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Departments of 1 Pediatrics and 2 Physiology and Biophysics, Indiana University School of Medicine, Indianapolis, Indiana 46223
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
FOOTNOTES
REFERENCES
ABSTRACT 
Shen, X., S. J. Gunst, and R. S. Tepper. Effect of
tidal volume and frequency on airway responsiveness in mechanically ventilated rabbits. J. Appl. Physiol.
83(4): 1202-1208, 1997.
We evaluated the effects of the rate and
volume of tidal ventilation on airway resistance (Raw) during
intravenous methacholine (MCh) challenge in mechanically ventilated
rabbits. Five rabbits were challenged at tidal volumes of 5, 10, and 20 ml/kg at a frequency of 15 breaths/min and also under static conditions
(0 ml/kg tidal volume). Four rabbits were subjected to MCh challenge at
frequencies of 6 and 30 breaths/min with a tidal volume of 10 ml/kg and
also under static conditions. In both groups, the increase in Raw with MCh challenge was significantly greater under static conditions than
during tidal ventilation at any frequency or volume. Increases in the
volume or frequency of tidal ventilation resulted in significant decreases in Raw in response to MCh. We conclude that tidal breathing suppresses airway responsiveness in rabbits in vivo. The suppression of
narrowing in response to MCh increases as the magnitude of the volume
or the frequency of the tidal oscillations is increased. Our findings
suggest that the effect of lung volume changes on airway responsiveness
in vivo is primarily related to the stretch of airway smooth muscle.
airway narrowing; tidal breathing; airway smooth
muscle
INTRODUCTION LUNG VOLUME HISTORY is known to have an important
effect on airway tone and the airway response to
bronchoconstrictors. In normal adults with induced
bronchoconstriction, a deep inspiration results in bronchodilation.
This effect has been measured as a decrease in airway resistance (Raw)
or as an increase in forced expiratory flow during full compared with
partial volume inspiratory maneuvers (1-5, 14-16, 18, 19).
Recently, Skloot et al. (23) demonstrated that the inhibition of deep
inspiration during methacholine (MCh) challenge results in a heightened
airway response in normal subjects. In these normal subjects, the MCh
challenge induced an airway response that was similar to that observed
in asthmatic subjects. The mechanism for the effect of deep inspiration
on airway responsiveness remains unclear, as does the mechanism for the
often absent bronchodilating effect of a deep inspiration in asthmatic
subjects (2, 17).
In isolated canine bronchi, the increase in transmural pressure induced
by acetylcholine is greater under static conditions than when volume
oscillations are imposed (9). As the size of the volume oscillation is
increased, there is greater suppression of the contraction caused by
the bronchoconstrictor. Similarly, in isolated canine tracheal smooth
muscle strips, active force is lower when length oscillations are
imposed than under static conditions (6, 22). As the amplitude of the
length oscillations is increased, force generation decreases. In both
isolated bronchi and tracheal smooth muscle strips, increasing the
frequency of volume or length oscillation also decreases active force.
Our recent studies of isolated canine tracheal smooth muscle strips suggest that non-cross-bridge mechanisms that function to adapt muscle
contractility to changes in muscle length may play an important role in
determining the effect of length oscillation on contractile force (7,
10, 13, 22).
We have previously shown that airway closure in response to MCh
challenge occurs less frequently during tidal ventilation than under
static conditions in rabbits and dogs (25, 27). These observations, in
combination with our observations obtained in muscles in vitro, have
led us to hypothesize that increasing the volume of tidal ventilation
in vivo will decrease airway narrowing in response to
bronchoconstrictors because it increases the magnitude of stretch on
the airway smooth muscle. Our previous studies of airway smooth muscle
in vitro also suggest that increasing the frequency of tidal volume
oscillation will result in less airway response to bronchoconstrictors.
In this study we evaluated the effects of the volume and frequency of
tidal ventilation on the increase in airway resistance in response to
MCh challenge in mechanically ventilated rabbits.
