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-adrenoceptor signal transmission pathway in bovine trachealis
Servizio di Fisiopatologia Respiratoria, Dipartimento di Medicina Interna e Specialità Mediche, Università di Genova, 16132 Genova, Italy
Submitted 13 January 2003 ; accepted in final form 23 April 2003
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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-adrenoceptor (AR) pathway, including the receptor, the receptor-coupled
Gs protein, and adenylyl cyclase, were studied by simultaneous
measurements of acetylcholine (ACh) release and isometric force evoked by
electric stimulation in isolated bovine trachealis. The -AR agonists
isoproterenol (10-6 and 10-5 M) and salbutamol
(10-7 to 10-5 M) significantly attenuated both ACh
release and contractile force. Forskolin, at 10-6 M, significantly
increased ACh release without effect on contractile force, whereas at
10-5 M it increased ACh release but significantly decreased force.
Activation of Gs protein by cholera toxin (10 µg/ml)
significantly attenuated both ACh release and contractile force, but its
effect on ACh release was abolished by calcium-activated potassium
(KCa)-channel blocker iberiotoxin (10-7 M). The
KCa-channel opener NS-1619 (10-4 M) attenuated
significantly both ACh release and contractile force. It is concluded that
-AR agonists attenuate cholinergic neurotransmission in isolated bovine
trachealis model by a mechanism not involving cAMP but KCa
channels. acetylcholine release; airway smooth muscle; Gs protein; cAMP; calcium-activated potassium channels
-adrenoceptors (ARs)
(3). Early studies based on
force measurement alone suggested that stimulation of -ARs inhibits
cholinergic neurotransmission
(1,
6,
10,
15). However, interpretation
of these data is seriously hampered by the large postjunctional effects of
-AR agonists. Studies based on direct measurement of ACh release from
guinea pig and horse trachealis have shown that stimulation of -ARs
enhances cholinergic neurotransmission in the absence
(4,
8,
19), but not in the presence,
of epithelium (18). Consistent
with the results of -AR stimulation
(4,
8,
19), direct activation of the
-AR-coupled Gs protein by cholera toxin (CTX), which
increases the activity of adenylyl cyclase
(9), caused an increase of ACh
release in epithelium-denuded guinea pig trachealis
(4). Moreover, direct
stimulation of adenylyl cyclase by forskolin
(16) or incubation with a cAMP
analog increased ACh release
(4), suggesting that
stimulation of the -AR pathway enhances cholinergic neurotransmission in
the airways. In airway smooth muscle cells, however, stimulation of
Gs protein directly opens large Ca2+-activated potassium
(KCa) channels
(11), which has been found to
decrease ACh release in guinea pig trachealis
(14). Therefore, it can be
hypothesized that -agonists have the potential to increase or decrease
ACh release depending on whether they mainly act through adenylyl cyclase or
KCa channels.
In the present study, we tested this hypothesis by simultaneous
measurements of electrically induced ACh release and force development in
bovine trachealis after stimulation of the components of the -AR signal
transmission pathway, either at the level of the receptor and the
receptor-coupled Gs protein or at the level of adenylyl cyclase,
and after direct opening or closing of KCa channels. Bovine tissue
was chosen because it is widely available and used as a model for studies on
airway responsiveness.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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Fifty tracheas were obtained from the local abattoir. Immediately after death of the animal, the trachea was removed and immersed in chilled (4°C) and aerated (95% O2-5% CO2) physiological salt solution (PSS) of the following composition: (in mM) 0.8 MgSO4, 1.2 KH2PO4, 3.4 KCl, 2.4 CaCl2, 110.5 NaCl, 25.7 NaHCO3, and 5.6 dextrose. After removal of the mucosa, rectangular muscle strips were prepared from the trachea.
