Search PubMed⌕ Search

Biomedical subjects

J M Drazen

Publications and source records attributed to J M Drazen.

At least 289 records · Page 16Linked to original sources
PubMed1981

Tidal volume and frequency dependence of carbon dioxide elimination by high-frequency ventilation.

Six patients with chronic respiratory failure received mechanical ventilation with tidal volumes less than or equal to the dead-space volume, at frequencies of 30 to 900 breaths per minute. The rate of elimination of carbon dioxide from the ventilator system during a brief trial of high-frequency ventilation accurately predicted the long-term effectiveness of a given combination of frequency and tidal volume. Below frequencies of about 200 breaths per minute, the volume of carbon dioxide eliminated from these patients was most strongly related to the product of frequency and tidal volume; at higher frequencies, carbon dioxide elimination was determined by the tidal volume and was independent of frequency. These results suggest that although the effectiveness of high-frequency ventilation is primarily a function of the product of tidal volume and frequency, above a critical frequency the mechanical characteristics of the lung reduce gas transport by limiting the volume transmitted to the periphery of the lung.

Adolescent↗
PubMed1981

Functional characterization of synthetic leukotriene B and its stereochemical isomers.

Leukotriene B (LTB), a potent lipid chemotactic factor for neutrophils, is 5S,12R-dihydroxy-6,14-cis,8,10-trans-eicosatetraenoic acid (Fig 1), based upon direct comparison of natural LTB with synthetic 5S,12R-dihydroxy-6,8,10,14-eicosatetraenoic acid (5,12-di-HETE) stereoisomers in three biological assays. Of the six synthetic stereoisomers evaluated, only the 5S,12R,6,14-cis,8,10-trans compound had chemotactic potency for human neutrophils in vitro that was comparable to that of natural LTB, with a concentration of 3 X 10(9-9) M eliciting a one-half maximum response. In contrast, the racemic mixture of 5R,12R- and 5S,12S-6,10-trans,8,14-cis, the racemic mixture of 5S,12R- and 5R,12S-6,10-trans,8,14-cis, the 5S,12R-6,8-trans,10,14-cis, the 5S,12R-6,8,10-trans,14-cis, and the 5S,12S-6,8,10-trans,14-cis stereoisomers required concentrations of 3 X 10(-7) to 1 X 10(-6) M to elicit comparable responses. Only natural LTB and its synthetic counterpart elicited a local neutrophil infiltration when injected into the skin of the rhesus monkey at 10 ng and 100 ng per site. Natural and synthetic LTB at a concentration of 3 X 10(-8) M each provoked an EC25 contractile response of guinea pig pulmonary parenchymal strips in vitro, whereas the other four tested stereoisomers of 5,12-di-HETE were inactive at this concentration. Structure-function analyses suggest that the neutrophil chemotactic activity depends critically upon the C-1 to C-12 domain, including the stereochemistry of the 6-,8-,and 10-olefinic bonds and the presence of both hydroxyl groups.

Animals↗
PubMed1981

Effects of beta adrenergic blockade on histamine and prostaglandin-F2 alpha responsiveness in the dog.

To examine whether either the degree of existing beta adrenergic tone or the magnitude of beta adrenergic response during bronchoconstriction might account for the differences that exist between dogs in their pulmonary responsiveness to aerosol challenge with bronchoconstrictor agents, dose-response curves were performed in a group of dogs to either histamine or prostaglandin-F2 alpha, both before beta blockade with propranolol. Beta blocked had no significant effect on control values of dynamic compliance (Cdyn) or resistance of the lung (RL) or on pulmonary responsiveness to prostaglandin f2 alpha. Although propranolol did not have a significant effect on aerosol responsiveness to histamine for the group of dogs taken together, those dogs initially least responsive to aerosol histamine did become more responsive after beta blockade. This effect of beta blockade was statistically significant only for Cdyn and not for RL, suggesting enhancement of peripheral airway effects. We conclude that a beta adrenergic mechanism may contribute to the range of responsiveness found among dogs in their pulmonary responsiveness to histamine but that other as yet undefined factors must also contribute to the differences that exist among dogs in their pulmonary responsiveness to bronchoconstrictor agents.