METHODS
) was measured with a screen
pneumotachometer (model 8410A, Hans Rudolph, Kansas City, MO) and a
differential pressure transducer (±2.25
cmH2O; Validyne MP45, Northridge,
CA) attached to the tracheotomy tube. Because the chest
was open, changes in Ptr could be used to assess changes in
transpulmonary pressure. Analog signals of flow and pressure were
analog filtered above 50 Hz, amplified, and digitized at 100 samples/s
(model DT2801-A, Data Translation, Marlborough, MA). Digital signals were stored in an IBM-compatible personal computer (Zeos 486, St. Paul,
MN) by using data-acquisition software (RHT Infodat, Montreal, PQ,
Canada).
Raw was assessed from changes in pressure and flow at the airway
opening produced by forced oscillation with very small volumes (0.2-0.3 ml/kg) at 6 Hz. These oscillations were generated by using a small piston attached to a linear motor that was in parallel with the ventilator (21, 24). The digital signals of pressure and flow
were digitally filtered to remove frequencies below 4 Hz, which were
related to mechanical ventilation. Raw was then calculated by using a
linear regression technique to fit pressure and flow signals to
Eq. 1
|
(1) |
RESULTS
). 
, End-inspiratory lung
volumes and transpulmonary pressures for tidal volumes of 5, 10, and 20 ml/kg.
Effect of tidal volume on the airway response to intravenous MCh challenge (protocol 1). The mean effect of MCh challenge on Raw in five animals under static conditions (0 ml/kg tidal volume) and during tidal ventilation at volumes of 5, 10, and 20 ml/kg at a frequency of 15 breaths/min (0.25 Hz) is illustrated in Fig. 2. In response to each intravenous MCh challenge, Raw increased with time and reached a plateau within 30 s. The increase in Raw was greater under static conditions (tidal volume = 0 ml/kg) than during ventilation at any volume amplitude. Each increase in the tidal volume amplitude decreased the response to MCh. Figure 3 compares the mean maximal increases in Raw in response to MCh challenge when the lungs were ventilated by using tidal volumes of 5, 10, and 20 ml/kg or were held under static conditions. Tidal ventilation at each volume suppressed the maximal increase in Raw compared with static conditions (0 ml/kg). Each increase in tidal volume produced a statistically significant decrease in the response to MCh. At a tidal volume of 20 ml/kg, bronchoconstriction in response to MCh was almost completely abolished (Fig. 3).
Effect of ventilation frequency on the airway response to intravenous MCh challenge (protocol 2). Increasing the tidal ventilation frequency from 6 to 30 breaths/min (from 0.1 to 0.5 Hz) significantly decreased Raw in response to MCh challenge (Fig. 4). In addition, the response to MCh under static conditions was greater than the response during ventilation at either frequency.
Airway response to intravenous MCh under static and dynamic conditions under similar conditions of alveolar ventilation (protocol 3). The increase in Raw in response to MCh was significantly greater under static conditions than during volume oscillations of 10 ml/kg at 15 breaths/min (Fig. 5) in a closed constant-volume circuit in which little or no gas exchange occurred. This indicates that differences in gas exchange under different ventilatory conditions cannot account for the reduction in the response to MCh during tidal ventilation.
Airway response to aerosolized MCh under static and dynamic conditions (protocol 4). The increase in Raw in response to MCh was four- to fivefold greater under static conditions than during volume oscillations of 20 ml/kg at 15 breaths/min (Fig. 6A) when the MCh was delivered to the airways by aerosol. These results obtained after challenge with aerosolized MCh are similar to the results obtained when the MCh was delivered by the intravenous route (protocol 1, Fig. 3). Therefore, the smaller airway response to MCh under dynamic than under static conditions cannot be attributed to an effect of volume oscillations on drug delivery.
Airway response to intravenous MCh under static and dynamic conditions in vagotomized animals (protocol 5). The increase in Raw in response to MCh was four- to fivefold greater under static conditions than during volume oscillations of 20 ml/kg at 15 breaths/min in vagotomized animals (Fig. 6B). These results were similar to the results obtained from animals with intact vagus nerves (protocol 1, Fig. 3). Therefore, the smaller airway response to MCh under dynamic than static conditions cannot be attributed to an effect of vagal reflexes.
