Harald Schwörer

Regulation of 5-HT release from enterochromaffin cells

Large amounts of 5-HT are present in the mammalian intestine where the amine is concentrated in the enterochromaffin cells (ECs) of the mucosa. ECs have the enzymes to synthesize 5-HT, are endowed with a specific, imipramine-sensitive 5-HT uptake mechanism and can store 5-HT in specific secretory vesicles. ECs can secrete 5-HT in a calcium-dependent manner. In particular, calcium influx through voltage-regulated channels and receptor-mediated liberation of intracellular calcium can evoke 5-HT release. 5-HT secretion from ECs occurs predominantly at the interstitial side and is controlled by a complex pattern of receptor-mediated mechanisms. Stimulatory receptors (beta-adrenoceptors, muscarine, nicotine and 5-HT3 receptors) and inhibitory receptors (alpha 2-adrenoceptors, histamine H3, GABAA- and GABAB-, A2 and P2y alpha purine and 5-HT4 receptors as well as receptors for vasoactive intestinal polypeptide (VIP), pituitary adenylate cyclase stimulating peptide (PACAP) and somatostatin) have been shown to be involved in the control of 5-HT release from the ECs.

Relief of cholestatic pruritus by a novel class of drugs: 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists: effectiveness of ondansetron

&NA; The objective of the present study was to determine whether ondansetron, a specific serotonin type 3 receptor antagonist (5‐HT3), relieves cholestatic pruritus in patients resistant to conventional antipruritic therapy (antihistamines and cholestyramine). In a placebo‐controlled study the acute effect of an intravenous injection of ondansetron (4 mg, 8 mg) or placebo (NaCl solution) was tested in 10 patients (41–66 years of age; 4 men, 6 women) with cholestatic itch. A successful treatment was assessed when the intensity of itch was reduced by 50% or more within 2 h after injection of ondansetron. Intensity of itch was determined by the patients on a visual rating scale from 0 to 10. Ondansetron reduced or abolished pruritus within 30–60 min after injection. A 50% reduction of the intensity of itch was observed up to 6 h after injection of 8 mg. The effect was reproducible in the same patient. In conclusion ondansetron is effective in the treatment of cholestatic itch. Serotonin may participate in the generation and/or sensation of cholestatic pruritus.

REGULATION OF SEROTONIN RELEASE FROM THE INTESTINAL MUCOSA

In the mammalian intestine serotonin (5-hydroxytryptamine, 5-HT) is present in high concentrations in the enterochromaffin cells. The release of 5-HT from the intestinal mucosa is regulated by a complex pattern of neuronal and humoral inputs to the enterochromaffin cells. The enterochromaffin cells appear to be endowed with different inhibitory (alpha 2-adrenoceptors, GABAA- and GABAB-receptors, histamine H3-receptors, receptors for vasoactive intestinal polypeptide and somatostatin) as well as stimulatory receptors (beta-adrenoceptors, muscarine and nicotine receptors). The physiological significance of this complex system of receptors is suggested by experiments which demonstrate that the respective intrinsic neurotransmitters (catecholamines, acetylcholine, GABA and vasoactive intestinal polypeptide) released within the gut are involved in the regulation of the release of 5-HT from the enterochromaffin cells.

Presence of melatonin in the human hepatobiliary-gastrointestinal tract

A variety of speculations about the possible origin and physiological role of the neurohormone melatonin in the gastrointestinal tract exist. However, the experimental evidence supporting any of these theories is not substantial and are missing for humans. We studied the distribution of melatonin which was measured with radioimmunoassay in the following compartments and organs of the human hepatobiliary-gastrointestinal tract: bile (obtained by endoscopic retrograde cholangiopancreaticography), peripheral venous and portal venous blood (obtained from patients undergoing liver transplantation), endoscopically derived biopsies (mainly consisting of mucosa and submucosa) of stomach, duodenum, large intestine as well as in resected liver tissue. Melatonin concentrations in gastrointestinal mucosa were between 136 +/- 27 pg/100 mg (stomach) and 243 +/- 37 pg/100 mg (descending colon, each n = 5). Biliary melatonin concentrations (85 +/- 45 pg/ml) correlated well with plasma concentrations (55 +/- 38 pg/ml, each n = 14) and a considerable amount of melatonin (about 51 ng/24 hours) appears to be excreted into the gut via the bile duct. Melatonin concentrations were slightly higher in portal than in peripheral venous blood and also the liver contained higher concentrations of melatonin than the blood. In conclusion the presence and distribution of melatonin in human gut, bile, liver and portal blood and the various reports on modulatory actions of melatonin on gut and liver functions suggest that melatonin may act as a mediator of inter-organ communication between gut and liver.

Pituitary adenylate cyclase activating peptide, a novel VIP-like gut-brain peptide, relaxes the guinea-pig taenia caeci via apamin-sensitive potassium channels.

SummaryEffects of pituitary adenylate cyclase activating peptide (PACAP-(1-27)) and vasoactive intestinal polypeptide (VIP) on the guinea-pig taenia caeci were studied in the presence of guanethidine and scopolamine. Both peptides (1 nmol/1-1 μmol/1) concentration-dependently relaxed the smooth muscle of the taenia. PACAP-(1-27) and VIP were nearly equipotent. Apamin (30 nmol/1), a selective blocker of calcium-activated potassium channels, abolished the relaxation induced by PACAP-(1–27) whereas the effect of VIP remained unaffected. PACAP-(1–27) may be a candidate for the noncholinergic, non-adrenergic inhibitory neurotransmitter which induces apamin-sensitive relaxation in the intestinal tract.

