Biomedical subjects

V Schusdziarra

Publications and source records attributed to V Schusdziarra.

At least 37 records · Page 2Linked to original sources

PubMed2000

Effects of oral casokefamide on plasma levels, tolerance, and intestinal transit in man.

Food-derived opioid peptides such as beta-casomorphins are of interest for treatment of chronic diarrhea. The beta-casomorphin analog casokefamide was administered orally at doses of 5.5, 8.0, and 16.0 mg to 10 healthy male volunteers, respectively. Dose-dependent increases of plasma levels with a maximum of 350 fmol/l were determined. No side-effects due to casokefamide has been observed. In comparison to placebo, casokefamide showed a trend toward prolongation of oro-caecal transit time. Orally applied casokefamide is well tolerated and may represent a useful tool for treatment of diarrhea in the future.

Administration, Oral↗

PubMed2000

Endomorphin-1 and -2, endogenous ligands for the mu-opioid receptor, inhibit striated and smooth muscle contraction in the rat oesophagus.

Recently, morphological evidence for an interaction of autonomic nerve fibres and extrinsic motor innervation of the rat oesophagus has emerged. The aim of the present study was to investigate the possible influence of endogenous and exogenous opioids on rat oesophageal smooth and striated muscle function in vitro. The entire oesophagus (excluding the lower oesophageal sphincter) with both Nervi (Nn) vagi, including the Nn recurrentes, was dissected and placed in an organ bath (100 mL, 37 degrees) with oxygenated Krebs-Ringer buffer. Contractile activity was measured in a longitudinal direction with a force transducer. Both Nn vagi were placed on a bipolar platinum electrode 2 cm distant from the oesophagus. Vagal stimulation (VS), applied for 1 s (40 V, 0.5 ms, 20 Hz) resulted in a biphasic contractile response that was completely blocked by 10(-6) M tetrodotoxin. The first part consisted of a tetanic striated muscle contraction, as it was abolished by tubocurarine (10(-5) M, n=5) but unaffected by atropine (10(-6) M, n=3) or hexamethonium (10(-4) M, n=4). In contrast, the second part was completely inhibited by hexamethonium (10(-4) M) and atropine (10(-6)M), whereas tubocurarine (10(-5) M) showed no influence, indicating a stimulation of preganglionic nerve fibres supplying oesophageal smooth muscle (muscularis mucosae) via relays in myenteric ganglia. In order to characterize opioid influence on the oesophageal striated and smooth muscle contractility, the following experiments were carried out. 10(-6) M endomorphin-1 and -2, endogenous mu-opioid-receptor agonists, reduced the contractile response of the striated (EM-2, -25.1+/-5.3%; n=16), and the smooth muscle (EM-2, -81.9+/-3.3%; n=11). Both effects were reversible by the opioid receptor antagonist naloxone (10(-6) M) and therefore, mediated via opioid receptors. Neither SNC-80, an agonist on the delta-opioid-receptor, U-69593, an agonist on the kappa-opioid-receptor, nor nociceptin, an agonist at the ORL1 (opioid receptor-like) receptor, had a significant effect on the striated muscle contraction. In contrast to SNC-80, U-69593 and nociceptin inhibited smooth muscle contraction but this relaxation could not be antagonized by naloxone. None of the opioid receptor antagonists used had an effect on basal tonus or muscle contraction following VS. Our data provide evidence for an autonomic modulation of vagal motor innervation of the striated and smooth oesophageal muscle. Endomorphin-1 and -2, both selective mu-opioid receptor agonists, cause an inhibition of striated and smooth muscle response which is reversible by naloxone, an opioid receptor antagonist. The location of the mu-opioid receptor still has to be established.

Animals↗

PubMed2000

Mechanisms of alpha,beta-methylene atp-induced inhibition in rat ileal smooth muscle: involvement of intracellular Ca2+ stores in purinergic inhibition.