DISCUSSION
Our findings demonstrate that tidal ventilation significantly decreases airway narrowing in response to MCh in rabbits in vivo. The suppression of the bronchoconstrictor response to MCh caused by tidal ventilation increased when either the amplitude or the frequency of the volume oscillations was increased. This effect of tidal ventilation on airway responsiveness cannot be attributed to effects on gas exchange, MCh delivery, or vagal reflexes because it was observed under conditions in which gas exchange was similar, when the MCh was administered by either the intravenous or aerosol route, and when the animals were vagotomized. These results are consistent with our previous observations that greater airway closure occurs in dogs and rabbits during bronchoconstriction under static conditions than in the presence of tidal ventilation (25, 27). The results of our present in vivo study are also consistent with our previous findings that isolated constricted bronchi and tracheal smooth muscle strips generate more pressure or force under static conditions than when volume or length oscillations are imposed (6, 9, 22). Our cumulative findings from both in vivo and in vitro studies suggest that increases in tidal volume during bronchoconstriction result in greater stretch of airway smooth muscle and that this decreases smooth muscle force generation and results in less airway narrowing.
In the present study, airway narrowing was assessed under both static and dynamic conditions of ventilation by using measurements of pulmonary impedance obtained by using very small-volume oscillations (0.2-0.3 ml/kg) at 6 Hz. Although we measured pulmonary impedance, we have previously shown that tissue resistance is negligible in rabbits at an oscillatory frequency of 6 Hz (24) and that changes in pulmonary impedance are correlated with changes in Raw at this frequency. Recent data suggest that increases in pulmonary resistance during bronchoconstriction are caused by airway narrowing and ventilation inhomogeneity and not by increases in lung parenchymal tissue resistance (12). In addition, our recent measurements in rabbits demonstrate that after MCh challenge, increases in pulmonary impedance at frequencies above 4 Hz are highly correlated with airway narrowing determined morphometrically (21). Therefore, we believe that the changes in pulmonary impedance that we measured are related to changes in Raw and reflect the effects of tidal ventilation on airway narrowing.
The changes in the frequency and volume of tidal ventilation in protocols 1 and 2 would be expected to result in differences in alveolar ventilation. In addition, under static conditions there is no alveolar ventilation. Therefore, we evaluated whether differences in alveolar ventilation could have accounted for the effects of ventilation on the airway response to MCh. The closed-circuit constant-volume system used in protocol 3 permitted no fresh gas to enter the system under either static or dynamic conditions. Greater airway narrowing was still observed under static than dynamic conditions even though little or no alveolar ventilation occurred under either condition. These results suggest that differences in alveolar ventilation during bronchoconstriction cannot account for the effects of tidal ventilation on the airway response to MCh in the present study.
The effect of large tidal volumes on airway responsiveness could potentially have been mediated by a decrease in the delivery of intravenous MCh to the bronchial circulation or by vagal reflexes in response to lung inflation (26). However, we observed a much greater airway response to MCh under static than dynamic conditions whether MCh was delivered by aerosol or intravenously. Thus it is not likely that decreased intravenous drug delivery during tidal ventilation can account for the effect of tidal ventilation on the airway response to MCh. In addition, because the much greater airway response to MCh under static than dynamic conditions was not abolished in vagotomized animals, it is unlikely that the results of protocols 1 and 2 can be attributed to the effects of vagal reflexes.
We found that increasing the magnitude of the tidal volume from 5-10 to 20 ml/kg resulted in a progressively greater suppression of the bronchoconstrictor response to MCh. In addition, at a constant tidal volume, an increase in the ventilation frequency from 6 to 30 breaths/min significantly decreased the response to MCh. The tidal volumes and frequencies employed in these studies were within the physiological range. Tidal volumes of 5-10 ml/kg are similar to those that occur in spontaneously breathing and mechanically ventilated animals and humans. The largest tidal volume (20 ml/kg) used in this study approached total lung volume at end inspiration and thus was similar to deep inspiration. Thus the observations suggest that changes in either the frequency or volume of tidal ventilation within the physiological range can modulate the airway response to bronchoconstrictors.
