Biomedical subjects

J H Linehan

Publications and source records attributed to J H Linehan.

At least 73 records · Page 4Linked to original sources

PubMed1986

Effect of hypoxia and hypercapnia on ACE activity in the cerebral microcirculation of anesthetized dogs.

Angiotensin-converting enzyme (ACE) activity of the cerebral microcirculation of anesthetized dogs was measured from cerebral venous outflow curves after bolus injection of a synthetic ACE substrate, [3H]benzoyl-phenylalanyl-alanylproline ([3H]BPAP), into a common carotid artery. Cerebral BPAP metabolism was quantified by measuring the concentration of [3H]benzoyl-phenylalanine (the product of BPAP hydrolysis by ACE) in blood samples from the sagittal sinus after occlusion of the lateral sinuses with bone wax. Instantaneous BPAP metabolism in each sample increased as a function of time after injection, suggestive of perfusion heterogeneity, and averaged 59 +/- 4% (n = 8) over a single pass during normoxia and normocapnia. The ratio of Vmax (the maximal rate of cerebral BPAP metabolism) to Km (the concentration at Vmax/2), was calculated from instantaneous outflow curves using a model based on first-order kinetics. Increases in cerebral blood flow during either hypoxia or hypercapnia significantly reduced BPAP metabolism to 33 +/- 3 (n = 7) and 24 +/- 3% (n = 5), respectively; however, Vmax/Km of ACE activity (0.19 +/- 0.03 ml/s) was not affected by either condition. The lack of change in apparent kinetics of ACE activity (i.e., in Vmax/Km) during hypoxia or hypercapnia suggests that recruitment of cerebral capillaries was not a quantitatively significant factor in controlling BPAP metabolism with this degree of either hypoxia or hypercapnia.

Anesthesia↗

PubMed1986

Location and mechanisms of pulmonary vascular volume changes.

We examined the influence of changing outflow pressure, P out, on the vascular and extravascular volumes (QV and QEV, respectively, as measured by indicator dilution) and on the outflow occlusion pressures in isolated dog lung lobes perfused with constant flow. Changing P out had a substantial effect on QV, but not on QEV, whether P out was less than or greater than alveolar pressure, PA. Since QEV did not change with QV, recruitment of previously unperfused vessels did not appear to contribute substantially to the increases in QV when P out was increased. The rapid jump in P out immediately following outflow occlusion was virtually independent of the difference between PA and P out suggesting that the alveolar vessels were an important volume storage site when P out was low relative to PA. We conclude that, over a certain range of pressures, alveolar vessel volume can be controlled by venous pressure even when the change in venous pressure has little effect on arterial pressure (zone 2). Further, we conclude that in zone 3 and within the transition from zone 2 to zone 3 increases in the intralobar blood volume occurring within the alveolar vessels may not require recruitment in the sense of opening of previously unperfused vessels.

Animals↗

PubMed1986

Pulmonary vascular compliance and viscoelasticity.

When dog lung lobes were perfused at constant arterial inflow rate, occlusion of the venous outflow (VO) produced a rapid jump in venous pressure (Pv) followed by a slower rise in both arterial pressure (Pa) and Pv. During the slow rise Pa(t) and Pv(t) tended to converge and become concave upward as the volume of blood in the lungs increased. We compared the dynamic vascular volume vs. pressure curves obtained after VO with the static volume vs. pressure curves obtained by dye dilution. The slope of the static curve (the static compliance, Cst) was always larger than the slope of the dynamic curve (the dynamic compliance, Cdyn). In addition, the Cdyn decreased with increasing blood flow rate. When venous occlusion (VO) was followed after a short time interval by arterial occlusion (AO) such that the lobe was isovolumic, both Pa and Pv fell with time to a level that was below either pressure at the instant of AO. In an attempt to explain these observations a compartmental model was constructed in which the hemodynamic resistance and vascular compliance were volume dependent and the vessel walls were viscoelastic. These features of the model could account for the convergence and upward concavity of the Pa and Pv curves after VO and the pressure relaxation in the isovolumic state after AO, respectively. According to the model analysis, the difference between Cst and Cdyn and the flow dependence of Cdyn are due to wall viscosity and volume dependence of compliance, respectively. Model analysis also suggested ways of evaluating changes in the viscoelasticity of the lobar vascular bed. Hypoxic vasoconstriction that increased total vascular resistance also decreased Cst and Cdyn and appeared to increase the vessel wall viscosity.

