Nervous control of the release of substance P and neurokinin A from the isolated perfused porcine ileum

doi:10.1016/0165-1838(92)90229-A

Journal of the Autonomic Nervous System

Volume 38, Issue 2, 1 May 1992, Pages 85-95

Journal of the Auton...

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Abstract

Using isolated perfused porcine ileum we studied the release of substance P (SP) and neurokinin A (NKA) in response to electrical stimulation of the mixed periarterial nerves and to infusion of different neuroactive agents. Nerve stimulation (8 Hz) had no significant effect on the release of SP and NKA. Nerve stimulation also had no effect on the release of SP and NKA during infusion of atropine (10⁻⁶ M) or phentolamine (10⁻⁵ M), whereas a significant increase (from 8.2 ± 1.9 to 20.1 ± 4.6 pmol/l for SP and from 12.3 ± 2.7 to 34.2 ± 7.7 pmol/l for NKA, n = 7) was observed during nerve stimulation after pretreatment with both atropine and phentolamine. This increase was abolished by hexamethonium (3 × 10⁻⁵M). Also acetylcholine infusion causes a significant release of SP and NKA after infusion of both atropine and phentolamine (to 172 ± 56% and 232 ± 69%) of basal release, n = 7), an effect that was abolished by hexamethonium infusion. Infusion of atropine alone increased the release of SP and NKA significantly (to 337 ± 92% and 386 ± 124% of basal output, n = 5). Norepinephrine (10⁻⁶ M) inhibited the release of SP and NKA (to 69 ± 6% and 80 ± 6% of basal release, n = 7). Our results suggest that the SP- and NKA-producing neurons receive intrinsic tonic muscarinic inhibitory impulses, extrinsic nicotinic excitatory impulses, and extrinsic adrenergic inhibitory impulses.

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Cited by (29)

