Effects of initial length on intrinsic tone in guinea pig tracheal smooth muscle

Martin Bard1, Sergio Salmeron1, Catherine Coirault2, Francois-Xavier Blanc2, and Yves Lecarpentier2,3

1 Unité de Pneumologie, Service de Médecine Interne, and 3 Service de Physiologie Cardio-Respiratoire, Hôpital Universitaire Bicêtre, 94275 Le Kremlin-Bicêtre; and 2 Laboratoire d'Optique Appliquée, École Nationale Supérieure de Techniques Avancées-Ecole Polytechnique, Institut National de la Santé et de la Recherche Médicale Unité 451, 91125 Palaiseau, France

    ABSTRACT
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

In the guinea pig, tracheal smooth muscle (TSM) exhibits intrinsic tone (IT). The active nature of IT suggests that it could be influenced by muscle length and load. In the guinea pig, IT is entirely suppressed by the cyclooxygenase inhibitor indomethacin. IT could be measured as the difference between resting tone before and after indomethacin addition. We examined, in electrically stimulated TSM strips (n = 9), the influence of initial muscle length (Li) on IT, the relationship between IT and the maximum extent of relaxation (Delta F1), and the influence of indomethacin on active isometric force. When Li decreased from 100 to 75% of optimal Li, there was a significant decrease in IT (from 12.0 ± 0.2 to 5.3 ± 0.1 mN; P < 0.001). Over the range of Li studied, Delta F1 underestimated the amount of IT, but there was a close linear relationship between Delta F1 and IT (r = 0.9). Compared with the basal state, indomethacin increased active isometric force (from 9.5 ± 1.0 to 19.7 ± 2.0 mN at optimal Li; P < 0.001) and induced its length dependency. In guinea pig TSM, Li was an important determinant of IT.

airway hyperreactivity; indomethacin; relaxation; mechanics

    INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

IN THE BASAL STATE, human and guinea pig airway smooth muscle exhibits spontaneous tone (1, 4, 17). In vascular smooth muscle, this spontaneous tone, called "intrinsic tone" (IT), has been shown to contribute, along with the passive resting tone (PRT), to the total resting tone (RT) (15, 16).

In guinea pig tracheal smooth muscle (TSM), IT generation involves the release of prostanoids, inasmuch as indomethacin suppresses IT (1, 7, 9, 18). Moreover, spontaneous basal tone has been shown to increase after immune sensitization to ovalbumin (17), suggesting a possible role in the pathophysiology of airway hyperreactivity.

Previous reports (1, 9, 17) have shown that, in the guinea pig, electrical field stimulation (EFS) of isolated TSM induces a biphasic response: the initial contraction phase developed during EFS is followed by a relaxation phase below baseline tone levels, followed by a slow and gradual recovery of force. Both phases have been reported to be tetrodotoxin sensitive, i.e., neurally mediated (9, 17). Moreover, it has been established that the contraction phase results from the activation of cholinergic mechanisms (9, 25). Conversely, the relaxation phase results from the activation of both adrenergic and nonadrenergic noncholinergic components (1, 9). Relaxation has been attributed, at least in part, to a transient inhibition of IT (1, 9, 17).

It has been demonstrated that initial muscle length (Li) is an important determinant of active isometric force (AF) in TSM (23). The aim of our study was to analyze, in electrically stimulated guinea pig TSM, the influence of Li on IT. We sought to determine whether the amplitude of relaxation accurately quantified the amount of IT and measured the AF-Li relationship in the presence and absence of IT.

    MATERIALS AND METHODS
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

TSM Preparation

The experiments were performed on tracheal segments of Hartley guinea pigs weighing 300-350 g. Care of the animals conformed to the recommendations of the Helsinki Declaration, and the study was approved by our institution (Institut National de la Santé et de la Recherche Médicale, Palaiseau, France). The animals were anesthetized with intraperitoneal pentobarbital sodium (100 mg/kg). A segment of five tracheal rings was rapidly removed and cut longitudinally. Metal clips were placed on the cartilage on either side of the posterior muscular band. The TSMs were vertically suspended at a predetermined initial tone in a physiological saline solution containing (in mM) 118 NaCl, 4.7 KCl, 1.2 MgSO4 · 7H2O, 1.1 KH2PO4, 24 NaHCO3, 2.5 CaCl2 · 6H2O, and 4.5 glucose. The solution was maintained at 37°C and bubbled with a 95% O2-5% CO2 gas mixture at a pH of 7.40. The lower end of the tracheal strip was anchored at the bottom of the bath. The upper end of the strip was connected to a force and length transducer. The experiments were performed after a 1-h stabilization period during which the tracheal strips were electrically stimulated every 5 min by means of two platinum electrodes longitudinally arranged on either side of the muscle. Alternating square-wave pulses were delivered at a frequency of 50 Hz, a pulse width of 10 ms for 10 s, and a supramaximal voltage of 30 V/cm. During the equilibration period, preload was held constant. Preload was defined as the load stretching the muscle at rest. Afterload was defined as the load added to the preload when the muscle was electrically stimulated. Li was determined after the equilibration period with a calibrated optical system (pocket micrometer model TS-L1, Sugitoh). In the range of muscle length studied, Li had a limited effect on AF due to IT. Therefore, optimal Li (Lo) was defined as the Li corresponding to maximum AF after indomethacin addition.