Experimental Procedures
Studies on electrically induced ACh release and force. Two muscle
strips from each of 44 animals were mounted horizontally in 2-ml organ baths
containing aerated PSS at 37°C. Each muscle strip was tied at one end to a
stationary wire platinum electrode and the other to a wire platinum electrode
connected to a force transducer (LC 4001 G0120, Litra) attached to a
micromanipulator. The tissues were superfused and loaded with
[3H]choline by two circuits connected to a calibrated roller pump
(Gilson Miniplus 3, Villiers Le Bel, France). One circuit was used to
superfuse and incubate the tissues with drugs, and the other was used for
loading of muscles with [3H]choline. Both muscles were superfused
at a flow of 1 ml/min with aerated PSS at 37°C containing 10-5
M indomethacin, 10-6 M propranolol (except for the studies with
-agonists), and 10-6 M choline chloride. They were contracted
simultaneously every 5 min for 30 s by electric stimulation at 25 Hz, 25 V,
0.5 ms from a direct current amplifier triggered by a stimulator (S44, Grass
Medical Instruments, Quincy, MA). The lengths of the muscles were
progressively increased until constant and maximal contractile responses to
electric stimulation resulted (optimal length). The lengths were not altered
during the experiments. Isometric forces of the muscles were recorded
continuously throughout the studies (Linseis L 250 E recorder, Selb, Germany).
For loading with [3H]choline, muscles were superfused at a flow of
2 ml/min with PSS containing 1.5 µCi/ml (specific activity 75 Ci/mM).
During loading, the muscles were stimulated continuously by electric
stimulation (25 Hz, 25 V, 0.5 ms) for 30 min to enhance neuronal uptake of
[3H]choline. After loading, the muscles were washed with PSS at a
flow of 20 ml/min to wash out [3H]choline not taken up by the
muscles. The PSS used for washing contained hemicholinium-3 (10-5
M) to inhibit neuronal uptake of choline. After 120 min of washout, the
superfusion flow was reduced to 1 ml/min, and collection of the superfusates
from both muscles began. This time point is referred to as time zero
(t0, where the subscript refers to the minute number).
Superfusates were collected separately but simultaneously from both muscles
for 3 min each in scintillation vials containing 14 ml of liquid scintillation
cocktail (Ready Safe Beckman Coulter, Fullerton CA). The collection of
superfusates was only temporarily interrupted to allow proper incubation with
drugs. Superfusates were assayed for radioactivity by a liquid scintillation
counter (LS 6500 multipurpose scintillation counter, Beckman Instruments).
Each vial was assayed three times for 5 min, and the average value was used.
The radioactivity was corrected for background counts [19 disintegrations/min
(dpm)]. All muscles were blotted dry and weighed at the end of each study.
Studies on exogenous ACh-induced force. Seven muscle strips from each of five animals and four strips from one animal were mounted vertically in 25-ml glass-jacketed tissue baths. The muscles were suspended between two vertical platinum electrodes (1 x 4 cm) in PSS (37°C) aerated with 95% O2 and 5% CO2. The lower ends of the muscles were tied to stationary hooks and the upper ends to force transducers (model FT03, Grass Medical Instruments) mounted on micromanipulators. This arrangement allowed the muscles to be gradually stretched to their optimal length and the isometric force to be continuously recorded (Gould model TA, 4000, Valley View, OH). The muscles were equilibrated with the PSS for 2 h while electric field stimulation (25 Hz, 25 V, 0.5 ms) was applied (model S44, Grass Medical Instruments) every 5 min. The muscles were stretched after each stimulation until the optimal length had been achieved; this length was not altered during the studies.
Effects of -agonists and forskolin on electrically induced ACh
release and force. Two muscles from each of 28 animals were used. At
t18, the first electric stimulation (4 Hz, 25 V, 0.5 ms)
was applied to both muscles for 3 min. At t39, superfusate
collection was stopped and 10-6 M isoproterenol (n = 6),
10-6 M salbutamol (n = 6), or 10-6 M forskolin
(n = 6) was added to one muscle of each pair, while the other muscle
was incubated with PSS alone to serve as control. At t48,
superfusate collections were resumed, and a second electric stimulation was
applied again at t66. A third electric stimulation was
applied after isoproterenol, salbutamol, or forskolin had been added to reach
cumulative concentrations of 10-5 M
(Fig. 1). In separate
experiments, S1 and S2 were applied before and after
muscle incubation with 10-7 M isoproterenol (n = 3),
10-7 M salbutamol (n = 4), or 10-7 M forskolin
(n = 3).
