Department of Biophysics, Universidade Federal de São Paulo, Escola Paulista de Medicina, 04023-062 São Paulo, Brazil
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ABSTRACT |
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Desensitization of ANG II tonic contractile response of the guinea pig ileum is related to membrane repolarization determined by Ca2+-activated K+ (maxi-K+) channel opening. ANG II-stimulated depolarized myocytes presented sustained activation of maxi-K+ channels, characterized by reduction from 415 to 12 ms of the closed time constant. ANG II desensitization was prevented by 100 nM iberiotoxin, being reversible within 30 min. Depolarization by KCl, higher than 4 mM, impaired desensitization, suggesting that the membrane potential must attain a threshold to counteract the repolarization induced by maxi-K+ channel opening. Once this value is attained, there is no time dependency because the desensitization process was shut off by addition of KCl along the time course of the tonic response. In contrast, the sustained ACh tonic component was not altered by these maneuvers. We conclude that desensitization of the ANG II tonic component is foremost due to the opening of maxi-K+ channels, leading to membrane repolarization, thus closing the voltage-dependent Ca2+ channels responsible for the Ca2+ influx that sustains the tonic component in this muscle.
isometric contraction; patch-clamp technique; acetylcholine; maxi-K+ channel; iberiotoxin
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INTRODUCTION |
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THE CONTRACTILE RESPONSE of the guinea pig ileum to stimulants, such as ANG II or ACh, depends on membrane depolarization, which leads to an increase of the intracellular free Ca2+ concentration (4). This increase is due to an enhanced Ca2+ influx, mainly through nonselective cation channels (NSCC) and/or voltage-dependent Ca2+ channels rather than the release of Ca2+ from intracellular pools (18, 27). ANG II, in addition to its potent vasoconstrictor action and other physiological effects, has a direct action on the guinea pig ileum (19, 21). Its contractile response presents two components: a fast and transient increase of the tonus, the phasic component, followed by a partial relaxation of the tissue to a sustained tonus, the tonic component. Prolonged treatment of this tissue with ANG II promotes a gradual decay of this component to near basal levels usually within 15 min (20). This response, named desensitization, does not occur when the guinea pig ileum is stimulated with ACh, since the tonic component remains sustained (1).
The molecular mechanisms underlying desensitization of AT1 receptor-mediated responses in vascular smooth muscles appear to involve receptor phosphorylation, downregulation, and internalization (29). In guinea pig ileum, it has been proposed that desensitization of the contractile response to ANG II may be due to a negative-feedback mechanism mediated by protein kinase C (PKC) affecting a step in the stimulus-response chain after phospholipase C activation (24). On the other hand, over the last years, the reports converge to the concept that K+ channels may be an important cell strategy for controlling smooth muscle function (6). The relationship between increased K+ channel activity and smooth muscle relaxation was explored in many tissues and K+ channel types, such as ATP-dependent K+ channels in intestinal smooth muscles (8), small-conductance Ca2+-dependent K+ channels in vascular smooth muscle (25), and high-conductance Ca2+-dependent K+ (maxi-K+) channels in vascular (9) and intestinal smooth muscles (28).
Maxi-K+ channels are ubiquitously distributed among tissues, and it has been suggested that they contribute to the resting potential (11, 26) and the repolarization of the action potential (3). In addition to its sensitivity to intracellular Ca2+ concentration and membrane potential (15), it has been reported that it is modulated by a wide variety of agents, including hormones, lipids, cyclic nucleotides, neurotransmitters, and PKC (for a review, see Ref. 2), thus providing a link between the metabolic and electric state of the cells. In a previous paper (23), we demonstrated that the pharmacomechanical coupling of ANG II to the AT1 receptor is well preserved in high-K+ depolarized longitudinal myocytes of the guinea pig ileum by indirect and persistent activation of maxi-K+ channels. This long-lasting ANG II effect contrasts with the suppression of Ca2+-dependent K+ currents by ACh in other tissues (7, 13), so that it raises a major possibility that there is a close relationship between ANG II desensitization and maxi-K+ channel activity.