Adrenergic beta-Antagonists↗
PubMed1981

Contractile activities of structural analogs of leukotrienes C and D: necessity of a hydrophobic region.

Sixteen structural analogs of leukotrienes C and D were tested for their contractile activities on guinea pig pulmonary parenchymal strip and ileum. The analogs differed from the native structures in the position of either the thioether-linked peptide side chain or the hydroxyl group (or both) or in the number and positions of ethylenic bonds. Analogs in which the thioether-linked peptide chain was attached other than at the C-6 position had substantial reductions in activity on both smooth muscle preparations, whereas analogs in which the various ethylenic bonds were saturated retained substantial contractile activity in both assays. These observations demonstrate that, although a hydrophobic region of the eicosinoid is necessary for contractile activity, the length of this segment is more critical than its precise stereochemistry. Analogs of leukotrienes based on the possibility of parallel biosynthetic routes deriving from 8-, 11-, and 15-hydroperoxyeicosatetraenoic acid as precursors were found to effect a comparatively weak contractile response so that their role as biological agents in this respect seems unlikely.

Animals↗
PubMed1981

Contractile activities of structural analogs of leukotrienes C and D: role of the polar substituents.

Twenty-three structural analogs of the leukotriene components of slow reacting substance of anaphylaxis (SRS-A), in which the polar regions of the leukotriene were systematically modified, were tested for their contractile activities on guinea pig pulmonary parenchymal strips and guinea pig ileum. The structural modifications allowed evaluation of the separate contributions of the four polar units in the C-1 to C-6 region of the SRS-A leukotrienes to smooth muscle spasmogenic activity. The free NH2-terminal amino group of the S-linked peptide was necessary for full activity, and its deletion or substitution reduced activity by more than one but less than two orders of magnitude. A similar level of importance was apparent for the free glycine carboxyl group. In contrast, a free eicosanoid carboxyl at C-1 is not required for full activity on the airway and for substantial activity on the ileum. A role for the C-5 hydroxyl is indicated by the inactivity of the one available 5-desoxy analog. Nucleophilic, divalent sulfur is not critical to leukotriene D (LTD) activity, in that one sulfoxide had substantial function. The conformational relationship between the eicosanoid and peptide moieties of LTD is of considerable importance in that epimers at the C-5 or C-6 position were less active than LTD by more than two orders of magnitude. Several lines of evidence suggest that the relative geometrical arrangement of the C20 chain and the peptide unit is important to activity, consistent with the existence of a true receptor for LTD.

Animals↗
PubMed1981

Direct and reflex bronchoconstriction induced by histamine aerosol inhalation in dogs.

Histamine aerosols were administered to nine anesthetized, paralyzed, mechanically ventilated mongrel dogs with the cervical vagi first intact, then sectioned, and then peripherally stimulated at two intensities. Pulmonary resistance (RL) was measured, and dose-response curves were constructed in the four conditions. All dogs had dose-related increases in RL with increasing histamine aerosol concentrations. After the vagi were cut, the degree to which constant levels of vagal stimulation altered the dose-response relationships was assessed by examining the slopes and positions of the RL vs. histamine curves. Four of the nine animals studied showed evidence of increasing vagal efferent activity as the concentration of histamine in the aerosol increased, but three did not. Two of the dogs had equivocal responses in that increasing activity was suggested but not clearly demonstrated. These results indicate that, in addition to direct effects of histamine, the extent of and basis for vagal interaction with this stimulus varies among dogs. The results suggest that the basis of vagal interaction is related to either constant efferent activity (tone) or increasing efferent activity (reflexes).