Electromagnetic Apparatus

The muscle strips were anchored to an electromagnetic lever cemented to a coil and suspended in the field of an electromagnet. The load applied to the TSM segment was determined by a servo-controlled current through the coil. The preload level, which determined the Li, was electronically held constant throughout the experiment. A photoelectric transducer measured the displacement of the lever induced by muscle shortening. The equivalent moving mass of the whole system was 150 mg and its compliance was 0.2 µm/mN. The system was linear up to 5 mm of muscle shortening (12). An adjustable electronic stop was set up to avoid muscle lengthening beyond Li when afterload was applied to the muscle. Two signals, force and length, were simultaneously recorded by a computer (IPC Dynasty LE), with a base time of 50 s. The software for calculating all the mechanical parameters was developed in our laboratory. The system is not auxotonic but enables us to measure both isometric and isotonic responses.

Mechanical Parameters

Contraction phase. Classic mechanical parameters describing contraction in electrically stimulated TSM were obtained from fully isometric contractions. Total isometric force (TF; in mN) and maximum AF (in mN) were measured (Fig. 1).


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Fig. 1.   Mechanical parameters characterizing contraction and relaxation phases before (A) and after (B) indomethacin (3 × 10-6 M) addition. Mechanical parameters were obtained from fully isometric contractions during which the initial muscle length was held constant. A: muscle force (F) vs. time. During contraction phase, maximum active isometric F (AF; in mN) and total resting tone (RT; in mN) were measured. Total F (TF; in mN) = RT + AF. During relaxation phase, lowest measurable F (Delta F2; in mN) and maximum extent of relaxation (Delta F1; in mN), i.e., difference between RT and Delta F2, were measured. EFS, electrical field stimulation. B: muscle F vs. time. After indomethacin addition and total suppression of intrinsic tone, relaxation phase below baseline tone level was abolished. AF and passive resting tone (PRT; in mN) at the same initial muscle length as before indomethacin addition were measured. TF = PRT + AF.

Relaxation phase. In electrically stimulated guinea pig TSM, the contraction phase is followed by a relaxation phase below baseline tone levels. Force then spontaneously returns to preload levels in 3-4 min. During this phase of relaxation, we measured the lowest measurable force (Delta F2; in mN) and the maximum extent of force decay below preload (Delta F1; in mN), i.e., the difference between RT and Delta F2 (Fig. 1A).

Resting tone. RT (in mN) is defined as the tone developed by the muscle before the electrically induced contraction. In isolated TSM of the guinea pig, RT is divided into active (IT) and passive (PRT) components: RT = IT + PRT, measured in millinewtons. At micromolar concentrations, the cyclooxygenase inhibitor indomethacin is known to totally abolish IT (9, 17, 18). Thus indomethacin made it possible to directly measure the PRT of TSMs and thus to calculate IT. IT was calculated as RT at baseline (i.e., before indomethacin addition; Fig. 1A) minus PRT (determined after indomethacin addition; Fig. 1B).

Experimental Protocols

Influence of Li on IT and Delta F1. To determine the effects of Li on IT and Delta F1, mechanical parameters of the isometric contraction were recorded at five different Li values ranging from 100 to 75% of Lo. These different Li values were obtained by reducing preload levels from 14 to 6 mN. Successive measurements of RT and Delta F1 were performed in the electrically induced isometric contractions before indomethacin addition. Thereafter, the resting length of the TSM was replaced at Lo, and indomethacin (3 × 10-6 M) was added to the Krebs solution. After an equilibrium period of 30 min, the remaining resting tone (i.e., PRT) was measured at the same corresponding Li values as before indomethacin addition. IT was calculated as the RT at baseline minus the RT after indomethacin (IT = RT - PRT).

