Department of Physiology and Biophysics and Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905
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ABSTRACT |
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Intracellular
recordings were made from the circular smooth muscle cells of the
canine jejunum to study the effect of exogenous ATP and to compare the
ATP response to the nonadrenergic, noncholinergic (NANC) inhibitory
junction potential (IJP) evoked by electrical field stimulation (EFS).
Under NANC conditions, exogenous ATP evoked a transient
hyperpolarization (6.5 ± 0.6 mV) and EFS evoked a NANC IJP (17 ± 0.4 mV). -Conotoxin GVIA (100 nM) and a low-Ca2+,
high-Mg2+ solution abolished the NANC IJP but had no effect
on the ATP-evoked hyperpolarization. The ATP-evoked hyperpolarization
and the NANC IJP were abolished by apamin (1 µM) and
NG-nitro-L-arginine (100 µM).
Oxyhemoglobin (5 µM) partially (38.8 ± 5.5%) reduced the amplitude
of the NANC IJP but had no effect on the ATP-evoked hyperpolarization.
Neither the NANC IJP nor the ATP-evoked hyperpolarization was affected
by P2 receptor antagonists or agonists, including suramin, reactive
blue 2, 1-(N,O-bis-[5-isoquinolinesulfonyl]-N-methyl-L-tyrosyl)-4-phenylpiperazine, pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid,
,
-methylene ATP, 2-methylthioadenosine 5'-triphosphate
tetrasodium salt, and adenosine 5'-O-2-thiodiphosphate.
The data suggest that ATP evoked an apamin-sensitive hyperpolarization
in circular smooth muscle cells of the canine jejunum via local
production of NO in a postsynaptic target cell.
nitric oxide; nonadrenergic, noncholinergic inhibitory junction potential; inhibitory innervation; small intestine
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INTRODUCTION |
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NONADRENERGIC, NONCHOLINERGIC (NANC) inhibitory nerves are widely distributed in the gastrointestinal tract, and they appear to play an important role in modulating motility (3). Electrical field stimulation (EFS) of enteric nerves in the presence of blockers of both cholinergic and adrenergic neurotransmission results in a NANC inhibitory junction potential (IJP) accompanied by smooth muscle relaxation. ATP (8, 10), nitric oxide (NO) (4, 31, 32), vasoactive intestinal peptide (VIP) (11, 18), pituitary adenylate cyclase-activating peptide (PACAP) (25, 30), and, recently, carbon monoxide (12, 29) have been proposed as mediators of NANC inhibitory neurotransmission.
NANC IJPs have been recorded in gastrointestinal smooth muscles of a number of mammals, including guinea pig, canine, mouse, and human. In human, guinea pig, and murine small intestine circular smooth muscle, the NANC IJP is a biphasic hyperpolarization consisting of an initial fast hyperpolarization followed by a slower, longer-lasting, and smaller-amplitude hyperpolarization (10, 31, 36). The fast component appears to be mediated by ATP, whereas the slow component appears to be mediated by NO (20, 31, 38). In contrast, in the canine jejunal circular smooth muscle, the NANC IJP consists of a fast uniphasic hyperpolarization, the amplitude of which is frequency dependent (32). Since the NANC IJP in the canine jejunum is completely abolished by NG-monomethyl-L-arginine and NG-nitro-L-arginine (L-NNA) and partially restored by L-arginine, it has been suggested that the final mediator of the NANC IJP in this tissue is NO (31, 32). However, when oxyhemoglobin (OxyHb), which binds and inactivates extracellular NO, was used for determining the source of endogenously formed NO, it was found that OxyHb only partially reduced the amplitude of the NANC IJP (32). The failure of OxyHb to completely abolish the NANC IJP raises the possibility that other inhibitory neurotransmitters are released along with NO.
Since 1970, when ATP was first proposed as a NANC inhibitory neurotransmitter by Burnstock and colleagues (8), there have been many convincing studies to support this hypothesis (10, 14, 38). For example, in the rat ileum, colon, and anococcygeus muscles, many of the neurons and nerve fibers in these tissues contain ATP, as evidenced by their quinacrine fluorescence (1). These neurons also contain nitric oxide synthase (NOS) indicating that some nitrergic nerves may use ATP as a cotransmitter (21). The aim of the present study was, therefore, to determine the effect of exogenously applied ATP on canine jejunal circular smooth muscle cells. A preliminary account of some of this work has been published as an abstract (39).
