Airway narrowing in excised canine lungs measured by high-resolution computed tomography.

The exact site of airway narrowing in asthma and chronic obstructive pulmonary disease is unknown. High-resolution computed tomography (HRCT) is a sensitive noninvasive imaging technique that can be used to measure airway dimensions. After determining the optimal computed tomographic parameters using a phantom, we measured lobe volume and airway dimensions of isolated canine lung lobes at a transpulmonary pressure of 25 cmH2O. These measurements were repeated after deflation and administration of aerosolized saline and carbachol (256 mg/ml). Lobe volume decreased with all treatments. The maximal lobar volume change was 26% at 6 cmH2O after carbachol. Average airway lumen area decreased with all treatments. After carbachol, at transpulmonary pressures of 25, 15, 10, 8, and 6 cmH2O, lumen area decreased by 7.3 +/- 4.1, 62.0 +/- 4.9, 77.5 +/- 3.0, 31.9 +/- 9.0, and 95.2 +/- 1.0% (SE), respectively. When the airways were divided into four categories on the basis of initial lumen diameter (less than 2, 2-4, 4-6, and greater than 6 mm), the greatest decreases in luminal area after carbachol were seen in intermediate-sized airways (2-4 mm, 56 +/- 4%; 4-6 mm, 59 +/- 3%). HRCT can be used to make accurate measurements of airway dimensions and airway narrowing in excised lungs. HRCT may allow measurement of airway wall thickness and determination of the site of airway narrowing in asthma.     

Positive end-expiratory pressure differentially alters pulmonary hemodynamics and oxygenation in ventilated, very premature lambs.

In mature lungs, elevated positive end-expiratory pressure (PEEP) reduces pulmonary blood flow (PBF) and increases pulmonary vascular resistance (PVR). However, the effect of PEEP on PBF in preterm infants with immature lungs and a patent ductus arteriosus is unknown. Fetal sheep were catheterized at 124 days of gestation (term approximately 147 days), and a flow probe was placed around the left pulmonary artery to measure PBF. At 127 days, lambs were delivered and ventilated from birth with a tidal volume of 5 ml/kg and 4-cmH(2)O PEEP; PEEP was changed to 0, 8, and 12 cmH(2)O in random order, returning to 4 cmH(2)O between each change. Increasing PEEP from 4 to 8 cmH(2)O and from 4 to 12 cmH(2)O decreased PBF by 20.5 and 41.0%, respectively, and caused corresponding changes in PVR; reducing PEEP from 4 to 0 cmH(2)O did not affect PBF. Despite decreasing PBF, increasing PEEP from 4 to 8 cmH(2)O and 12 cmH(2)O improved oxygenation of lambs. Increasing and decreasing PEEP from 4 cmH(2)O significantly changed the contour of the PBF waveform; at a PEEP of 12 cmH(2)O, end-diastolic flow was reduced by 82.8% and retrograde flow was reestablished. Although increasing PEEP improves oxygenation, it adversely affects PBF and PVR shortly after birth, alters the PBF waveform, and reestablishes retrograde flow during diastole.     

Airway closure with high PEEP in vivo.

When airway smooth muscle is contracted in vitro, the airway lumen continues to narrow with increasing concentrations of agonist until complete airway closure occurs. Although there remains some controversy regarding whether airways can close in vivo, recent work has clearly demonstrated that, if the airway is sufficiently stimulated with contractile agonists, complete closure of even large cartilaginous conducting airways can readily occur with the lung at functional residual capacity (Brown RH and Mitzner W. J Appl Physiol 85: 2012-2017, 1998). This result suggests that the tethering of airways in situ by parenchymal attachments is small at functional residual capacity. However, at lung volumes above functional residual capacity, the outward tethering of airways should increase, because both the parenchymal shear modulus and tethering forces increase in proportion to the transpulmonary pressure. In the present study, we tested whether we could prevent airway closure in vivo by increasing lung volume with positive end-expiratory pressure (PEEP). Airway smooth muscle was stimulated with increasing methacholine doses delivered directly to airway smooth muscle at three levels of PEEP (0, 6, and 10 cmH(2)O). Our results show that increased lung volume shifted the airway methacholine dose-response curve to the right, but, in many airways in most animals, airway closure still occurred even at the highest levels of PEEP.     