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Effects of -agonists and forskolin on response to exogenous
ACh. Muscle strips from six animals were used. Six strips from each of
five animals and three strips from one animal each were incubated for 30 min
with two of the following drugs: isoproterenol (10-7,
10-6, and 10-5 M), salbutamol
(10-7,10-6, and 10-5 M), forskolin
(10-7,10-6, and 10-5 M). One strip from each
animal served as control. Thereafter, ACh was added cumulatively from
10-9 to 10-5 M in half-log increments. Force was
measured after a plateau of response to each concentration increment had been
attained.
Effect of CTX on electrically induced ACh release and force. Two muscles from each of six animals were used. At t18, electric stimulation (4 Hz, 25 V, 0.5 ms) was applied to both muscles for 3 min. At t39, superfusate collection was stopped, and 10 µg/ml CTX was added to one muscle of each pair, while the control muscle was incubated with PSS alone. At t162, superfusate collections were resumed, and electric stimulation was applied again at t180.
Effect of NS-1619 on electrically induced ACh release and force. Two muscles from each of six animals were used. At t18, electric stimulation (4 Hz, 25 V, 0.5 ms) was applied to both muscles for 3 min. At t39, superfusate collection was stopped, and 10-4 M NS-1619 was added to one muscle of each pair, while the control muscle was incubated with PSS alone. At t71, superfusate collections were resumed, and electric stimulation was applied again at t89.
Effects of iberiotoxin on electrically induced ACh release and force. Studies on the effects of CTX and forskolin on ACh release and force were repeated, with the use of the same procedures as described above, in muscle strips from four additional animals by having the incubations with 10 µg/ml CTX or 10-5 M forskolin preceded by a 30-min incubation with 10-7 M iberiotoxin.
Drugs
Indomethacin, propranolol, choline chloride, isoproterenol, salbutamol, forskolin, CTX, NS-1619 {1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one}, iberiotoxin, and ACh were purchased from Sigma-Aldrich (Milan, Italy). Methyl [3H]choline was obtained from NEN Life Science Products (Boston, MA), and liquid scintillation cocktail Ready Safe was obtained from Beckman Coulter (Fullerton CA). Indomethacin, forskolin, and NS-1619 were dissolved in ethanol, and all other drugs were dissolved in distilled water.
Data Analysis
The [3H]ACh outflow was expressed as disintegrations per minute
per gram of tissue (dpm/g). The [3H]ACh releases evoked by
electrical stimulations 1, 2, and 3 were determined from the
three respective areas (A1, A2, and
A3, respectively) bounded by the extrapolated baseline
[3H]ACh outflow and all points above it
(Fig. 1). The
[3H]ACh releases evoked by electrical stimulations 2 and
3 (A2 and A3) and the
corresponding isometric forces (F2 and F3) in test
muscles were corrected for the effect of time on control muscles by using the
following equation: T2 or 3 corrected
=T1[(T2 or 3/T1) +
1 - (C2 or 3/C1)], where
T1 and C1 are ACh
release or force evoked by stimulation 1 in test and control muscles,
respectively. To evaluate the effects of drugs on [3H]ACh release
and contractile force, the ratios
A2/A1,
A3/A1, F2/F1,
and F3/F1 were calculated and compared with the
corresponding ratios of the control muscle. The concentration of exogenous ACh
causing a contractile response (g/g of tissue) of a magnitude similar to that
induced by electric stimulation was determined by interpolation of control
concentration-response curves and found to be close to 10-5 M.
Therefore, the effects of -agonists and forskolin on electrically
induced forces were compared with those induced by exogenous ACh at
10-5 M.