Animals↗

PubMed1986

Cat lung hemodynamics: comparison of experimental results and model predictions.

Commonly, attempts have been made to learn about the structure and function of the pulmonary vascular bed from measurements of arterial and venous pressures and blood flow rate under steady-state conditions (e.g., from pressure vs. flow data) or dynamic conditions (e.g., from vascular occlusion data). Zhuang et al. (J. Appl. Physiol. 55: 1341-1348, 1983) have presented a detailed model of steady-state cat lung hemodynamics based on direct measurements of anatomical and elasticity data. This model provides an opportunity to better understand the information content of the hemodynamic data. Therefore, in the present study we carried out a series of steady-state and dynamic experiments on isolated cat lungs. We then compared the results with those predicted by the model. We found that the model provided a good fit to the steady-state data. However, to fit the dynamic data, some modifications were necessary to account for the viscous behavior of the vessel walls and to move the first moment of the distribution of vascular resistance toward the arterial end of the vascular bed relative to that of the distribution of vascular compliance. Due to the sensitivity of the vascular resistance to small changes in vessel diameters and branching ratio, the modifications in morphometry represent small changes in morphometric data and are probably within the range of uncertainty in such data. The modifications had little effect on the steady-state model simulations but substantially improved the dynamic model simulations, suggesting that the dynamic data are quite sensitive to small changes in the relative distributions of vessel diameters and elasticity.

Animals↗

PubMed1985

Limits on the continuous distribution of pulmonary vascular resistance versus compliance from outflow occlusion.

Rapid occlusion of the venous outflow from a lung lobe perfused with constant flow causes the arterial and venous pressure to increase with time. Pressure values obtained by linear extrapolation of the nearly linear portions of the resulting arterial and venous pressure versus time curves back to the instant of occlusion provide data which can be used to place limits on the actual unknown distribution of resistance versus compliance. This has been proven deductively for the case of compartmental models having a small number of resistances and compliances. For compartmental models having a large number of resistances and compliances approaching a continuous distribution, an inductive approach was used in which a large number of simulations indicated that the actual continuous distribution is confined by the experimental data to the same limits as those for the small number of resistances and compliances.

Animals↗

PubMed1985

Sleeve device functions as a Starling resistor to record sphincter pressure.

In 1976 Dent (Gastroenterology 71: 263-267) introduced a sleeve-catheter device for obtaining continuous recording of lower esophageal sphincter pressure. The infused sleeve accommodates for axial sphincter movement by providing a large surface of collapsible membrane that is capable of sensing maximal sphincter pressure at any point along the sleeve. Although sleeve performance was tested previously, the precise physical principal of its function has not been delineated. This study tests the hypothesis that the sleeve device functions as a Starling resistor. The term "Starling resistor" is an eponym that designates the physics of fluid flow through collapsible tubes. When pressure at any point along an infused collapsible conduit is greater than the intraluminal pressure at the distal end of the conduit, partial collapse occurs at some axial location along the conduit where the transmural pressure equals zero. The location of zero transmural pressure is termed the "equal pressure point" (EPP). The partial collapse at the EPP causes a local change in luminal resistance that is directly related to the magnitude of the external pressure at the EPP and accompanied by a corresponding change in the pressure upstream from the EPP. A correlate to the performance of Starling resistors is that the pressure upstream to the EPP is not affected by the downstream pressure, so long as the downstream pressure is less than the external pressure. To test our hypothesis, we evaluated sleeve performance in vitro using a two-chambered model that allowed application of static or oscillatory pressures at one or two sites along the sleeve.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

Influence of pulmonary embolism on absorption of inhaled iodide-125.