1. In order to investigate purinergic effects on rat ileal smooth muscle, we used alpha,beta-methylene ATP (alpha,beta-MeATP), ATP, ADP and UTP. alpha,beta-Methylene ATP and ATP were the only agonists that caused a concentration-dependent inhibition of carbachol-precontracted smooth muscle. The inhibitory effect of alpha,beta-MeATP was completely blocked by pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (3 x 10(-5) mol/L), a selective antagonist of the P2X > > P2Y receptor. 2. Using reverse transcription-polymerase chain reaction we demonstrated the presence of both, P2X and P2Y receptor mRNA within the rat ileal longitudinal muscle/myenteric plexus layer preparation. 3. The alpha,beta-MeATP-induced inhibition was blocked in a concentration-dependent manner in the presence of the K+ channel blocker apamin, but was unaffected by other K+ channel blockers, such as charybdotoxin (10(-7) mol/L), 4-aminopyridine (10(-4)mol/L), glibenclamide (10(-5) mol/L) and tetraethylammonium (10(-3) mol/L). 4. The alpha,beta-MeATP-induced inhibition was unaffected by pretreatment with atropine (10(-6) mol/L), phentolamine (10(-6) mol/L), propranolol (10(-6) mol/L), nitrendipine (10(-7) mol/L), pertussis toxin (10(-6) mol/L) NG-nitro-L-arginine (3 x 10(-4) mol/L) and tetrodotoxin (10(-6) mol/L), excluding an involvement of adrenergic, cholinergic, neural, nitrinergic or G-protein involvement in purinergic-mediated inhibition. 5. In order to investigate whether the internal Ca2+ stores participated in the inhibitory effect observed, we depleted internal Ca2+ stores with cyclopiazonic acid, a specific Ca2+-ATPase inhibitor. The inhibitory effect of alpha,beta-MeATP was completely abolished after depletion of the intracellular Ca2+ stores. 6. This is in contrast with the effects seen for neurotensin, where neurotensin-induced inhibition was unchanged after depletion of intracellular Ca2+ stores, suggesting at least two different pathways of apamin-sensitive non-adrenergic, non-cholinergic inhibition in rat ileal smooth muscle. 7. According to our results, the inhibitory effect of alpha,beta-MeATP in rat ileum longitudinal smooth muscle is mediated via a P2 purinoceptor, most likely a P2X receptor, involves G-protein-independent activation of an apamin-sensitive K+ channel and requires filled intracellular Ca+ stores.

Adenosine Triphosphate↗

PubMed2000

Modulatory effect of endogenous and exogenous opioids on the excitatory reflex pathway of the rat ileum.

The ascending excitatory reflex is part of the peristaltic reflex, an important participant in intestinal propulsion. The aim of this study was to characterize the role of different opioid receptors in the ascending reflex through exogenous application of non-selective (Met-enkephalin) and selective opioid agonists (mu-PLO17, delta-DPDPE, kappa-U-50, 488) as well as selective opioid receptor antagonists (mu: CTOP-NH(2), delta: ICI-174,864, kappa: Nor-Binaltorphimine). Metenkephalin (IC(50): 0.06 microM) and morphine (IC(50): 1.8 microM) inhibited the ascending reflex response concentration-dependently. Both the mu-selective agonist PLO17 (IC(50): 0.83 microM, n =11) and the kappa-selective agonist U-50,488 (IC(50): 0.68 microM, n =8) concentration-dependently inhibited the magnitude of the ascending contractile reflex response, whereas the delta-agonist DPDPE (10(-10)-10(-6)M) had no significant effect. In contrast, the latency of the response (time interval between start of the stimulus and onset of the contraction) was significantly prolonged by PLO17 > morphine > Met-enkephalin > DPDPE, whereas U-50,488 showed no effect. When the effect of the receptor-specific antagonists was tested, only CTOP-NH(2)and Nor-BNI caused a significant increase of the contractile response, whereas ICI-174 864 was ineffective. On the other hand, CTOP-NH(2)> ICI-174 864 decreased the latency significantly but the kappa-receptor agonist Nor-BNI had no influence. Thus, mu- and kappa-receptors seem to be involved in regulating the contraction strength of the ascending reflex, whereas both mu- and delta-receptors seem to be involved in the timing of the reflex response.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed2000

Are guidelines followed in Helicobacter pylori diagnosis and therapy? An inquiry among gastroenterologists, referring physicians and patients in Munich.

