer and then occluded. During this time, the right lung increased its volume from 70 to 100%. Then both lungs were quick frozen, freeze dried, and embedded in glycol methacrylate, and 1- to 2-microns-thick histological sections cut. Lungs from a control group of gerbils were similarly inflated to 30 cmH2O, both left and right were occluded, the left was quick frozen immediately, and the right was frozen 10 min later. Chord lengths of air spaces from cranial and caudal lobes of lungs were acquired using a Dapple Systems image analyzer, and a two-population frequency distribution was generated for analysis with an IBM PC. The results indicate that the volume increase during continuous inflation at 30 cmH2O Ptp was associated with a shift in the chord length distribution toward the smaller chord lengths. A two-population statistical analysis indicated that the inflation resulted in an increase in the relative proportion of smaller chord lengths, with no increase in the mean of this smaller population. We conclude that continuous inflation at 30 cmH2O Ptp results in alveolar recruitment.