Maintenance of airway caliber in isolated airways by deep inspiration and tidal strains.

Deep inspirations (DIs) are large periodic breathing maneuvers that regulate airway caliber and prevent airway obstruction in vivo. This study characterized the intrinsic response of the intact airway to DI, isolated from parenchymal attachments and other in vivo interactions. Porcine isolated bronchial segments were constricted with carbachol and subjected to transmural pressures of 5-10 cmH2O at 0.25 Hz (tidal breathing) interspersed with single DIs of amplitude 5-20 cmH2O, 5-30 cmH2O, or 5-40 cmH2O (6-s duration) or DI of amplitude 5-30 cmH2O (30-s duration). Tidal breathing was ceased after DI in a subset of airways and in control airways in which no DI was performed. Luminal cross-sectional area was measured using a fiber-optic endoscope. Bronchodilation by DI was amplitude dependent; 5-20 cmH2O DIs produced less dilation than 5-30 cmH2O and 5-40 cmH2O DIs (P=0.003 and 0.012, respectively). Effects of DI duration were not significant (P=0.182). Renarrowing after DI followed a monoexponential decay function to pre-DI airway caliber with time constants between 27.4+/-4.3 and 36.3+/-6.9 s. However, when tidal breathing was ceased after DI, further bronchoconstriction occurred within 30s. This response was identical in both the presence and absence of DI (P=0.919). We conclude that the normal bronchodilatory response to DI occurs as a result of the direct mechanical effects of DI on activated ASM in the airway wall. Further bronchoconstriction occurs by altering the airway wall stress following DI, demonstrating the importance of continual transient strains in maintaining airway caliber.     

Respiratory system responsiveness in rabbits in vivo is reduced by prolonged continuous positive airway pressure.

Active, nonanesthetized, tracheotomized rabbits were subjected to continuous positive airway pressure (CPAP) for 4 days to determine the effects of chronic mechanical strain on lung and airway function. Rabbits were maintained for 4 days at a CPAP of 6 cmH(2)O (high CPAP), at a CPAP of 0 cmH(2)O (low CPAP), or without tracheostomy (no CPAP). After treatment with CPAP, changes in respiratory resistance in response to increasing concentrations of inhaled ACh were measured during mechanical ventilation to evaluate respiratory system responsiveness in vivo. Intraparenchymal bronchial segments were isolated from the lungs of all animals to evaluate airway smooth muscle responsiveness and bronchial compliance in vitro. Rabbits maintained for 4 days at high CPAP demonstrated significantly lower responsiveness to ACh compared with rabbits that were maintained at low CPAP or with no CPAP. Airways isolated from the lungs of animals subjected to the chronic application of high CPAP were also less responsive to ACh in vitro than the airways isolated from animals subjected to low CPAP or no CPAP. The persistence of the decreased responsiveness in the excised airway tissues suggests that the decreased respiratory system responsiveness observed in vivo results primarily from direct effects on the airways. The results demonstrate that the application of prolonged mechanical strain in vivo can reduce airway reactivity.     

