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(Chest. 2004;125:236-242.)
© 2004 American College of Chest Physicians

Mechanical Properties of Tracheal Smooth Muscle Are Impaired in the Rabbit With Experimental Cardiac Pressure Overload*

François-Xavier Blanc, MD; Olivier Langeron, MD, PhD; Catherine Coirault, MD, PhD; Sergio Salmeron, MD; Francine Lambert; Bruno Riou, MD, PhD and Yves Lecarpentier, MD, PhD

* From the Institut National de la Santé et de la Recherche Médicale (INSERM), ENSTA, Ecole Polytechnique (Drs. Blanc, Coirault, and Lambert), Palaiseau; Département d’Anesthésie-Réanimation, Groupe Hospitalier Pitié-Salpétrière, Assistance Publique-Hôpitaux de Paris (Dr. Langeron), Paris; Service d’Explorations Fonctionnelles Cardiovasculaires et Respiratoires, Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris (Dr. Lecarpentier), Le Kremlin Bicêtre; Service de Pneumologie, Fondation Hôpital Saint-Joseph (Dr. Salmeron), Paris; and Service d’Accueil des Urgences, Groupe Hospitalier Pitié-Salpétrière, Assistance Publique-Hôpitaux de Paris, Université Pierre et Marie Curie (Dr. Riou), Paris, France.

Correspondence to: François-Xavier Blanc, MD, Unité de Pneumologie, Service de Médecine Interne, Hôpital de Bicêtre, 78 rue du Général Leclerc, 94275 Le Kremlin-Bicêtre Cedex, France; e-mail: xavier.blanc{at}bct.ap-hop-paris.fr


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives/design: Impaired function of striated and arterial smooth muscle is known to occur in humans and animals with various forms of cardiac diseases, but limited information is available on the mechanical behavior of airway smooth muscle. We tested the hypothesis that the baseline mechanical properties of tracheal smooth muscle (TSM) were impaired at an early stage of cardiac overload.

Animals: We used a model of cardiac hypertrophy induced by surgical abdominal aortic stenosis (AS) in adult rabbits. Twelve animals with AS and 8 sham-operated control rabbits were studied 12 weeks after surgery. In rabbits with AS, the heart weight/body weight ratio was higher than in control rabbits (2.36 ± 0.43 g/kg vs 1.98 ± 0.20 g/kg, p < 0.05) [mean ± SD], attesting to moderate cardiac hypertrophy. No clinical signs of congestive heart failure were observed.

Measurements: Isolated TSM strips were electrically stimulated at 37°C, 2.5 mM [Ca2+]0, against 8 to 10 load levels, from zero load to full isometry. Force-velocity relationship was elicited using the conventional afterloaded isotonic method.

Results: Peak isometric tension was lower in rabbits with AS than in control rabbits (25 ± 11 mN/mm2 vs 34 ± 14 mN/mm2, p < 0.05), whereas maximum unloaded shortening velocity, maximum extent of muscle shortening, and relaxation parameters did not differ between groups. The curvature of the force-velocity relationship (which reflects the myothermal economy of force generation) and peak mechanical efficiency were lower in rabbits with AS than in control rabbits.

Conclusions: These results indicate that the contraction of isolated rabbit TSM was less powerful and less economical in cardiac hypertrophy, attesting to early impairment of the mechanical properties of TSM during cardiac overload.

Key Words: airways • cardiac hypertrophy • force-velocity relationship • smooth muscle


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Impaired skeletal muscle function has been widely documented in both humans and animals with cardiac diseases.1 2 Respiratory muscles exhibit impaired mechanical properties during various etiologic forms of cardiopathies,3 4 5 6 as well as muscles of the limbs. There is also evidence that the mechanical properties of vascular smooth muscle can be modified during cardiac hypertrophy.7 Thus, altered myocardial function appears to be associated with mechanical impairment of several muscular systems. However, only limited information is available on the intrinsic contractile properties of airway smooth muscle during cardiac overload.