BACKGROUND AND STUDY AIMS: Attempts to standardize Helicobacter pylori (Hp) diagnosis and therapy have led to the publication of guidelines by various national gastroenterological societies in Europe and the USA. However, little information is available either regarding the compliance of gastroenterologists and referring physicians with these guidelines, or regarding the patients' perspective. PATIENTS AND METHODS: A retrospective analysis was conducted of all outpatient upper gastrointestinal endoscopy reports for a one-month period in eleven different centers (two university hospitals and nine private practice gastroenterology offices) with a total of 24 gastroenterologists. Endoscopy reports from patients wit the indications of reflux, diarrhea, and tumors were excluded. Diagnoses and treatment recommendations given by gastroenterologists were recorded. Questionnaires concerning Hp diagnosis, treatment indications and performance, and follow-up were sent to referring physicians and patients. RESULTS: A total of 772 endoscopy reports were included in the study; analyzable questionnaires were returned by 287 referring physicians (47%) and by 265 patients (59%). Gastroenterologists recommended Hp eradication in all ulcers and in 29% of gastritis/nonulcer dyspepsia (NUD) cases. Referring physicians thought that 94% of ulcers should be treated by Hp eradication, which was also considered to be an absolute and relative indication in NUD by 15% and 53% of the referring physicians, respectively. Among the patients who replied, 52% had received Hp eradication regimens; ulcers were found in 22% of the total patient group. Check-up examinations after Hp therapy were considered necessary by 75% of the referring physicians, but only 22% of the responding patients actually underwent some form of check-up (upper gastrointestinal endoscopy in 91%). CONCLUSIONS: Gastroenterologists and (to a somewhat lesser extent) referring physician appear to be following the current guidelines for Hp treatment. As expected, two thirds of referring physicians consider NUD to be absolute or relative indication for Hp eradication. Check-up examinations are apparently being performed less frequently than recommended.

Adolescent↗

PubMed2000

Endoscopic ultrasound criteria for vascular invasion in the staging of cancer of the head of the pancreas: a blind reevaluation of videotapes.

BACKGROUND: It has been claimed in several prospective studies that endoscopic ultrasonography (EUS) is highly accurate in the locoregional staging of pancreatic cancer. However, the value of the EUS criteria for the diagnosis of vascular involvement is less well established. To totally exclude potential bias introduced by the availability of prior information, a completely blinded analysis of videotapes of patients with cancer of the pancreatic head was therefore conducted. METHODS: Videotape sequences of 75 patients with cancer of the head of the pancreas with surgical confirmation or unequivocally positive angiography demonstrating vascular invasion were reevaluated without any clinical data or information from other imaging studies. Involvement of the vascular system (portal vein with confluence, superior mesenteric vein, celiac axis) was assessed on EUS with special emphasis on EUS parameters of the tumor-vessel relationship. RESULTS: The overall sensitivity and specificity of EUS in the diagnosis of venous invasion were 43% and 91%, respectively, when using predetermined parameters (visualization of tumor in the lumen, complete obstruction, or collateral vessels). If the parameter "irregular tumor-vessel relationship" had been added to these criteria, the sensitivity would have risen to 62%, but the specificity would have fallen to 79%. The only vascular system that could be properly visualized by EUS was the portal vein/confluence area. The positive and negative predictive values for the single parameters chosen to diagnose portal venous involvement were as follows: 42% and 33% for irregular tumor-vessel relationship, 36% and 34% for visualization of tumor in the vascular lumen, 80% and 28% for complete vascular obstruction, and 88% and 18% for collateral vessels. CONCLUSIONS: In a completely blinded evaluation of the EUS diagnosis of vascular invasion by cancer of the head of the pancreas it was not possible to find suitable morphologic parameters with clinically useful sensitivity and specificity values (over 80%).

Adult↗

PubMed2000

Modern imaging methods versus clinical assessment in the evaluation of hospital in-patients with suspected pancreatic disease.