To evaluate the influence of embolus size on the absorption of 125I- deposited on the bronchoalveolar surface, we exposed isolated perfused rabbit lungs to an aerosol containing 125I- for 5 min. We monitored the blood radioactivity for the subsequent 2 h. Several groups of lungs were studied, including those in which blood flow was varied and those in which enough glass beads ranging in size from 58 to 548 micron were injected into the pulmonary artery to approximately double the vascular resistance. The results indicated that under control conditions approximately 94% of the 125I- deposited on the intrapulmonary bronchoalveolar surface was able to reach the pulmonary circulation during the 2-h perfusion period, and the bronchoalveolar surface was sufficiently perfused so that absorption was limited by the rate of diffusion into the blood rather than the rate of blood flow. In the absence of embolization, the initial absorption rate was approximately 10.4%/min regardless of the total flow rate. The 58-micron beads reduced the rate to approximately 7.5%/min, whereas the beads greater than or equal to 194 micron in diameter reduced the rate to approximately 4.5%/min. Thus the effect of the embolization on the absorption rate was directly related to the bead diameter, even though the number of beads injected was adjusted to produce about the same increase in vascular resistance.

Absorption↗

PubMed1985

Lung damage and pulmonary uptake of serotonin in intact dogs.

We examined the influence of glass bead embolization and oleic acid, dextran, and imipramine infusion on the pulmonary uptake of trace doses of [3H]serotonin and the extravascular volume accessible to [14C]antipyrine in anesthetized dogs. Embolization and imipramine decreased serotonin uptake by 53 and 61%, respectively, but no change was observed with oleic acid or dextran infusion. The extravascular volume accessible to the antipyrine was reduced by 77% after embolization and increased by 177 and approximately 44% after oleic acid and dextran infusion, respectively. The results suggest that when the perfused endothelial surface is sufficiently reduced, as with embolization, the uptake of trace doses of serotonin will be depressed. In addition, decreases in serotonin uptake in response to imipramine in this study and in response to certain endothelial toxins in other studies suggest that serotonin uptake can reveal certain kinds of changes in endothelial function. However, the lack of a response to oleic acid-induced damage in the present study suggests that serotonin uptake is not sensitive to all forms of endothelial damage.

Animals↗

PubMed1985

Isolated total lung perfusion as a means to deliver organ-specific chemotherapy: long-term studies in animals.

The objectives of this study were to develop a surgical procedure that would allow for bilateral isolated lung perfusion in vivo as a means of delivering organ-specific chemotherapy and to evaluate the influence of the procedure on certain pulmonary physiologic parameters. The sterile surgical procedure that was carried out in dogs involved the setting up of two separate perfusion circuits. Once standard systemic cardiopulmonary bypass was established, a second circuit was devised to perfuse the lungs by placing an inflow cannula into the main pulmonary artery and collecting venous effluent in the left atrium. Cross-contamination between perfusion circuits was determined in acute studies with labeled plasma protein or red blood cells and was found to be in an acceptable range if the aorta was cross-clamped and the heart arrested. Only about 0.4 ml/min of pulmonary perfusate leaked into the systemic circulation, indicating that systemic toxicity should not be a major concern when chemotherapy agents are added to the pulmonary perfusate. Chronic studies demonstrated that hemodynamic parameters, lung water, pulmonary endothelial serotonin extraction, and histologic findings all showed minimal changes after 50 minutes of isolated lung perfusion. Five days after perfusion, lung dynamic compliance and peak serotonin extraction showed significant decreases. However, all of the measured parameters had returned toward baseline levels by the end of the 8-week postoperative study period. The procedure offers significant advantages over the previously described single lung perfusion and may provide a method of delivering immediate high-concentration adjuvant chemotherapy to coincide with resection of primary or metastatic lung tumors.

Animals↗

PubMed1984

A model of the vascular resistance and compliance distribution in a lung lobe.

The arterial and venous pressure curves obtained after occluding the venous outflow from a dog lung lobe perfused with constant flow contain information about the intralobar longitudinal distribution of vascular resistance (R) and compliance (C). To utilize this information, a lumped model consisting of four parallel C's separated by three serial R's was used. Solutions of the governing differential equations yield a nonlinear system of four algebraic equations in the seven unknowns and the measured data. Three of the equations form a linear subsystem in which the unknowns are the three R's and the coefficients are functions of the four C's. This is an underdetermined system, but when nonnegativity and boundedness constraints are adjoined, the solution set falls within a narrow band of distributions of cumulative R relative to cumulative C. The shape of this band changes when data are obtained from lobes influenced by various vasoactive stimuli revealing the changes in the longitudinal distribution of the vascular resistance relative to the vascular compliance.

Animals↗

PubMed1984

Pediatric endotracheal tube designed for high-frequency ventilation.

