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1 Department of Physiology and Biophysics, 2 Division of Gastroenterology and Hepatology, and 3 Department of Surgery, Mayo Clinic, Rochester, Minnesota 55905
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The
neurotransmitter(s) that generates the fast component of the inhibitory
junction potential (IJP-F) in human jejunal circular smooth muscle is
not known. The aim of this study was to determine the role of ATP and
purinergic receptors in the generation of the IJP-F in human jejunal
circular smooth muscle strips. The P2-receptor antagonist suramin
(100 µM) reduced the IJP-F by 28%. Apamin (1 µM) reduced the IJP-F
by 25%. Desensitization of muscle strips with the putative
P2x-receptor agonist
,
-methylene ATP (,-MeATP, 100 µM) decreased the IJP-F by
44%, and desensitization with the putative
P2y-receptor agonist adenosine
5'-O-2-thiodiphosphate (ADPS) completely abolished the
IJP-F. Desensitization with the putative
P2y-receptor agonist
2-methylthioATP had no effect on the IJP-F. Exogenous ATP evoked a
hyperpolarization with a time course that matched the IJP-F. The
ATP-evoked hyperpolarization was reduced by apamin and suramin, reduced
by desensitization with ,-MeATP (69% decrease), and abolished by
desensitization with ADPS. These data suggest that the IJP-F in
human jejunal circular smooth muscle is mediated in part by ATP through
an ADPS-sensitive P2 receptor.
neurotransmission; microelectrodes; purinergic receptors
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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ELECTRICAL FIELD stimulation (EFS) of enteric nerves in the presence of blockers of both cholinergic and adrenergic receptors results in a nonadrenergic, noncholinergic (NANC) inhibitory junction potential (IJP) in mammalian gastrointestinal smooth muscle accompanied by smooth muscle relaxation (3). The NANC IJP can alter gastrointestinal motility by directly inducing smooth muscle relaxation as a result of membrane hyperpolarization or indirectly by inhibiting action potentials and hence decreasing contractility. The shape of the NANC IJP and the neurotransmitter(s) that mediates the NANC IJP have been studied extensively in various animal species. In the canine small intestine, the NANC IJP evoked by EFS consists primarily of a fast monophasic hyperpolarization, the amplitude of which is frequency dependent (21). The duration of the fast hyperpolarization evoked by EFS at 30 Hz is on the order of 2.5 s (21). The NANC IJP in the canine jejunum can be abolished by inhibitors of nitric oxide synthase (NOS) such as NG-nitro-L-arginine methyl ester (L-NAME) and NG-nitro-L-arginine (L-NNA); moreover, the change in membrane voltage evoked by exogenous application of nitric oxide (NO) mimics the IJP. These observations suggest that the IJP in canine small intestine is mediated by NO (21). In contrast, in human and guinea pig gastrointestinal circular smooth muscle, the NANC IJP consists of an initial fast hyperpolarization (IJP-F), similar to the IJP in the canine smooth muscle, followed by a slower, longer-lasting hyperpolarization of smaller amplitude (IJP-S). (7, 18-20). In human jejunal circular smooth muscle, EFS at 30 Hz evokes an IJP-F with a duration of 2 s followed by the IJP-S with a duration of about 13 s (20). A similar but less pronounced biphasic NANC IJP is also seen in guinea pig circular smooth muscle (7, 18-19). In both human and guinea pig, the NANC IJP-S can be abolished by pretreatment with L-NAME and L-NNA and mimicked by exogenous application of NO (13, 20). However, in both human and guinea pig, inhibitors of NOS have no effect on the IJP-F, suggesting it is not mediated by NO.
ATP was proposed by Burnstock and colleagues (4) in 1970 as a
NANC-inhibitory neurotransmitter in gastrointestinal smooth muscle.