OBJECTIVE: Various modern imaging procedures such as endoscopic retrograde cholangiopancreatography (ERCP), computed tomography (CT), and endoscopic ultrasonography (EUS) have been shown to be highly accurate in the diagnosis of specific disorders of the pancreas. However, prior information often causes bias in the interpretation of these results. Little information is available concerning the value of these examinations in the primary and differential diagnosis of suspected pancreatic disease-particularly in comparison with clinical evaluation, including laboratory tests and transabdominal ultrasound (TUS). METHODS: Clinical and imaging information (EUS, ERCP, and CT) was collected for 184 inpatients who were referred over a 5-yr period for evaluation of suspected pancreatic disease. On the basis of patient history, laboratory tests, and the results of routine TUS, one gastroenterologist, who was unaware of any of the other procedures or the final diagnosis, made a presumptive clinical diagnosis. CT and ERCP images and EUS videotapes were then analyzed by three different and independent examiners, who had the same clinical information except for the TUS results, but were completely blinded to the results of the other examinations and the patients' diagnoses. The final diagnoses were obtained by surgery, histology, and cytology, plus a follow-up of at least 1 yr (mean 35 months) in all noncancer cases. RESULTS: The final diagnoses were: normal pancreas (n = 36), chronic pancreatitis without a focal inflammatory mass (n = 53) or with a focal inflammatory mass (n = 18), and pancreatic malignancy (n = 77). Clinical evaluation, including ultrasonography, achieved a sensitivity for pancreatic disease of 94% but a specificity of only 35%. The figures for the sensitivity and specificity of the three imaging procedures were 93% and 94%, respectively, for EUS; 89% and 92% for ERCP; and 91% and 78% for CT (p < 0.05 for the specificity of clinical assessment vs all three imaging tests, p > 0.05 for comparison of the three imaging procedures). In the differential diagnosis between cancer and chronic pancreatitis as well as between malignant and inflammatory tumors, there was no difference among clinical assessment and the three imaging tests. CONCLUSIONS: In a group of patients with a high suspicion of pancreatic disease, little additional sensitivity in the diagnosis of pancreatic disease is provided by sophisticated imaging procedures such as EUS, ERCP, and CT, in comparison with clinical assessment including laboratory values and TUS. However, the specificity can be substantially improved. To confirm the diagnosis, one of the three examinations is needed, depending on the suspected disease and local expertise. The imaging procedures should be performed in a stepwise fashion for specific purposes, such as exclusion of pancreatic disease and the planning of treatment in chronic pancreatitis and pancreatic cancer.

Adolescent↗

PubMed2000

Inhibition of small conductance K+ -channels attenuated melatonin-induced relaxation of serotonin-contracted rat gastric fundus.

The aim of this study was to investigate the effects of melatonin on rat gastric fundus smooth muscle. Melatonin (10(-4) to 10(-3) M) had no effect on the basal tone of gastric smooth muscle. After precontraction with carbachol (10(-6) M) or serotonin (10(-7) M), melatonin caused a concentration dependent inhibitory action. The half maximal effect on serotonin-induced contraction was found with 1.12 +/- 0.86 x 10(-5) M of melatonin. Increasing concentrations of melatonin (10(-5) to 10(-3) M) resulted in a right shift of the serotonin concentration response curve (10(-10) to 10(-5) M). This inhibitory effect of melatonin was partially blocked in the presence of apamin (10(-10) to 10(-7) M), a specific blocker of the small conductance calcium-dependent potassium channel, but not in the presence of other potassium channel blockers like charybdotoxin (10(-8) M), glibenclamide (l0(-5) M), or tetraethylammonium (ODQ, 10(-4) M). The inhibitory effect was not changed in the presence of the neuronal blocker tetrodotoxin (10(-6) M), the selective P2-receptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (3 x 10(-5) M), the nitric-oxide synthase inhibitor N-nitro-L-arginine (3 x 10(-4) M), or the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]-quinoxalin-1-one (10(-4) M), suggesting that neither the purinergic, nitrergic, nor guanylate cyclase pathways were involved. We further investigated inhibitory responses to electrical field stimulation (EFS) at different frequencies under non-adrenergic, non-cholinergic (NANC) conditions on a serotonin-induced contraction in the presence of melatonin (10)-5 to 10(-4) M). Melatonin significantly reduced these inhibitory NANC responses in higher (8-32 Hz), but not lower (05-4 Hz), frequencies (16 Hz without melatonin, 103 +/- 6.3%; melatonin 10(-5) M, 80.4 +/- 7.5%; melatonin 10(-4) M, 39.1 +/- 17.1%). Melatonin had no effect on contractile responses induced by EFS under basal tone. These results demonstrate that the inhibitory effect of melatonin in rat gastric fundus smooth muscle is apamin sensitive, but is not affected by other potassium channel blockers. This suggests that melatonin may be another transmitter candidate for the apamin sensitive responses within the gastrointestinal tract.