Using pediatric endotracheal tubes (ETs) designed for high-frequency jet ventilation (HFJV), we demonstrated that when the fraction of the ventilatory cycle spent in inflation (Ti) was 0.3 or greater, entrainment of air flow was unaffected by frequencies up to at least 900 cycle/min. Flow through the jet opening was related to drive pressure (PD) at the ventilator, and to the diameter of the external connector to the jet tube in the ET. Maximal entrainment was completed within a 2.5-cm section downstream from the jet opening in these small ETs. When the jet opening was closer than 2.5 cm to the tip, output from the ET was compromised. Pressure measured in the lumen of the ET was most negative at the axial location of the jet opening. Its amplitude at that point reflected a balance between jet-flow velocity (a reflection of PD) and back-pressure (or airway pressure). ET lumen diameter had little effect on entrainment or on total flow through the ET. PD, Ti, and frequency can be regulated to optimize the output for an ET.

Humans↗

PubMed1984

Influence of plasma protein on the inhibitory effects of indocyanine green and bromcresol green on pulmonary prostaglandin E1 extraction.

The purpose of this study was to examine the influence of plasma protein on the inhibitory effects of the anionic dyes indocyanine green and bromcresol green on prostaglandin E1 (PGE1) uptake by the lungs. Dog lung lobes were isolated and perfused with either autologous plasma or Krebs-Ringer bicarbonate solution (KRB) containing no protein but with dextran used as a colloid. PGE1 uptake was determined by injecting a bolus, containing radiolabelled PGE1 into the lobar artery and then analysing ethanolic extracts of the venous effluent for radioactivity in PGE1 and PGE1 metabolites by thin layer chromatography and scintillation counting. When the lobes were perfused with KRB, bromcresol green at an average initial concentration of 28.5 microM, reduced PGE1 by an average of 56%. When the lobes were perfused with plasma, similar concentrations of bromcresol green reduced the uptake by less than 2%. A similar result was obtained with indocyanine green, which at an average initial concentration of 17.5 microM reduced uptake by about 70% when the lobes were perfused with KRB, but when the lobes were perfused with plasma similar concentrations of the dye reduced uptake by less than 3.5%. The results suggest that plasma protein binding interferes with the inhibitory effects of these dyes on PGE1 uptake in the lungs.

Alprostadil↗

PubMed1984

Influence of embolism and imipramine on kinetics of serotonin uptake by dog lung.

We previously presented a model from which the kinetic parameters Km and Vmax for serotonin uptake by the lung can be obtained from multiple indicator-dilution data. The purpose of the present study was to determine whether experimentally induced changes in lung endothelial function would be revealed in the kinetic parameters calculated using the model. In experiments using isolated dog lung lobes, embolization with 550-microns glass beads was used to reduce the vascular volume and perfused surface area. Imipramine was used to inhibit the serotonin uptake mechanism. In addition, we studied the influence of the vasodilator papaverine, which in previous studies had been used to block the serotonin-induced vasoconstriction. Embolization, imipramine, and papaverine all significantly reduced percentage uptake of serotonin. The kinetic analysis revealed a significant decrease in the maximum serotonin uptake rate (Vmax) with all three experimental manipulations. In addition, imipramine significantly increased Km. The results indicate that the kinetic parameters obtained from the model do respond to transport inhibition and changes in endothelial surface area, further supporting their usefulness as indexes of endothelial function.

Animals↗

PubMed1984

Lung serotonin uptake kinetics from indicator-dilution and constant-infusion methods.

The kinetics of the pulmonary endothelial uptake of serotonin (5-HT) were evaluated in isolated dog lung lobes using three methods. In method A serotonin was infused at various constant rates to provide a range of capillary concentrations that included Km. The arterial and venous concentrations measured by high-performance liquid chromatography were then used to determine the effect of concentration on the rate of 5-HT uptake. In method B trace doses of 5-[3H]HT and a reference indicator (indocyanine green dye) were injected during each constant infusion of unlabeled 5-HT to provide a measure of unidirectional 5-HT uptake at each background concentration. In method C boluses containing different amounts of unlabeled 5-HT, along with the 5-[3H]HT and the dye, were injected such that each bolus resulted in a range of concentrations and provided a measure of the unidirectional uptake at each concentration. Each method provided the data needed to calculate the maximum uptake rate (Vmax) and the concentration at Vmax/2 (Km), assuming that the uptake kinetics can be represented by the Michaelis-Menten equation. However, the mathematical model underlying each method involved different assumptions about the returning flux of the 5-HT which entered the endothelial cell and the heterogeneity of vascular transit times. The results obtained, considered in light of the different assumptions involved, indicate that all three methods can provide reasonable estimates of the mass transfer kinetic constants if the constant infusions of 5-HT are of short duration and/or the boluses are adequately dispersed prior to reaching the capillary bed.