Production mechanism of crackles in excised normal canine lungs

Lung crackles may be produced by the opening of small airways or by the sudden expansion of alveoli. We studied the generation of crackles in excised canine lobes ventilated in an airtight box. Total airflow, transairway pressure (Pta), transpulmonary pressure (Ptp), and crackles were recorded simultaneously. Crackles were produced only during inflation and had high-peak frequencies (738 +/- 194 Hz, mean +/- SD). During inflation, crackles were produced from 111 +/- 83 ms (mean +/- SD) prior to the negative peak of Pta, presumably when small airways began to open. When end-expiratory Ptp was set constant between 15 and 20 cmH2O and end-expiratory Ptp was gradually reduced from 5 cmH2O to -15 or -20 cmH2O in a breath-by-breath manner, crackles were produced in the cycles in which end-expiratory Ptp fell below -1 to 1 cmH2O. This pressure was consistent with previously known airway closing pressures. When end-expiratory Ptp was set constant at -10 cmH2O and end inspiratory Ptp was gradually increased from -5 to 15 or 20 cmH2O, crackles were produced in inspiratory phase in which end-inspiratory Ptp exceeded 4-6 cmH2O. This pressure was consistent with previously known airway opening pressures. These results indicate that crackles in excised normal dog lungs are produced by opening of peripheral airways and are not generated by the sudden inflation of groups of alveoli.     

Chronic strain alters the passive and contractile properties of rabbit airways.

Pathophysiological conditions of the lung may shift the balance of forces so as to chronically alter the amount of strain imposed on the airways. This chronic strain could result in changes in the structure and/or function of the airways that affect its physiological properties. We evaluated the effects of imposing physiological levels of chronic mechanical strain on the passive and active physiological properties of intraparenchymal rabbit airways. Isolated bronchial segments were cultured for 48 h at transmural pressures of 0 cmH(2)O (No Strain) or 7 cmH(2)O (Strain). Effects of strain on small parenchymal airways were evaluated in lung tissue slices cultured under conditions of No Strain or approximately 50% increased in diameter (Strain). Chronic strain resulted in a higher passive compliance of the bronchial segments and larger airway lumen size. In addition, bronchi not subjected to chronic Strain were more responsive to ACh than bronchi subjected to chronic Strain, and airways in lung slices subjected to No Strain narrowed more in response to ACh than airways in lung slices subjected to Strain. The greatest effects of chronic strain occurred in the smallest sized airways. Our results suggest that chronic distension of the airways has physiologically important effects on their passive and active properties, which are most prominent in the smaller, more peripheral airways.     

Tissue viscance during induced constriction in rabbit lungs: morphological-physiological correlations.

Tissue viscance (Vti), the pressure drop across the lung tissues in phase with flow, increases after induced constriction. To gain information about the possible site of response, we induced increases in Vti with methacholine (MCh) and attempted to correlate these changes with alterations in lung morphology. We measured tracheal (Ptr) and alveolar pressure (PA) in open-chest rabbits during mechanical ventilation [frequency = 1 Hz, tidal volume = 5 ml/kg, positive end-expiratory pressure (PEEP) = 5 cmH2O] under control conditions and after administration of saline or MCh (32 or 128 mg/ml) aerosols. We calculated lung elastance (EL), lung resistance (RL), Vti, and airway resistance (Raw) by fitting the equation of motion to changes in Ptr and PA. The lungs were then frozen in situ with liquid nitrogen (PEEP = 5 cmH2O), excised, and processed using freeze substitution techniques. Airway constriction was assessed by measuring the ratio of the airway lumen (A) to the ideally relaxed area (Ar). Tissue distortion was assessed by measuring the mean linear intercept between alveolar walls (Lm), the standard deviation of Lm (SDLm), and an atelectasis index (ATI) derived by calculating the ratio of tissue to air space using computer image analysis. RL, Vti, and EL were significantly increased after MCh, and Raw was unchanged. A/Ar, Lm, SDLm, and ATI all changed significantly with MCh. Log-normalized change (% of baseline) in Vti significantly correlated with A/Ar (r = -0.693), Lm (r = 0.691), SDLm (r = 0.648), and ATI (r = 0.656). Hence, changes in lung tissue mechanics correlated with changes in morphometric indexes of parenchymal distortion and airway constriction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of transpulmonary pressure on airway diameter and responsiveness of immature and mature rabbits.

