Evidence for nitric oxide as mediator of non‐adrenergic, non‐cholinergic relaxations induced by ATP and GABA in the canine gut

Boeckxstaens, Guy E.; Pelckmans, Paul; Bult, Hidde; Man, Joris G. De; Herman, Arnold G.; Maercke, Y. M. Van

doi:10.1111/j.1476-5381.1991.tb12191.x

Cited by 120 publications

(60 citation statements)

References 26 publications

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“…Influence of L-NIVA on the actions of ATP, VlIP and NO It has been reported that ATP may exert its inhibitory action in the dog small bowel by releasing NO from enteric nerves (Boeckxstaens, Pelckmans, Bult, De Man, Herman & van Maercke, 1991 . NO (100 ,ul of concentrated solution added to 3 ml bath) caused a large hyperpolarization which was also not modified by L-NNA (P > 0 05; 1-2 observations in 13 cells from 7 animals).…”

Section: Resultsmentioning

confidence: 99%

“…Most of the prior studies have focussed on providing evidence for or against the involvement of a particular neurotransmitter such as ATP (Rattani & Goyal, 1980;Frew & Lunidy, 1982;Daniel, Helmy-Elkholy, Jager & Kannan, 1983: Hovle & Burnstock, 1989, VIP (Goyal, Rattan & Said, 1980;Daniel et al 1983;Grider & Makhlouf, 1988;Behar, Guenard, Walsh & Biancani, 1989), and NO (Gillespie, Lui & Martin, 1989;Bult et al 1990;Boeckxstaens et al 1991;Du et al 1991;Tottrup, Svane & Forman, 1991;Desai, Sessa & Vane, 1991: Dalziel et al 1991. Until recently, the possibility that more than one neurotransmitter may be simultaneously involved was not seriously investigated, although such a possibility has been considered because of the incomplete nature of antagonism of the nervemediated inhibitory responses by antagonists of VIP.…”

Section: Discussionmentioning

confidence: 99%

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Nitric oxide involvement in the peptide VIP‐associated inhibitory junction potential in the guinea‐pig ileum.

Goyal

1993

The Journal of Physiology

109

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SUMMARY1. Intracellular membrane potential recordings were made from circular smooth muscle cells of the guinea-pig ileum in the presence of atropine (1 /tM) and nifedipine (0 Il/tM) at 30 'C.2. Electrical field stimulation with one or four pulses produced a fast inhibitory junction potential (IJP) which lasted around 1 s. It was abolished by tetrodotoxin (1 /LM), apamin (0 3 1aM), and a, /3-methylene ATP tachyphylaxis.3. Nitric oxide synthase inhibitor N-nitro-L-arginine (L-NNA; 200 saM) had no effect on the resting membrane potential or the fast IJP.4. Electrical field stimulation in the presence of apamin and substance P desensitization produced a slow IJP which was abolished by tetrodotoxin (1 /tM).5. L-NNA significantly reduced the amplitude of the slow IJP (P < 001). The antagonistic effect of L-NNA was reversed by L-arginine but not by D-arginine.6. Injections of a, ,-methylene ATP, nitric oxide (NO), and vasoactive intestinal polypeptide (VIP) into the recording chamber caused tetrodotoxin-resistant hyperpolarizations of the smooth muscle membrane. Substance P desensitization did not modify the amplitudes of the hyperpolarizing response to ATP or NO, but increased the VIP hyperpolarization by 150% (P < 0-01).7. L-NNA did not modify the amplitude of hyperpolarization due to ATP or NO; however, it antagonized VIP-induced hyperpolarization (P < 0 01).8. These studies show that in the guinea-pig ileum circular muscle: (a) NO is not involved in the fast IJP which is mediated by ATP; (b) NO is involved in the slow IJP which is mediated by VIP and NO acting in series, and (c) the hyperpolarizing effects of VIP and the slow IJP are normally masked by overlapping depolarization due to concomitant release of substance P by the peptide VIP.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Nitric oxide involvement in the peptide VIP‐associated inhibitory junction potential in the guinea‐pig ileum.