In this study, we explored the role of maxi-K+ channel on the desensitization mechanism of the guinea pig ileum to ANG II. We compared the maxi-K+ channel activity resulting from prolonged treatment of the cells with ANG II and ACh and studied the contractile response to these agonists when the membrane potential was altered, by either blocking maxi-K+ channel activity or adding KCl in the physiological solution. We conclude that desensitization of the tonic component of the contractile response to ANG II is largely due to the sustained opening of maxi-K+ channel population, leading to repolarization of the membrane potential, thus closing the voltage-dependent Ca2+ channels responsible for the Ca2+ influx that sustains the tonic component in this smooth muscle.
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METHODS |
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Animals. Either male or female albino guinea pigs, weighing between 200 and 250 g, were used in this study.
Cell preparation. Guinea pig ileum smooth muscle cells were isolated according to the method described by Romero et al. (23). Briefly, 2.5-cm segments of the longitudinal muscle layer of the guinea pig ileum were washed in 5 ml of Ca2+-free solution and exposed to Ca2+-free solution containing 0.5 mg/ml collagenase, 0.3 mg/ml pronase (from Streptomyces griseus), and 2.0 mg/ml BSA for 7 min at room temperature. The enzymatic digestion was interrupted by washing the tissue fragments in high-Ca2+ solution containing 2.0 mg/ml BSA and 0.1% trypsin inhibitor. The digested fragments were rinsed in Ca2+-free solution, and the cells were released by successively drowning the tissue fragments in and out of a blunt glass pipette. Cells were collected by centrifugation at 700 g for 30 s, and the cell pellet was resuspended in Ca2+-free solution, seeded on circular coverslips, and kept at 4°C for 1 h. At the time of the experiment, one coverslip was washed with the appropriate saline solution and transferred to the stage of a microscope for electrophysiological measurements.
Recording techniques.
Single-channel currents were recorded using either the inside-out or
cell-attached modes of the patch-clamp technique (10). Patch electrodes
were made of borosilicate glass (Garner Glass, Claremont, CA) through a
two-stage puller (model PP-83; Narishige, Japan) and fire-polished
(model MF-83 forge; Narishige) to a final pipette tip resistance of
5-10 M. A 1 M KCl-agar bridge connecting the Ag-AgCl reference
electrode was used to ground the bath solution. The cells and the
electrode were visualized with an inverted microscope (model Diaphot,
Nikon, Japan). Single-channel currents were captured and amplified
through a patch-clamp amplifier (EPC7; List Electronics, Darmstadt,
Germany) and were stored on videotape (model PVC-6000; Philco-Hitachi,
São Paulo, Brazil) through an analog-to-digital converter (model
DR-384; Neuro-Corder, Neuro Data Instruments, New York, NY). Data were
displayed on-line or from the videotape to a physiograph (model RS
3200; Gould, Cleveland, OH) and to an oscilloscope (model MO 1221;
Minipa, São Paulo, Brazil) via a low-pass filter (8-pole Bessel
filter; Frequency Devices, Haverhill, MA) at 3 kHz. All experiments
were done at room temperature and at
40 mV membrane potential.
Data acquisition and analysis.
Currents were acquired through a 16-bit analog-to-digital converter
(TL-1 DMA interface; Axon Instruments, Foster City, CA) controlled by
the Fetchex software (pClamp 5.1, Axon). Records were analyzed using
the computer program Transit (version 1.0, kindly offered by R. Latorre, Universidad de Chile). The duration and amplitude of each
current level were determined using idealized records from the original
data, constructed through the recognition of the transitions between
distinct levels. Transitions were detected any time
dI/dt
(where I is current amplitude) was
higher than the slope threshold criterion, usually set at ±3 of
the mean baseline noise.
NPo values, where
N is the number of channels in the
patch available to open and
Po is the open
probability of the channel, were calculated by the ratio of the mean
current to the unitary single-channel current. The mean current was
obtained from the amplitude current distribution histogram, using the
following expression:
Imean = A1f1 + A2f2 + ...... Anfn,
where A1,
A2, and An represent the
area under the Gaussian curve for each current level
(f1,
f2,
fn) present in
the patch.
Tension measurements. Guinea pig ileum longitudinal smooth muscle strips were prepared as previously described (22). Segments of the longitudinal muscle ileum (3-3.5 cm) were suspended in a 5-ml chamber containing Tyrode solution at 37°C and bubbled with air. The isometric tension was recorded through a Narco Bio-System model F-60 force transducer connected to an ECB model 102-B potentiometric recorder. The agonist concentrations used were maximal, the time contact of the tissues with the agonist was 15 min, and a control response was obtained before any experimental protocol and between two successive agonist challenges after a 30-min resting period to fully recover the initial contractile response (21).