We previously demonstrated that airway responsiveness is greater in immature than in mature rabbits; however, it is not known whether there are maturational differences in the effect of transpulmonary pressure (Ptp) on airway size and airway responsiveness. The relationship between Ptp and airway diameter was assessed in excised lungs insufflated with tantalum powder. Diameters of comparable intraparenchymal airway segments were measured from radiographs obtained at Ptp between 0 and 20 cmH(2)O. At Ptp > 8 cmH(2)O, the diameters were near maximal in both groups. With diameter normalized to its maximal value, changing Ptp between 8 and 0 cmH(2)O resulted in a greater decline of airway caliber in immature than mature airways. The increases in lung resistance (RL) in vivo at Ptp of 8, 5, and 2 cmH(2)O were measured during challenge with intravenous methacholine (MCh: 0.001-0.5 mg/kg). At Ptp of 8 cmH(2)O, both groups had very small responses to MCh and the maximal fold increases in RL did not differ (1.93 +/- 0.29 vs. 2.23 +/- 0.19). At Ptp of 5 and 2 cmH(2)O, the fold increases in RL were greater for immature than mature animals (13.19 +/- 1.81 vs. 3.89 +/- 0.37) and (17.74 +/- 2.15 vs. 4.6 +/- 0.52), respectively. We conclude that immature rabbits have greater airway distensibility and this difference may contribute to greater airway narrowing in immature compared with mature rabbits.     

Sound transmission between 50 and 600 Hz in excised pig lungs filled with air and helium.

This study measured transit time (TT) and attenuation of sound transmitted through six pairs of excised pig lungs. Single-frequency sounds (50-600 Hz) were applied to the tracheal lumen, and the transmitted signals were monitored on the tracheal and lung surface using microphones. The effect of varying intrapulmonary pressure (Pip) between 5 and 25 cmH(2)O on TT and sound attenuation was studied using both air and helium (He) to inflate the lungs. From 50 to approximately 200 Hz, TT decreased from 4.5 ms at 50 Hz to 1 ms at 200 Hz (at 25 cmH(2)O). Between approximately 200 and 600 Hz, TT was relatively constant (1.1 ms at upper and 1.5 ms at lower sites). Gas density had very little effect on TT (air-to-He ratio of approximately 1.2 at upper sites and approximately 1 at lower sites at 25 cmH(2)O). Pip had marked effects (depending on gas and site) on TT between 50 and 200 Hz but no effect at higher frequencies. Attenuation was frequency dependent between 50 and 600 Hz, varying between -10 and -35 dB with air and -2 and -28 dB with He. Pip also had strong influence on attenuation, with a maximum sensitivity of 1.14 (air) and 0.64 dB/cmH(2)O (He) at 200 Hz. At 25 cmH(2)O and 200 Hz, attenuation with air was about three times higher than with He. This suggests that sound transmission through lungs may not be dominated by parenchyma but by the airways. The linear relationship between increasing Pip and increasing attenuation, which was found to be between 50 and approximately 100 Hz, was inverted above approximately 100 Hz. We suggest that this change is due to the transition of the parenchymal model from open to closed cell. These results indicate that acoustic propagation characteristics are a function of the density of the transmission media and, hence, may be used to locate collapsed lung tissue noninvasively.     

Effect of different levels of positive end-expiratory pressure on lung water content

To compare the effects of 2-, 5-, and 10-cmH2O positive end-expiratory pressure (PEEP) on pulmonary extravascular water volume (PEWV), pulmonary blood volume (PBV), pulmonary dry weight (PDW), and distensibility, we separately ventilated perfused dogs' lungs in situ and produced pulmonary edema with oleic acid (0.06 ml/kg). Three groups were studied: I, PEEP, 5 cmH2O in both lung; II, PEEP, 2 cmH2O in one lung and 10 cmH2O in the other; and III, PEEP, same as II, but the chest was rotated to compensate for differences in heights. The PEWV and distensibility were less (P less than 0.05) in lungs exposed to 10-cmH2O than to either 2- or 5-cmH2O PEEP. After chest rotation, the difference between 10- and 2-cmH2O PEEP on PEWV was eliminated but that on distensibility was not. We conclude that 10-cmH2O PEEP 1) decreased water content because of lung volume-induced effects on intravascular hydrostatic pressure and 2) improved distensibility by recruitment of alveoli, irrespective of PEWV.     