Animals↗

PubMed1999

NO releases bombesin-like immunoreactivity from enteric synaptosomes by cross-activation of protein kinase A.

The effect of nitric oxide (NO) on the release of bombesin-like immunoreactivity (BLI) was examined in synaptosomes of rat small intestine. The NO donor S-nitroso-N-acetylpenicillamine (SNAP; 10(-7) to 10(-4) M) significantly stimulated BLI release. In the presence of the NO scavenger oxyhemoglobin (10(-3) M) or the guanylate cyclase inhibitor ODQ (10(-5) M), SNAP-induced BLI release was antagonized. In addition, SNAP increased the synaptosomal cGMP content and elevation of cGMP levels by zaprinast (3 x 10(-5) M), an inhibitor of the cGMP-specific phosphodiesterase (PDE) type 5, and increased basal and SNAP-induced BLI release. NO-induced BLI release was blocked by Rp-adenosine 3',5'-cyclic monophosphorothioate (3 x 10(-5) M and 10(-4) M), an inhibitor of the cAMP-dependent protein kinase A, whereas KT-5823 (3 x 10(-6) M) and Rp-8-(4-chlorophenylthio)-cGMP (5 x 10(-5) M), inhibitors of the cGMP-dependent protein kinase G, had no effect. Because cGMP inhibits the cAMP-specific PDE3, thereby increasing cAMP levels, the role of PDE3 was investigated. Trequinsin (10(-8) M), a specific blocker of PDE3, stimulated basal BLI release but had no additive effect on NO-induced release, suggesting a similar mechanism of action. These data demonstrate that because of a cross-activation of cAMP-dependent protein kinase A by endogenous cGMP BLI can be released by NO from enteric synaptosomes.

Animals↗

PubMed1999

Evidence for a feedback inhibition of NO synthesis in enteric synaptosomes via a nitrosothiol intermediate.

The exact mechanisms controlling nitric oxide synthase (NOS) activity within enteric neurons are largely unknown. In this study, the effect of exogenous nitric oxide (NO) on NOS activity was investigated in enteric synaptosomes of rat ileum. 3-Morpholinosydnonimine (SIN-1; 10(-4) M) and S-nitroso-N-acetylpenicillamine (SNAP; 10(-4) M) significantly inhibited NOS activity by 53% and 48%, respectively. However, superoxide dismutase (SOD; 160 U/ml) as well as the NO scavenger oxyhemoglobin (10(-3) M) did not influence NO donor-induced inhibition. In contrast, the inhibitory effect was antagonized by diethyldithiocarbamate (3 x 10(-4) M), an inhibitor of endogenous Cu/Zn SOD. Inhibition of NOS by exogenous NO was dependent on glutathione (GSH), since the inhibitory effect was augmented in the presence of GSH (5 x 10(-4) M) and antagonized by the GSH-depletor DL-buthionine-SR-sulfoximine (5 x 10(-4) M), suggesting that NO might be protected from extracellular breakdown by reaction with GSH. The reaction product of SIN-1/SNAP and GSH was identified as a nitrosothiol. In the presence of the Cu(+)-chelator neocuproine (10(-5) M), inhibition of NOS by SNAP/SIN-1 was reversed, suggesting that nitrosothiol formation is intermediary. These findings are indicative of a feedback inhibition of enteric NOS, presumably via formation of a nitrosothiol intermediate.

Animals↗

PubMed1999

Characterization of prejunctional and postjunctional muscarinic receptors of the ascending reflex contraction in rat ileum.

