Relaxant effect of capsaicin in the rat gastric fundus

doi:10.1016/0014-2999(91)90390-C

European Journal of Pharmacology

Volume 195, Issue 1, 19 March 1991, Pages 131-137

https://doi.org/10.1016/0014-2999(91)90390-C Get rights and content

Abstract

The effect of capsaicin was studied in precontracted longitudinal muscle strips of the rat gastric fundus. Capsaicin induced a relaxation in the concentration range 10⁻⁷-10⁻⁶ M. The relaxation induced by 10⁻⁶ M capsaicin was completely prevented by extrinsic denervation of the stomach. The adrenoceptor antagonists phentolamine and propranolol did not influence the effect of capsaicin while hexamethonium potentiated it; this potentiation was not observed with another nicotinic receptor antagonist trimethaphan. Tetrodotoxin did not have a consistent effect as it reduced the capsaicin-induced relaxation in some but not all tissues. The peptidase trypsin consistently reduced the action of capsaicin but vasoactive intestinal polypeptide (VIP) antiserum, desensitization to calcitonin gene-related peptide (CGRP), and CGRP antiserum had no influence. The neuropeptide involved in the relaxant effect of capsaicin in the rat gastric fundus has thus still to be determined.

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Diabetic gastroparesis (DGP) is characterized by delayed gastric emptying of solid food. Nitrergic neuron–mediated fundus relaxation and intragastric peristalsis are pivotal for gastric emptying and are impaired in DGP. Transient receptor potential vanilloid 1 (TRPV1) ion channels are expressed in gastrointestinal vagal afferent nerves and have a potential role in relevant gastrointestinal disorders. In this study, mice with high-fat diet (HFD)-induced type 2 diabetes mellitus (T2DM), associated with gastroparesis, were used to determine the role of TRPV1 in DGP. After feeding with HFD, mice exhibited obesity, hyperglycemia, insulin resistance, and delayed gastric emptying. Cholinergic- and nitrergic neuron–mediated neuromuscular contractions and relaxation were impaired. The antral tone of the DGP mice was attenuated. Interestingly, activating or suppressing TRPV1 facilitated or inhibited gastric fundus relaxation in normal mice. These effects were neutralized by using a nitric oxide synthase (NOS) inhibitor. Activation or suppression of TRPV1 also increased or reduced NO release. TRPV1 was specifically localized with neuronal NOS in the gastric fundus. These data suggest that TRPV1 activation facilitates gastric fundus relaxation by regulating neuronal NOS and promoting NO release. However, these effects and mechanisms disappeared in mice with DGP induced by HFD diet. TRPV1 expression was only marginally decreased in the fundus of DGP mice. TRPV1 dysfunction may be a potential mechanism underlying the dysfunction of DGP gastric nitrergic neuromuscular relaxation.
Role of KATP channels and TRPV1 receptors in hydrogen sulfide-enhanced gastric emptying of liquid in awake mice
2012, European Journal of Pharmacology
Citation Excerpt :
It was demonstrated that capsaicin activates enteric cholinergic neurons in guinea-pig small intestine and induces contractile effect and your inhibition slower gastric emptying (Benko et al., 2005). Likewise, capsaicin induced a relaxation in precontracted muscle strips of the rat gastric fundus (Lefebvre et al., 1991). In the stomach, we also demonstrated that pretreatment with capsazepine abolishes the gastroprotective effects of l-cysteine, NaHS, or Lawesson’s reagent on ethanol-induced gastric lesions (Medeiros et al., 2009).
Hydrogen sulphide (H₂S) has shown to relax gastrointestinal muscle. Here in, we evaluated the effects of H₂S donors on gastric emptying and in pyloric sphincter muscle relaxation, and whether these effects involved K_ATP channels or TRPV1 receptors. Mice were treated with l-cysteine (alone or with propargylglycine-an inhibitor of H₂S synthesis), NaHS, Lawesson’s reagent (H₂S donors) or saline. After 30 min, mice were gavaged with a liquid meal containing a nonabsorbable marker and then killed at 10, 20 or 30 min intervals to assess marker recovery from the stomach and intestine. This experiment was repeated in mice pre-treated with K_ATP channel (glibenclamide) or TRPV1 receptor (capsazepine) antagonists. In addition, pyloric sphincter muscles were mounted in an organ bath, incubated with saline, glibenclamide or capsazepine, and NaHS dose–responses were determined. H₂S donors and l-cysteine enhanced gastric emptying in a dose-dependent manner; propargylglycine reversed the effect of l-cysteine. Both glibenclamide and capsazepine abolished l-cysteine and H₂S donors’ augmentation of gastric emptying. Dose-dependent inductions of pyloric sphincter relaxation by NaHS were abolished by glibenclamide or capsazepine. These data suggest that H₂S donors-induced acceleration of gastric emptying and relaxation of pyloric sphincter muscle by K_ATP channel and TRPV1 receptor activations.
Contractile effect of TRPA1 receptor agonists in the isolated mouse intestine
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TRPA1 is a member of the transient receptor potential (TRP) channel family expressed in sensory neurons. The present study focused on the effects of TRPA1 activation on contractile responses in isolated mouse intestine preparations. The jejunum, ileum, and proximal and distal colon were surgically isolated from male ddY mice. Intestinal motility was recorded as changes in isotonic tension. TRPA1, TRPM8, and TRPV1 expressions were examined by reverse transcription-polymerase chain reaction (RT-PCR). A TRPA1 agonist allyl isothiocyanate (AITC) dose-dependently induced contractions in the proximal and distal colon, whereas in the jejunum and ileum, even 100 μM AITC caused very little contraction. Likewise, a TRPA1 and TRPM8 agonist icilin, a TRPA1 agonist allicin, and a TRPV1 agonist capsaicin induced contractions in the colon. However, a TRPM8 agonist menthol induced long-lasting relaxation in the colon. Repeated exposure to AITC produced desensitization of its own contraction in the colon. Moreover, contractions induced by AITC generate cross-desensitization with icilin and capsaicin. Tetrodotoxin completely abolished AITC-induced contractions in the colon, whereas atropine significantly attenuated AITC-induced contractions in the distal colon, but not in the proximal colon. Menthol-induced relaxation in the colon was not inhibited by tetrodotoxin and atropine. RT-PCR analysis revealed the expression of TRPA1 and TRPV1, but not TRPM8, throughout the mouse intestine. These results suggest that TRPA1, but not TRPM8, are functionally expressed in the enteric nervous system throughout the mouse intestine on neurons that may also co-express TRPV1, yet the contractile responses to TRPA1 activation differ depending on their location along the intestine.
Combined determination with functional and morphological studies of origin of nerve fibers expressing transient receptor potential vanilloid 1 in the myenteric plexus of the rat jejunum
2004, Autonomic Neuroscience: Basic and Clinical
The aim of this study was to determine the action of capsaicin in isolated rat intestine and the origin of nerve fibers expressing transient receptor potential vanilloid 1 (TRPV1: capsaicin receptor) in the rat jejunum by combination of functional and immunohistochemical experiments. Capsaicin (1 μM) produced a prolonged relaxation response (52.8±15.3% of the relaxation response to papaverine, mean±S.D., n=27) of the isolated jejunum in the presence of atropine and guanethidine. Pretreatment with the TRPV1 antagonist, capsazepine (10 μM) and ruthenium red (3 μM) significantly reduced the relaxation response to capsaicin by 78% (P<0.01) and 38% (P<0.05), respectively. Tetrodotoxin and calcitonin gene-related peptide (CGRP)-desensitization significantly reduced the response to capsaicin by 72% (P<0.01) and 42% (P<0.01), respectively. Therefore, we investigated the distribution of TRPV1-immunoreactivity (IR) in the myenteric plexus of the rat jejunum. Using antisera raised against either the N-terminal or C-terminal domains of rat TRPV1, TRPV1-IR was present in the nerve fibers, but not in the cell bodies of myenteric neurons. These TRPV1-immunoreactive nerve fibers were running in myenteric ganglia and their interconnecting strands. Most TRPV1-immunoreactive nerve fibers showed CGRP-IR, whereas few VR1-immunoreactive nerve fibers showed substance P-IR. After chronic denervation of the extrinsic nerve supply to the jejunum, both the relaxation response to capsaicin and TRPV1-immunoreactive nerve fibers completely disappeared. These findings indicate that these TRPV1-immunoreactive nerve fibers in the rat jejunum derive from extrinsic neurons and that activation of TRPV1 produces the relaxation response in the rat jejunum, at least in part, through the release of CGRP from nerve fibers expressing TRPV1.