Since then, convincing evidence supports this hypothesis (2, 12). In
guinea pig ileal circular smooth muscle, ATP mediates the
apamin-sensitive NANC IJP-F (9). Also in guinea pig ileal circular
smooth muscle, the NANC IJP-F appears to be mediated by ATP because it
is antagonized by ,-methylene ATP (,-MeATP) desensitization
and by reactive blue 2, a purinergic receptor agonist and antagonist,
respectively, and it is blocked by apamin, a blocker of a class of
small and intermediate conductance calcium-activated potassium channels
(9). ATP, acting through P2
receptors, is also implicated in the NANC IJP-F in guinea pig colonic
circular smooth muscle (16, 24).
The identity of the neurotransmitter mediating the NANC IJP-F in the human small intestine is, however, not known. The aim of the present study was to determine whether ATP mediates the IJP-F in human jejunal circular smooth muscle.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Smooth muscle of the human jejunum was obtained as surgical waste
tissue from 29 patients undergoing gastric bypass surgery for morbid
obesity after approval by the Institutional Review Board at the Mayo
Clinic. The segment of jejunum was taken ~30-45 cm from the
duodenojejunal junction and placed immediately in iced, preoxygenated
Krebs solution and transported to the laboratory consistently
within 30 min. The jejunal segments were opened along their
antimesenteric borders and transferred to fresh oxygenated Krebs
solution. After removal of the mucosal using a binocular microscope,
full-thickness muscle strips (1 × 10 mm) were prepared with the long axis cut parallel to the circular muscle. Muscle strips
were then placed in a 3-ml recording chamber with the circular muscle
facing up. One end of the muscle strip was pinned to a Sylgard-coated
(Dow Corning, Midland, MI) floor of the chamber to record intracellular
electrical activity, whereas the other end was attached to an isometric
force transducer to record mechanical activity. The chamber was
perfused with prewarmed (37°C) and preoxygenated Krebs solution at
a constant 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.
Intracellular electrical recordings were obtained from circular smooth
muscle cells using glass capillary microelectrodes filled with 3 M KCl and with resistances ranging from 30 to 80 M
.
Intracellular potentials were amplified using a WPI M-707 amplifier
(WPI, New Haven, CT) and displayed on an oscilloscope (Tektronix 5113, Tektronix, Beaverton, OR). Force was measured isometrically and
amplified with a bridge circuit amplifier. Both electrical signals and
mechanical activity were 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 parallel to
the long axis of the preparation and connected through 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 evaluated was 1-30 Hz with six pulses per application. ATP was administered by a pressure application device (picospritzer, General Valve Company, East Hanover, NJ). A micropipette (10 µm diam)
filled with 0.1 M ATP was placed as close as possible to the recording
electrode. Pressure pulses at 12 psi and 60-ms duration were used to
deliver ATP.
Krebs solution had the following ionic composition (in mM): 127.4 Na+, 5.9 K+, 2.5 Ca2+, 1.2 Mg2+, 134 Cl
, 15.5 HCO3, 1.2 H2PO4, and 11.5 glucose. The
solution was aerated with 97% oxygen-3%
CO2, and maintained at pH 7.4. Atropine, propranolol, and phentolamine (1 µM each) were present in
all solutions used in the study. These drugs and apamin, suramin, TTX,
L-NNA, ATP, ,-MeATP,
adenosine 5'-O-2-thiodiphosphate (ADPS), and
2-methylthioATP (2-MeSATP) were obtained from Sigma Chemical (St.
Louis, MO).
All observed values are expressed as the means ± SE. Statistical significance was determined using paired and nonpaired Student's t-test. P < 0.05 was considered significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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General observations.
The mean resting membrane potential recorded from circular smooth
muscle cells of the human jejunum was 
59.9 ± 0.4 mV
(n = 108 cells from 25 preparations).