Data were tested for statistically significant differences by analysis of variance or Student's paired t-test. P < 0.05 was considered statistically significant. Data are presented as means ± SD.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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Effects of Isoproterenol
The electrically induced [3H]ACh release was not significantly different between control muscles and muscles incubated with 10-7 M isoproterenol, but it was reduced significantly by 18 ± 11% (P < 0.05) with 10-6 M isoproterenol and by 23 ± 9% (P < 0.01) with 10-5 M isoproterenol (Fig. 2A). The contractile response to electric stimulation was not significantly altered by 10-7 M isoproterenol, but it was significantly reduced by 35 ± 10% (P < 0.001) with 10-6 M isoproterenol and by 79 ± 27% (P < 0.001) with 10-5 M isoproterenol. The inhibitory effect of isoproterenol on the contractile response to exogenous ACh was significant at 10-6 and 10-5 M (P < 0.05), but it was significantly less at 10-6 and 10-5 M(P < 0.05) than on electrically induced force.
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Effects of Salbutamol
The electrically-induced [3H]ACh release was significantly reduced by 20 ± 15% (P < 0.05) in muscles incubated with 10-7 M salbutamol, by 25 ± 9% (P < 0.001) in muscles incubated with 10-6 M salbutamol, and by 28 ± 17% (P < 0.01) with 10-5 M salbutamol (Fig. 2B). The contractile response to electric stimulation was reduced by 36 ± 13% (P < 0.01), 71 ± 14% (P < 0.001), and 88 ± 9% (P < 0.001), respectively. The inhibitory effect of salbutamol on the contractile response to exogenous ACh was significant at 10-5 M (P < 0.05), and it was significantly less (P < 0.01) than on electrically induced forces.
Effects of Forskolin
The electrically induced [3H]ACh release was not significantly different between control muscles and muscles incubated with 10-7 M forskolin. It was significantly increased by 40 ± 31% (P < 0.01) in muscles incubated with 10-6 M forskolin and by 68 ± 23% (P < 0.001) with 10-5 M forskolin (Fig. 2C). The contractile response to electric stimulation was not significantly affected by forskolin at 10-7 or 10-6 M, but it was reduced significantly by 50 ± 27% (P < 0.05) at 10-5 M. The inhibitory effect of forskolin on contractile response to exogenous ACh was significantly less than in control muscles at 10-5 M forskolin (P = 0.01). Furthermore, the effect of forskolin on the contractile response to exogenous ACh tended to be greater than on electrically induced contractile response, although statistical significance was not achieved.
Effects of CTX
As compared with control muscles, the electrically induced [3H]ACh release was reduced by 33 ± 19% (P < 0.01) and contractile response by 20 ± 18% (P < 0.05) in muscles incubated with 10 µg/ml CTX (Fig. 3A).
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Effects of Iberiotoxin
In muscles preincubated with iberiotoxin, the inhibitory effect of CTX on electrically induced [3H]ACh release was abolished, whereas the inhibitory effect on contractile response was reduced (Fig. 3A). The enhancing effect of forskolin on electrically induced [3H]ACh release was not changed by incubation with iberiotoxin, whereas the inhibitory effect on contractile response was abolished (Fig. 3B).
Effect of NS-1619
In muscles incubated with 10-4 M NS-1619, the electrically induced [3H]ACh release was decreased by 32 ± 7% (P < 0.001) and force by 26 ± 12% (P < 0.01) compared with control muscles (Fig. 3C).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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-AR by isoproterenol or salbutamol or
stimulation of the receptor-coupled Gs protein by CTX attenuated
ACh release and contractile response to electric stimulation; 2)
stimulation of adenylyl cyclase by forskolin enhanced the electrically induced
ACh release but decreased contractile response; 3) inactivation of
KCa channels by iberiotoxin abolished the attenuating effect of CTX
on ACh release in response to electric stimulation but did not alter the
enhancing effect of forskolin; and 4) opening of KCa
channels by NS-1619 attenuated both electrically evoked ACh release and
force. Comments on Methodology
ACh release was inferred from measurements of tritium radioactivity on the basis of the assumption that the electrically evoked [3H] outflow is a reliable indicator for the release of neuronal ACh (5). In epithelium-denuded guinea pig trachealis, nerve endings primarily release [3H]ACh in response to electric field stimulation, without significant amounts of [3H]phosphorylcholine (17). In the present study, the mucosa was removed and mainly [3H]ACh should have been released, if responses of bovine and guinea pig trachealis to electric stimulation are similar. The effectiveness of nonradioactive choline in preventing or minimizing absorption of [3H]ACh to the walls of the experimental circuits was tested in one study. A circuit containing no muscle was perfused for 30 min with 1.5 µCi/ml [3H]choline. After 120 min of washout with PSS at 20 ml/min, the radioactivity of the superfusate contained only 19 dpm (equal to background counts), suggesting that radioactivity released from the circuit did not contribute to the measured radioactivity of the superfusates. The baseline radioactivity was therefore due to constant progressively decreasing spontaneous release of [3H]ACh from the muscles, which were not affected by any of test drugs.