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MATERIALS AND METHODS |
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Adult mongrel dogs of either sex were anesthetized with thiopental
sodium, using a protocol approved by the Institutional Animal Care and Use Committee. After the abdomen was opened, a segment
of jejunum ~20 cm distal to the ligament of Treitz was removed and
placed in oxygenated Krebs solution at room temperature. Other organs
were removed by other investigators for other studies. The jejunal
segments were opened along their antimesenteric border and transferred
to fresh oxygenated Krebs solution at room temperature. The mucosa was
removed under a binocular microscope, and full-thickness muscle strips
(1 mm × 10 mm) were prepared with the long axis cut parallel to
the circular muscle layer. Muscle strips were then placed in a
recording chamber with the circular muscle facing up and pinned to a
Sylgard (Dow Corning, Midland, MI)-coated floor of the chamber to
record intracellular electrical activity. The chamber (3-ml volume) was
perfused with prewarmed (37°C) and preoxygenated Krebs solution at
a constant flow rate of 3 ml/min. After an equilibration period of at
least 2 h, the muscle strips were stretched to an initial tension of
250 mg from baseline tension. Recordings of intracellular electrical
activity from smooth muscle cells were obtained using glass capillary
microelectrodes that were filled with 3 M KCl and had resistances
ranging from 30 to 80 M. Intracellularly recorded potentials were
amplified using a WPI M-707 amplifier (WPI, New Haven, CT), displayed
on an oscilloscope (Tektronix 5113; Tektronix, Beaverton, OR), and
recorded on chart paper (Gould 220; Gould, Cleveland, OH) and also with
an FM tape recorder (Hewlett Packard 3964A; Hewlett Packard, San Diego,
CA). Two platinum wires placed parallel to the long axis of the
preparation and connected to a square wave stimulator (Grass 588;
Grass, Quincy, MA) and a stimulus isolation unit (Grass SIU 5A) were
used to apply EFS. Individual electrical pulses were of 0.35-ms
duration and 100- to 150-V intensity. The range of frequencies used was
1-30 Hz. ATP was administered by a pressure application device
(Picospritzer; General Valve, East Hanover, NJ). A micropipette
(10-µm diameter) filled with 0.1 M ATP was placed as close as
possible to the recording microelectrode site. Pressure pulses at 12 psi and 60-ms duration were used to deliver ATP. NO solutions were
prepared and applied using methods similar to those reported previously
(31).
The Krebs solution had the following ionic composition (mM): 137.4 Na+, 5.9 K+, 2.5 Ca2+, 1.2 Mg2+, 134 Cl, 15.5 HCO
3, 1.2 H2PO
4, and 11.5 glucose. The
solution was aerated with 97% O2-3% CO2 and maintained at pH 7.4. Atropine, propranolol, and phentolamine (each 1 µM) were present in all solutions used in this study. These drugs and
apamin, atropine sulfate, suramin, TTX,
-conotoxin GVIA,
L-NNA, phentolamine hydrochloride, propranolol
hydrochloride, ATP,
,
-methylene ATP (
,
-MeATP), reactive
blue 2, pyridoxal phosphate-6-azophenyl-2',4'-disulfonic
acid (PPAD), 2-methylthioadenosine 5'-triphosphate tetrasodium salt,
(2-MeSATP), (S)-5-isoquinoline sulfonic acid,
1-(N,O-bis-[5-isoquinolinesulfonyl]-N-methyl-L-tyrosyl)-4-phenylpiperazine (KN-62), adenosine 5'-O-2-thiodiphosphate (ADP
S),
substance P (SP), and VIP were obtained from Sigma Chemical (St. Louis,
MO). (p-Chloro-D-Phe6,Leu17)-VIP
[VIP-(6-17)], PACAP-(1-27), and PACAP-(6-38)
were obtained from Bachem California (Torrance, CA). OxyHb was prepared
as a hemolysate by a modification of the method of Bowman et al. (7). Briefly, red blood cells were obtained from the Mayo Clinic Blood Bank.
After the erythrocytes were washed three times with an isotonic phosphate buffer, 1 ml of washed red blood cells was added to 4 ml of
hypotonic phosphate buffer (20 mosM, pH 7.4) and kept at
4°C overnight to lyse the cells. Cell membranes were then removed by centrifugation at 20,000 g for 40 min. The concentration of hemoglobin in the supernatant was measured spectrophotometrically as met-hemoglobin. The solution was stored at
20°C and used
within two days of preparation.
