Center for Swallowing and Motility Disorders, Brockton/West Roxbury Department of Veterans Affairs Medical Center, West Roxbury 02132; and Harvard Medical School, Boston, Massachusetts 02215
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ABSTRACT |
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A nitric oxide (NO)-like product of the L-arginine NO synthase pathway has been shown to be a major inhibitory neurotransmitter that is involved in the slow component of the inhibitory junction potential (IJP) elicited by stimulation of nonadrenergic, noncholinergic nerves. However, the exact nature of the nitrergic transmitter, the role of cGMP, and the involvement of a potassium or a chloride conductance in the slow IJP remain unresolved. We examined the effects of soluble guanylate cyclase inhibitors LY-83583 and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), potassium-channel blockers and putative chloride-channel blockers diphenylamine-2-carboxylate (DPC) and niflumic acid (NFA) on the hyperpolarization elicited by an NO · donor, diethylenetriamine/NO adduct (DNO), NO in solution, and an NO+ donor, sodium nitroprusside (SNP), in the guinea pig ileal circular muscle. Effects of these blockers on purinergic (fast) and nitrergic (slow) IJP were also examined. DNO-induced hyperpolarization and nitrergic slow IJP were suppressed by LY-83583 or ODQ and DPC or NFA but not by the potassium-channel blocker apamin. In contrast, hyperpolarization caused by SNP or solubilized NO gas and purinergic fast IJP were antagonized by apamin but not by inhibitors of guanylate cyclase or chloride channels. These results demonstrate biological differences in the actions of different redox states of NO and suggest that NO · is the nitrergic inhibitory neurotransmitter.
enteric nervous system; chloride channels; potassium channels; sodium nitroprusside; neuromuscular transmission; amine/nitric oxide adduct
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INTRODUCTION |
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NITRERGIC AND PURINERGIC pathways constitute two major components of nonadrenergic, noncholinergic (NANC) inhibitory neurotransmission in the gut (8, 13, 20). Purinergic smooth muscle relaxation and membrane hyperpolarization are caused by an increase in an apamin-sensitive potassium conductance (8). However, several key questions regarding nitrergic neurotransmission remain unresolved (25, 30). Although nitric oxide (NO) is generally thought to be the nitrergic neurotransmitter, the redox form of the NO molecule involved in the neurotransmission is controversial (9, 16). Moreover, the signal transduction cascade stimulated by the nitrergic neurotransmitter within the smooth muscle remains unclear. It is assumed that the nitrergic neurotransmitter acts by stimulating guanylate cyclase to cause intracellular cGMP accumulation and opening of a potassium conductance (25, 30). However, several studies showed that cGMP accumulation does not fully account for the inhibitory neurotransmission (15, 34), and the nature of the potassium conductance activated by the nitrergic motor nerves is uncertain (3, 14, 22, 24, 29). Furthermore, suppression of a chloride conductance was suggested to be involved in the nitrergic NANC neurotransmission (6, 7). Recently, cGMP and NO donors were shown to suppress chloride and nonselective cation currents on dispersed smooth muscle cells (36, 39).
There are several possible reasons for these confounding conclusions. First, the intracellular messengers and conductance changes associated with the inhibitory responses reflect a mixture of distinct sets of changes associated with coexisting nitrergic and purinergic NANC inhibitory neurotransmission (13, 20). Therefore, the signal transduction pathway that is associated with purinergic neurotransmission may be incorrectly assigned to nitrergic neurotransmission. The inhibitory junction potential (IJP) in many tissues consists of two overlapping components called the fast and the slow IJP (8, 20). The fast IJP is insensitive to NO synthase (NOS) inhibitors and is caused by a purinergic neurotransmitter. The slow IJP is sensitive to NOS inhibitors and is therefore caused by a nitrergic inhibitory NANC neurotransmitter (8, 20). Second, the effects of the inhibitory transmitter may vary with the membrane potential of the smooth muscle. For example, the stimulatory effect of NO on the large-conductance calcium-dependent potassium (BK) channels may be seen at depolarized potentials but not in unstimulated smooth muscle cells, because the BK channels are generally active only at depolarized potentials (1). Third, sodium nitroprusside (SNP), S-nitrosothiols, sydnonimines, and NO gas in physiological solution have been used to define the cellular actions of the endogenous nitrergic neurotransmitter (9, 16). However, these NO donors yield different redox forms of NO that may not mimic the endogenous neurotransmitter (28).