The aim of the present study was therefore to assess the baseline mechanical properties of isolated airway smooth muscle during moderate cardiac hypertrophy. It has previously been shown that the posterior membranous portion of the rabbit trachealis is a useful preparation for studying the mechanical properties of airway smooth muscle.8 This preparation was used to test the hypothesis that intrinsic contractile properties of tracheal smooth muscle (TSM) were impaired at an early stage of chronic cardiac overload. We used a model of experimental cardiac pressure overload induced by surgical abdominal aortic stenosis (AS) in adult rabbits.9 In this model, a link has been demonstrated between chronic cardiac overload and impaired performance of isolated skeletal muscles such as diaphragm and soleus.10 For the present study, we analyzed classic mechanical variables and the force-velocity relationship of isolated TSM in animals with cardiac over load, and we compared the data to the ones found in sham-operated control rabbits in order to determine a potential impairment of the contractile properties of TSM at an early stage of chronic pressure overload.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Preparation of Animals and Surgical Procedure
All experiments were conducted with adult New Zealand white rabbits (n = 20). Care of the animals conformed to the recommendations of the Helsinki Declaration, and the study was approved by our institution. Anesthesia was induced with IV administration of 0.07 mg/kg of flunitrazepam (Roche; Neuilly-sur-Seine, France) and 1.5 mg/kg of etomidate (Janssen-Cilag; Issy-les-Moulineaux, France) and maintained with 7 mg/kg/h of etomidate. All animals underwent a median laparotomy under spontaneous ventilation. They were then classified into two groups. In the first group (n = 12), abdominal AS was performed with subtotal, subdiaphragmatic, and suprarenal banding of the abdominal aorta. The abdominal aorta was surgically isolated just below the diaphragm, and a piece of polyethylene catheter (external diameter, 2.4 mm) [Biotrol; Paris, France] was positioned alongside it. The catheter and the aorta were ligated together just above the right renal artery, and the catheter was then gently removed. This procedure reduced the abdominal aortic lumen by approximately 45%.11 In the sham-operated control group (n = 8), there was no banding around the aorta after laparotomy. In both groups, postoperative care was meticulous, and all animals had free access to the same laboratory food and water. The experimental protocol was conducted 12 weeks after the surgical procedure, as previously described.9

TSM Preparation
After brief pentobarbital anesthesia, animals were weighed, laparotomized, and then thoracotomized, and both the heart and the liver were quickly removed and weighed. Hearts were weighed without atria. Each animal was examined for physical signs of congestive heart failure (subcutaneous edema, ascites, pericarditis, pleural effusion, hepatic congestion, or pulmonary congestion). There were no physical signs of congestive heart failure in the AS group and in control rabbits. Compared with control rabbits, the heart weight/body weight ratio of the AS group was increased by approximately 20%, attesting to moderate cardiac hypertrophy (Table 1 ). At this stage, rabbits with AS have been shown to exhibit an alteration of the diastolic compliance, diminished coronary blood flow, and myocardial oxygen consumption.9


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  		Table 1. Characteristics of the Studied Populations*

 
The trachea was immediately removed, and two tracheal rings consisting of four tracheal segments each were carefully dissected per animal (in three cases, only one ring was dissected due to technical reasons, so that 22 TSMs and 15 TSMs were available in the AS and control groups, respectively). The rings were opened with a dorsal midline section through the cartilage in order to obtain approximately 6 x 4 x 2-mm strips of the posterior membranous portion of the trachea. The epithelium was not removed. Each strip was then vertically suspended in a 100-mL organ bath containing a Krebs-Henseleit solution, bubbled with 95% O2/5% CO2 and maintained at 37°C, pH 7.4. Composition of Krebs-Henseleit solution was as follows: NaCl, 118 mM; KCl, 4.7 mM; MgSO4, 1.2 mM; KH2PO4, 1.1 mM; NaHCO3, 24 mM; CaCl2, 2.5 mM; and glucose, 4.5 mM. The lower end of each strip was held by a stationary clip at the bottom of the bath, while the upper extremity was held in a spring clip linked to an electromagnetic lever system. Supramaximal electrical field stimulation (EFS) [30 V/cm, 50 Hz alternating current, 10-ms pulse duration, 12-s train duration] was applied every 5 min by means of two platinum electrodes arranged in parallel on either side of the muscle preparation. Mechanical experiments were conducted after a 1-h equilibration period.