Aerosols↗
PubMed1981

Serial distribution of bronchoconstriction induced by vagal stimulation or histamine.

We compared the relative site of airway responses with histamine aerosol and electrical stimulation of the vagi in dogs that were anesthetized, vagotomized, mechanically ventilated, and treated with propranolol. We made measurements of pulmonary resistance by forced oscillations and of dead-space volume as indirect indicators of airway size. Direct measures of airway size were obtained from radiographic bronchograms and from acoustically equivalent airway areas as a function of distance, computed from pulse response data. During vagal stimulation there were marked increases in pulmonary resistance, decreases in dead space, and reduction in acoustic cross-sectional area at all distances. In contrast, after inhalation of enough aerosol histamine to increase pulmonary resistance approximately as much as it did during vagal stimulation, we observed little ro no reduction in dead space and reductions in acoustic cross-sectional area that were most marked in distal airways. The findings were confirmed by the radiographic bronchograms and are consistent with observations reported by others. These observations confirm previous data and demonstrate the utility of this technique for in vivo measurements.

Airway Resistance↗
PubMed1981

Oscillatory flow and quasi-steady behavior in a model of human central airways.

We studied biased oscillatory flow in a model of human central airways to examine under what conditions oscillatory flow deviated from steady flow. Although the steady flow resistance of the model was 25% less than the oscillatory flow resistance of the model at 15Hz, the overall inertance of the model did not change over the range of frequencies from 5 to 15 Hz, suggesting that frequency-dependent inertial distortion of velocity profiles did not alter central airway pressure-flow relationships over this frequency range. In a given terminal branch of the model, instantaneous oscillatory flow at 2 and 5 Hz could be predicted well from the steady flow distribution, but with increasing frequency the oscillatory flow from the branch deviated more from the steady flow predictions. A significant component of this deviation was due to a phase shift between predicted and measured oscillatory flow. We conclude that the major frequency-dependent behavior flow in the human central airways is a phasic redistribution of flow above 7 Hz, resulting from the asymmetric distribution of inertances in this structure.

Airway Resistance↗
PubMed1981

Vagal stimulation and aerosol histamine increase hysteresis of lung recoil.

Bronchoconstriction changes pulmonary resistance and dynamic compliance by altering both airway properties and dynamic lung tissue recoil. To assess the contribution of recoil, we measured transpulmonary pressure in anesthetized open-chest dogs during sinusoidal ventilation with gas flow and during sinusoidal compression of intrapulmonary gas without flow. Measurements with gas flow characterized total pulmonary behavior, including the contribution of gas flow in airways, whereas measurements during gas compression characterized lung tissue recoil alone. Histamine aerosol produced a 54% decrease in dynamic compliance, a 465% increase in total pulmonary resistance, and a 153% increase in pressure-volume hysteresis of dynamic recoil. Vagal stimulation produced a 31% decrease in dynamic compliance, a 135% increase in total pulmonary resistance, an 82% increase in the hysteresis of recoil, and a 15% increase in mean recoil pressure. At slow oscillation frequencies (0.2 Hz) and high transpulmonary pressures (10 cmH2O), hysteresis of lung recoil contributes substantially to total pulmonary resistance, and changes in dynamic lung recoil can account for much (35%) of the increase in pulmonary resistance seen with bronchoconstriction.

Aerosols↗
PubMed1981

Alveolar pressure-airflow characteristics in humans breathing air, He-O2, and SF6-O2.

In a system of rigid tubes under steady flow conditions, the coefficient of friction [CF = 2 delta P/(rho V2/A2)] (where delta P is pressure drop, rho is density, V is flow, and A is cross-sectional area) should be a unique function of Reynolds' number (Re). Recently it has been shown that at any given Re, the value of CF using transpulmonary pressure (PL) was lower when breathing He-O2 compared with air (Lisboa et al., J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 48: 878-885, 1980). One explanation for this discontinuity is that PL includes the pressure drop due to tissue viscance, which is independent of V, and thus would lead to an overestimate of CF on air compared with He-O2 at any Re. We tested this hypothesis by measuring V related to alveolar pressure, rather than PL, in normal subjects breathing air, He-O2, and SF6-O2. In each subject, for a given Re, CF was greatest breathing SF6-O2 and lowest breathing He-O2, similar to results using PL. Thus tissue viscance is not the sole cause of the discontinuous plot of CF vs. Re, and this phenomenon must be due to other factors, such as changing geometry or nonsteady behavior.