Solutions and drugs. The following solutions were used for isolation of the cells. Ca2+-free solution contained (in mM) 132.4 NaCl, 5.9 KCl, 1.2 MgCl2 · 6H2O, 11.5 glucose, and 10 HEPES, pH 7.4 (1 M NaOH), in the presence of 100 U/ml penicillin and 100 µg/ml streptomycin. For high-Ca2+ solution plus albumin, 2.0 mg/ml BSA and 2.5 mM CaCl2 · 2H2O were added to Ca2+-free solution. For patch-clamp experiments, the composition of both the bath and pipette solutions was (in mM) 150 KCl, 1 MgCl2 · 6H2O, and 10 HEPES, pH 7.4 (1 M KOH), referred to as high-K+ solution. In cell-attached experiments, all chemicals were added to the cells by perfusion of homogeneous solutions, and data were obtained after 3 min, so that the complete substitution of the volume of the chamber was guaranteed. The composition of the Tyrode solution was (in mM) 137 NaCl, 2.68 KCl, 1.36 CaCl2 · 2H2O, 0.49 MgCl2 · 6H2O, 12 NaHCO3, 0.36 NaH2PO4, and 5.5 D-glucose.
Chemicals. All chemicals were of analytical grade. Penicillin, streptomycin, HEPES, trypsin inhibitor, BSA, iberiotoxin, and ACh were purchased from Sigma (St. Louis, MO). Collagenase I (217 U/ml) was from Worthington Biochemical (Freehold, NJ), and pronase was from Boehringer (Mannheim, Germany). ANG II and [2-lysine]ANG II (Lys2-ANG II) were purified peptides routinely synthesized in our laboratory. Stock solutions (1 mg/ml) were prepared in water and kept at 0°C, and an appropriate dilution was made at the moment of the experiment. Other salts and D-glucose were from Merck (Darmstadt, Germany).
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RESULTS |
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Indirect effect of ANG II and ACh on
maxi-K+ channel
activity.
To test the possibility that desensitization of the contractile
response might be related to repolarization of the membrane potential
through activation of K+ channels,
we compared the effect of prolonged exposure of the guinea pig
intestinal myocytes, bathed in
high-K+ solution, to maximal
concentration of 107 M ANG
II and 10
6 M ACh on
maxi-K+ currents recorded through
cell-attached configuration of the patch-clamp technique at
40
mV membrane potential. ANG II invariably enhanced
maxi-K+ channel activity by
keeping NPo
values elevated as long as the peptide was maintained in the bath
solution, as already reported by Romero et al. (23). It usually caused
simultaneous channel openings as illustrated by the multiple current
levels in Fig. 1. Contrasting with ANG II,
prolonged exposure to maximal ACh concentration caused quite variable
effects on maxi-K+ channel
activity: a transient activation returning to the control activity
within 12 min even in the presence of ACh in the bath solution (Fig. 1;
in 4 of 8 experiments), no effect at all (data not shown; in 2 of 8 experiments), or a sustained increase, which was reversible upon
washout (data not shown; in 2 of 8 experiments). In this latter group,
the ACh activation was lower than that caused by ANG II challenged at
the same patches. The observed sustained Po induced by ANG
II strongly suggests that relaxation of the whole tissue might be
related to the repolarization of the cell.
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Desensitization and membrane potential.
If a sustained activation of
maxi-K+ channels by ANG II would
repolarize the cell, leading to tissue relaxation, it would be expected
that maxi-K+ channel blockers
would interfere with the desensitization of its contractile response.
Thus we investigated the effects of iberiotoxin, a specific
maxi-K+ channel blocker (5), on
the contractile response of the muscle tissue to ANG II, its synthetic
analog Lys2-ANG II, or ACh.