We investigated the ion conductances underlying the purinergic fast IJP and the nitrergic slow IJP separately and those caused by exogenous administration of the NO+ donors SNP and S-nitroso-N-acetylpencillamine (SNAP) (28), NO in solution, and NO · donors 3-morpholinosydnonimine hydrochloride (SIN-1) in the presence of superoxide dismutase (SOD) and a recently developed amine/NO · adduct (DNO) (19). Our results show that the nitrergic slow IJP involves generation of cGMP and suppression of a diphenylamine-2-carboxylate (DPC)- and niflumic acid (NFA)-sensitive conductance and that these effects are best mimicked by the NO · donor DNO. On the other hand, the NO+ donor SNAP and NO solution cause smooth muscle membrane hyperpolarization by a cGMP-independent increase in an apamin-sensitive potassium conductance, a pathway that is normally used by purinergic inhibitory neurotransmission. These studies reveal redox-based differences in the action of NO on the smooth muscle membrane potential and suggest that NO · or an amine/NO adduct is the nitrergic NANC inhibitory neurotransmitter.
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METHODS |
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Animals. Adult guinea pigs weighing between 150 and 400 g were killed by CO2 narcosis, and a segment of ileum was prepared for intracellular microelectrode recording from the circular layer of smooth muscle as described previously (8, 20). The bath had a volume of 3 ml and was continuously perfused with oxygenated, warmed Krebs solution at a rate of 3 ml/min. The bath was further oxygenated by bubbling a 95% O2-5% CO2 mixture directly into it. The bath temperature was maintained at 30 ± 0.5°C.
Drugs.
Drugs and chemicals used in this study included apamin,
D-arginine, L-arginine, atropine sulfate,
,
-methylene ATP, DMSO, guanethidine, hemoglobin,
N
-nitro-L-arginine
(L-NNA), SNP, substance P (SP),
tetraethylammonium (TEA), tetrodotoxin (TTX), and
1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (obtained from Sigma, St. Louis, MO); DPC (obtained from Aldrich,
Milwaukee, WI) and NFA; LY-83583 (from Calbiochem, La Jolla, CA); SOD,
glibenclamide, DNO, SIN-1, and SNAP (from Research Biochemicals
International, Natick, MA); and NO gas (from Matheson Gas Products,
Rutherford, NJ).
Intracellular recordings.
Intracellular membrane potentials were recorded from smooth muscle
cells of circular muscle strips dissected from the guinea pig ileum
using standard techniques as described earlier (7). The microelectrodes
were filled with 3 M KCl and had tip resistance between 30 and 80 M.
The fast inhibitory junction potential (fast IJP) was evoked by
electrical field stimulation (EFS) with silver-silver chloride
electrodes on the muscle strips perfused with oxygenated Krebs solution
containing atropine and guanethidine. Guanethidine and atropine
suppress adrenergic and cholinergic excitatory responses, respectively,
and unmask the NANC nerve-mediated IJP. The slow IJP was expressed by
blocking the fast IJP with a saturating concentration of apamin and SP
receptor desensitization of the muscle strips in the presence of
atropine and guanethidine. Desensitizing SP receptors obliterates the
SP-mediated excitatory junction potential. EFS consisting of four
pulses (0.5-ms pulse duration, 30 mA at 20 Hz) was used because these
stimulus parameters produced maximal IJP amplitudes. These responses
were neurogenic, because they were abolished by TTX (0.1 µM). Effects
of chemical antagonists were studied in the same cell whenever
possible. However, when electrode displacement made it impossible
recordings were made from adjacent cells.