Goyal

1993

The Journal of Physiology

109

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“…In the canine ileocolonic junction, we have previously demonstrated that NO mimicked and mediated NANC (nerve-induced) relaxations in response to electrical impulses, adenosine 5'-triphosphate (ATP), y-aminobutyric acid (GA-BA), acetylcholine (ACh) and 5-hydroxytryptamine (5-HT) (Boeckxstaens et al, 1990a;1991b;Bogers et al, 1991). Furthermore, using a superfusion bioassay, we provided evidence indicating the release of a transferable factor in response to electrical and nicotinic receptor stimulation of the NANC nerves in this preparation (Bult et al, 1990;Boeckxstaens et al, 1991c).…”

Section: Introductionmentioning

confidence: 99%

Ca²⁺ dependency of the release of nitric oxide from non‐adrenergic non‐cholinergic nerves

Boeckxstaens

Man

Pelckmans

et al. 1993

British J Pharmacology

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1 The role of Ca2" in nitrergic neurotransmission was studied in the canine ileocolonic junction. 2 The specific N-type voltage-sensitive Ca2" channel blocker w-conotoxin GVIA (CTX, 10-100 nM) significantly reduced the electrically-evoked (2-16 Hz, 1-2 ms pulse width) non-adrenergic noncholinergic (NANC) relaxations, preferentially affecting those to low frequency stimulation, in circular muscle strips of the ileocolonic junction. In contrast, the nerve-mediated NANC-relaxations in response to acetylcholine (30 JAM), y-aminobutyric acid (100IM) and adenosine 5'-triphosphate (100 I1M), as well as the relaxations to nitric oxide (NO) (3-10 IOM) and nitroglycerin (1 JAM), remained unaffected. 3 A NO-related substance (NO-R), released from the ileocolonic junction in response to NANC nerve stimulation (4 and 16 Hz, 2 ms pulse width), was assayed with a superfusion bioassay cascade. CTX (50 nM) reduced the release of NO-R induced by electrical impulses (4 Hz: from 18 ± 4% to 6 ± 4%; 16 Hz: from 33 ± 2% to 14 + 4%, n = 5), but not that in response to the nicotinic receptor agonist, 1,1-dimethyl-4-phenylpiperazinium (DMPP, 0.3 mM). In Ca2"-free medium, the release of NO-R evoked by electrical impulses or DMPP was inhibited. The L-type Ca2" channel blockers verapamil (1)(2)(3) and nifedipine (1 JM) had no effect.4 From these results we conclude that the release of NO-R in response to NANC nerve stimulation is Ca2"-dependent. The electrically-evoked release of NO-R results from Ca2" entry through CTX-sensitive N-type voltage-sensitive Ca2" channels, whereas that induced by nicotinic receptor activation involves CTX-insensitive Ca2" channels, different from the L-or N-type.

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“…Thus, the generation and release of NO has been demonstrated on electrical stimulation of NANC nerves in the canine ileocolonic junction (12) and rat stomach fundus (13). Also, the inhibition of NO formation prevents the relaxation of gastrointestinal smooth muscle, induced by electrical field stimulation of NANC nerves (13)(14)(15) or by other putative NANC neurotransmitters such as vasoactive intestinal peptide (VIP) (15), adenosine 5'-triphosphate (ATP), or -t-aminobutyric acid (16).…”

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Nitroxergic nerves mediate vagally induced relaxation in the isolated stomach of the guinea pig.