Effect of inspiratory resistance and PEEP on 99mTc-DTPA clearance

Experiments were performed to determine the effect of markedly negative pleural pressure (Ppl) or positive end-expiratory pressure (PEEP) on the pulmonary clearance (k) of technetium-99m-labeled diethylenetriaminepentaacetic acid (99mTc-DTPA). A submicronic aerosol containing 99mTc-DTPA was insufflated into the lungs of anesthetized intubated sheep. In six experiments k was 0.44 +/- 0.46% (SD)/min during the initial 30 min and was unchanged during the subsequent 30-min interval [k = 0.21 +/- 12%/min] when there was markedly increased inspiratory resistance. A 3-mm-diam orifice in the inspiratory tubing created the resistance. It resulted on average in a 13-cmH2O decrease in inspiratory Ppl. In eight additional experiments sheep were exposed to 2, 10, and 15 cmH2O PEEP (20 min at each level). During 2 cmH2O PEEP k = 0.47 +/- 0.15%/min, and clearance increased slightly at 10 cmH2O PEEP [0.76 +/- 0.28%/min, P less than 0.01]. When PEEP was increased to 15 cmH2O a marked increase in clearance occurred [k = 1.95 +/- 1.08%/min, P less than 0.001]. The experiments demonstrate that markedly negative inspiratory pressures do not accelerate the clearance of 99mTc-DTPA from normal lungs. The effect of PEEP on k is nonlinear, with large effects being seen only with very large increases in PEEP.     

Parenchymal interdependence and airway response to methacholine in excised dog lobes

The objective of this investigation was to determine the minimum transpulmonary pressure (PL) at which the forces of interdependence between the airways and the lung parenchyma can prevent airway closure in response to maximal stimulation of the airways in excised canine lobes. We first present an analysis of the relationship between PL and the transmural pressure (Ptm) that airway smooth muscle must generate to close the airways. This analysis predicts that airway closure can occur at PL less than or equal to 10 cmH2O with maximal airway stimulation. We tested this prediction in eight excised canine lobes by nebulizing 50% methacholine into the airways while the lobe was held at constant PL values ranging from 25 to 5 cmH2O. Airway closure was assessed by comparing changes in alveolar pressure (measured by an alveolar capsule technique) and pressure at the airway opening during low-amplitude oscillations in lobar volume. Airway closure occurred in two of the eight lobes at PL = 10 cmH2O; in an additional five it occurred at PL = 7.5 cmH2O. We conclude that the forces of parenchymal interdependence per se are not sufficient to prevent airway closure at PL less than or equal to 7.5 cmH2O in excised canine lobes.     

Different ventilation strategies alter surfactant responses in preterm rabbits.

The effect of ventilation strategy on in vivo function of different surfactants was evaluated in preterm rabbits delivered at 27 days gestational age and ventilated with either 0 cmH2O positive end-expiratory pressure (PEEP) at tidal volumes of 10-11 ml/kg or 3 cmH2O PEEP at tidal volumes of 7-8 ml/kg after treatment with one of four different surfactants: sheep surfactant, the lipids of sheep surfactant stripped of protein (LH-20 lipid), Exosurf, and Survanta. The use of 3 cmH2O PEEP decreased pneumothoraces in all groups except for the sheep surfactant group where pneumothoraces increased (P < 0.01). Ventilatory pressures (peak pressures - PEEP) decreased more with the 3 cmH2O PEEP, low-tidal-volume ventilation strategy for Exosurf-, Survanta-, and sheep surfactant-treated rabbits (P < 0.05), whereas ventilation efficiency indexes (VEI) improved only for Survanta- and sheep surfactant-treated rabbits with 3 cmH2O PEEP (P < 0.01). Pressure-volume curves for sheep surfactant-treated rabbits were better than for all other treated groups (P < 0.01), although Exosurf and Survanta increased lung volumes above those in control rabbits (P < 0.05). The recovery of intravascular radiolabeled albumin in the lungs and alveolar washes was used as an indicator of pulmonary edema. Only Survanta and sheep surfactant decreased protein leaks in the absence of PEEP, whereas all treatments decreased labeled albumin recoveries when 3 cmH2O PEEP was used (P < 0.05). These experiments demonstrate that ventilation style will alter a number of measurements of surfactant function, and the effects differ for different surfactants.     