Capsaicin-sensitive afferents and their role in gastroprotection: An update
2001, Journal of Physiology Paris
The pivotal role of capsaicin-sensitive peptidergic sensory fibers in the maintenance of gastric mucosal integrity against injurious interventions was suggested by the authors 20 years ago. Since then substantial evidence has accumulated for the local sensory-efferent function of the released CGRP, tachykinins and NO in this gastroprotective mechanism. This overview outlines some recent achievements which shed light on new aspects and further horizons in this field. (1) Cloning the capsaicin VR-1 receptor (an ion channel-coupled receptor) and raising the VR-1 knockout mice provided a definite molecular background for the existence of capsaicin-sensitive afferents with both sensory and mediator releasing functions in the stomach. This cation channel is also sensitive to hydrogen ions. (2) VR-1 agonists (capsaicin, resiniferatoxin, piperine) protect against gastric ulcer of the rat parallel with their sensory stimulating potencies. (3) Antidromic stimulation of capsaicin-sensitive vagal and somatic afferents results in the release of CGRP, tachykinins, NO and somatostatin. Somatostatin with gastroprotective effect is released from D cells and sensory nerve endings. (4) The recent theory for the existence of spinal afferents without sensory function [P. Holzer, C.A. Maggi, Dissociation of dorsal root ganglion neurons into afferent and efferent-like neurons, Neuroscience 86 (1998) 389–398] is discussed. Data proposed to support this theory are interpreted here on the basis of a dual sensory-efferent function of VR-1 positive afferents, characterized by a frequency optimum of discharges for release vasodilatory neuropeptides below the nociceptive threshold. (5) Recent data on the effect of capsaicin in healthy human stomach are summarized. These results indicate that the gastroprotective effect of capsaicin in the human stomach involves additional mechanisms to those already revealed in the rat.
Capsaicin increases gastric emptying rate in healthy human subjects measured by <sup>13</sup>C-labeled octanoic acid breath test
1999, Journal of Physiology Paris
The role of capsaicin-sensitive primary afferent sensory nerves in the regulation of gastrointestinal motility in human is not clarified yet. In this study, we investigated the effect of 400 μg capsaicin given intragastrically on gastric emptying measured by ¹³C-octanoic acid breath test in ten healthy human subjects. Four parameters of gastric emptying curves were taken into consideration: 1) maximum value of the curve, 2) time belonging to this maximum, 3) slope of the rising part of the curve and 4) time belonging to the 50% of the area under the curve. Administration of 400 μg capsaicin significantly increased the slope of gastric emptying curve (from 0.1 ± 0.01 to 0.139 ± 0.014 U.min^–1, P < 0.05) and significantly decreased the time belonging to the maximum value of emptying curve (from 150 ± 18 to 75 ± 12 min, P < 0.05) and the time belonging to the 50% of the area under the curve (from 112 ± 15 to 99 ± 14 min, P < 0.05). According to our results 400 μg capsaicin enhances gastric emptying rate in healthy human subjects.

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Relaxant effect of capsaicin in the rat gastric fundus

Abstract

European J. Pharmacol.

European J. Pharmacol.

European J. Pharmacol.

Gen. Pharmacol.

Neurosci. Lett.

European J. Pharmacol.

Neurosci. Lett.

Neuroscience

Regul. Pept.

Gastroenterology

The neuropharmacology of capsaicin: review of some recent observations

Pharmacol. Rev.

Influence of α-chymotrypsin and trypsin on the non-adrenergic non-cholinergie relaxation in the rat gastric fundus

Br. J. Pharmacol.

Vasoactive intestinal polypeplide as possible mediator of relaxation in the rat gastric fundus

J. Pharm. Pharmacol.