The ascending reflex contraction of the small intestine involves predominantly cholinergic neurotransmission. The orally projecting neural excitatory pathway of the myenteric reflex was studied in an in vitro model of rat ileal segments. The contractile response elicited by aboral field stimulation was significantly inhibited by a range of muscarinic receptor antagonists. Methoctramine and tripitramine (both M(2) selective, pIC(50) = 9.3 and 8.8, respectively), darifenacin and hexahydrosiladifenidol (both M(3) selective, pIC(50) = 7.3 and 7.7, respectively), and pirenzepine (M(1) selective, pIC(50) = 7.0). In radioligand binding experiments on synaptosomal and smooth muscle plasma membrane fractions, we examined whether prejunctional or postjunctional muscarinic receptors exist that could potentially contribute to the reflex contraction. In the synaptosomal fraction, the muscarinic ligand [(3)H]N-methylscopolamine labeled a homogeneous population of receptors (Hill coefficient = 1) with a K(d) value of 0.31 +/- 0.09 nM and a B(max) value of 185 +/- 16.6 fmol/mg protein. The ratio of potency of subtype-selective muscarinic receptor antagonists in competition studies was tripitramine (pK(i) = 8.7 +/- 0.3) > 1/6 x methoctramine (pK(i) = 7.9 +/- 0.02) > 1/25 x darifenacin (pK(i) = 7. 3 +/- 0.2) > 1/316 x hexahydrosiladifenidol (pK(i) = 6.2 +/- 0.1) > 1/2511 x pirenzepine (pK(i) = 5.3 +/- 0.1). In the smooth muscle plasma membrane fraction, the K(d) value was 0.29 +/- 0.05 nM and the B(max) value was 770 +/- 29 fmol/mg. The competition studies revealed a similar ratio of potency of the respective antagonists. These data suggest that muscarinic M(2) receptors, located at prejunctional and postjunctional sites, are predominantly involved in the ascending reflex contraction.

Animals↗

PubMed1999

[Glucagonoma--somatostatinoma].

Glucagonoma and somatostatinoma are tumors which produce the respective hormone. When these peptides are also secreted into the circulation the clinical syndromes are characterized by the signs and symptoms due to hormone overproduction. In case of the glucagonoma-syndrome diabetes and typical skin lesions are dominating while patients with the somatostatinoma syndrome have diabetes frequently associated with steatorrhea. Surgical resection of the tumor and its metastases as far as possible is the therapy of choice. For symptomatic relief and inhibition of the growth of the metastases interferon-a and somatostatin analogues can be employed.

Diabetes Mellitus↗

PubMed1998

Xenin--a novel suppressor of food intake in rats.

Peptides related to the amphibian octapeptide xenopsin are present in various locations in mammalians, such as the gastrointestinal mucosa or brain tissue. In the gastrointestinal tract, xenopsin-related peptides induce partially neurogenic contractions of the colon in humans. In brain, however, their function is not known. Structural similarities of xenopsin-related peptides with neurotensin, a known modulator of ingestive behavior, suggest a possible role in feeding regulation. Therefore, we examined the effect of xenin, a recently identified xenopsin-related pentacosa peptide, on feeding behavior of fasted rats. Male Wistar rats (n=12) were intracerebroventricularly (i.c.v.) injected with either saline (10 microl) or xenin at 0.5, 1.5, 5 or 15 microg dissolved in an identical volume of 10 microl, respectively. In further experiments, xenin 15 microg/0.5 microl or 0.5 microl saline were injected into the lateral hypothalamus (LH). After injections, food intake (g), percentage of time spent with feeding (%) and prandial water intake (ml) were subsequently recorded for 2 h. After i.c.v. injection of 15 microg of xenin 1-h food intake was significantly reduced by 42% and 2-h food intake was diminished by 25%, respectively, compared to saline injection (p<0.01). This reduction of food intake was paralleled by a significant decrease of time spent with feeding by 41% (after 1 h) or 23% (after 2 h). The xenin-induced suppression of feeding behavior was dose-dependent. Thus, the minimal effective dose of xenin was 1.5 microg, while the dose of 0.5 microg was ineffective. Prandial water intake was significantly reduced only by the highest dose of xenin. Following injection of 15 microg of xenin into the lateral hypothalamus food intake was not different from control experiments. These data demonstrate a potent feeding suppressive action of xenin following intracerebroventricularly injection but not injection into the lateral hypothalamus suggesting a possible role of xenin in the central control of feeding termination and satiety.