Comparison of IT and Delta F1. To determine whether the amplitude of relaxation accurately characterized IT in guinea pig TSM, baseline values of Delta F1 were compared with the corresponding values of IT at different Li values.

AF-Li relationship in presence and absence of IT. The influence of the amount of IT on AF was determined at five Li values ranging from 100 to 75% of Lo. For each Li value, AF was measured before indomethacin addition. Thereafter, the resting length of TSM was replaced at Lo, and indomethacin (3 × 10-6 M) was added to the Krebs solution. After an equilibration period of 30 min, AF was recorded at the same five Li values as before indomethacin addition.

Effects of afterload level on relaxation. To determine the effects of afterload and/or muscle shortening on Delta F1, five to eight contractions with afterloads regularly increased from preload up to isometric load were applied to each muscle strip (Fig. 2). No indomethacin was added in the course of this protocol.


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Fig. 2.   Typical recording of superimposed contractions during which afterload was progressively increased (1-5) from isotonic contraction loaded with preload only (contraction 1) up to fully isometric contraction (contraction 5). A: muscle shortening length [L/optimal initial muscle length (Lo)] vs. time. B: F vs. time. Variations in F during relaxation were not influenced by afterload level.

Statistical Analysis

Results are expressed as means ± SE. In all experiments, mean values were compared with analysis of variance and Student's paired t-test with the Bonferroni correction. In all cases, significance required a P value < 0.05.

    RESULTS
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

Mechanical Characteristics of TSM

At baseline, electrically stimulated guinea pig TSM exhibited a contraction phase followed by a phase of relaxation (Fig. 1A). The mechanical characteristics of TSM in the basal state are given in Table 1. At Lo, baseline values of AF and RT corresponded to 40 and 60% of TF, respectively. The effects of indomethacin are shown in Fig. 1B. As expected, indomethacin significantly reduced RT (Table 1) and abolished the phase of relaxation below the baseline tone level (Fig. 1B). Moreover, at Lo, indomethacin induced a 107% increase in AF compared with the baseline value (Table 1). There was no significant difference in TF after indomethacin addition (23.5 ± 1.0 vs. 21.7 ± 1.9 mN; P = 0.3; Table 1).

                              
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Table 1.   Mechanical characteristics of guinea pig TSM

Influence of Li on IT

Figure 3 depicts the relationship between Li and both IT and Delta F1. At Lo, IT averaged 12.0 ± 0.2 mN and represented 86% of baseline RT. When Li was progressively decreased from 100 to 75% of Lo, there was a significant decrease in the amount of IT (P < 0.001; Fig. 3). Decreasing Li from 100 to 75% of Lo also significantly reduced Delta F1 (P < 0.001; Fig. 3). This indicates that in guinea pig TSM the values of both IT and Delta F1 depend on Li.


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Fig. 3.   Influence of initial muscle length (Li) on both intrinsic tone (IT) and Delta F1 in guinea pig tracheal smooth muscle (TSM; n = 9 strips). Li is expressed as a percentage of Lo, the Li corresponding to maximum AF after indomethacin addition. Results are means ± SE. Student's paired t-test with the Bonferroni correction was used, and mean values were compared with mean values at Lo (* P < 0.001). For range of Li values studied (from 100 to 75% of Lo), a significant decline in IT was observed. This indicates that, in guinea pig TSM, amount of IT depends on Li. Moreover, over range of Li values studied, Delta F1 significantly declined with Li and Delta F1 was lower than IT.

Comparison Between IT and Delta F1

To determine whether Delta F1 was a good estimate of IT, the relationship between IT and Delta F1 was analyzed at varying Li values (Figs. 3 and 4). Over the range of Li values studied, Delta F1 was significantly lower than IT (Fig. 3). However, there was a close linear relationship between IT and Delta F1: the higher the values of IT, the higher those of Delta F1 (Fig. 4).


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Fig. 4.   Relationship between IT and Delta F1 in guinea pig TSM (n = 9 strips). A close linear relationship was observed between IT and Delta F1: IT = 1.10Delta F1 + 0.12 (r = 0.9).

AF-Li Relationship in Presence and Absence of IT

Before indomethacin addition, the reduction in Li from 100 to 75% of Lo did not significantly modify AF (Fig. 5). After indomethacin addition, decreasing Li from 100 to 75% of Lo was associated with a progressive and significant reduction in AF (P < 0.001; Fig. 5). Moreover, compared with the basal state and for any Li value studied, AF was greater after indomethacin addition (Fig. 5).