Adult↗
PubMed1981

Effects of lung inflation on airway and tissue responses to aerosol histamine.

The pulmonary effects of aerosol histamine exposure include an increase in pulmonary resistance (RL) and a decrease in dynamic compliance (Cdyn). These changes are substantially reversed by inflation of the lungs to 30 cmH2O transpulmonary pressure (TLC). Although histamine has been shown to change both the airway and tissue components of RL and Cdyn, it is not known whether lung inflation reverses the changes in airways, in tissue, or in both. We studied six anesthetized, paralyzed, open-chest dogs. We sequentially measured RL and Cdyn during oscillations in lung volume at 0.6 Hz with the airway open and during compression-decompression of the lungs without tracheal airflow. In the control state after saline aerosol, inflation to TLC resulted in a slight increase in compliance and a decrease in the tissue component of RL. Aerosol histamine exposure caused an increase in resistance and a decrease in compliance due to both airway and tissue changes. Inflation of the lungs to TLC largely reversed the changes due to airway constriction without consistently affecting the changes due to tissue. We conclude that after histamine exposure smooth muscle responsible for airway narrowing is stretched by lung inflation but that contractile elements responsible for alterations in air-space distensibility and hysteresis of dynamic lung recoil are either not stretched by lung inflation or are stretched and shorten again rapidly.

Aerosols↗
PubMed1981

Airway responsiveness to inhaled mediators: relationship to epithelial thickness and secretory cell number.

Naturally occurring variations in airway responsiveness to inhaled mediators were correlated with various anatomic indexes thought to be related to airway responsiveness. Specifically, the airways of 2 relatively unresponsive and 3 relatively responsive dogs were compared in terms of epithelial thickness, secretory cell number, smooth muscle thickness, and airway mucous gland number and size. More responsive dogs were found to have thinner epithelium and higher secretory cell counts than less responsive dogs. No significant differences between the 2 groups were noted with respect to smooth muscle thickness or mucous gland number and size. Although these observations identify an association between these anatomic features and airway responsiveness, it does not imply a causal relationship.

Airway Resistance↗
PubMed1981

Effects of frequency, tidal volume, and lung volume on CO2 elimination in dogs by high frequency (2-30 Hz), low tidal volume ventilation.

Recent studies have shown that effective pulmonary ventilation is possible with tidal volumes (VT) less than the anatomic dead-space if the oscillatory frequency (f) is sufficiently large. We systematically studied the effect on pulmonary CO2 elimination (VCO2) of varying f (2-30 Hz) and VT (1-7 ml/kg) as well as lung volume (VL) in 13 anesthetized, paralyzed dogs in order to examine the contribution of those variables that are thought to be important in determining gas exchange by high frequency ventilation. All experiments were performed when the alveolar PCO2 was 40 +/- 1.5 mm Hg. In all studies, VCO2 increased monotonically with f at constant VT. We quantitated the effects of f and VT on VCO2 by using the dimensionless equation VCO2/VOSC = a(VT/VTo)b(f/fo)c where: VOSC = f X VT, VTo = mean VT, fo = mean f and a, b, c, are constants obtained by multiple regression. The mean values of a, b, and c for all dogs were 2.12 X 10(-3), 0.49, and 0.08, respectively. The most important variable in determining VCO2 was VOSC; however, there was considerable variability among dogs in the independent effect of VT and f on VCO2, with a doubling of VT at a constant VOSC causing changes in VCO2 ranging from -13 to +110% (mean = +35%). Increasing VL from functional residual capacity (FRC) to the lung volume at an airway opening minus body surface pressure of 25 cm H2O had no significant effect on VCO2.