Our findings support our hypothesis that the bronchodilating effect of changes in lung volume is caused by the direct effect of stretch on force generation by the airway smooth muscle (6, 8, 9, 22, 25, 27). In the present study, we found a direct relationship between the magnitude of the increase in lung volume during tidal ventilation and the magnitude of the suppression of airway narrowing during bronchoconstriction. Increases in the magnitude of the tidal volume were associated with increases in end-inspiratory transpulmonary pressure (Fig. 1), which should result in an increase in the transmural pressure across the airway wall. The increased airway transmural pressure during volume oscillation should result in greater stretch of the smooth muscle in the airway wall.
The effects of the amplitude of volume oscillations on the airway responsiveness may result from a plasticity of smooth muscle cell structure (7, 10, 11, 20). We have postulated that the suppression of the contractile response of tracheal smooth muscle caused by stretch or length oscillation is related to an effect of stretch on the organization of the contractile filaments in smooth muscle cells, which might involve adjustments in the sites of attachment of actin filaments to the membrane as well as changes in actin or myosin filament length and orientation (7, 10, 20, 22). When the amplitude of the length oscillations is increased, the organization of the contractile filaments within the cells adapts to the longest length to which the muscle is being stretched, effectively lengthening the contractile element in relation to cell length. As the muscle length is decreased during each individual oscillation cycle, active shortening of the contractile element begins from a longer starting point, resulting in lower overall active force development during the imposed shortening. If the magnitude of the stretch of the muscle is reduced by decreasing the amplitude of the oscillation, the contractile element length "set point" adjusts to a shorter length; however, adjustments of the contractile element length set point occur slowly relative to the active shortening velocity of the muscle. Because the rate of adjustment of the contractile element length set point is slow relative to the rate of active shortening, changes in the contractile element length set point do not occur during a single oscillation cycle unless the oscillation frequency is extremely slow, probably much slower than the frequencies associated with normal ventilation.
The prolonged depression of airway responsiveness that has been observed when tidal breathing is resumed after deep inspiration may also be explained on the basis of the plastic properties of the smooth muscle. A sudden decrease in the amplitude of volume oscillation would abruptly reduce the magnitude of the stretch on the muscle. Under these conditions, the contractile element length set point would adjust slowly to accommodate the reduced amplitude of smooth muscle stretch. This would result in a prolonged depression of airway responsiveness until the contractile element length set point readjusted to the reduction in stretch on the muscle. In the absence of large stretches of the airway smooth muscle, force generation is greater and approaches the static response (6, 22). This mechanism can also account for the heightened airway responsiveness observed in normal subjects when deep inspiration is inhibited during the bronchial challenge (23).
In the present study, we also observed an effect of ventilation frequency on airway responsiveness. This is also consistent with our previous observations of airway tissues in vitro in which force generation decreased with increases in the frequency of oscillation (6, 22). The effects of frequency on the contractile response are likely to be related to the rate of imposed shortening relative to the rate of active shortening. An increase in the frequency of oscillation at constant oscillation amplitude would not alter the contractile element length set point but would decrease the time allowed for active shortening of the contractile element and thereby lower force development during the shortening phase of the oscillation cycle. If the rate of oscillation were increased sufficiently above the shortening velocity, active shortening of the contractile element would not occur at all and the oscillation would result only in stretch and retraction of series elastic elements. However, our previous calculations suggest that at oscillation frequencies comparable to normal rates of tidal ventilation, some active shortening of the contractile element probably occurs (22).
Asthmatic subjects often exhibit an absence of bronchodilation with a deep inspiration (1-4, 14-16, 18). This phenomenon may be related to inherent differences in the contractility of the smooth muscle of asthmatic subjects or to lower forces of interdependence between the airways and the lung parenchyma in asthmatic subjects. In the latter case, deep inspiration may not produce the same stretch of the airway smooth muscle of asthmatic individuals as occurs in nonasthmatic individuals, thus resulting in greater airway responsiveness.