Statistical analyses. Statistical comparisons were made using Student's standard paired and unpaired t-statistics, and all data are expressed as means ± SE.
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RESULTS |
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Responses to NO donors. Administration of a bolus injection of the NO donors SNP (66 µM), DNO (100 µM), and NO solution (100 µl in a 3-ml chamber) in the perfusion bath produced a transient (~10 s) membrane hyperpolarization (5-10 mV) of the circular smooth muscle of guinea pig ileum (Figs. 1 and 2). Other NO donors, SIN-1 (100 µM) in the presence of SOD (3 U/ml) and SNAP (66 µM), produced similar hyperpolarizations.
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Fast and slow IJP. The NANC nerve-mediated fast IJP evoked by EFS in the guinea pig ileum circular muscle was recorded in the presence of atropine (1 µM) and guanethidine (5 µM). Under these conditions the slow IJP was masked by an SP-mediated excitatory junction potential and was revealed more fully after SP receptors were desensitized. The slow IJP was isolated in the additional presence of apamin to block the fast IJP (Fig. 4).
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DISCUSSION |
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The main findings of this study are that in producing membrane hyperpolarization in the guinea pig ileum circular smooth muscle 1) the NO · donors DNO and SIN-1 in the presence of SOD mimic the action of the endogenous nitrergic neurotransmitter and 1) the NO+ donors SNP and SNAP mimic the purinergic inhibitory neuromuscular transmission (Fig. 3).
DNO is a nucleophile adduct that was developed to provide a source of pure NO · under physiological conditions (19). DNO elicited smooth muscle hyperpolarization that was suppressed by a blocker of sGC, LY-83583, or ODQ. This is consistent with the view that NO · is a natural activator of sGC. The slow IJP was also suppressed by the sGC inhibitors, supporting the view that this slow IJP is caused by NO ·.
The ion conductances associated with the slow IJP were similar to those underlying the DNO-induced hyperpolarization. The DNO-induced hyperpolarization and the slow IJP were both apamin resistant and were not suppressed by either TEA or glibenclamide. These observations are similar to previous reports of the failure of these potassium-channel blockers to inhibit the action of NO donors or to suppress IJP (7, 14). The report of smooth muscle hyperpolarization by 8-bromoguanosine 3',5'-cyclic monophosphate, which is insensitive to these potassium-channel blockers (3), also suggests that intracellular cGMP accumulation may hyperpolarize smooth muscles by a mechanism other than the opening of potassium channels. However, cGMP-activated G kinase is well known to activate the TEA-sensitive BK channels in patch-clamp studies on single circular smooth muscle cells (14, 22) These channels are operative mainly at depolarized potentials, suggesting that the NO-cGMP pathway may cause hyperpolarization of smooth muscles that are already depolarized, by activation of BK channels (1). It has been also reported that quinine in millimolar concentrations blocks the apamin-resistant IJP, suggesting that an "unusual" potassium conductance was activated in the muscle during nitrergic neurotransmission (3). However, these results are difficult to interpret because quinine also blocks chloride and nonselective cation channels (12).
Our observation that the hyperpolarization produced by DNO as well as the slow IJP were suppressed by DPC, which is a known blocker of chloride and nonselective cation channels (5, 31), further supports the view that NO · is the mediator of the slow IJP. The action of DNO was also suppressed by the chloride conductance inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) (unpublished observations). The slow IJP was previously shown to be suppressed by chloride substitution and by DIDS (7). Moreover, the slow IJP was shown to be associated with an increase in the membrane resistance, suggesting its association with decreased ionic conductance (7). Chloride ion substitution with nonpermeant anions and chloride channel blockers causes membrane hyperpolarization by suppressing the resting chloride conductance. Under these conditions the NO ·-cGMP signaling pathway cannot further close the chloride conductance to produce smooth muscle membrane hyperpolarization. This hypothesis is validated by the fact that chloride channels have been recently identified in the gut smooth muscle (34, 39). Finally, NFA, a known chloride-channel blocker, also suppressed the slow IJP and hyperpolarization caused by DNO. Further studies are needed, however, to define the nature of the chloride channels involved in the NO ·-cGMP signal transduction pathway.