Low-volume ventilation causes peripheral airway injury and increased airway resistance in normal rabbits.

Lung mechanics and morphometry of 10 normal open-chest rabbits (group A), mechanically ventilated (MV) with physiological tidal volumes (8-12 ml/kg), at zero end-expiratory pressure (ZEEP), for 3-4 h, were compared with those of five rabbits (group B) after 3-4 h of MV with a positive end-expiratory pressure (PEEP) of 2.3 cmH(2)O. Relative to initial MV on PEEP, MV on ZEEP caused a progressive increase in quasi-static elastance (+36%) and airway (Rint; +71%) and viscoelastic resistance (+29%), with no change in the viscoelastic time constant. After restoration of PEEP, quasi-static elastance and viscoelastic resistance returned to control levels, whereas Rint remained elevated (+22%). On PEEP, MV had no effect on lung mechanics. Gas exchange on PEEP was equally preserved in groups A and B, and the lung wet-to-dry ratios were normal. Both groups had normal alveolar morphology, whereas only group A had injured respiratory and membranous bronchioles. In conclusion, prolonged MV on ZEEP induces histological evidence of peripheral airway injury with a concurrent increase in Rint, which persists after restoration of normal end-expiratory volumes. This is probably due to cyclic opening and closing of peripheral airways on ZEEP.     

Effect of airway and left atrial pressures on microcirculation of newborn lungs

To determine the effect of lung inflation and left atrial pressure on the hydrostatic pressure gradient for fluid flux across 20- to 60-microns-diam venules, we isolated and perfused the lungs from newborn rabbits, 7-14 days old. We used the micropuncture technique to measure venular pressures in some lungs and perivenular interstitial pressures in other lungs. For all lungs, we first measured venular or interstitial pressures at a constant airway pressure of 5 or 15 cmH2O with left atrial pressure greater than airway pressure (zone 3). For most lungs, we continued to measure venular or interstitial pressures as we lowered left atrial pressure below airway pressure (zone 2). Next, we inflated some lungs to whichever airway pressure had not been previously used, either 5 or 15 cmH2O, and repeated venular or interstitial pressures under one or both zonal conditions. We found that at constant blood flow a reduction of left atrial pressure below airway pressure always resulted in a reduction in venular pressure at both 5 and 15 cmH2O airway pressures. This suggests that the site of flow limitation in zone 2 was located upstream of venules. When left atrial pressure was constant relative to airway pressure, the transvascular gradient (venular-interstitial pressures) was greater at 15 cmH2O airway pressure than at 5 cmH2O airway pressure. These findings suggest that in newborn lungs edema formation would increase at high airway pressures only if left atrial pressure is elevated above airway pressure to maintain zone 3 conditions.     

Comparison of lung protection strategies using conventional and high-frequency oscillatory ventilation.