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Fig. 5.   Influence of Li on AF in guinea pig TSM (n = 9 strips) before and after indomethacin (3 × 10-6 M) addition. Results are means ± SE. Student's paired t-test with Bonferroni correction was used, and mean values were compared with mean values at Lo (* P < 0.001). At baseline, reduction in Li from 100 to 75% of Lo did not significantly modify AF. Conversely, after indomethacin addition, decreasing Li was associated with a significant reduction in AF.

Influence of Muscle Afterload on Relaxation

Figure 2 shows a series of afterloaded contractions obtained at baseline. When the load was increased from preload up to isometric load, the maximum amplitude of muscle shortening decreased (Fig. 2A). Conversely, relaxation was not modified by this procedure (Fig. 2B). The quantitative results of the afterloaded contractions are given in Table 2. The increase in afterload induced a decrease in the maximum amplitude of muscle shortening. However, no variations in Delta F2 and Delta F1 were observed. This indicates that relaxation was not influenced by load variations occurring during the initial contraction phase.

                              
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Table 2.   Effects of afterload level on relaxation and muscle shortening in guinea pig TSM

    DISCUSSION
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

IT, which occurs spontaneously in guinea pig TSM, is totally abolished by the cyclooxygenase inhibitor indomethacin (1, 7, 9, 18). In this animal model, analysis of the effects of indomethacin on RT made it possible to calculate the value of IT. Our results show that 1) Li is a major determinant of IT, 2) Delta F1 underestimates IT, 3) Delta F1 is not influenced by afterload conditions, and 4) indomethacin increases AF and induces its length dependency.

Our results pertain strictly to the animal species and experimental conditions used. The stimulation parameters were set at a pulse width of 10 ms, which is larger than that used in previous studies (9, 17). However, the mechanical properties and effects of indomethacin are similar to those previously reported.

The level of IT was a linear function of Li: as Li fell below Lo, IT declined linearly. Because Ca2+ plays a major role in regulating actomyosin interactions in TSM (2, 5, 23), it could be hypothesized that the mechanical effects induced by changes in Li reflect changes in the intracellular Ca2+ concentration and/or myofilament Ca2+ sensitivity. Li may influence both Ca2+ homeostasis and Ca2+ sensitivity of regulatory proteins such as G proteins and inhibitor proteins (20-22). In line with this hypothesis, previous authors have demonstrated a decrease at short length in both myoplasmic intracellular Ca2+ concentration (14) and Ca2+ sensitivity of myosin light chain kinase (6). The length dependency of IT may be compared with the phenomenon of reduced activation at short length demonstrated in both striated and smooth muscles (10, 23, 24). The mechanisms underlying the AF decrease with muscle length may be related to a reduction in cytosolic Ca2+ release at short length. Alternatively, an increase in prostaglandin release induced by TSM distension has been suggested (3). A decrease in myoplasmic prostaglandin content could be another putative hypothesis to explain the lower amount of IT measured at short Li.

Numerous studies (1, 9, 17) have shown that, in isolated guinea pig TSM, a relaxation phase below baseline tone level follows the electrically induced contraction phase. A relaxation phase below baseline tone level has also been reported in isolated human TSM (8). To determine whether Delta F1 was a good estimate of IT, we studied the relationship between Delta F1 and the amount of IT at various Li values. Our results showed that Delta F1 underestimated the amount of IT; i.e., Delta F1 represented ~80% of IT values. Thus IT was not totally abolished during relaxation. However, there was a close linear relationship between Delta F1 and IT (Fig. 3). These results support the hypothesis that, in electrically stimulated TSM, relaxation corresponds to a transient and incomplete inhibition of IT but that Delta F1 does not accurately quantify IT. The precise influence of IT on the relaxation process was difficult to assess because of the simultaneous changes in Li, IT, and Delta F1.

In guinea pig TSM, several mechanical and pharmacological studies have analyzed initial force development and relaxation. Selective anticholinergic drugs, such as atropine, have been shown to inhibit the initial contraction phase without modifying the relaxation phase (1, 9, 11, 17). This suggests that Delta F1 is independent of the cholinergic pathway. On the other hand, it has been reported that the characteristics of EFS modulate both the contraction and relaxation phases (1, 9). The effects of loading conditions on Delta F1 (particularly afterload level and muscle shortening length) have not been previously reported. Our results show that, for a given preload, Delta F1 was not influenced by the afterload level. This suggests that intracellular mechanisms underlying relaxation remain uninfluenced by changes in muscle length and/or load during the contraction phase.

