Vol. 275, Issue 6, L1026-L1030, December 1998
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 |
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
(
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, F1 underestimated the amount of
IT, but there was a close linear relationship between
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 |
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 |
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
(F2; in mN) and maximum extent
of relaxation (F1; in mN),
i.e., difference between RT and
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.
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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
(F2; in mN) and the maximum
extent of force decay below preload
(F1; in mN), i.e., the
difference between RT and 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
F1.
To determine the effects of
Li on IT and
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
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 × 106
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 F1.
To determine whether the amplitude of relaxation accurately
characterized IT in guinea pig TSM, baseline values of
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 × 106
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
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.
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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.
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RESULTS |
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).
Influence of Li on IT
Figure 3 depicts the relationship between
Li and both IT
and 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 F1
(P < 0.001; Fig. 3). This indicates
that in guinea pig TSM the values of both IT and
F1 depend on
Li.
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Fig. 3.
Influence of initial muscle length
(Li) on both
intrinsic tone (IT) and 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, F1
significantly declined with
Li and
F1 was lower than IT.
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Comparison Between IT and
F1
To determine whether F1 was a
good estimate of IT, the relationship between IT and
F1 was analyzed at varying
Li values (Figs.
3 and 4). Over the range of
Li values
studied, F1 was significantly
lower than IT (Fig. 3). However, there was a close linear relationship
between IT and F1: the higher
the values of IT, the higher those of
F1 (Fig. 4).
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Fig. 4.
Relationship between IT and F1
in guinea pig TSM (n = 9 strips). A
close linear relationship was observed between IT and
F1: IT = 1.10F1 + 0.12 (r = 0.9).
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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 × 106 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.
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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 F2 and
F1 were observed. This
indicates that relaxation was not influenced by load variations
occurring during the initial contraction phase.
| |
DISCUSSION |
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)
F1 underestimates IT,
3)
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 F1 was a
good estimate of IT, we studied the relationship between
F1 and the amount of IT at
various Li
values. Our results showed that
F1 underestimated the amount of
IT; i.e., F1 represented
~80% of IT values. Thus IT was not totally abolished during
relaxation. However, there was a close linear relationship between
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 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
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 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 F1 (particularly
afterload level and muscle shortening length) have not been previously
reported. Our results show that, for a given preload,
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
(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.
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ACKNOWLEDGEMENTS |
We thank D. Chemla for helpful discussions and J. Kenneth Hilton
for assistance in the preparation of the manuscript.
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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.
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D. Weinreich.
Vagal innervation of guinea pig bronchial smooth muscle.
J. Appl. Physiol.
69:
1336-1346,
1990[Abstract/Free Full Text].
Am J Physiol Lung Cell Mol Physiol 275(6):L1026-L1030
0002-9513/98 $5.00
Copyright © 1998 the American Physiological Society
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Abstract
Introduction
