Biomedical subjects

W Mitzner

Publications and source records attributed to W Mitzner.

At least 73 records · Page 4Linked to original sources

PubMed1991

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.

Airway Resistance↗

PubMed1991

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.

Albuterol↗

PubMed1991

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.

Airway Resistance↗

PubMed1990

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.

Animals↗

PubMed1990

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.

Animals↗

PubMed1990

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.

Animals↗

PubMed1990

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.

Animals↗

PubMed1989

Protective role of epithelium in the guinea pig airway.

We developed an in vitro system to assess the role of the epithelium in regulating airway tone using the intact guinea pig trachea (J. Appl. Physiol. 64: 466-471, 1988). This method allows us to study the response of the airway when its inner epithelial surface or its outer serosal surface is stimulated independently. Using this system we evaluated how the presence of intact epithelium can affect pharmacological responsiveness. We first examined responses of tracheae with intact epithelium to histamine, acetylcholine, and hypertonic KCl when stimulated from the epithelial or serosal side. We then examined the effect of epithelial denudation on the responses to these agonists. With an intact epithelium, stimulation of the inner epithelial side always caused significantly smaller changes in diameter than stimulation of the outer serosal side. After mechanical denudation of the epithelium, these differences were almost completely abolished. In the absence of intact epithelium, the trachea was 35-fold more sensitive to histamine and 115-fold more sensitive to acetylcholine when these agents were applied to the inner epithelial side. In addition, the presence of an intact epithelium almost completely inhibited any response to epithelial side challenge with hypertonic KCl. These results indicate that the airway epithelial layer has a potent protective role in airway responses to luminal side stimuli, leading us to speculate that changes in airway reactivity measured in various conditions including asthma may result in part from changes in epithelial function.

Acetylcholine↗

PubMed1989

Autosomal recessive inheritance of airway hyperreactivity to 5-hydroxytryptamine.

We have previously reported that airway hyperresponsiveness to acetylcholine (ACh) is inherited as an autosomal recessive trait in A/J and C3H/HeJ mice and the progeny of crosses between them (FASEB J. 2: 2605-2608, 1988). In the present report, we have extended these studies by evaluating the biological variability in the airway response to 5-hydroxytryptamine (5-HT) and ACh among multiple genetically standardized inbred strains of mice. The pattern of airway responsiveness to ACh differed significantly from that of 5-HT in nine inbred strains of mice. A/J mice showed nonspecific airway hyperresponsiveness to both 5-HT and ACh. DBA/2J mice were hyperresponsive to 5-HT but not to ACh. An airway phenotype that resembled these inbred strains is termed HYPERREACTIVE. The C3H/HeJ and C57BL/6J inbred strains were minimally reactive to either ACh or 5-HT. Airway phenotypes that resembled these minimally reactive strains are termed HYPOREACTIVE. The frequency of HYPERRACTIVE and HYPOREACTIVE offspring from crosses between A/J and C3H/HeJ mice or DBA/2J and C57BL/6J mice is consistent with a single autosomal recessive gene, primarily determining airway hyperresponsiveness to 5-HT. We report linkage studies which suggest that these genes are not closely linked and that 5-HT and ACh airway hyperresponsiveness is inherited independently. The results of these studies suggest that murine nonspecific airway hyperresponsiveness is determined by multiple genes.

Acetylcholine↗

PubMed1989

In vivo and in vitro lung reactivity in elastase-induced emphysema in hamsters.

Although patients with chronic obstructive lung disease often show airway hyperresponsiveness to constrictor challenge, the mechanisms underlying this hyperreactivity are unknown. In this study, we tested whether the elastase-induced hamster model of emphysema and bronchial secretory cell metaplasia shows a similar hyperreactivity. Four weeks after intratracheal administration of 0.2 mg/100 g body weight porcine pancreatic elastase, the animals were anesthetized and ventilated with a constant tidal volume of 5 ml/kg. Changes in airway pressure (Paw) were monitored before and after intravenous challenge with 0.7 mg/kg acetylcholine (ACh). There was a significant decrease in baseline Paw from 5.7 +/- 0.6 cm H2O in control animals (n = 6) to 4.0 +/- 0.6 cm H2O in emphysematous animals (n = 6). The peak Paw response to the intravenous challenge, normalized to the baseline Paw, was 2.9 +/- 0.4 in control animals, but it was significantly increased in the emphysematous animals to 4.4 +/- 1.1. Trachea, bronchi, and parenchyma from these lungs were challenged with cumulative dose of ACh and KCl. Sensitivity of the trachea and bronchi to ACh challenge, assessed as the log ED50, did not show differences between the two groups. However, the emphysematous parenchyma showed greater sensitivity to ACh compared with the control parenchyma. Trachea and bronchi from emphysematous animals showed significantly decreased maximal contractility to challenge with both ACh and KCl. In contrast, the emphysematous parenchyma showed significantly greater maximal contractility. These findings were independent of the baseline passive tension. This increased responsiveness may relate to increased passive distensibility of the emphysematous parenchyma.