Values in the text are expressed as means ± SE. Statistical significance was determined using paired and unpaired Student's t-test. A probability of <5% (P < 0.05) was considered significant.
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RESULTS |
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General observations.
Spontaneously occurring electrical slow waves were recorded with a mean
frequency of 8.9 ± 0.2 min (n = 10 cells from 10 preparations) and a mean amplitude of 10.5 ± 1.7 mV (n = 10 cells from 10 preparations). The mean maximum membrane potential
between slow waves was 59.4 ± 0.3 mV (n = 327 cells
from 108 preparations). Application of EFS (0.35-ms pulse width; 100 V)
with frequencies ranging from 1 to 30 Hz elicited a
frequency-dependent, fast monophasic NANC IJP, as previously described
(32). The mean peak amplitude of the NANC IJP at 30 Hz was 17 ± 0.4 mV (n = 120 cells from 90 preparations); the mean duration
measured from onset of EFS to the end of the IJP was 2,560 ± 66 ms
(n = 120 cells from 90 preparations). TTX (1 µM) abolished
NANC IJPs (17 ± 1.2 mV in control vs. 0 ± 0 mV in the presence of
TTX; P < 0.05; n = 3). NANC IJPs were
usually, but not invariably, followed by a rebound depolarization (Fig. 1), a common feature of NANC nerve-evoked
IJPs in gastrointestinal smooth muscle (2). We have no explanation for
why some preparations generated this rebound depolarization and others
did not.
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Response to exogenous ATP.
ATP (0.1 M) applied between electrical slow waves by a Picospritzer
evoked an immediate and transient (4-10 s) membrane
hyperpolarization. The mean amplitude of the hyperpolarizing response
was 6.5 ± 0.6 mV (n = 30 cells from 10 preparations). The
amplitude of the ATP-evoked response was significantly less compared
with the NANC IJP amplitude recorded from the same cells (6.5 ± 0.6 mV vs. 16 ± 0.6 mV; P < 0.05). The times to 50% maximum
amplitude and to peak amplitude of the ATP-evoked hyperpolarizing
response were 674 ± 45 ms and 945 ± 26 ms, respectively (n = 10 cells from 10 preparations). For the NANC IJP (30 Hz), these
values were 556 ± 34 ms and 781 ± 52 ms, respectively (n = 10 cells from 10 preparations). A typical hyperpolarizing response to
exogenous ATP is shown in Fig. 2B. Note that a rebound depolarization followed the ATP-evoked
hyperpolarization. In 19 cells from 10 preparations, the mean amplitude
of the rebound depolarization was 4.4 ± 0.6 mV. The
hyperpolarizing response evoked by ATP (0.1 M) and the NANC IJP
recorded in the same cell were compared by superimposition (Fig.
2C) and by measuring the rate of membrane hyperpolarization
between 25% and 75% of the maximum amplitude. The rate of
hyperpolarization evoked by ATP was 13.7 ± 2.5 mV/s, whereas the rate
of hyperpolarization of the NANC IJP was 36.5 ± 3.9 mV/s (P < 0.05). The significantly slower rate of hyperpolarization of the
ATP response compared with the NANC IJP most likely was due to
diffusional delay of the exogenously applied ATP to its receptor site.
ATP-evoked responses were unaffected by TTX (1 µM; 5.1 ± 1.2 mV in
control vs. 5.5 ± 1.1 mV in the presence of TTX; P > 0.05;
n = 2 cells from 2 preparations). Application by a
Picospritzer of the vehicle used to dissolve ATP had no effect on
membrane potential and no effect on electrical slow waves (n = 3).
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Response to exogenous NO. NO (1% vol/vol) applied between slow waves by a Picospritzer evoked a membrane hyperpolarization similar to that previously described (31, 32). The amplitude of the hyperpolarizing response was 9.8 ± 0.9 mV (n = 3). In the presence of apamin (1 µm), the NO-evoked hyperpolarization was significantly reduced to 1.3 ± 0.3 mV (P < 0.05; n = 3).
Effect of purinergic receptor agonists and antagonists on the
response to EFS and exogenous ATP.
In visceral tissues, the apamin-sensitive component of the NANC IJP is
thought to be mediated by ATP via a P2 receptor (40). We tested for the
possibility that the P2 receptor mediated the apamin-sensitive
ATP-evoked hyperpolarizing response and the apamin-sensitive NANC IJP.
Preparations were superfused with suramin or reactive blue 2, two
putative nonselective P2 receptor antagonists (13). Suramin up to 100 µM had no effect on the NANC IJP (Figs.