Localisation and neural control of the release of calcitonin gene-related peptide (CGRP) from the isolated perfused porcine ileum
2001, Regulatory Peptides
By immunohistochemistry, CGRP-like immunoreactive (CGRP-LI) nerve fibres were found in the lamina propria along small vessels and in the lamina muscularis mucosae in the porcine ileum. Immunoreactive nerve cell bodies were found in the submucous and myenteric plexus. Upon HPLC-analysis of ileal extracts, CGRP-LI corresponded entirely to porcine CGRP plus smaller amounts of oxidised CGRP. Using isolated vascularly perfused segments of the ileum, we studied the release of CGRP-LI in response to electrical stimulation of the mixed extrinsic periarterial nerves and to infusion of different neuroblockers. In addition, the effect of infusion of capsaicin was studied. The basal output of CGRP-LI was 2.9±0.7 pmol/5 min (mean±S.D.). Electrical nerve stimulation (8 Hz) significantly increased the release of CGRP-LI to 167±16% (mean±S.E.M.) of the basal output (n=13). This response was unaffected by the addition of atropine (10⁻⁶ M). Nerve stimulation during infusion of phentolamine (10⁻⁵ M) with and without additional infusion of atropine resulted in a significant further increase in the release of CGRP-LI to 261±134% (n=5) and 240±80% (n=9), respectively. This response was abolished by infusion of hexamethonium (3×10⁻⁵ M). Infusion of capsaicin (10⁻⁵ M) caused a significant increase in the release of CGRP-LI to 485±82% of basal output (n=5). Our results suggest a dual origin of CGRP innervation of the porcine ileum (intrinsic and extrinsic). The intrinsic CGRP neurons receive excitatory input by parasympathetic, possibly vagal, preganglionic fibres, via release of acetylcholine acting on nicotinic receptors. The stimulatory effect of capsaicin suggests that CGRP is also released from extrinsic sensory neurons.
Tachykinin-dependent and -independent components of peristalsis in the guinea pig isolated distal colon
2001, Gastroenterology
Citation Excerpt :
This is consistent with the observation that a significant tachykinergic contribution to excitatory neuromuscular transmission is unmasked when postjunctional muscarinic receptors are partly blocked.22 In addition, the tachykinergic contribution to colonic propulsion might become more evident after blockade of prejunctional (or presynaptic) muscarinic inhibitory receptors, which induces increased release of tachykinins.44,45 Circumstantial evidence suggesting a synergistic interaction between muscarinic and NK2 receptors in the gastrointestinal tract was previously obtained by study of guinea pig ileal peristalsis20 and rabbit colonic propulsion, in which the slight inhibitory effect caused by micromolar concentrations of MEN 10627 was markedly enhanced by threshold concentrations of atropine.42
Background & Aims: In the intestine, tachykinins regulate motility by participating in neuromuscular and neuro-neuronal transmission. The aim of this study was to test the hypothesis that colonic propulsion is regulated by an interplay between tachykinergic and cholinergic transmission. Methods: Propulsion was elicited by intraluminal distention of a thin rubber balloon, which traveled from the oral to the anal end of guinea pig isolated distal colon segments. The overall contribution of endogenous tachykinins to colonic propulsion was examined by blocking NK₁, NK₂, and NK₃ receptors simultaneously. Results: NK₂-receptor blockade by MEN 11420 inhibited propulsion, whereas blockade of NK₁ by SR 140333 or of NK₃ receptors by SR 142801 had minor effects on motility. Blockade of muscarinic or nicotinic receptors by hyoscine or hexamethonium decelerated peristalsis up to propulsion arrest. In the presence of partial muscarinic receptor blockade, the NK₁-receptor antagonist SR 140333 and the NK₂-receptor antagonist MEN 11420 markedly inhibited propulsion. Propulsion was also inhibited by the NK₃-receptor antagonist SR 142801 in the presence of partial nicotinic receptor blockade. The simultaneous administration of the 3 tachykinin antagonists inhibited propulsion by 50%. Conclusions: This study demonstrates the existence of an interplay between tachykinergic and cholinergic pathways during peristalsis and the importance of endogenous tachykinins acting at multiple receptor sites in the control of colonic propulsion.
GASTROENTEROLOGY 2001;120:938-945
Use of antagonists to define tachykininergic control of intestinal motility in pigs
1997, Peptides
Schmidt, P. T. and J. J. Holst. Use of antagonists to define tachykininergic control of intestinal motility in pigs. Peptides 18(3), 373–379, 1997.—The involvement of the tachykinins in extrinsic nervous control of motility was studied in isolated, vascularly perfused, porcine ileal segments. Substance P and neurokinin A (10⁻⁸M) stimulated motility, and nonpeptide NK₁ and NK₂ receptor antagonists (10⁻⁶M) abolished this. Electrical stimulation of the mixed extrinsic nerves (8 Hz) had no effect alone or with atropine (10⁻⁶M) or phentolamine (10⁻⁵M), but increased motility during coinfusion of both blockers. This effect was abolished by hexamethonium (3 × 10⁻⁵M), and was reduced by over 80% by the NK₁ receptor antagonist. As previously shown, substance P and neurokinin A were released during nerve stimulation, only during blockade of α-adrenergic and muscarinic receptors, and the release was abolished by hexamethonium. Capsaicin infusions (10⁻⁵M) increased substance P and neurokinin A release, and weakly stimulated small intestinal motility, but this was not inhibited by the tachykinin antagonists. Our results suggest that intrinsic tachykinin-producing neurons, controlled by extrinsic, nicotinic, excitatory neural pathways, and extrinsic adrenergic, inhibitory pathways, participate in the regulation of small intestinal motility.
Tachykinins in the gut. Part I. Expression, release and motor function
1997, Pharmacology and Therapeutics