Although cGMP involvement and ion conductances associated with predictable NO · donors such as amine/NO adducts (19) on the gut smooth muscle membrane potential have not been reported before, several reports are available on smooth muscle hyperpolarization by NO donors such as SNP, S-nitrosothiols such as SNAP, and aqueous solution of NO gas (14, 25, 30). SIN-1 is metabolized by tissues to produce peroxynitrite that is largely involved in toxic reactions, but in the presence of SOD, SIN-1 yields NO · (26). SNP spontaneously yields NO+. S-nitrosothiols act as NO+ donors in addition to spontaneously releasing NO · (18). In our studies a transient hyperpolarization lasting several seconds elicited by a bolus of SNP and SNAP in a continuously perfusing bath was not suppressed by LY-83583 but was markedly suppressed by apamin. This may be caused by the fact that NO+ yielded by these donors may nitrosate cell surface thiols and directly activate some SK channels (17, 28). Osthaus and Galligan (23) made similar observations, and Kitamura and colleagues (15) reported that apamin blocked an early component of hyperpolarization caused by S-nitrosocysteine. Apamin is a selective blocker of calcium-dependent SK channels, which normally mediate purinergic fast IJP (20, 33). It is possible the fast IJP is also nitrergic and caused by NO+ redox form. However, because the fast IJP is not sensitive to block by L-NNA and is present in neuronal constitutive NOS-negative animals, this possibility is not tenable (13, 20). Under our experimental conditions, administration of a solution of NO gas in the oxygenated bath mimicked the actions of SNP, indicating that the NO was being converted to an intermediate that was an NO+ donor. In oxygenated physiological solutions, NO · gas has been shown to react rapidly with oxygen to produce oxides of nitrogen such as N2O3 and N2O4, which are effective NO+ donors (28). NO · donors such as DNO are distributed to the immediate vicinity of the smooth muscle cells and release NO · slowly, thereby making NO · available near the smooth muscle cells.
Apart from SNP being an NO+ donor, cellular metabolism of SNP produces a potpourri of biologically active intermediates including S-nitrosothiols (19). SNP, therefore, may produce a variety of cGMP-independent and -dependent actions (17, 28). Moreover, intermediates of SNP stimulate both soluble form and particulate form (not suppressible by inhibitors of sGC) leading to a very large but gradual (over minutes) increase in intracellular cGMP (21). Therefore, the actions and antagonism of its action by an inhibitor of soluble cGMP may vary in different tissues and with different experimental conditions. In many smooth muscles, ODQ has been shown to antagonize mechanical relaxation caused by SNP (4, 27, 38). SNP and S-nitrosothiols, at depolarized potentials, activate BK channels through cGMP to elicit hyperpolarization (14, 22). In guinea pig proximal colon, SNP causes hyperpolarization by activating apamin-sensitive and -insensitive potassium currents (35). In the canine proximal colon the hyperpolarizing action of SNP is all ODQ sensitive (10). In the mouse anococcygeus muscle, SNP has been shown to act by inhibiting a nonselective cation (36).
In conclusion, our studies suggest that NO · or NO+ redox forms of NO produce smooth muscle hyperpolarization by different ionic mechanisms. The early hyperpolarization of NO+ donors such as SNP or SNAP is caused by activation of apamin-sensitive potassium channels. On the other hand, NO · donors such as DNO act by cGMP-mediated suppression of chloride conductance. The action of DNO resembles that of the nitrergic slow IJP, suggesting that NO · is the nitrergic neurotransmitter.