5A and 6B) and also had no
effect on the ATP-evoked hyperpolarization (Figs. 5A and
6A). Reactive blue 2 up to 300 µM also failed to inhibit the
NANC IJP and the hyperpolarizing response to exogenous ATP (Figs.
5B and 6). Preincubation with ,
-MeATP, a P2X receptor agonist (13), for 30 min to desensitize the receptor had no effect on
the NANC IJP and no effect on the ATP-evoked hyperpolarization (Figs.
5C and 6). Other agonists and antagonists of the P2 receptor subtype, including the P2X antagonist PPAD (50 µM), the putative P2Y
agonists 2-MeSATP (50 µM) and ADP
S (100 µM), and the P2Z/P2X antagonist KN-62 (10 µM), were tested in 28 preparations. None of
these agonists nor this antagonist had an effect on either the NANC IJP
(Fig. 6B) or the ATP-evoked
hyperpolarization (Fig. 6A).
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Effect of SP. To determine the basis of the rebound depolarization that followed the NANC IJP, we tested the effect of desensitization of the tissue to exogenously applied SP. In four experiments, superfusion with SP (1 µM) depolarized the membrane by 13.2 ± 2.5 mV. After 30 min of pretreatment with SP, the membrane potential returned to the control level, and in the continuous presence of SP the amplitude of the rebound depolarization was 3.3 ± 0.3 mV, a value not significantly different from control (3.8 ± 0.5 mV; P > 0.05).
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DISCUSSION |
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The two key observations made in the present study were 1) L-NNA, a specific inhibitor of NOS, completely inhibited both the NANC IJP and the hyperpolarizing response to exogenously applied ATP, and 2) OxyHb reduced but did not completely inhibit the NANC IJP and had no effect on the ATP-evoked hyperpolarizing response. The effect of L-NNA implies a role for NO in both the NANC IJP and the ATP-evoked hyperpolarization, whereas the effect of OxyHb implies at least two different sites where NO was generated. The OxyHb-sensitive component most likely was due to NO released from intrinsic nerve fibers since there is ample evidence for the existence of nitrergic nerves in the circular muscle layer of canine (36), human (34), and guinea pig (15) intestines. Previous studies of mechanical and intracellular electrical activities have shown that the NANC inhibitory innervation is in part mediated by NO released from intrinsic nerves (5, 6, 31, 32). The present work confirms these observations.
The OxyHb-insensitive (but L-NNA-sensitive) component suggests that NO was formed, released, and physiologically active in target cells postsynaptic to the innervating NANC inhibitory nerves. The mediator of the OxyHb-insensitive (but L-NNA-sensitive) component of the NANC IJP became the focus of this study. Because ATP-containing nerves are present in the small intestine (1), and because there is ample evidence that ATP also functions as a mediator of the NANC IJP (10, 40), we investigated whether exogenously applied ATP could evoke a hyperpolarization in canine jejunal circular smooth muscle cells and whether the ATP response was also OxyHb insensitive and L-NNA sensitive. The ATP hyperpolarizing response was completely inhibited by L-NNA and was OxyHb insensitive. These data suggest that ATP may function as a neurotransmitter mediating a part of the NANC IJP and that when ATP is released from intrinsic nerves, it causes the production of NO in the target cell. In a previous study on the canine ileum, Boeckxstaens et al. (5) found that exogenous ATP evoked an L-NNA-sensitive relaxation that was blocked by TTX and only partially inhibited by OxyHb, data similar to that obtained in the present study. Boeckstaens et al. (5) suggested that the portion of the ATP-evoked inhibitory response that was OxyHb insensitive was due to the inability of OxyHb to penetrate all actively transmitting sites at which NO was released. On the basis of the data obtained in the present study, we suggest that in the canine jejunum NO was inaccessible to OxyHb because it was generated in the target cell. In previous studies in the guinea pig gut, the NO-evoked component of the NANC IJP was found to be apamin insensitive, whereas the ATP-evoked hyperpolarization appeared to be apamin sensitive (6, 20). Others however, have reported that NO is responsible for the apamin-sensitive component of the NANC IJP (9, 38, 39). In the present study, both L-NNA and apamin abolished the NANC IJP, and exogenous NO evoked a hyperpolarization that was also nearly abolished by apamin. These data support the notion that NO mediated the apamin-sensitive component of NANC IJP in canine jejunum and that the blocking effect of apamin occurred after the formation of NO. Since ATP causes formation of NO, the effect of ATP would also be blocked by apamin, as observed.