Acetylcholine↗

PubMed1988

Expression of airway hyperreactivity to acetylcholine as a simple autosomal recessive trait in mice.

An increased airway response to various bronchoconstricting agents is one of the hallmarks of asthma. An interdependence of heredity and environment appears to determine this nonspecific hyperreactivity of the airways. The present study describes the patterns of inheritance of the airway response to a direct mediator of smooth muscle contraction (acetylcholine) in A/J and C3H/HeJ inbred mice and their offspring. The mean airway response to acetylcholine was greater than sixfold higher in A/J mice as compared with C3H/HeJ mice. Two phenotypes were easily distinguished on the basis of airway responses to acetylcholine in the progeny of A/J and C3H/HeJ mice. These two phenotypes were termed HYPERREACTIVE (after the A/J strain) and HYPOREACTIVE (after the C3H/HeJ strain). The observed frequencies of HYPERREACTIVE and HYPOREACTIVE phenotypes in the (A/J x C3H/HeJ) F1; (C3H/HeJ x A/J) F1 x C3H/HeJ (C3H/HeJ backcross); and the [(A/J x C3H/HeJ) F1 x (C3H/HeJ x A/J) F1] F2 are consistent with a single autosomal recessive gene primarily controlling acetylcholine-mediated airway responses. This single gene difference in airway response is completely inhibited by atropine and therefore mediated entirely by the muscarinic acetylcholine receptor.

Acetylcholine↗

PubMed1988

Osmotic stimuli induce epithelial-dependent relaxation in the guinea pig trachea.

Epithelium in airways, like endothelium in blood vessels, may regulate responses of adjacent smooth muscle. To study the intact trachea from guinea pigs we developed an in vitro preparation that permits independent stimulation from either the inner epithelial surface or the outer serosal surface. The whole guinea pig trachea was excised, cannulated, and perfused at a constant flow with Krebs-Henseleit (KH) solution that was in direct contact with the inner epithelial-lined surface. The outer serosal surface of the trachea was immersed in a separate system (bath) containing KH solution. Tracheal responses were assessed by measuring the pressure drop between the tracheal inlet and the outlet under conditions of constant flow. When the trachea was precontracted with carbachol or KCl, hyperosmolar stimuli (KCl, mannitol, urea, or NaCl) produced concentration-dependent relaxation when applied to the inner epithelial surface. Relaxation was not produced when the hyperosmolar stimulus was applied to the serosal surface and was markedly reduced or abolished when the epithelial surface had been physically damaged or removed. These results indicate that hyperosmotic stimuli induce epithelial-dependent relaxation of trachea. A defect in this mechanism may be partially responsible for the bronchoconstriction seen in asthmatic subjects after exercise.

Airway Resistance↗

PubMed1988

Chemical and mechanical determinants of apnea during high-frequency ventilation.

The factors responsible for the apnea observed during high-frequency ventilation (HFV) were evaluated in 14 pentobarbital sodium-anesthetized cats. A multiple logistic regression analysis provided an estimate of the probability of apnea during HFV as a function of four respiratory variables: mean airway pressure (Paw), tidal volume (VT), frequency, and arterial PCO2 (PaCO2). When mean Paw was 2 cmH2O, PaCO2, VT, and their interaction contributed significantly to the probability of apnea during HFV. At a low value of PaCO2 (25 Torr), the probability of apnea had a minimum value of 0.19 and gradually increased toward 1.0 as VT increased from 0.5 to 7 ml/kg. At higher levels of PaCO2 (30 and 35 Torr) the probability of apnea was zero in the low range of VT but sharply approached 1.0 above a VT of approximately 2.0 ml/kg. However, when Paw was increased to 6 cmH2O, only PaCO2 was an important determinant of apnea. In this case, the probability of apnea was 0.51 when PaCO2 was 25 Torr but decreased to 0.22 when PaCO2 was raised to 25 Torr. At neither Paw was the probability of apnea dependent on frequency. These results suggest that chemoreceptor inputs, in addition to both static and dynamic lung mechanoreceptor afferents, are responsible for determining the output of the central respiratory centers during HFV.

Airway Resistance↗

PubMed1988

Effect of tidal volume and frequency on the temporal fall in lung compliance.

In this study we have investigated how changes in respiratory frequency and tidal volume in anesthetized dogs affect the fall in dynamic compliance (Cdyn) that occurs with time after a hyperinflation. Results showed that increasing frequency [at controlled arterial (PaCO2)] PCO2 from 16 to 32 breaths/min had no effect on either the rate of fall or the magnitude of the fall up to 1 h after the hyperinflation. However, increasing the tidal volume from 300 to 750 ml abolished the fall in Cdyn from 10 to 50 min after the hyperinflation; the fall within the first 10 min remained unchanged. We also examined the effect of a simulated "hyperinflation" on the compliance of strips of parenchymal tissue in vitro. This result indicated that in the absence of surface forces, parenchymal tissue demonstrates a fall in compliance, which is complete within 10 min. Overall our findings are consistent with the hypothesis that the fall in Cdyn after hyperinflation is a two-phase process. The initial rapid fall in Cdyn (i.e., within 10 min) may simply represent a passive recovery process from the hyperinflation stress on the parenchymal tissue. The slower fall occurring after 10 min likely results from progressive increases in surface tension, and this increase can apparently be blocked by increases in tidal volume.