In guinea pig TSM, indomethacin induces an increase in all the mechanical parameters of contraction. Muscle shortening, velocity of contraction, and AF are all increased by indomethacin. The mechanisms underlying the effect of indomethacin may involve variations in neurotransmitter release or in contraction regulation. The close relationship between IT and AF makes it difficult to study the effect of cyclooxygenase blockade on AF generation. Linden et al. (13) have recently demonstrated the role of the level of histamine-induced tone in the response to electrical stimulation. In this study, it has not been possible to examine IT because indomethacin was systematically added in all experiments. However, this study has demonstrated that, when a high histamine-induced tone is present, the response to EFS is relaxant. Conversely, when no tone is present, a contractile response to EFS is measured. The comparison between IT and histamine-induced tone is hazardous, but this result confirms that the level of tone is an important determinant of airway response to stimulation.

In striated muscle, it is well known that Li modulates AF (Frank-Starling relationship). Similarly, in dog TSM, in which IT is absent, AF declines with Li (23). Our results show that, in the presence of indomethacin, i.e., after the suppression of IT, AF significantly declines when Li falls below Lo. Conversely, before indomethacin addition, the reduction in Li from 100 to 75% of Lo is not associated with significant changes in AF (Fig. 5). It could be hypothesized that, in the absence of indomethacin, a given proportion of cross bridges are involved in the maintenance of IT. Consequently, the remaining cross bridges that could develop AF during the initial contraction phase may be less numerous before than after IT suppression. Recently, variations in TSM plasticity have been hypothesized to explain the length dependency of mechanical parameters in canine TSM (19). Variations in muscle length may induce variations in the number of contractile units. Similar phenomena may be hypothesized to explain the length dependency of both AF and IT in guinea pig TSM. Further studies are needed to elucidate the regulation of cross bridges involved in IT generation.

In conclusion, our results show that, in electrically stimulated guinea pig TSM, Li modulates IT and relaxation (Delta F1). Moreover, over the range of Li values studied, relaxation reflects a transient and incomplete inhibition of IT. Finally, IT modulates the muscle length-AF relationship.

    ACKNOWLEDGEMENTS

We thank D. Chemla for helpful discussions and J. Kenneth Hilton for assistance in the preparation of the manuscript.

    FOOTNOTES

Address for reprint requests: Y. Lecarpentier, INSERM U451-LOA-ENSTA-Ecole Polytechnique, batterie de l'Yvette, 91125 Palaiseau Cedex, France.

Received 4 August 1997; accepted in final form 21 August 1998.

    REFERENCES
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

1.   Coleman, R. A., and G. P. Levy. A non-adrenergic inhibitory nervous pathway in guinea pig trachea. Br. J. Pharmacol. 52: 167-174, 1974[Medline].

2.   De Lanerolle, P., and R. J. Paul. Myosin phosphorylation/dephosphorylation and regulation of airway smooth muscle contractility. Am. J. Physiol. 261 (Lung Cell. Mol. Physiol. 5): L1-L14, 1991[Abstract/Free Full Text].

3.   Douglas, J. S., and C. Brink. Mediators: histamine and prostanoids. Am. Rev. Respir. Dis. 136: S21-S37, 1987[Medline].

4.   Ellis, J. L., and B. J. Undem. Role of cysteinyl-leukotrienes and histamine in mediating intrinsic tone in isolated human bronchi. Am. J. Respir. Crit. Care Med. 149: 118-122, 1994[Abstract].

5.   Gerthoffer, W. T. Regulation of the contractile element of airway smooth muscle. Am. J. Physiol. 261 (Lung Cell. Mol. Physiol. 5): L15-L28, 1991[Abstract/Free Full Text].

6.   Gunst, S. J. Effects of muscle length and load on intracellular Ca2+ in tracheal smooth muscle. Am. J. Physiol. 256 (Cell Physiol. 25): C807-C812, 1989[Abstract/Free Full Text].

7.   Ito, M., K. Baba, K. Takagi, T. Satake, and T. Tomita. Some properties of calcium-induced contraction in the isolated human and guinea pig tracheal smooth muscle. Respir. Physiol. 59: 143-153, 1985[Medline].

8.   Jiang, H., X. Su, H. Unruh, and N. L. Stephens. Isotonic and isometric properties of human bronchial smooth muscle (Abstract). Am. J. Respir. Crit. Care Med. 149: A905, 1994.