Electromagnetic Lever System
The electromagnetic device has been described previously.12 Briefly, an aluminum lever is cemented to a coil suspended in the strong field of a permanent magnet and a force couple develops when an electric current passes through the coil. Force-measurement amplitude ranges from 0 to 140 mN. The error in measured force is < 0.1%. The equivalent moving mass of the whole system is 155 mg, and its compliance is 0.2 µm/mN. Lever displacement is measured by means of a photoelectric transducer comprising an incandescent lamp, a miniature photodiode, and a preamplifier acting as a current-to-voltage converter. The light emitted by the lamp is modulated by the displacement of the lever, and current alterations in the photodiode are converted into voltage alterations. System linearity ranges from 0 to 5 mm of muscle shortening. The error in measured displacement is < 0.5% of the full-scale deflection.

All analyses were based on digital recordings obtained by means of a personal computer. Two signals, force and length, were recorded simultaneously. The recording speed was one analog-to-digital conversion of each signal every 1 ms. Total recording time ranged from 45 to 60 s. A program developed in our laboratory was used to calculate the mechanical parameters.

Experimental Protocol
At the end of the equilibration period, the resting length of the preparation was progressively increased. Preloads ranging from 7 to 25 mN were applied in steps 10 min prior to stimulation of the tracheal strips under fully isometric conditions. Optimal initial muscle length (L0) was defined as the resting length at which the peak value of active isometric tension was measured. This procedure was used to assess the shallow maximum of the length-tension curve,13 and thus the optimal preload that was held constant throughout the study.

Isotonic and isometric mechanical variables were recorded at L0 over the entire load continuum. We studied 8 to 10 EFS-elicited contractions against increasing loads, from zero load up to the fully isometric contraction. At the end of the study, cross-sectional area (millimeters squared) was calculated from the ratio of muscle weight (milligrams) to muscle length at L0 (millimeters), assuming a muscle density of 1.14 Mean cross-sectional area did not differ between groups: 2.78 ± 1.16 mm2 in rabbits with AS vs 2.72 ± 1.14 mm2 in control rabbits (p = 0.87) [mean ± SD].

Classic Mechanical Variables
At least three different conditions were required in order to determine the baseline mechanical variables characterizing EFS-induced contraction/relaxation in rabbit TSM (Fig 1 ). Contraction 1 was loaded with preload only and abruptly clamped to zero load 4 ms after the onset of the electrical stimulus, using the zero-load clamp technique.15 Contraction 2 was loaded with preload only. The last contraction (contraction 10 in the example shown in Fig 1 ) was performed against a heavy load that the muscle could not overcome, so that the contraction was fully isometric.



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  		Figure 1. Typical experimental recording of instantaneous length (L) vs time (upper trace) and tension vs time (lower trace) during various afterloaded contractions in electrically stimulated rabbit TSM. Contractions were performed successively against 10 increasing loads, from zero load (using the zero-load clamp technique, contraction 1) up to the fully isometric contraction (contraction 10). Contraction 2 was performed at preload only. For the contraction phase, the measured parameters were VMAX, {Delta}L, and P0. Vr and - dP0/dt characterized TSM relaxation under isotonic and isometric conditions, respectively. The 10 contractions were also used to determine the force-velocity relationship.

 
During the EFS-elicited contraction phase, the following indexes were recorded: maximum unloaded shortening velocity (VMAX) of contraction 1 (L0 per second); maximum extent of muscle shortening at preload ({Delta}L) of contraction 2 (percentage of L0); peak isometric force F0 [millinewtons], normalized per cross-sectional area to obtain peak isometric tension (P0) [millinewtons per millimeters squared]. During the EFS-elicited relaxation phase, the maximum lengthening velocity at preload (Vr) of contraction 2 (L0 per second) and the negative peak of isometric tension derivative (- dP0/dt) [millinewtons per millimeters squared per second] were recorded.