EFS elicited IJPs and smooth muscle relaxation in all preparations. No
excitatory junction potentials were observed. The NANC IJPs evoked by
an EFS stimulus of six pulses, each 0.35 ms at 30 Hz, consisted of a
fast hyperpolarization (IJP-F: amplitude 26.7 ± 0.7 mV, duration
1.55 ± 0.1 s, n = 96 from 25 preparations) followed by a slow hyperpolarization (IJP-S: amplitude
4.8 ± 0.2 mV, duration 5.5 ± 2.3 s,
n = 96 from 25 preparations). The
amplitude and duration of both the IJP-F and IJP-S increased in a
frequency-dependent manner. A simultaneous recording of electrical and
mechanical activity showing the response to several different frequencies of EFS is shown in Fig. 1. The
characteristics of IJPs and smooth muscle relaxation in the human
jejunum were similar to those previously reported for the canine small
intestine (21).
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Effect of NOS inhibition on NANC IJP.
L-NNA (100 µM), an inhibitor
of NOS, had no effect on the IJP-F (26.2 ± 2.4 mV in Krebs solution
compared with 26.6 ± 2.2 mV in presence of
L-NNA,
P > 0.05, n = 5 from 5 preparations, Fig.
2A) but
completely abolished the IJP-S (5.5 ± 0.6 mV in Krebs solution
compared with 0 ± 0 mV in presence of
L-NNA,
n = 5 from 5 preparations,
P < 0.05, Fig.
2A).
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Effect of purinergic receptor agonists and antagonists on NANC IJP induced by EFS. Suramin (100 µM), a nonspecific P2-purinoceptor antagonist, was used to determine whether ATP, acting through P2 purinoceptors, mediated the NANC IJP-F and IJP-S. Suramin significantly reduced IJP-F (26.8 ± 1.2 mV in Krebs solution compared with 19.3 ± 1.8 mV in the presence of suramin, n = 5 from 3 preparations, P < 0.05, Fig. 2B) but had no significant effect on IJP-S (3.25 ± 0.8 mV in Krebs solution compared with 4.25 ± 1.8 mV in the presence of suramin, n = 5 from 3 preparations, P > 0.05, Fig. 2A).
In gut smooth muscle, the apamin-sensitive component of the NANC IJP is thought to be mediated by ATP (26). Apamin (1 µM) partially inhibited both the IJP-F and IJP-S. The amplitude of IJP-F evoked by EFS (6 pulses each of 0.35 ms at 30 Hz) was significantly reduced (27%) by apamin (28.5 ± 1.2 mV in Krebs solution compared with 20.5 ± 0.9 mV in the presence of apamin, n = 7 from 4 preparations, P < 0.001, Fig. 2C). The amplitude of the IJP-S was reduced by 58% (5.2 ± 0.5 mV in Krebs solution compared with 2.2 ± 0.3 mV in the presence of apamin, n = 7 from 4 preparations, P < 0.001, Fig. 2C). Increasing the concentration of apamin tenfold (10 µM) failed to further reduce the amplitude of either the IJP-F or IJP-S (data not shown).Effect of P2x- and
P2y-receptor agonists and antagonists on
NANC IJP.
To determine which subtype of P2
receptors mediated the effects of suramin and apamin on the IJP-F, the
putative P2x-receptor agonist
,-MeATP was used to desensitize the
P2x receptor. Tissues were
incubated for 30 min in ,-MeATP (100 µM), and the amplitude and
duration of the IJP were recorded. A transient hyperpolarization (6.6 ± 0.4 mV, n = 9 from 4 preparations) lasting 9.5 ± 1 min occurred on adding ,-MeATP
to the bath after which the membrane potential repolarized back to the
baseline value. After desensitization with ,-MeATP, the amplitude
of IJP-F decreased (35.5 ± 1.4 mV in Krebs solution compared with
20.0 ± 1.1 mV in the presence of ,-MeATP,
n = 9 from 4 preparations,
P < 0.05, Fig.
3A),
whereas the amplitude of IJP-S was unchanged (4.5 ± 0.4 mV in Krebs
solution compared with 5.4 ± 0.3 mV in the presence of
,-MeATP desensitization, n = 9 from 4 preparations, P > 0.05, Fig. 3A). Desensitization (30 min, n = 3 from 2 preparations) with
,-MeATP (100 µM) in the presence of apamin (1 µM) did not
further inhibit the IJP-F (Fig. 3B).