Animals↗

PubMed1984

Kinetics of serotonin uptake by the dog lung is pH independent in the physiological range.

Given the strong pH dependence of platelet serotonin uptake, the many similarities between platelet and pulmonary endothelial serotonin uptake and the potential importance of a pH dependence on the interpretation of changes in pulmonary endothelial serotonin uptake in diseased lungs, we examined the influence of pH on the kinetics of serotonin uptake in isolated dog lung lobes using a multiple indicator technique. A range of pH values from about 7.2 to 8.0 were obtained by ventilating the lobes with gas containing different concentrations of CO2. Over the pH range studied, no significant changes in serotonin uptake were observed, nor were significant changes detected in the kinetic parameters, Km and Vmax, for the uptake process. The lack of a significant pH effect represents a difference between platelet and lung endothelial serotonin uptake. It also indicates that correlations between PCO2 and serotonin uptake which might occur in diseased lungs do not imply causality.

Animals↗

PubMed1983

Model-free deconvolution techniques for estimating vascular transport functions.

In this paper we present two methods which can be used to numerically deconvolve indicator dilution curves to obtain vascular transport functions. In the first method, direct algebraic deconvolution is made stable and practical by the damped least squares method. The second method involves a time-shift of the output curve which is based on the first and second moments of the input and output curves. This method is stable, computationally simple and can provide reasonable estimates of the transport function.

Animals↗

PubMed1983

Influence of pulmonary vasoconstriction on lung water and perfusion heterogeneity.

To determine the influence of pulmonary vasoconstriction on lung tissue perfusion, we examined the effects of hypoxia, sympathetic nerve stimulation, and histamine on vascular resistance, blood, and extravascular volumes, weight, and the distribution of vascular transit times in dog left lower lung lobes perfused in situ. Hypoxia, sympathetic stimulation, and histamine increased pulmonary vascular resistance by 1.96, 1.42, and 2.02 times and increased the relative dispersion of the transit time distributions by 1.49, 1.30, and 1.71 times the control values, respectively. Hypoxia and sympathetic stimulation tended to decrease the blood volume accessible to indocyanine green dye and the lobe weight. On the other hand, histamine infusion, which also decreased the volume accessible to the dye, increased the lobe weight. Despite this increase in weight, histamine infusion resulted in a decrease in the extra-vascular volume accessible to 3HOH. These results indicate that these vasoconstrictor stimuli increased the heterogeneity of transit times through the lung lobe and decreased the flowing blood volume. In addition, histamine decreased the size of the perfused microvascular bed, indicating that pulmonary vasoconstriction can influence the local pattern of microvascular perfusion.

Animals↗

PubMed1983

A three-compartment model of the pulmonary vasculature: effects of vasoconstriction.

The venous occlusion experiments provide sufficient data to permit the vascular bed of a dog lung lobe to be mathematically modeled as three serial compartments, each containing a quantifiable resistance separated by equal parallel compliances. To determine how these compartments are related to the sites of vasomotion in the pulmonary vascular bed we investigated the effects of various pulmonary vasomotor stimuli. We found that serotonin, sympathetic nerve stimulation, hypoxia, and prostaglandin F2 alpha increased the pressure drop upstream (arterial) from the site of major lobar compliance. On the other hand, histamine, norepinephrine, epinephrine, and elevation of the cerebrospinal fluid pressure increased the pressure drop downstream (venous) from the site of major lobar compliance. These stimuli either did not affect the pressure drop across the middle compartment or increased it slightly. Thus we conclude that the middle compartment represents vessels located between the muscular arteries and veins including the capillary bed and possibly other small nonmuscular vessels. Further, the average preocclusion pressure in the middle compartment is a microvascular pressure that can be used to evaluate the impact of vasoconstriction on the lobar microcirculation.

Animals↗