9.   Jones, T. R., J. T. Hamilton, and N. M. Lefcoe. Pharmacological modulation of cholinergic neurotransmission in guinea pig trachea in vitro. Can. J. Physiol. Pharmacol. 58: 810-822, 1980.

10.   Kromer, U., and N. L. Stephens. Airway smooth muscle mechanics: reduced activation and relaxation. J. Appl. Physiol. 54: 345-348, 1983[Abstract/Free Full Text].

11.   Leblanc, P. H., C. K. Buckner, D. B. Brunson, R. B. Laravuso, and J. A. Will. Differential effect of ketamine on cholinergic- and noncholinergic-induced contractions of isolated guinea-pig bronchi. Arch. Int. Pharmacodyn. Ther. 287: 120-132, 1987[Medline].

12.   Lecarpentier, Y., C. Coirault, G. Lerebours, P. Desche, E. Scalbert, F. Lambert, and D. Chemla. Effects of angiotensin converting enzyme inhibition on crossbridge properties of diaphragm in cardiomyopathic hamsters of the dilated bio 53-58 strain. Am. J. Respir. Crit. Care Med. 155: 630-636, 1997[Abstract].

13.   Linden, A., C.-G. Löfdahl, A. Ullman, and B.-E. Skoogh. Nonadrenergic, noncholinergic responses stabilize smooth muscle tone, with and without parasympathic activation, in guinea-pig isolated airways. Eur. Respir. J. 6: 425-433, 1993[Abstract].

14.   Mehta, D., M.-F. Wu, and S. J. Gunst. Role of contractile protein activation in the length-dependent modulation of tracheal smooth muscle force. Am. J. Physiol. 270 (Cell Physiol. 39): C243-C252, 1996[Abstract/Free Full Text].

15.   Morgan, K. G. Calcium and vascular smooth muscle tone. Am. J. Med. 82: 9-15, 1987[Medline].

16.   Murphy, R. A. Mechanics of vascular smooth muscle. In: Handbook of Physiology. The Cardiovascular System. Vascular Smooth Muscle. Bethesda, MD: Am. Physiol. Soc., 1980, sect. 2, vol. II, chapt. 13, p. 325-351.

17.   Ndukwu, I. M., J. Solway, K. Arbetter, K. Uzendoski, A. R. Leff, and R. W. Mitchell. Immune sensitization augments epithelium-dependent spontaneous tone in guinea pig trachealis. Am. J. Physiol. 266 (Lung Cell. Mol. Physiol. 10): L485-L492, 1994[Abstract/Free Full Text].

18.   Orehek, J., J. S. Douglas, and A. Bouhuys. Contractile responses of the guinea pig trachea in vitro: modification by prostaglandin synthesis-inhibiting drugs. J. Pharmacol. Exp. Ther. 194: 554-564, 1975[Abstract].

19.   Pratusevich, V. R., C. Y. Seow, and L. E. Ford. Plasticity in canine airway smooth muscle. J. Gen. Physiol. 105: 73-94, 1995[Abstract].

20.   Savineau, J. P., and R. Marthan. Activation properties of chemically skinned fibers from human isolated bronchial smooth muscle. J. Physiol. (Lond.) 474: 433-438, 1994[Abstract].

21.   Somlyo, A. P., and A. V. Somlyo. Signal transduction and regulation in smooth muscle. Nature 372: 231-236, 1994[Medline].

22.   Sparrow, M. P., G. Pfitzer, M. Gagelmann, and J. C. Rüegg. Effect of calmodulin, Ca2+, and cAMP protein kinase on skinned tracheal smooth muscle. Am. J. Physiol. 246 (Cell Physiol. 15): C308-C314, 1984[Abstract].

23.   Stephens, N. L., and C. Y. Seow. Airway smooth muscle: physiology, bronchomotor tone, pharmacology and relation to asthma. In: Bronchial Asthma: Mechanisms and Therapeutics (3rd ed.), edited by E. B. Weiss, and M. Stein. Boston, MA: Little, Brown, 1993, p. 314-332.

24.   Taylor, S. R., and R. Rüdel. Striated muscle fibers: inactivation of contraction induced by shortening. Science 167: 882-884, 1970[Medline].

25.   Undem, B. J., A. C. Myers, H. Barthlow, and D. Weinreich. Vagal innervation of guinea pig bronchial smooth muscle. J. Appl. Physiol. 69: 1336-1346, 1990[Abstract/Free Full Text].


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