Animals↗

PubMed1987

Interaction between high frequency jet ventilation and cardiovascular function.

We have studied the interaction of high frequency jet ventilation with cardiovascular pressures and flows. Results in dogs show that the amplitude of all intrathoracic pressures and flows fluctuate with a frequency equal to the difference between the heart rate and ventilator rate. The magnitude of this amplitude variation may be sufficient to obliterate periodically the pulsations in pulmonary artery and right atrial pressures. It is also shown that these cardiovascular beats can occur when the ventilator rate is close to integral multiples of the heart rate. Direct measurement of pleural pressure and the observation that the beats are markedly reduced when the chest is open support the hypothesis that the primary mechanism responsible for these beats is the interaction of the respiratory fluctuations in pleural pressure with the cardiac-generated pressure pulsations.

Animals↗

PubMed1987

In vivo hysteresis of airspace dimensions measured by aerosol recovery.

In anesthetized mongrel dogs, we made measurements of single breath aerosol recovery (RC) at equal volume points on the inflation and deflation limb of the quasi-static pressure-volume (P-V) curve of the lungs. Using a 1.2 micron monodisperse aerosol, a large aerosol tidal volume (Vt), and a breathing period of 5 sec, we found that losses of particles were primarily due to sedimentation in pulmonary airspaces distal to anatomic dead space. Thus, the RC measurements could be related to a mean radius (R) of airspaces filled with aerosol over the course of the breath. Furthermore, at a given volume, differences between inflation and deflation limb RC could be attributed to differences in R for the two measurements (i.e., RI vs RD). We found that at isovolume, RC as measured from the inflation limb was larger than that measured from the deflation limb for low lung volumes (less than 0.75 TLC). However, the recoveries were similar as lung volume approached TLC (greater than 0.75 TLC). These results implied that at the same volume, RI greater than RD expect at volumes approaching TLC, i.e. a larger mean airspace dimension on the inflation limb than on the deflation limb at equal volume. The findings of this study support a model of nonuniform changes in airspace dimensions associated with in vivo inflation and deflation of the lungs.

Aerosols↗

PubMed1987

A species comparison of alveolar size and surface forces.

The independent roles of alveolar size and surface tension in relation to lung stability were investigated in 11 different mammalian species whose body weight ranged from 0.03 to 50 kg. This range in species provided a wide variation in subgross anatomy as well as a fourfold range in alveolar diameter. Alveolar diameter was estimated from the mean linear intercept (Lm) of fixed lungs. Quasi-static pressure-volume curves were determined in excised lungs and the percent volume remaining on deflation from total lung capacity at 30 cmH2O to 10 cmH2O (%V10) provided an index of deflation stability related to functional surfactant. Surface tension of lung extract was measured in the Wilhelmy balance, and the minimum surface tension measured provided an index of surface tension lowering capacity of surfactant. Relationships of %V10 with alveolar diameter and surface tension with alveolar diameter were examined for correlations. Our results indicated that despite a range in Lm between 31 and 133 micron (mouse to pig), %V10 did not change in proportion with Lm across species. Similarly, minimum surface tension was about the same (6.1 to 8.8 dyn/cm) across a threefold difference in alveolar diameter. These results suggest that a stable alveolar configuration is maintained by both surface and tissue forces in a complex manner yet to be analyzed.

Animals↗

PubMed1987

Effect of high-frequency ventilation on lung mechanics at high transpulmonary pressure.

The different tidal volumes and frequencies of high-frequency ventilation (HFV) compared with conventional mechanical ventilation (CMV) may have different effects on lung mechanics. To test this hypothesis, we compared the effects of 3 h of HFV and CMV on total lung capacity (TLC), functional residual capacity (FRC), the shape of the pressure-volume (PV) curve (%V10), and dynamic compliance (Cdyn), as well as venous admixture and alveolar-arterial O2 gradient. We studied a total of 12 dogs at lung inflations equivalent to 15 cmH2O positive end-expiratory pressure (PEEP) (group I) and 8 dogs at lung inflations equivalent to 0 cmH2O PEEP (group II). For CMV, we used a standard-volume ventilator at a mean tidal volume of 13.8 ml/kg. For HFV, we used an oscillator-type ventilator at 15 Hz and an average tidal volume of 4.3 ml/kg. Our results showed that ventilation with 3 h of PEEP raised lung volume, and lung volumes on HFV were higher than those on CMV in both groups. Specifically, in group I, the volume during ventilation rose on both CMV (150 ml) and HFV (250 ml). These volume changes persisted beyond the ventilation period, such that TLC was unchanged on CMV but had risen 200 ml on HFV. FRC also rose 200 and 300 ml after HFV and CMV, respectively. In group II, the volume during ventilation fell 100 ml on CMV and rose slightly (40 ml) on HFV. TLC and FRC both tended to fall more on CMV.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