In summary, the results of this study demonstrate that airway narrowing during bronchoconstriction is greater under static conditions than during tidal ventilation in mechanically ventilated rabbits. The suppression of airway narrowing in response to MCh increases as the magnitude of the volume oscillations is increased from normal tidal breathing to deep inspiration and as the frequency of tidal volume oscillations is increased. These findings are consistent with previous in vitro data obtained in isolated bronchi and tracheal smooth muscle strips. Our findings suggest that the effect of a change of lung volume on airway responsiveness in vivo is related to the effects of stretch on the airway smooth muscle.
FOOTNOTES
Address for reprint requests: R. S. Tepper, James Whitcomb Riley Hospital for Children, Dept. of Pediatrics, Pulmonary Sect., 702 Barnhill Dr., Indianapolis, IN 46223 (E-mail: RTEPPER{at}INDYVAX.IUPUI.EDU).
Received 5 March 1997; accepted in final form 19 June 1997.
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M. L. Dowell, O. J. Lakser, W. T. Gerthoffer, J. J. Fredberg, G. L. Stelmack, A. J. Halayko, J. Solway, and R. W. Mitchell Latrunculin B increases force fluctuation-induced relengthening of ACh-contracted, isotonically shortened canine tracheal smooth muscle J Appl Physiol, February 1, 2005; 98(2): 489 - 497. [Abstract] [Full Text] [PDF]
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R. K. Lambert and K. C. Beck Airway area distribution from the forced expiration maneuver J Appl Physiol, August 1, 2004; 97(2): 570 - 578. [Abstract] [Full Text] [PDF]
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F.G. Salerno, A. Fust, and M.S. Ludwig Stretch-induced changes in constricted lung parenchymal strips: role of extracellular matrix Eur. Respir. J., February 1, 2004; 23(2): 193 - 198. [Abstract] [Full Text] [PDF]
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V. Brusasco and R. Pellegrino Invited Review: Complexity of factors modulating airway narrowing in vivo: relevance to assessment of airway hyperresponsiveness J Appl Physiol, September 1, 2003; 95(3): 1305 - 1313. [Abstract] [Full Text] [PDF]
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R. C. Anafi, K. C. Beck, and T. A. Wilson Impedance, gas mixing, and bimodal ventilation in constricted lungs J Appl Physiol, March 1, 2003; 94(3): 1003 - 1011. [Abstract] [Full Text] [PDF]
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 J. J. Fredberg Airway narrowing in asthma: does speed kill? Am J Physiol Lung Cell Mol Physiol, December 1, 2002; 283(6): L1179 - L1180. [Full Text] [PDF]
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 N. J. Vanacker, E. Palmans, R. A. Pauwels, and J. C. Kips Effect of Combining Salmeterol and Fluticasone on the Progression of Airway Remodeling Am. J. Respir. Crit. Care Med., October 15, 2002; 166(8): 1128 - 1134. [Abstract] [Full Text] [PDF]
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R. K. Lambert, R. Ramchandani, X. Shen, S. J. Gunst, and R. S. Tepper Computational model of airway narrowing: mature vs. immature rabbit J Appl Physiol, August 1, 2002; 93(2): 611 - 619. [Abstract] [Full Text] [PDF]
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J. Kovar, P. D. Sly, and K. E. Willet Postnatal alveolar development of the rabbit J Appl Physiol, August 1, 2002; 93(2): 629 - 635. [Abstract] [Full Text] [PDF]
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S. J. Gunst, X. Shen, R. Ramchandani, and R. S. Tepper Bronchoprotective and bronchodilatory effects of deep inspiration in rabbits subjected to bronchial challenge J Appl Physiol, December 1, 2001; 91(6): 2511 - 2516. [Abstract] [Full Text] [PDF]
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R. C. Anafi and T. A. Wilson Airway stability and heterogeneity in the constricted lung J Appl Physiol, September 1, 2001; 91(3): 1185 - 1192. [Abstract] [Full Text] [PDF]