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ACKNOWLEDGEMENTS |
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The authors thank Drs. Hiroshi Mashimo and Fivos Vogalis for helpful suggestions.
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FOOTNOTES |
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This work was supported in part by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-31092.
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: R. K. Goyal, Research and Development Program (151), Brockton-West Roxbury VA Medical Center, 1400 VFW Parkway, West Roxbury, MA 02132.
Received 11 February 1998; accepted in final form 1 July 1998.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Carl, A.,
O. Bayguinov,
C. W. Shuttleworth,
S. M. Ward,
and
K. M. Sanders.
Role of Ca2+-activated K+ channels in electrical activity of longitudinal and circular muscle layers of canine colon.
Am. J. Physiol.
268 (Cell Physiol. 37):
C619-C627,
1995
2.
Casteels, R., G. Droogman G., and L. Raeymaekers.
Distribution and exchange of electrolytes in gastrointestinal
muscle cells. In: Handbook of Physiology. The
Gastrointestinal System. Motility and Circulation.
Bethesda, MD: Am. Physiol. Soc, 1989, sect. 6, vol. I, pt. 1, chapt. 3, p. 141-162.
3.
Cayabyab, F. S.,
and
E. E. Daniel.
K+ channel opening mediates hyperpolarizations by nitric oxide donors and IJPs in opossum esophagus.
Am. J. Physiol.
268 (Gastrointest. Liver Physiol. 31):
G831-G842,
1995
4.
Cellek, S.,
L. Kasakov,
and
S. Moncada.
Inhibition of nitrergic relaxations by a selective inhibitor of the soluble guanylate cyclase.
Br. J. Pharmacol.
118:
137-140,
1996[Abstract].
5.
Chen, S.,
R. Inoue,
and
Y. Ito.
Pharmacological characterization of muscarinic receptor-activated cation channels in guinea-pig ileum.
Br. J. Pharmacol.
109:
793-801,
1993[Abstract].
6.
Crist, J.,
X. D. He,
and
R. K. Goyal.
Chloride-mediated inhibitory junction potentials in opossum esophageal circular smooth muscle.
Am. J. Physiol.
261 (Gastrointest. Liver Physiol. 24):
G752-G762,
1991
7.
Crist, J. R.,
X. D. He,
and
R. K. Goyal.
Chloride-mediated junction potentials in circular muscle of the guinea pig ileum.
Am. J. Physiol.
261 (Gastrointest. Liver Physiol. 24):
G742-G751,
1991
8.
Crist, J. R.,
X. D. He,
and
R. K. Goyal.
Both ATP and the peptide VIP are inhibitory neurotransmitters in guinea-pig ileum circular muscle.
J. Physiol. (Lond)
447:
119-131,
1992[Abstract].
9.
De Man, J. G.,
G. E. Boeckxstaens,
B. Y. De Winter,
T. G. Moreels,
M. E. Misset,
A. G. Herman,
and
P. A. Pelckmans.
Comparison of the pharmacological profile of S-nitrosothiols, nitric oxide and the nitrergic neurotransmitter in the canine ileocolonic junction.
Br. J. Pharmacol.
114:
1179-1184,
1995[Abstract].
10.
Franck, H.,
K. M. Sweeney,
K. M. Sanders,
and
C. W. Shuttleworth.
Effects of a novel guanylate cyclase inhibitor on nitric oxide-dependent inhibitory neurotransmission in canine proximal colon.
Br. J. Pharmacol.
122:
1223-1229,
1997[Abstract].
11.
Garthwaite, J.,
E. Southam,
C. L. Boulton,
E. B. Nielson,
K. Schmidt,
and
B. Mayers.
Potent and selective inhibition of nitric oxide-sensitive guanylyl cyclase by 1H-[1,2,4]oxadiazolo[4,3-a] quinoxalin-1-one.
Mol. Pharmacol.
48:
184-188,
1995[Abstract].
12.
Gogelein, H.,
and
K. Capek.
Quinine inhibits chloride and nonselective cation channels in isolated rat distal colon cells.