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S, both putative
P2y agonists, was also tested.
2-MeSATP had no significant effect on the amplitude of IJP-F (22.2 ± 1.9 mV in Krebs solution compared with 19.1 ± 2.4 mV in the
presence of 2-MeSATP, n = 3 from 3 preparations, P > 0.05, Fig.
3C) nor did it affect the amplitude
of IJP-S (3.2 ± 0.54 mV in Krebs solution compared with 2.5 ± 0.4 mV in the presence of 2-MeSATP,
n = 3 from 3 preparations, P > 0.05, Fig.
3C). In contrast, desensitization
for 20 min with ADPS (100 µM, n = 4 from 2 preparations) completely abolished the IJP-F (21.8 ± 2 mV
in Krebs solution compared with 0 ± 0 mV in the presence of
ADPS; P < 0.001, Fig.
4) without affecting the IJP-S (4.8 ± 0.6 mV in Krebs solution compared with 5.5 ± 1.3 mV in the presence
of ADPS, P > 0.05). A transient
hyperpolarization occurred on adding ADPS to the bath after which
the membrane potential repolarized back to the baseline
value. The transient hyperpolarization was not blocked by
TTX (1 µM, n = 2, data not shown),
suggesting that it was due to a postjunctional effect of ADPS. In
tissue strips pretreated with
L-NNA (100 µM,
n = 2 from 1 preparation), addition of
ADPS blocked completely both the IJP-F and the IJP-S (Fig.
4B). The effects of apamin, suramin, ,-MeATP, 2-MeSATP, ADPS, and
L-NNA on the IJP-F and the IJP-S are summarized in Fig. 5,
A and
B, respectively.
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Effect of exogenous ATP.
The partial inhibition of the IJP-F by the
P2-purinoceptor antagonist suramin
and by ,-MeATP desensitization, and the complete block of the
IJP-F by ADPS suggested that ATP, acting through P2 purinoceptors, was involved in
the generation of IJP-F. Therefore, the effect of exogenous ATP was
tested to determine if exogenous ATP, applied via a picospritzer, would
mimic the IJP-F. ATP (0.1 M) evoked a membrane hyperpolarization of 7.1 ± 0.6 mV with a duration of 16,571.4 ± 1,435 ms
(n = 43 from 19 preparations, Fig.
6). The time to 50% maximum amplitude and
to peak hyperpolarization were 1,200 ± 114.6 ms and 2,657.1 ± 193.6 ms, respectively (n = 33 from 14 preparations). The voltage trajectory of the initial hyperpolarizing
response evoked by exogenous ATP was similar to that of an IJP-F evoked
by EFS. The time to 50% maximum amplitude and to peak
hyperpolarization of the IJP-F were 760 ± 161 ms and 1,700 ± 220 ms, respectively (n = 9 from 5 preparations). Unlike the initial hyperpolarizing response, the
duration of the hyperpolarizing response to exogenous ATP varied from
preparation to preparation (Fig. 6, A
and B). Superimposition of the time
course of an ATP-evoked hyperpolarization and an IJP evoked by EFS is
shown in Fig. 6.
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,-MeATP, 2-MeSATP, or ADPS. Apamin (1 µM, Fig. 7A)
abolished the hyperpolarization evoked by ATP (0.1 M). Suramin (100 µM) reduced the ATP-evoked hyperpolarization (10.1 ± 1.2 mV in
Krebs solution compared with 4.8 ± 0.7 mV in the presence of
suramin, n = 3 from 3 preparations,
P < 0.05, Fig.
7B). Desensitization for 15 min with
,-MeATP (100 µM) inhibited the ATP-evoked hyperpolarization (8 ± 0.8 mV in Krebs solution compared with 2.5 ± 0.7 mV in the presence of ,-MeATP, n = 3 from
3 preparations, P < 0.05, Fig. 7C). Desensitization for 15 min with
ADPS (100 µM) completely abolished the effect of ATP (10 ± 1 mV in Krebs solution compared with 0 ± 0 mV in the presence of
ADPS, n = 2 from 2 preparations, P < 0.05, Fig.