This study compared pathophysiological and biochemical indexes of acute lung injury in a saline-lavaged rabbit model with different ventilatory strategies: a control group consisting of moderate tidal volume (V(T)) (10-12 ml/kg) and low positive end-expiratory pressure (PEEP) (4-5 cmH(2)O); and three protective groups: 1) low V(T) (5-6 ml/kg) high PEEP, 2-3 cmH(2)O greater than the lower inflection point; 2) low V(T) (5-6 ml/kg), high PEEP (8-10 cmH(2)O); and 3) high-frequency oscillatory ventilation (HFOV). The strategy using PEEP > inflection point resulted in hypotension and barotrauma. HFOV attenuated the decrease in pulmonary compliance, the lung inflammation assessed by polymorphonuclear leukocyte infiltration and tumor necrosis factor-alpha concentration in the alveolar space, and pathological changes of the small airways and alveoli. Conventional mechanical ventilation using lung protection strategies (low V(T) high PEEP) only attenuated the decrease in oxygenation and pulmonary compliance. Therefore, HFOV may be a preferable option as a lung protection strategy.     

Respiratory mechanics and lung development in the rat from early age to adulthood.

The purpose of the present study was to establish how the dependence of respiratory mechanics on lung inflation changes during development. We studied seven groups of rats from 10 days to 3 mo of age at five levels of positive end-expiratory pressure (PEEP) from 0 to 7 hPa (1 hPa = 0.1 kPa approximately 1 cmH(2)O). At each PEEP level, we measured respiratory system resistance and elastance at both 0.9 and 4.8 Hz to partition the mechanical properties into its airway and tissue components. Elastance increased more rapidly with PEEP in the younger animals, which we interpret as reflecting a more pronounced strain stiffening of the younger parenchyma. However, the decrease in airway resistance with PEEP was more pronounced in the older animals. Morphometric analysis showed that mean tissue density decreased and total alveolar surface area increased with age. Our data suggest that the mechanical interdependence between airways and parenchyma is weaker in very young animals compared with mature animals. This may play a role in the hyperresponsiveness of immaturity.     

Perfused bronchial segment and bronchial strip: narrowing vs. isometric force by mediators

When bronchial segments were perfused with Krebs solution at a constant pressure (5-6 cmH2O), the resistance rose exponentially with increasing concentrations of either carbachol or histamine in the lumen. The pressure-flow relationship was linear. Histamine and carbachol caused 43 and 47% muscle shortening, respectively, and produced the same maximum effect (Emax) because they both stopped perfusion. In bronchial strips the maximum isometric force or isotonic shortening to carbachol was more than twice that of histamine and the responses showed a plateau. There were no significant differences in sensitivities [negative log of the concentration producing half-maximal response (EC50)] to either carbachol or histamine in the strips (isotonic and isometric) and the segments perfused at constant pressure. When airway segments were perfused at a constant flow, however, responses plateaued and the sensitivities to carbachol and histamine were reduced more than tenfold compared with the strips [4.71 +/- 0.20 and 6.22 +/- 0.08 (SE) for carbachol in segments and isometric strips, respectively, and 3.92 +/- 0.13 and 4.94 +/- 0.11 (SE) for histamine]. We conclude that when segments are perfused at a constant pressure, airway closure occurs before maximal pharmacological activation, as seen in airway strips.     

Rapidly adapting receptor activity in dogs is inversely related to lung compliance

We examined the response of pulmonary rapidly adapting receptors (RAR's) to changes in dynamic lung compliance (Cdyn) in the physiological range. RAR impulse activity was recorded from the cervical vagus nerves in anesthetized open-chest dogs whose lungs were ventilated at constant rate and tidal volume (VT), with a positive end-expiratory pressure (PEEP) of 3-4 cmH2O. After hyperinflation to produce maximal Cdyn, RAR's were silent or fired sparsely and irregularly. Reducing Cdyn in steps by briefly removing PEEP increased firing proportionately, and RAR's began to discharge vigorously in inflation. Activity was restored to control by hyperinflating the lungs. Activity also increased when we increased inflation rate, and hence the rate of change of airway pressure (dP/dt), by reducing inflation time, keeping VT and cycle length constant. RAR's were stimulated more when dP/dt was increased by reducing compliance than when dP/dt was increased by increasing inflation rate. We conclude that RAR's are sensitive to changes in Cdyn and speculate that excitatory input from RAR's may help to maintain VT as the lungs become stiffer.