To exclude a postjunctional effect of electric stimulation, one muscle from each of two additional animals was incubated with 10-6 M tetrodotoxin. Both ACh release and contractile response to electric stimulation were abolished (data not shown). To exclude noncholinergic responses to electric stimulation, one muscle from six animals was incubated with 10-6 M atropine. The contractile response to electric stimulation was abolished despite an increase of ACh release (data not shown).
Comments on Results
Airway smooth muscle tone and, by inference, airway responsiveness to
nerve-mediated constrictor stimuli depends both on the contractile properties
of the muscle and on the stimuli it receives. Therefore, any study based on
measurement of force alone cannot distinguish between changes in airway smooth
muscle contractility and neural stimulus. Only simultaneous measurements of
ACh release and force allow separate assessments. Indeed, studies based on
force measurements invariably led to the conclusion that -AR agonists
decreased airway cholinergic neurotransmission
(1,
6,
10,
15). But these findings can
also be explained by the potent inhibitory effect of -AR agonists on
airway smooth muscle contractility or by a dual effect on contractility and
cholinergic neurotransmission. More recent studies based on direct
measurements of ACh release have shown that stimulation of the components of
-AR pathway at any level resulted in an increase of ACh release in both
guinea pig (4,
8) and horse
(19), but not human
(4), trachealis. At variance
with these studies, we found that -AR agonists inhibited electrically
induced release of ACh in bovine trachealis. Different subtypes of -AR
may be present in airway smooth muscle or nerve endings. It is, however,
unlikely that a different distribution of -AR subtypes determined the
results of the present study because the effects of the
2-selective salbutamol and the nonselective isoproterenol on
ACh release and force were not different.
-AR agonists may stimulate not only pre- and postjunctional receptors
of airway smooth muscle, but also receptors of other tissues. Indeed,
inhibition of ACh release was observed
(18) when epithelium was
present and cyclooxygenase was not blocked. These data were interpreted as
suggesting that -AR agonists promote release of bronchodilator
prostaglandins from epithelial cells
(7). In the present study,
bovine trachealis was denuded from epithelium and incubated with indomethacin,
which rules out any effect mediated by epithelium-derived prostaglandins.
Second, the effect of -AR stimulation may differ depending on the
preferential intracellular signaling pathway.
Intracellular -AR signal transduction occurs via the receptor-coupled
Gs protein, which stimulates adenylyl cyclase to increase cAMP and
also directly activates KCa channels
(Fig. 4). At variance with
previous studies on trachealis from other animal species
(4), activation of
Gs protein by CTX resulted in a decrease of the electrically
induced ACh release from bovine trachealis, consistent with the effects of
isoproterenol and salbutamol in this species. By contrast, direct stimulation
of adenylyl cyclase by forskolin increased the electrically induced ACh
release, which is consistent with findings in guinea pigs
(4). Therefore, the increase in
cAMP does not appear to be the major mechanism for modulation of ACh release
by -AR agonists in this model of bovine trachealis.
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Activation of KCa channels hyperpolarize the cell membrane, thus
causing reductions of intracellular Ca2+ concentration and ACh
release in prejunctional cholinergic nerves
(12). Consistent with data
obtained in guinea pigs (14),
the selective KCa channel opener NS-1619
(13) attenuated the
electrically induced ACh release in bovine trachealis. Furthermore, the
KCa-channel blocker iberiotoxin abolished the inhibitory effect of
Gs protein on electrically induced ACh release. Because
transduction of -AR signal occurs via the receptor-coupled Gs
protein, these findings strongly suggest that KCa channels are
involved in the modulation of ACh release by -AR agonists in bovine
trachealis.