Biochim. Biophys. Acta
1027:
191-198,
1990[Medline].
13.
He, X. D.,
and
R. K. Goyal.
Nitric oxide involvement in the peptide VIP-associated inhibitory junction potential in the guinea-pig ileum.
J. Physiol. (Lond)
461:
485-499,
1993[Abstract].
14.
Jury, J.,
K. R. Boev,
and
E. E. Daniel.
Nitric oxide mediates outward potassium currents in opossum esophageal circular smooth muscle.
Am. J. Physiol.
270 (Gastrointest. Liver Physiol. 33):
G932-G938,
1996
15.
Kitamura, K.,
Q. Lian,
A. Carl,
and
H. Kuriyama.
S-nitrosocysteine, but not sodium nitroprusside, produces apamin-sensitive hyperpolarization in rat gastric fundus.
Br. J. Pharmacol.
109:
415-423,
1993[Abstract].
16.
Knudsen, M. A.,
D. Svane,
and
A. Tottrup.
Action profiles of nitric oxide, S-nitroso-L-cysteine, SNP, and NANC responses in opossum lower esophageal sphincter.
Am. J. Physiol.
262 (Gastrointest. Liver Physiol. 25):
G840-G846,
1992
17.
Koh, S. D.,
J. D. Campbell,
A. Carl,
and
K. M. Sanders.
Nitric oxide activates multiple potassium channels in canine colonic smooth muscle.
J. Physiol. (Lond)
489:
735-743,
1995[Abstract].
18.
Kowaluk, E. A.,
and
H. L. Fung.
Spontaneous liberation of nitric oxide cannot account for in vitro vascular relaxation by S-nitrosothiols.
J. Pharmacol. Exp. Ther.
255:
1256-1264,
1990[Abstract].
19.
Maragos, C. M.,
D. Morley,
D. A. Wink,
T. M. Dunams,
J. E. Saavedra,
A. Hoffman,
A. A. Bove,
L. Isaac,
J. A. Hrabie,
and
L. K. Keefer.
Complexes of NO with nucleophiles as agents for the controlled biological release of nitric oxide. Vasorelaxant effects.
J. Med. Chem.
34:
3242-3247,
1991[Medline].
20.
Mashimo, H.,
X. D. He,
P. L. Huang,
M. C. Fishman,
and
R. K. Goyal.
Neuronal constitutive nitric oxide synthase is involved in murine enteric inhibitory neurotransmission.
J. Clin. Invest.
98:
8-13,
1996
21.
McDonald, L. J.,
and
F. Murad.
Nitric oxide and cGMP signaling.
In: Nitric Oxide, edited by L. Ignarro,
and F. Murad. San Diego: Academic, 1995, p. 263-275.
22.
Murray, J. A.,
E. F. Shibata,
T. L. Buresh,
H. Picken,
B. W. O'Meara,
and
J. L. Conklin.
Nitric oxide modulates a calcium-activated potassium current in muscle cells from opossum esophagus.
Am. J. Physiol.
269 (Gastrointest. Liver Physiol. 32):
G606-G612,
1995
23.
Osthaus, L. E.,
and
J. J. Galligan.
Antagonists of nitric oxide synthesis inhibit nerve-mediated relaxations of longitudinal muscle in guinea pig ileum.
J. Pharmacol. Exp. Ther.
260:
140-145,
1992[Abstract].
24.
Robertson, B. E.,
R. Schubert,
J. Hescheler,
and
M. T. Nelson.
cGMP-dependent protein kinase activates Ca2+-activated K+ channels in cerebral artery smooth muscle cells.
Am. J. Physiol.
265 (Cell Physiol. 34):
C299-C303,
1993
25.
Sanders, K. M.,
and
S. M. Ward.
Nitric oxide as a mediator of nonadrenergic noncholinergic neurotransmission.
Am. J. Physiol.
262 (Gastrointest. Liver Physiol. 25):
G379-G392,
1992
26.