7E). Desensitization for 30 min with
2-MeSATP (100 µM) had no effect on the ATP-evoked hyperpolarization
(8.3 ± 1.5 mV in Krebs solution compared with 7.9 ± 1.0 mV in
the presence of 2-MeSATP, n = 2 from 2 preparations, P > 0.05, Fig.
7D).
L-NNA applied to the bath for 30 min had no effect on the ATP-evoked hyperpolarization (Fig.
7F). The effects of apamin, suramin,
,-MeATP, 2-MeSATP, ADPS, and
L-NNA on the ATP-evoked
hyperpolarization are summarized in Fig. 8.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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This report provides data supporting the hypothesis that ATP is one of the neurotransmitters that mediates the IJP-F in human jejunum circular smooth muscle. Three lines of evidence support this conclusion: 1) purinergic receptor block by the P2-purinoceptor antagonist suramin or desensitization of purinergic receptors inhibited the IJP-F evoked by EFS, 2) application of ATP via a picospritzer mimicked closely the IJP-F, and 3) desensitization of purinergic receptors or P2-purinoceptor blockade by suramin markedly decreased the effects of exogenous ATP.
In this study suramin decreased the amplitude of the IJP evoked by EFS
and blocked the effect of exogenous ATP on membrane voltage. These data
suggest that the effect of ATP was mediated by a
P2 receptor. The
P2 receptor subtypes are a family
of ion channels that conduct Na+, K+, and
rarely Ca2+. The P2
receptors identified so far are
P2x,
P2y, and
P2z receptors, each having several
subtypes (11). P2x receptors are
ligand-gated ion channels that conduct
K+,
Na+, and rarely
Ca2+.
P2y receptors are coupled to
intracellular second-messenger systems. Unequivocal identification of
the subtype that mediates the EFS-evoked IJP-F in human jejunal
circular smooth muscle and the response to exogenous ATP is not
possible for two reasons. First, currently available
P2-receptor agonists and
antagonists do not allow absolute and confident discrimination between
P2 receptor subtypes (cf. Ref.
25). For example, ,-MeATP, a putative selective
P2x agonist, acts as a
P2y agonist in guinea pig taenia coli (1), and ADPS, a putative
P2y receptor agonist, acts on
P2x receptors in rat urinary
bladder (22). Second, several P2
receptor types are expressed in the same tissue. In a recent study
(25), the effect of ADPS was carefully examined in circular muscle
of guinea pig colon. At least three types of
P2 receptors were found, including
inhibitory P2 receptors activated
by ,-MeATP and endogenous purines and blocked by suramin and
pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid
(PPADS), inhibitory P2 receptors
activated by ADPS but resistant to suramin and PPADS, and excitatory
P2 receptors activated by ADPS
and blocked by suramin and PPADS. In addition, there was evidence for a
pool of specialized junctional P2
receptors mediating the NANC IJP (25).
In the present study on human jejunal circular smooth muscle, prolonged
application of ,-MeATP, a putative selective
P2x agonist, decreased the
amplitude of the IJP-F evoked by EFS and blocked the effect of
exogenous ATP, effects presumably mediated by receptor desensitization.
Similar attempts at desensitization of the
P2y receptor by prolonged
application of the putative P2y agonist 2-MeSATP had no effect on the IJP. However, the putative P2y agonist ADPS completely
abolished the IJP-F and blocked the effect of exogenous ATP. These data
suggest that the IJP-F and the effect of ATP on membrane voltage in
human jejunal circular smooth muscle cells were mediated through an
ADPS-sensitive P2 receptor that was also partly sensitive to ,-MeATP. This receptor appears to be different from the receptor thought to mediate the NANC
IJP in guinea pig colonic circular smooth muscle as the pharmacology of
the P2 receptor activated by
,-MeATP in guinea pig matched the pharmacology of the IJP,
whereas the receptor activated by ADPS did not (25).