Autoreceptors can modulate 5-hydroxytryptamine release from porcine and human small intestine in vitro

AbstractThe effects of 5-hydroxytryptamine (5-HT) receptor agonists and antagonists were studied on the release of 5-HT from enterochromaffin cells of incubated strips of porcine and human small intestine. Tetrodotoxin (1 μmol/l) was present in the incubation medium to block neuronally mediated inputs to the enterochromaffin cells. The 5-HT1A receptor agonist (+)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT, 1 μmol/l) and the 5-HT2 receptor agonist α-methyl-5-HT (1 μmol/l) increased 5-HT release by 40% in about 60% of the human preparations.These agonists showed no effect on 5-HT release in porcine intestinal mucosa. The 5-HT3 receptor agonist 2-methyl-5-HT (3–100 μmol/l) increased 5-HT release in both species by 60% (pig) and 90% (man), respectively. These stimulatory effects were antagonized by tropisetron (10 nmol/l). The 5-HT4 receptor agonist 5-methoxytryptamine (0.3–30 μmol/l) reduced 5-HT release by about 50% in both species. These inhibitory effects were antagonized by tropisetron (3 μmol/l). The basal outflow of 5-HT from the intestinal mucosa was not significantly affected by tropisetron (10 nmol/l; 3 μmol/l). The specific 5-HT4 receptor antagonist GR 113808 ((1-[2-methylsulphonyl)amino]ethyl]-4-piperidinyl]methyl-1-methyl-1H-indole-3-carboxylate) (0.1 μmol/l) which by itself did not significantly affect 5-HT release from human duodenal specimens blocked the inhibitory effect of 5-methoxytryptamine (30 μmol/l). These findings indicate that stimulatory 5-HT3 and inhibitory 5-HT4 receptors are present on enterochromaffin cells of the porcine and human intestinal mucosa. Under the present experimental conditions endogenous 5-HT does not significantly activate these receptors. Stimulatory 5-HT1A and 5-HT2 receptors may additionally be present on human enterochromaffin cells.

Glucocorticoid receptor expression in inflammatory bowel disease: evidence for a mucosal down-regulation in steroid-unresponsive ulcerative colitis.

Background : Glucocorticoids (GC) play a major role in the attenuation of inflammation. Glucocorticoid receptor (GR) expression is an important determinant of steroid sensitivity.

Characterization of histamine H3 receptors inhibiting 5-HT release from porcine enterochromaffin cells: Further evidence for H3 receptor heterogeneity

The nature of the histamine receptor mediating inhibition of 5-HT release was investigated in strips of the porcine small intestine by investigating the effects of histamine ligands on the overflow of endogenous 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA). The overflow was measured by HPLC, combined with electrochemical detection and represents calcium-sensitive 5-HT release from enterochromaffin cells, as reported previously. The histamine H3 receptor selective agonists (R)-α-methyl-histamine and imetit inhibited the overflow of 5-HT maximally by 50–60%, with EC50 values of 48 and 3.2 nmol/l, respectively. Effects on 5-HT overflow were always accompanied by similar effects on the overflow of 5-HIAA. Thioperamide (100 nmol/l) shifted the concentration response curve of (R)-α-methyl-histamine to the right (pKB value 8.38). The inhibitory effect of 1 μmol/l (R)-α-methyl-histamine was antagonized in a concentration-dependent manner by thioperamide (IC50: 65 nmol/l) and dimaprit (IC50: 8.6 μmol/l); however, the effect of (R)-α-methyl-histamine was weakly antagonized by burimamide (by 38% at 100 μmol/l) and not significantly affected by other H3 receptor antagonists, such as impromidine, betahistine and phenylbutanoyl-histamine (each up to 100 μmol/l). In conclusion, H3 receptors mediating inhibition of 5-HT release from porcine enterochromaffin cells have a particular pharmacological profile indicating that heterogeneity of H3 receptors may exist. The data suggest that histamine H3 receptors modulating 5-HT release in pig small intestine do not belong to either H3A or H3B receptors as defined in rat tissue.

Pituitary Adenylate Cyclase-Activating Peptide is a Potent Modulator of Human Colonic Motility

Pituitary adenylate cyclase-activating peptide (PACAP) represents a novel brain-gut peptide with high sequence homology to vasoactive intestinal polypeptide (VIP). Since PACAP has been identified in the human gut, the effect of the two molecular forms PACAP-(1-38) and PACAP-(1-27), the hybrid PACAP-(1-23)VIP-(24-28), and VIP on the contractility of the longitudinal muscle of human sigmoid colon was tested in vitro. All peptides inhibited the spontaneous phasic contractions and relaxed concentration-dependently carbachol-precontracted preparations. The effects of the peptides remained unaffected by tetrodotoxin, by inhibition of phosphodiesterase activity, and by inhibition of nitric oxide synthesis. Apamin reduced only the effects of the PACAP peptides, whereas tetraethylammonium blocked only the effect of VIP. In conclusion, PACAP peptides and VIP mediate their relaxant effects via activation of specific PACAP and VIP receptors coupled to different potassium channels.

Pituitary adenylate cyclase activating polypeptide (PACAP) is a potent relaxant of the rat ileum

The effect and mode of action of pituitary adenylate cyclase activating polypeptide (PACAP) were studied in rat ileal strips. PACAP relaxed, concentration dependently, rat ileum and was 50 times more potent than the structurally related vasoactive intestinal polypeptide (VIP). The inhibitory action of PACAP was not modified by TTX, omega-conotoxin, adrenergic, or ganglionic blockade, antagonists of adrenoreceptors and muscarinic receptors, indicating a direct myogenic effect probably through specific PACAP receptors. The lack of cross-tachyphylaxis between PACAP and VIP suggests that both peptides act by activation of distinct receptors. Structure-function analysis revealed that the N-terminal region of the PACAP molecule is crucial for biological activity.