Force-Velocity Relationship
The force-velocity relationship of airway smooth muscle was originally described in canine TSM by Stephens et al.16 The conventional afterloaded isotonic method was chosen for the present study after verification that the force-velocity relationship of rabbit TSM was hyperbolic, according to the classic equation of Hill.17 For the 8 to 10 contractions studied (Fig 1) , peak shortening velocity (V) was plotted against total isotonic load normalized per cross-sectional area (P). Data of the force-velocity curve were fitted according to Hill’s hyperbolic equation: (P + a)(V + b) = (cPMAX + a)b, where cPMAX is the maximum calculated value of P when the contraction is fully isometric, and -a and -b are the asymptotes of the force-velocity hyperbola. The curvature of the force-velocity relationship (G) was calculated as cPMAX/a. In striated muscle, the G value reflects the myothermal economy of force generation, such that the more curved Hill’s hyperbola (ie, the higher G), the more economical the contraction.18 Peak mechanical efficiency (EffMAX) was defined as the maximum ratio of the rate of mechanical work to the rate of total energy. As previously described,19 EffMAX is equal to {G/(G + 2)}2.

Statistical Analysis
Data are expressed as mean ± SD. Statistical comparisons between the two groups were carried out by using the Student unpaired t test. For the force-velocity curve, unpaired correlation coefficient r between measured values of force and velocity and the model estimate was used to test the accuracy of the hyperbolic fit. Correlation between two variables was calculated by linear regression using the least-squares method. p < 0.05 was considered significant. All p values are two tailed.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Classic Mechanical Variables
During the contraction phase, F0 was significantly lower in rabbits with AS (61 ± 16 mN) than in control rabbits (81 ± 23 mN, p < 0.01). Since mean cross-sectional area was the same in both groups, P0 obtained after normalization was also significantly lower in rabbits with AS (Table 2 ). VMAX and {Delta}L did not differ between the two groups (Table 2) . Whatever the loading conditions, and in both groups, the EFS-elicited contraction phase was followed by a relaxation phase with no subsequent decline in tension below preload level. During the relaxation phase, the Vr and the - dP0/dt did not differ significantly between rabbits with AS and control rabbits (Table 2) . There was no correlation between the heart weight/body weight ratio and the measured mechanical parameters.


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  		Table 2. Mechanical Variables Characterizing Contraction and Relaxation in Electrically Stimulated Rabbit TSM*

 
Force-Velocity Relationship
Figure 2 shows the force-velocity curves in rabbits with AS and control rabbits. In both groups, the force-velocity relationship was accurately fitted by a hyperbola. The correlation coefficient r between experimental data and Hill’s model was 0.992 ± 0.006 in control rabbits and 0.988 ± 0.012 in rabbits with AS (not significant). As shown in Figure 3 , both G and EffMAX were significantly lower in rabbits with AS than in control rabbits. There was no significant correlation between the heart weight/body weight ratio and the characteristics of the force-velocity relationship.



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  		Figure 2. P - V curves in electrically stimulated TSM of rabbits with surgical AS and sham-operated control rabbits. cP0 = calculated P0; cVMAX = calculated VMAX. Left panel: absolute P and V values. Right panel: normalized P and V values, used to determine the curvature of Hill’s hyperbola.

 


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  		Figure 3. The G and EffMAX of electrically stimulated rabbit TSM. Comparisons between animals with surgical AS and sham-operated control animals (C). Values are mean ± SD.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The major finding of the study is that the baseline contraction of electrically stimulated TSM was less powerful and less economical in rabbits with mild cardiac hypertrophy, attesting to early impairment of the mechanics and energetics of TSM in chronic cardiac pressure overload. Our results indicate that the force-generating capacity of isolated TSM was decreased at an early stage of cardiac overload, at a time when no clinical signs of congestive heart failure had been observed. Decreased muscle force-bearing capacity is generally explained by a decrease in the number of actomyosin crossbridges and/or by impairment of the elementary force produced by each crossbridge. Whether the decrease in developed tension was associated with a decrease in the number of actomyosin crossbridges and/or with impairment of the elementary force produced per crossbridge remains to be established. Impaired performance of skeletal muscles such as diaphragm and soleus has been reported in the same model of chronic cardiac overload.10 We cannot exclude the possibility that a common etiologic factor was involved in the mechanical impairment of both TSM and striated muscles in rabbits with cardiac hypertrophy. It can be speculated that the hemodynamic changes that have been previously described in that model9 were associated with the release of circulating mediators acting on both TSM and striated muscles. One of the potential candidates could be the proinflammatory cytokine tumor necrosis factor (TNF), which has been shown to play a role in the pathogenesis of heart failure.20 It is known that there is a direct relationship between the level of TNF expression and the severity of cardiac disease.20 Together with other cytokines, TNF-{alpha} can induce myopathy and apoptosis.21 Whether TNF-{alpha} is increased in the present model remains to be established.