Desai

Zembowicz

Sessa

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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Here we show that the relaxation induced by stimulation of the vagus nerve in the presence of cholinergic (muscarinic) and adrenergic blockade in the isolated stomach of the guinea pig is mediated by nitric oxide (NO). This is substantiated by inhibition of vagal relaxation by NGmonomethyl-L-arginine, an inhibitor of NO synthesis. The effect of NG-monomethyl-L-arginine was partially reversed by coincubation with L-anine but not with D-arginne. NO activates soluble guanylate cyclase, and relaxation of the stomach induced by vagal stimulation was prevented by an inhibitor of soluble guanylate cyclase, methylene blue, further supporting our conclusions. The relaxant effect of vagal stimulation was also ablated by hexamethonium, an inhibitor of ganglionic nicotinic receptors, thereby showing that gangionic transmission did not rely on NO, through its release from pr onic neurons. However, hexamethonium did not inhibit the gastric relaxation brought about by increasing the inragastric pressure, which is also mediated by NO as previously described by us. The selective inhibition by hexamethonum of only the vagafly mediated relaxation but not of the pressure-induced relaxation of the stomach indicates the existence of at least two separate neuronal pathways able to generate NO and bring about gastric accommodation of food or fluid.Endothelium-derived relaxing factor, or nitric oxide (NO; ref. 1), plays important roles in the cardiovascular and immune systems (2, 3). Demonstration of the biosynthesis of NO by neuronal cells in the central nervous system (4) suggested a role for NO in intercellular communication in the brain. NO synthase, an NADPH-dependent dioxygenase that catalyzes formation of NO from one of the guanidino nitrogens of L-arginine, has been purified from the rat brain (5), sequenced, and expressed from its cDNA (6). The enzyme has been immunolocalized in nerve fibers and cell bodies of neurons in the brain and in the myenteric plexus in the gastrointestinal tract (7). Moreover, the myenteric plexus is an abundant source of neurons showing NADPH diaphorase activity (8), and NADPH diaphorase is a NO synthase (9). All these findings suggest the existence of nerves that release NO as a transmitter ("nitroxergic" nerves) in the central and peripheral nervous system. Inhibitory nerves were described in the stomach (10) and nonadrenergic, noncholinergic (NANC) inhibitory nerves have now been recognized in many parts of the gastrointestinal tract (11). Recent evidence demonstrates that these nerves are nitroxergic at some sites. Thus, the generation and release of NO has been demonstrated on electrical stimulation of NANC nerves in the canine ileocolonic junction (12) and rat stomach fundus (13). Also, the inhibition of NO formation prevents the relaxation of gastrointestinal smooth muscle, induced by electrical field stimulation of NANC nerves (13-15) or by other putative NANC neurotransmitters such as vasoactive intestinal peptide (VIP) (15), adenosine 5'-triphosphate (ATP), or -t-aminobutyric acid (1...

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Evidence for nitric oxide as mediator of non‐adrenergic, non‐cholinergic relaxations induced by ATP and GABA in the canine gut

Cited by 120 publications

References 26 publications

Nitric oxide involvement in the peptide VIP‐associated inhibitory junction potential in the guinea‐pig ileum.

Nitric oxide involvement in the peptide VIP‐associated inhibitory junction potential in the guinea‐pig ileum.

Ca²⁺ dependency of the release of nitric oxide from non‐adrenergic non‐cholinergic nerves

Nitroxergic nerves mediate vagally induced relaxation in the isolated stomach of the guinea pig.

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Evidence for nitric oxide as mediator of non‐adrenergic, non‐cholinergic relaxations induced by ATP and GABA in the canine gut

Cited by 120 publications

References 26 publications

Nitric oxide involvement in the peptide VIP‐associated inhibitory junction potential in the guinea‐pig ileum.

Nitric oxide involvement in the peptide VIP‐associated inhibitory junction potential in the guinea‐pig ileum.

Ca2+ dependency of the release of nitric oxide from non‐adrenergic non‐cholinergic nerves

Nitroxergic nerves mediate vagally induced relaxation in the isolated stomach of the guinea pig.

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Ca²⁺ dependency of the release of nitric oxide from non‐adrenergic non‐cholinergic nerves