The preprotachykinin-A gene-derived peptides substance P and neurokinin (NK) A are expressed in distinct neural pathways of the mammalian gut. When released from intrinsic enteric or extrinsic primary afferent neurons, tachykinins have the potential to influence both nerve and muscle by way of interaction with three different types of tachykinin receptor, termed NK₁, NK₂ and NK₃ receptors. Most prominent among the effects of tachykinins is their excitatory action on gastrointestinal motor activity, which is seen in virtually all regions and layers of the mammalian gut. This action depends not only on a direct activation of the muscle through NK₁ and/or NK₂ receptors, but also on stimulation of excitatory enteric motor pathways through NK₃ and/or NK₁ receptors. In addition, tachykinins can inhibit motor activity by stimulating either inhibitory neuronal pathways or interrupting excitatory rekys. A synopsis of the available data indicates that endogenous substance P and NKA interact with other enteric transmitters in the physiological control of gastrointestinal motor activity. Derangement of the regulatory roles of tachykinins may be a factor in the gastrointestinal dysmotility associated with infection, inflammation, stress and pain. In a therapeutic perspective, it would seem conceivable, therefore, that tachykinin agonists and antagonists are adjuncts to the treatment of motor disorders that involve pathological disturbances of the gastrointestinal tachykinin system.
Effect of niflumic acid on electromechanical coupling by tachykinin NK<inf>1</inf> receptor activation in rabbit colon
1996, European Journal of Pharmacology
We have investigated the effect of the Cl⁻ channel blocker, niflumic acid, on the contractile response and electromechanical coupling activated by stimulation of the tachykinin NK₁ receptor in the longitudinal muscle of rabbit proximal colon, in the presence of indomethacin (5 μM). The application of submaximal equieffective concentrations of the tachykinin NK₁ receptor-selective agonist [Sar⁹]substance P sulfone (30 nM), of carbachol (300 nM) and KCl (40 mM0, produced distinct phasic and tonic components of contraction. Niflumic acid (10–100 μM) preferentially and markedly inhibited the tonic component of the response to [Sar⁹]substance P sulfone and to carbachol, without affecting the response to KCl. Nifedipine (1 μM) abolished the response to KCl and greatly reduced the response to [Sar⁹]substance P sulfone and carbachol. The nifedipine-resistant response to [Sar⁹]substance P sulfone was attenuated by niflumic acid (100 μM), while that to carbachol was unaffected. In sucrose gap experiments, superfusion with niflumic acid (100 μM), in the presence of nifedipine (3 μM), produced membrane hyperpolarization, which was totally blocked by tetraethylammonium (10 mM). Niflumic acid inhibited both depolarization and contraction induced by [Sar⁹]substance P sulfone, both in the absence or in the presence of tetraethylammonium. The present findings support the idea that a niflumic acid-sensitive mechanism, probably an effect on Cl⁻ channels, takes part in the post-receptorial events activated by tachykinin NK₁ receptor stimulation in the longitudinal muscle of rabbit colon, and suggest that this mechanism would be more important for generating the sustained tonic than the phasic component of contraction.
Neuronal tachykinin NK<inf>2</inf> receptors mediate release of non-adrenergic non-cholinergic inhibitory transmitters in the circular muscle of guinea-pig colon
1995, Neuroscience
The aims of this study were: (i) verify the usefulness of the recently described non-peptide antagonist, SR 142801, for blocking tachykinin NK₃ receptors in the circular muscle of the guinea-pig colon and (ii) after occulsion of NK₃ receptors by SR 142801, test the hypothesis that tachykinins may activate non-adrenergic non-cholinergic inhibitory neurons via non-NK₃ receptors. In sucrose gap, we found that SR 142801 (0.1 μM) time-dependently inhibited the senktide-induced atropine (1 μM)-sensitive depolarization, action potentials and contractions of circular muscle of guinea-pig colon without affecting the cholinergic excitatory junction potential and contraction produced by single pulse electrical field stimulation. Likewise, SR 142801 (0.1 μM) time-dependently inhibited the senktide-induced non-adrenergic non-cholinergic hyperpolarization and relaxation of the circular muscle, without affecting the non-adrenergic non-cholinergic inhibitory junction potentials and relaxation produced by single pulse electrical field stimulation. Therefore, SR 142801 is a suitable tool to occlude neuronal NK₃ receptors in guinea-pig colon. In the presence of SR 142801 (0.1 μM), atropine (1 μM), guanethidine (3 μM), indomethacin (3 μM) and nifedipine (1 μM) superfusion with neurokinin A (0.3 μM) produced depolarization on which a series of inhibitory junction potentials were superimposed. The incidence, number and amplitude of the inhibitory junction potentials evoked by neurokinin A was partly reduced by pretreatment with either apamin (0.1 μM) orl-nitroarginine (30 μM) and was totally blocked by pretreatment with apamin plusl-nitroarginine or by tetrodoxin (1 μM). None of these treatments affected the depolarization and contraction produced by neurokinin A. The NK₁ receptor selective antagonist, GR 82,334 (3 μM), did not affect the responses to neurokinin A, which were abolished by the NK₂ receptor-selective antagonist GR 94,800 (0.1 μM). Substance P (0.3 μM) produced a large depolarization of the membrane but was poorly effective in producing superimposed inhibitory junction potentials. The NK₁ receptor-selective agonist [Sar⁹]substance P sulfone (0.3 μM) produced large depolarization without inducing superimposed inhibitory junction potentials, while the NK₂ receptor-selective synthetic agonist [β-Ala⁸]neurokinin A(4–10) (0.3 μM) produced depolarization and superimposed inhibitory junction potentials.
We conclude that neurokinin A, in addition to direct excitation and contraction of circular muscle activates, via neuronal NK₂ receptors, inhibitory non-adrenergic non-cholinergic motorneurons. Thus, neuronal NK₂ receptors should be considered as targets for endogenous tachykinins in enteric circuitries leading to descending relaxation in guinea-pig colon.

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Research paperNervous control of the release of substance P and neurokinin A from the isolated perfused porcine ileum

Abstract

Neuroscience

Gastroenterology

Biochem. Biophys. Res. Comm.

Regul. Pept.

Peptides

Biochem. Biophys. Res. Comm.

Colonic motor and vascular responses to pelvic nerve stimulation and their relation to local peptide release in the cat

J. Physiol.

On the role of vasoactive intestinal polypeptide and tachykinins in the secretory reflex elicited by chemical peritonitis in the cat small intestine

Acta Physiol. Scand.

Sympathetic postganglionic mechanism

Nature

Conversion of neuropeptide K to neurokinin A and vesicular colocalization of neurokinin A and substance P in neurons of the guinea-pig small intestine

J. Neurochem.

Neutral endopeptidase inhibitors potentiate substance P-induced contraction in gut smooth muscle

Am. J. Physiol.

Research paper
Nervous control of the release of substance P and neurokinin A from the isolated perfused porcine ileum