When studying the mechanics of airway smooth muscle, it is important to measure not only isometric variables but also isotonic contractions against various load levels. In the present study, no significant differences in shortening capacity were found between rabbits with AS and control rabbits (Table 2) . A few studies8 22 23 have described the baseline isotonic properties of isolated rabbit TSM. The VMAX value found in control rabbits of the present study (0.331 ± 0.097 L0/s) was of the same order of magnitude as that previously reported by Roepke et al23 (0.246 ± 0.043 L0/s), although different methods were used to obtain this value. Roepke et al23 calculated VMAX as the mean Y-axis intercept value of linear regression for extrapolation of the EFS-elicited force-velocity curves, whereas we measured VMAX according to the zero-load clamp technique.15 Our results confirm that both methods are equivalent for determining VMAX, as previously shown in cardiac muscle15 and in canine TSM.24 The fact that VMAX was unchanged in rabbits with AS could suggest that the actin-activated myosin adenosine triphosphatase activity might be unchanged.25 However, studies26 27 28 have shown that the VMAX and the turnover rate of myosin adenosine triphosphatase per myosin site were not systematically related in skeletal muscles. Whether this is the case for airway smooth muscle remains to be determined.

It should be pointed out that our model was not intended to study the mechanical features of airway hyperresponsiveness. Airway hyperresponsiveness has been documented in patients with impaired left ventricular function, and has been shown to contribute at least in part to the wheezy dyspnea commonly observed in such patients.29 30 31 32 Observed airway hyperresponsiveness has been attributed to vasodilation of bronchial vessels and submucosal thickening due to extravasation of plasma,33 but a possible role of airway smooth muscle has also been suggested.29 From a mechanical point of view, airway hyperresponsiveness has been shown to be generally associated with an increase in both VMAX and {Delta}L, without any change in P0, in isolated TSM studied at baseline and compared with TSM of nonhyperreactive animals.34 35 In our study, both VMAX and {Delta}L did not differ between groups, while P0 was lower in rabbits with AS than in control rabbits. Thus, in rabbits with AS, the baseline mechanical properties of TSM were different from the baseline TSM properties of animal models with airway hyperresponsiveness.

In the present study, both isotonic and isometric parameters characterizing the relaxation phase were similar in rabbits with AS and control rabbits (Table 2) . In numerous models of experimental myocardial or skeletal muscle failure, the relaxation phase is often impaired sooner and more profoundly than the contraction phase. Slowed and/or incomplete relaxation generally precipitates contractile failure. It is important to note that in our study, isolated selective impairment of TSM contractile properties was documented without any relaxation abnormalities. Thus, in our model of moderate cardiac hypertrophy, intracellular mechanisms responsible for the relaxation phase in TSM seemed to play a virtually negligible role compared with the mechanisms involved in the contraction.

We also sought to determine whether or not impairment of force-generating capacity was associated with an altered force-velocity relationship in TSM in rabbits with cardiac overload. In tetanic isolated skeletal muscles, analysis of the curvature of the force-velocity relationship provides a useful way of calculating mechanical efficiency.19 In the present study, such analysis was applied to nonstriated muscles, after verification that the force-velocity relationship of rabbit TSM was hyperbolic, both in rabbits with AS and control rabbits, without any obvious deviation at high loads, according to the classic equation of Hill.17 Using the conventional afterloaded method, we found that G was significantly lower in rabbits with AS when compared to control rabbits (Fig 3) . In striated muscles, G has been found to be linked to the myothermal economy of force generation: the more curved Hill’s hyperbola (ie, the higher G), the greater the economy of force generation.19 Assuming that the fundamental properties of actomyosin crossbridges do not differ strikingly between smooth and striated muscles,36 our results suggest that isolated TSM exhibited impaired economy of force generation in cardiac overload. It was also found that calculated peak mechanical efficiency was decreased in AS (Fig 3) ; the contraction of isolated TSM was less economical in rabbits with moderate cardiac hypertrophy.