In the present study, simultaneous measurements of contractile force and
ACh release were obtained, which allowed distinction between pre- and
postjunctional effects of the compounds tested. Both isoproterenol and
salbutamol potently reduced electrically induced smooth muscle contraction
and, to a much lesser extent, ACh release, suggesting that the postjunctional
effects of -AR agonists exceeded the prejunctional effects. Expectedly,
both isoproterenol and salbutamol had a dose-related inhibitory effect on
contractile response, but their effect on electrically induced ACh release was
only weakly dose related. It is reasonable to assume that the number of
-AR on nerve endings is less than on airway smooth muscle cells and may
be, therefore, saturated at lower agonist concentrations. The greater effects
of -AR agonists on contraction induced by electric stimulation than
exogenous ACh suggests that their inhibitory effects on ACh release and airway
smooth muscle contractility are additive. Forskolin (10-6 and
10-5 M) increased ACh release, but only the higher concentration
attenuated smooth muscle contraction. These findings suggest that, at a low
concentration of forskolin, the inhibitory effect of the increase in cAMP on
airway smooth muscle contraction was offset by its enhancing effect on ACh
release. By contrast, with the high concentration of forskolin, the inhibitory
postjunctional effect prevailed over the stimulatory prejunctional effect. The
weaker protective effect of forskolin on contraction induced by electric
stimulation than exogenous ACh further supports this interpretation.
The KCa-channel blocker iberiotoxin abolished the inhibitory
effect of CTX on ACh release, suggesting that the prejunctional effect of
-AR pathway stimulation is mediated by KCa channels. Opening
of KCa channels in airway smooth muscle is also mediated by a
cAMP-induced increase in PKA concentration
(9). The enhancement of ACh
release by direct stimulation of adenylyl cyclase, which was not affected by
iberiotoxin, suggests that opening prejunctional KCa channels via
cAMP is not involved in the modulation of ACh release in bovine
trachealis.
In conclusion, the results of the present study in a model of bovine
trachealis show that -AR pathway agonists may attenuate ACh release by a
mechanism not involving adenylyl cyclase
(Fig. 4). Iberiotoxin abolished
the attenuating effect of CTX on electrically induced ACh release, suggesting
that KCa channels are involved in the modulation of cholinergic
neurotransmission by -AR agonists. This conclusion is further supported
by the observation that activation of KCa channels attenuated the
electrically induced ACh release. Further studies are needed to establish
whether -AR agonists can attenuate airway responsiveness to vagally
mediated stimuli in other species, including humans.
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DISCLOSURES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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ACKNOWLEDGMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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Original submission in response to a special call for papers on "Airway Hyperresponsiveness: From Molecules to Bedside."
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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2-adrenoceptors. J Appl
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2-Adrenoceptor activation
augments acetylcholine release from tracheal parasympathetic nerves.
Am J Physiol Lung Cell Mol Physiol
268: L950-L956,
1995.This article has been cited by other articles:
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  M. Baroffio, E. Crimi, and V. Brusasco Review: Airway smooth muscle as a model for new investigative drugs in asthma Therapeutic Advances in Respiratory Disease, June 1, 2008; 2(3): 129 - 139. [Abstract] [PDF]
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 V. Brusasco Reducing cholinergic constriction: the major reversible mechanism in COPD Eur. Respir. Rev., December 1, 2006; 15(99): 32 - 36. [Abstract] [Full Text] [PDF]
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, measurement of
radioactivity in a superfusate collection.
, broken line) and force
(
, solid line) induced by electric stimulation (4 Hz, 25 V, 0.5 ms, for
3 min), and on force induced by exogenous ACh (
, solid line) in bovine
trachealis. Percent inhibition and enhancements were normalized to control
responses. Bottom of each panel shows %inhibition; top of
each panel shows %enhancement. Note the dissociation between the effects of
10-5 M forskolin on ACh release and contractile force. Data are
means ± SD. See text for statistically significant differences.