Apamin, a blocker of subtypes of small and intermediate conductance
calcium-activated potassium channels, inhibited a component of the
human jejunal IJP-F. Also, receptor desensitization with ,-MeATP
following preincubation with apamin did not further block the IJP-F,
suggesting that ATP mediated its effects through an apamin-sensitive
pathway. Because apamin also blocked part of the slow component of the
IJP mediated by NO (20), it appears that the effects of apamin in human
jejunal circular smooth muscle cannot be used as a selective marker of
purinergic involvement in inhibitory neurotransmission by ATP.
The single channel ionic conductances that mediate the effects of ATP on human gastrointestinal smooth muscle membrane voltage are unknown. Recently, small conductance (5-10 pS) and intermediate conductance (~39 pS) apamin-sensitive potassium channels have been described in murine ileal and colonic smooth muscle (14, 23). P2y-purinoceptor agonists activated both the small and intermediate conductance potassium channels, suggesting that these channels may mediate membrane hyperpolarization evoked by ATP in the mouse. Whether similar channels are also present in human jejunal circular smooth muscle is unknown. Together with potassium channels, other channels may also be involved in the generation of the IJP. In the guinea pig ileum, chloride channels have been suggested to play a role in the generation of excitatory junction potential as well as NANC IJPs (8).
In 3 of 15 preparations studied in the present report, exogenous ATP evoked a biphasic change in the membrane potential, which consisted of an initial hyperpolarization followed by a long-lasting depolarization. Similar effects of local application of ATP have been reported in chicken rectum and in guinea pig urinary bladder, suggesting that ATP may function not only as an inhibitory neurotransmitter but also may have a role as an excitatory neurotransmitter (5, 15). Purine-related rebound excitation may be another possible explanation for the depolarization noted in the small number of preparations in this report. The messengers involved in purine-related rebound excitation are not fully understood, but in the guinea pig taenia coli (6), rat duodenum (17), and mouse colon (10) they appear to depend on prostaglandin synthesis because indomethacin attenuates the rebound excitation.
In summary, exogenous application of ATP in human jejunal circular
smooth muscle evokes a membrane hyperpolarization accompanied by smooth
muscle relaxation. The effect of ATP appears to be mediated via an
ADPS-sensitive P2 receptor. ATP
appears to be involved in the generation of the IJP-F because exogenous
ATP closely mimicked the IJP-F, and desensitization of purinergic
receptors or use of the
P2-receptor antagonist suramin
attenuated the IJP-F. These data suggest that the IJP in human jejunal
circular smooth muscle appears to be mediated by several
neurotransmitters. ATP appears to be one of the mediators of the IJP-F,
whereas NO mediates the IJP-S.
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ACKNOWLEDGEMENTS |
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We thank Gary Stoltz for technical assistance and Kristy Zodrow for secretarial assistance.
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FOOTNOTES |
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This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-17238, DK-52766, and DK-39337.
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: G. Farrugia, Mayo Clinic, Guggenheim 8, 200 First St. SW, Rochester, MN 55905.
Received 29 September 1998; accepted in final form 23 February 1999.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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, 6 pulses each 0.35 ms at 30 Hz) in presence of atropine, phentolamine,
and propranolol (each 1 µM) in human jejunal circular smooth muscle.
Nonadrenergic, noncholinergic (NANC) inhibitory junction potential
(IJP) consisted of initial fast (IJP-F) followed by slow
hyperpolarization (IJP-S) accompanied by muscle relaxation. Amplitudes
of IJP-F and IJP-S were frequency dependent.
).
A: apamin (1 µM for 20 min)
abolished hyperpolarization evoked by ATP.
B: suramin (100 µM for 28 min)
decreased amplitude of ATP-evoked hyperpolarization.
C: desensitization by 