Because there were no previous reports that the maxi-K+ channels present in our
experimental model are sensitive to iberiotoxin, we first tested its
effect at single-channel level, in inside-out patches of longitudinal
layer myocytes bathed in symmetrical
high-K+ solutions. Iberiotoxin
(100 nM) in the pipette solution inhibited the channel activity in a
similar pattern as it is usually described for this toxin blockade in
other tissues (5). The channel presented prolonged silent periods
lasting several seconds alternated with bursts of activity (data not
shown), a quite different behavior as compared with the usual activity
pattern recorded in the absence of the blocker (23). In whole tissue
experiments, 100 nM iberiotoxin increased the fluctuation of basal
tension as well as ANG II and ACh-induced tonic contractions.
Furthermore, this blocker completely prevented the desensitization of
the tonic contraction to
107 M
Lys2-ANG II (or
10
6 M ANG II) applied 5 min
after the toxin, while the steady amplitude of the ACh tonic component
was not altered (Fig. 3). For all agonists, the contractile waveform did not fully recover within 30 min, as
assessed by the delayed onset for dissipation of the
Lys2-ANG II tonic component and
slower increase of the tonus for ACh (Fig. 3).
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DISCUSSION |
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In this study we provide evidence that desensitization of the contractile response induced by ANG II in the longitudinal layer of the guinea pig ileum is intimately related to the membrane potential. This conclusion was supported by the fact that ANG II activated maxi-K+ channels in cell-attached patches and the desensitization of the contractile response was abolished by iberiotoxin and elevation of extracellular K+ concentration.
In intestinal smooth muscles, ACh and ANG II share some common pathways of the transduction signaling. Both activate a NSCC population (12, 17) promoting Ca2+ and/or Na+ influx, depolarization, activation of L-type Ca2+ channels, rise in intracellular Ca2+ concentration, and thus contraction. In guinea pig ileum, the NSCC channels activated by ACh and ANG II present different characteristics. Although both are permeable to Ca2+, the first is very sensitive to intracellular Ca2+ (12), whereas the second is not, being a Na+- and voltage-sensitive channel (17). Both receptors, namely, the AT1 and M3 muscarinic receptors, are coupled to the Gq/G11 protein class (16, 30). However, the effector response differs in the maintenance of the tonic component during prolonged contact of the tissue with ANG II or ACh. ANG II invariably promotes dissipation of the tonic component to basal level (desensitization), whereas ACh does not (1; Fig. 5).
In cell-attached membrane patches, prolonged treatment of the myocytes
with ANG II peptides promoted a sustained increase of the
maxi-K+ channel activity (23; Fig.
1). Because the pharmacomechanical coupling of ANG II to its receptor
was preserved in this preparation (23), it was attractive to verify
whether there is a relationship between the enhanced
maxi-K+ channel activity that
would lead to the repolarization of the membrane potential and the
dissipation of the ANG II tonic contractile response (Fig. 3). ACh was
used as a counterproof in the electrophysiological studies as well as
in the whole tissue contraction experiments. In contrast to the
homogeneity of the sustained increase of
maxi-K+ channel activity in
long-term ANG II-stimulated myocytes (Fig. 1), ACh caused variable
responses. Most of the cells tested presented transient (50% of the
cells) or no activation (25%) of
maxi-K+ channels, and just in 25%
of the ACh-stimulated cells there was a sustained
maxi-K+ channel activation,
although lower than the ANG II effect. Similarly, ACh-induced
contractile response of the guinea pig ileum also presented some
variability concerning the amplitude of the steady tonic component,
which however never attains basal level in the presence of this
agonist. The most usual ACh waveform presents a tonic component already
sustained at its onset (Fig. 5), and in a few cases, there is a partial
relaxation before a steady level is attained (Fig. 5,
inset). This parallelism between
ACh-induced maxi-K+ channel
activity and ACh contraction suggests that the major contribution to
the most usual ACh contractile response results from myocytes that
presented transient or no activation of
maxi-K+ channels. This would lead
to a sustained depolarization of the cell membrane, favoring
Ca2+ currents through L channels,
and thus contraction. On the other hand, the observations that
iberiotoxin increased the fluctuation of basal and stimulated tension
in ACh contraction (Fig. 3) and the partial relaxation of the tonic
component in 25% of the cases (Fig. 5,
inset) indicate an active
involvement of maxi-K+ channels
throughout the contraction induced by this agent. However, the eventual
repolarization of the membrane potential, as a consequence of
maxi-K+ channel activity, would