Schmidt, M. J.,
B. D. Sawyer,
L. L. Truex,
W. S. Marshall,
and
J. H. Fleisch.
LY83583: an agent that lowers intracellular levels of cyclic guanosine 3',5'-monophosphate.
J. Pharmacol. Exp. Ther.
232:
764-769,
1985[Abstract].
27.
Selemidis, S.,
D. G. Satchell,
and
T. M. Cocks.
Evidence that NO acts as a redundant NANC inhibitory neurotransmitter in the guinea-pig isolated taenia coli.
Br. J. Pharmacol.
121:
604-611,
1997[Abstract].
28.
Stamler, J. S.,
D. J. Singel,
and
J. Loscalzo.
Biochemistry of nitric oxide and its redox-activated forms.
Science
258:
1898-1902,
1992[Medline].
29.
Standen, N. B.,
J. M. Quayle,
N. W. Davies,
J. E. Brayden,
Y. Huang,
and
M. T. Nelson.
Hyperpolarizing vasodilators activate ATP-sensitive K+ channels in arterial smooth muscle.
Science
245:
177-180,
1989[Medline].
30.
Stark, M. E.,
and
J. H. Szurszewski.
Role of nitric oxide in gastrointestinal and hepatic function and disease.
Gastroenterology
103:
1928-1949,
1992[Medline].
31.
Stutts, M. J.,
D. C. Henke,
and
R. C. Boucher.
Diphenylamine-2-carboxylate (DPC) inhibits both Cl conductance and cyclooxygenase of canine tracheal epithelium.
Pflügers Arch.
415:
611-616,
1990[Medline].
32.
Tomita, T.
Conductance change during the inhibitory potential in the guinea-pig taenia coli.
J. Physiol. (Lond)
225:
693-703,
1972[Medline].
33.
Vogalis, F.,
and
R. K. Goyal.
Activation of small conductance Ca2+-dependent K+ channels by purinergic agonists in smooth muscle cells of the mouse ileum.
J. Physiol.
502:
497-508,
1997[Abstract].
34.
Wang, Q.,
H. I. Akbarali,
N. Hatakeyama,
and
R. K. Goyal.
Caffeine and carbachol induced Cl and cation currents in single opossum esophageal circular smooth muscle cells.
Am. J. Physiol.
271 (Cell Physiol. 40):
C1725-C1734,
1996
35.
Watson, M. J.,
R. A. Bywater,
G. S. Taylor,
and
R. J. Lang.
Effects of nitric oxide (NO) and NO donors on the membrane conductance of circular smooth muscle cells of the guinea-pig proximal colon.
Br. J. Pharmacol.
118:
1605-1614,
1996[Abstract].
36.
Wayman, C. P.,
I. McFadzean,
A. Gibson,
and
J. F. Tucker.
Inhibition by sodium nitroprusside of a calcium store depletion-activated non-selective cation current in smooth muscle cells of the mouse anococcygeus.
Br. J. Pharmacol.
118:
2001-2008,
1996[Abstract].
37.
White, M. M.,
and
M. Aylevin.
Niflumic and flufenaminic acid are potent reversible blockers of Ca2+-activated Cl channels in Xenopus oocytes.
Mol. Pharmacol.
37:
720-724,
1990[Abstract].
38.
Young, H. M.,
D. Ciampoli,
P. J. Johnson,
and
M. J. Stebbing.
Inhibitory transmission to the longitudinal muscle of the mouse caecum is mediated largely by nitric oxide acting via soluble guanylyl cyclase.
J. Aut. Nerv. Sys.
61:
103-108,
1996[Medline].
39.
Zhang, Y.,
F. Vogalis,
and
R. K. Goyal.
Nitric oxide suppresses a Ca2+-stimulated Cl current in smooth muscle cells of opossum esophagus.
Am. J. Physiol.
274 (Gastrointest. Liver Physiol. 37):
G886-G890,
1998