It is important to point out that impairment of TSM mechanical properties was observed early in chronic cardiac overload, at a time when the animals exhibited mild cardiac hypertrophy without any physical signs of congestive heart failure. Since impairment developed early in the course of the disease, it seems unlikely that it could have been the consequence of extravasation of plasma, thereby suggesting an impairment of intrinsic TSM properties. However, one cannot exclude the possibility that extramuscular phenomena (eg, decreased perfusion33 ) might have accounted, at least in part, for the observed differences described in our study.

The model used in the present study has been shown to be associated with an alteration of the diastolic compliance, diminished coronary blood flow, and myocardial oxygen consumption.9 The cardiac hypertrophy found in the animals of our study was moderate but remained comparable to the one found in a previous study.9 Left ventricular weight was in the same order of magnitude in both studies; heart weight was slightly higher in the study of Ouattara et al9 than in our study, probably because we weighed hearts without atria whereas they weighed whole hearts. It is of importance to note that, in this model, systolic function is preserved, as attested by identical slopes of the end-systolic pressure-volume relation in both groups.9 Therefore, our results suggest that mechanical properties of isolated TSM can be impaired at a stage where contractility is still preserved, long before the occurrence of cardiac failure.

The clinical relevance of our findings needs to be discussed. Whereas numerous studies1 2 have shown that skeletal muscle function is impaired in humans and animals with cardiac diseases, the possibility of airway smooth muscle impairment has rarely been evoked. However, if we admit that muscular dysfunction is part of the syndrome of heart failure,37 it is conceivable that smooth muscle, and not only skeletal muscle, can be impaired because of a common factor. Careful examination of airway function shows that patients with acute heart failure generally exhibit a predominant obstructive pattern with an usual improvement of airway obstruction following the treatment of heart failure, whereas patients with chronic stable heart failure exhibit a restrictive pattern that can be due to a stiffening of the lung parenchyma and the presence of chronically fluid-filled alveolar spaces.38 The contribution of airway smooth muscle in airway obstruction has not been specifically addressed in humans or animals with cardiac hypertrophy. Further studies are needed to determine whether abnormal airway smooth-muscle function contributes to airway obstruction during chronic heart failure.

In an experimental model of moderate cardiac hypertrophy induced by surgical stenosis of the suprarenal abdominal aorta in adult rabbits, the EFS-elicited contraction of isolated TSM was found to be less powerful and less economical than in sham-operated control animals. Impairment in the force-generating capacity was not associated with impaired shortening capacity or impaired relaxation. Whether factors involved in such an impairment are specific to TSM or bear witness to a general muscular impairment remains to be determined.


   Footnotes
 
Abbreviations: AS = aortic stenosis; cPMAX = maximum calculated value of P when the contraction is fully isometric; - dP0/dt = negative peak of isometric tension derivative; EffMAX = peak mechanical efficiency; EFS = electrical field stimulation; {Delta}L = maximum extent of muscle shortening at preload; F0 = peak isometric force; G = curvature of the force-velocity relationship; L0 = optimal initial muscle length; P = total isotonic load normalized per cross-sectional area; P0 = peak isometric tension; TNF = tumor necrosis factor; TSM = tracheal smooth muscle; V = peak shortening velocity; VMAX = maximum unloaded shortening velocity; Vr = maximum lengthening velocity at preload

Animal operations were performed at the Département d’Anesthésie-Réanimation, Groupe Hospitalier Pitié-Salpétrière, Assistance Publique, Hôpitaux de Paris, Paris, France.

Experiments were performed at the Institut National de la Santé et de la Recherche Médicale (INSERM), ENSTA, Ecole Polytechnique, Palaiseau, France.

Received for publication February 21, 2003. Accepted for publication June 5, 2003.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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