The target cell for ATP was not intrinsic nerve fibers because TTX,
-conotoxin GVIA, and a low-Ca2+, high-Mg2+
solution had no effect on the ATP-hyperpolarizing response. These data
also indicate that the NO formed by the action of ATP did not diffuse
back to act presynaptically to enhance further release of
neurotransmitter(s). The target cell most likely was either the smooth
muscle cell or the network of the interstitial cells of Cajal (ICC).
Our results do not provide definitive evidence either way. Although
there is no information regarding the ability of ATP to generate NO in
small intestinal smooth muscle cells, it is known that other inhibitory
neurotransmitters such as VIP stimulate NO production in smooth muscle
cells (19), that endothelial NOS is present in human and rabbit
gastrointestinal smooth muscle (33), and that inducible macrophage NOS
is present in vascular (17) and uterine myometrial smooth muscle cells
(21). The possibility that the target cells were the ICC also has merit because ICC in the canine large intestine and rat small intestine may
contain the constitutive form of NOS (27, 37). The OxyHb-insensitive component of the NANC IJP and the OxyHb insensitivity of the
ATP-hyperpolarizing response would indicate that if NO was produced by
ATP in ICC, then the diffusional path of NO would had to have been
across an OxyHb-inaccessible pathway.
The nature of the receptor mediating the response to exogenously added
ATP is uncertain. The failure of the P2 receptor agonists and
antagonists tested, including ,
-MeATP, 2-MeSATP, ADP
S, suramin, reactive blue 2, PPAD, and KN-62, to inhibit the NANC IJP and
the hyperpolarizing response to exogenous ATP was a surprise. One
explanation for the failure of these agents to alter the NANC IJP and
the response to exogenous ATP is that none is completely selective for
the P2 receptor. An alternative explanation is that the action of ATP
was not mediated by a "classical" purinergic receptor. Although
we have no further evidence on this point, it is interesting to note
that in bovine brain arteries, activation of a K+ channel
and enhancement of intracellular Ca2+ concentration induced
by ATP appear to be caused by a direct action of ATP on the G protein
-subunits (24).
In many but not all myenteric neurons, NO is colocalized with VIP and/or PACAP, raising the possibility that these peptides, along with ATP, might also be released during EFS. The failure of either VIP or PACAP to evoke hyperpolarization as well as the failure of VIP and PACAP receptor antagonists to alter the NANC IJP rule out the possibility that either of these peptides was involved in inhibitory transmission.
There remains to be discussed the rebound depolarization seen following the NANC IJP and following the hyperpolarizing response to exogenous ATP. Similar effects of local application of ATP have been reported in the chicken rectum and guinea pig urinary bladder, suggesting that ATP may not only function as an inhibitory neurotransmitter but may also have a role as an excitatory neurotransmitter (26). Another possible explanation for the rebound depolarization may be related to the phenomenon known as purine-related rebound excitation (22). The messengers involved in this type of rebound excitation are unclear, but in the guinea pig taenia coli, mouse colon, and rat duodenum, it appears to involve prostaglandin synthesis since the cyclooxygenase inhibitor indomethacin attenuates the rebound effect (3). NO is also considered to be a possible candidate mediator for the rebound excitation because inhibitors of NOS greatly reduce the rebound excitatory response in canine colon (35). However, in the present study, the failure of L-NNA and OxyHb to block the rebound depolarization following the NANC IJP excludes the possibility of NO mediating this electrical phenomenon. Another possibility is that the rebound depolarization was mediated by the release of SP during EFS. However, this does not appear to be the case, since the rebound response was unaffected when the muscle was desensitized by prolonged exposure to SP.
In summary, exogenous application of ATP evoked an apamin-sensitive membrane hyperpolarization in canine jejunal circular smooth muscle cells. ATP appears to be involved in generation of the NANC IJP via production of NO in a postsynaptic target cell. The receptor mediating this action of ATP is unknown.
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ACKNOWLEDGEMENTS |
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We thank Gary Stoltz for technical assistance and Jan Applequist for secretarial assistance.
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FOOTNOTES |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-17238 and DK-52766.
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. H. Szurszewski, Dept. of Physiology and Biophysics, Mayo Clinic and Mayo Foundation, 200 First St. SW, Rochester, MN 55905 (E-mail: gijoe{at}mayo.edu).
Received 13 July 1999; accepted in final form 13 January 2000.
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