Animals↗
PubMed1980

In vivo effect of cimetidine on canine pulmonary responsiveness to aerosol histamine.

A series of experiments were designed to discover whether pulmonary histamine H2 receptors might be of physiologic importance in vivo in the dog. Dose-response curves were performed to aerosol histamine in 11 dogs both before and 1 hr after H2 receptor blockade with cimetidine (1 mg/kg as a rapid intravenous infusion). Cimetidine had no significant effect on control values of dynamic compliance or resistance of the lung. In the 11 dogs tested H2 receptor antagonism significantly potentiated (p less than 0.05) the animals' pulmonary responsiveness to aerosol histamine. The potentiation of histamine constrictor e-fects produced by cimetidine were more marked on those dogs initially least responsive to aerosol histamine (p less than 0.01). We have found evidence for the presence of inhibitory H2 receptors in canine airways and for the distribution of these receptors among dogs, explaining in part the previously described differences among dogs in the pulmonary responsiveness to aerosol histamine.

Aerosols↗
PubMed1980

Two rat mononuclear cell-derived slow reacting substances: kinetic evidence that the peripheral airways-selective spasmogen is derived from a nonselectively acting precursor.

The purpose of this study was to extend our knowledge of two slow reacting substances that are formed in rat mononuclear cells upon stimulation by the ionophore A 23187. Slow reacting substance (SRS) preparations were further purified through the sequential high performance liquid chromatographic procedures starting with exudates from cells that had been prelabeled with tritiated arachidonate. Approximately 2% of the released radioactivity (0.3% of the radioactivity that was taken up by the cells) cochromatographed with biologic activity in both preparations. Kinetic studies revealed that one of the SRSs was formed more rapidly than the other and analysis by nonlinear computer modeling techniques suggests a possible product-precursor relationship between the two substances. Activity of the preparations on guinea pig lung parenchyma and trachea was compared using a histamine standard; only the more slowly formed substance had the selective activity on the parenchyma that we associate with slow reacting substance of anaphylaxis (SRS-A). Taken together, these findings suggest that a material which may be a precursor of SRS-A, if it is also formed and accumulated in vivo, may contribute to the more central airway constriction which is seen in some asthmatics.

Animals↗
PubMed1980

Slow reacting substances of anaphylaxis: identification of leukotrienes C-1 and D from human and rat sources.

Slow reacting substance(s) of anaphylaxis (SRS-A) was isolated from both human (lung) and rat sources and compared with three synthetic SRS-As of known structure-leukotrienes (LTs) C-1, C-2, and D. Reversed-phase liquid chromatography was used both as a final purification step and a means of comparison of biologically derived and synthetic substances. Two major peaks of SRS-A activity of both rat and human origin corresponded chromatographically with LTC-1 and LTD, respectively, and had equivalent specific activities on the guinea pig ileum. With guinea pig ileum, the specific activities (units/pmol) for synthetic leukotrienes and anaphylactic peaks were (mean +/- SEM): synthetic LTC-1, 1.93 +/- 0.13; SRS-A(rat) peak I, 1.69 +/- 0.43; synthetic LTD, 6.10 +/- 1.15; SRS-A(rat) peak II, 7.14 +/- 0.51; and SRS-A(hu) peak II, 1.90. Both synthetic LTC-1 and LTD and their SRS-A natural counterparts had a preferential contractile activity on guinea pig peripheral airway compared to central airways and were at least 200 times more active than histamine on peripheral airways on a molar basis. Leukotriene D is the major SRS-A of human lung and accounts for almost all of the biological activity. It likely is formed from leukotriene C-1 in vivo by an enzymic process of the well-known gamma-glutamyltransferase type.

Animals↗