not be enough to overcome the initial depolarization induced by ACh,
which involves activation of Ca2+-
sensitive NSCC (12) sustaining the depolarization level of the
membrane. In the case of ANG II, on the contrary, the cell balance does
converge to the repolarization of the cell membrane and thus relaxation
of the tissue. Indeed, repolarization due to sustained
maxi-K+ channel activation would
exert a negative-feedback modulation on L-type
Ca2+ channels. The
nondesensitization in the presence of iberiotoxin (Fig. 3) reinforces
the close dependency of maxi-K+
channel activity and modulation of the ANG II tonic component. When
this channel population is blocked, the contractile response to ANG II
is similar to the ACh contraction (Fig. 3), as sustained ANG II
depolarization should occur, probably by maintaining elevated the
Po of
voltage-dependent channels, mainly NSCC and L channels, thus keeping
the tissue contracted. If this interpretation is correct, then any
maneuver causing membrane depolarization should prevent this
phenomenon. Indeed, exposure of the tissue to KCl concentrations, which
did not cause a sustained response per se, prevented the fade of the
ANG II tonic component (Fig. 4) and did not alter the time
course of the most usual ACh response (Fig. 5). Moreover, it appears
that the membrane potential must attain a threshold to counteract the
repolarization induced by maxi-K+
opening (Fig. 4), but once it is attained, there is no time dependency along the tonic component because the desensitization process was shut
off by addition of KCl at any moment of the tonic response time course
(Fig. 6). This prompt response suggests that the balance of
the voltage-dependent channels recruited by ANG II
(maxi-K+, NSCC, and L channels) is
a very effective regulatory mechanism for the contractility of the
guinea pig ileum. However, our data also suggest that this is probably
not the only mechanism underlying desensitization, since it is not
clear how ACh and ANG II, which initiate their response through the
same G protein (16, 30), may present differential channel type
coupling. Our data convey the notion that the two receptors must
differentially activate distinct G proteins and hence balance the types
of channels activated and the responses achieved. Nevertheless, some
caution is required for this straightforward conclusion because no data
are yet available focusing this intriguing point, and alternatively,
the signaling transduction of one or both agonists may involve other
pathways. It has been shown that tyrosine kinase activity is of great
functional importance in regulating muscarinic NSCC in guinea pig ileum
(for a review, see Ref. 14) or that muscarinic activation enhanced production of arachidonic acid, thereby increasing
Ca2+ influx into the cell (14).
Another point liable to speculation concerns the molecular mechanism
for the gating properties of the channels recruited by ACh and ANG II.
It has been proposed that the concentration of active G protein
-subunits might critically determine the state of voltage dependence
of the channel (14). Furthermore, one must also consider that different
,
-subunits can also regulate a number of cellular effectors,
including ionic channels (14). Finally, we cannot rule out the
involvement of PKC or some other unknown intracellular mechanisms that
transduce cell-surface signals to the channel proteins (14), which
might be different according to the agonist used. Indeed, it has been proposed that desensitization to ANG II in guinea pig ileum may be due
to a negative-feedback mechanism exerted by PKC on a step of the
stimulus-response chain after phospholipase C activation (24).
In conclusion, ANG II desensitization in guinea pig ileum is likely to rely on membrane repolarization, assigning a relevant role to maxi-K+ channel population to the modulation of this phenomenon, although the precise type and contribution of G protein other than Gq/G11 remains unclear.
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ACKNOWLEDGEMENTS |
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We are grateful to Nelson A. Mora, Chandler Tahan, Andréa Simonato, and Alexandre L. F. Pascotto for technical assistance.
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FOOTNOTES |
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B. A. Silva was on a fellowship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior.
This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico and Fundação de Amparo à Pesquisa do Estado de São Paulo.
Present address of B. A. Silva: Laboratório de Tecnologia Farmacêutica, Universidade Federal da Paraíba, Paraíba, PB, Brazil.
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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: J. Aboulafia, Departamento de Biofísica, Universidade Federal de São Paulo, Escola Paulista de Medicina, Rua Botucatu 862, 7° andar. CEP 04023-062 São Paulo, Brazil (E-mail: jan{at}biofis.epm.br).
Received 16 March 1999; accepted in final form 6 July 1999.
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