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D. D. Tang and S. J. Gunst Signal Transduction in Smooth Muscle: Selected Contribution: Roles of focal adhesion kinase and paxillin in the mechanosensitive regulation of myosin phosphorylation in smooth muscle J Appl Physiol, September 1, 2001; 91(3): 1452 - 1459. [Abstract] [Full Text] [PDF]
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C. Y. Seow and J. J. Fredberg Signal Transduction in Smooth Muscle: Historical perspective on airway smooth muscle: the saga of a frustrated cell J Appl Physiol, August 1, 2001; 91(2): 938 - 952. [Abstract] [Full Text] [PDF]
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K. R. LUTCHEN, A. JENSEN, H. ATILEH, D. W. KACZKA, E. ISRAEL, B. SUKI, and E. P. INGENITO Airway Constriction Pattern Is a Central Component of Asthma Severity . The Role of Deep Inspirations Am. J. Respir. Crit. Care Med., July 15, 2001; 164(2): 207 - 215. [Abstract] [Full Text] [PDF]
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R. K. Lambert, P. D. Pare, and M. Okazawa Stiffness of peripheral airway folding membrane in rabbits J Appl Physiol, June 1, 2001; 90(6): 2041 - 2047. [Abstract] [Full Text] [PDF]
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O. E. Suman and K. C. Beck Role of nitric oxide during hyperventilation-induced bronchoconstriction in the guinea pig J Appl Physiol, April 1, 2001; 90(4): 1474 - 1480. [Abstract] [Full Text] [PDF]
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S. J. Gunst and M.-F. Wu Plasticity in Skeletal, Cardiac, and Smooth Muscle: Selected Contribution: Plasticity of airway smooth muscle stiffness and extensibility: role of length-adaptive mechanisms J Appl Physiol, February 1, 2001; 90(2): 741 - 749. [Abstract] [Full Text] [PDF]
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J. A. Silverman, L. Z. Sommer, A. Robicsek, J. Dickstein, A. Greenberg, J. Kruger, J. Rucker, G. Volgyesi, J. A. Fisher, and S. Iscoe Tracheal constrictor drive above the apneic threshold in anesthetized dogs J Appl Physiol, December 1, 2000; 89(6): 2258 - 2262. [Abstract] [Full Text] [PDF]
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M. Okazawa, P. D. Pare, and R. K. Lambert Compliance of peripheral airways deduced from morphometry J Appl Physiol, December 1, 2000; 89(6): 2373 - 2381. [Abstract] [Full Text] [PDF]
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W. MITZNER and R. H. BROWN Potential Mechanism of Hyperresponsive Airways Am. J. Respir. Crit. Care Med., May 1, 2000; 161(5): 1619 - 1623. [Abstract] [Full Text]
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F. G. Salerno, N. Shinozuka, J. J. Fredberg, and M. S. Ludwig Tidal volume amplitude affects the degree of induced bronchoconstriction in dogs J Appl Physiol, November 1, 1999; 87(5): 1674 - 1677. [Abstract] [Full Text] [PDF]
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R. S. Tepper, B. Wiggs, S. J. Gunst, and P. D. Pare Comparison of the shear modulus of mature and immature rabbit lungs J Appl Physiol, August 1, 1999; 87(2): 711 - 714. [Abstract] [Full Text] [PDF]
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Am. J. Respir. Crit. Care Med., May 1, 1999; 159(5): 1684 - 1684. [Full Text]
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J. J. FREDBERG, D. S. INOUYE, S. M. MIJAILOVICH, and J. P. BUTLER Perturbed Equilibrium of Myosin Binding in Airway Smooth Muscle and Its Implications in Bronchospasm Am. J. Respir. Crit. Care Med., March 1, 1999; 159(3): 959 - 967. [Abstract] [Full Text]
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B. J. MOORE, G. G. KING, Y. D'YACHKOVA, H. R. AHMAD, and P. D. PARE Mechanism of Methacholine Dose-Response Plateaus in Normal Subjects Am. J. Respir. Crit. Care Med., August 1, 1998; 158(2): 666 - 669. [Abstract] [Full Text] [PDF]
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