Amino Acid Sequence↗

PubMed1998

Effect of capsaicin-containing red pepper sauce suspension on upper gastrointestinal motility in healthy volunteers.

Afferent nerves play a major role in the regulation of gastrointestinal motility. The questions remains if specific food ingredients can selectively activate such fibers. The aim of the study was to investigate the effect of intraesophageal application of a capsaicin-containing red pepper sauce (Tabasco) suspension on upper gastrointestinal motility in a controlled trial. After a baseline recording [esophageal motility, balloon distension, electrogastrogram (EGG)], red pepper or saline solution was infused intraesophageally in seven healthy volunteers. At 30 min gastric emptying and orocecal transit time were determined using a [13C]acetate and H2-lactulose breath test. Infusion of red pepper sauce suspension significantly increased the amplitudes (65.8 +/- 3 to 78.5 +/- 4.7 mm Hg, P < 0.05) and propagation velocity (2.9 +/- 0.3 to 4.25 +/- 0.3 sec, P < 0.05) of esophageal pressure waves and LES pressure (17.8 +/- 1.4 to 23.7 +/- 2.6 mm Hg, P < 0.05). It significantly decreased perception and discomfort threshold of intraesophageal balloon distension, reduced the percentage of normal electrical activity in the EGG, and delayed gastric emptying (saline: T(1/2) 42.9 +/- 12.0 min vs red pepper: T(1/2) 66.8 +/- 19.0 min, P < 0.05). Despite the prolongation of gastric emptying, orocecal transit time was not altered, indicating an actual increase of intestinal transit. Esophageal application of capsaicin-containing red pepper sauce suspension had profound changes on upper gastrointestinal motility, which could improve clearance and protection of the esophagus and could lead to retention of the irritant in the stomach and faster transit through the small bowel.

Adult↗

PubMed1998

Involvement of intracellular Ca2+ stores in inhibitory effects of NO donor SIN-1 and cGMP.

We investigated the role of K+ channels and intracellular Ca2+ stores in the relaxations induced by the NO donor 3-morpholinosydnonimine (SIN-1) and 8-bromo-cGMP (8-BrcGMP), 8-(4-chlorophenylthio)-cGMP (pCPT-cGMP), and alpha, beta-methylene-ATP in isolated segments of rat ileum. The inhibitory responses to SIN-1 and the cGMP analogs were not influenced by the K+ blockers apamin, charybdotoxin, iberiotoxin, or glibenclamide, whereas relaxations induced by alpha,beta-methylene-ATP were abolished by apamin and tetraethylammonium. The NO-donor SIN-1 and the cGMP analogs were able to inhibit contractions induced by activation of L-type Ca2+ channels (BAY-K-8644), by carbachol (CCh), and by cyclopiazonic acid (CPA), a blocker of sarcoplasmic Ca2+-ATPase. However, the inhibition of the combined CPA and CCh response was reduced and the dose-response curve of SIN-1 shifted to the right. Intracellular Ca2+ stores were emptied by incubation in Ca2+-free buffer and repetitive stimulation with CCh or BAY-K-8644. After restoration of extracellular Ca2+, the inhibitory effect of SIN-1 and pCPT-cGMP was only attenuated, whereas in the additional presence of CPA, the inhibitory effect of SIN-1 was blocked and the effect of 8-BrcGMP reduced. Thus depleting intracellular Ca2+ stores attenuated the effect of SIN-1 and 8-BrcGMP, suggesting an involvement of functional Ca2+ stores.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1998

Protein kinase G expression in the small intestine and functional importance for smooth muscle relaxation.

In functional experiments, the nitric oxide (NO) donor N-morpholino-N-nitroso-aminoacetonitrile or the cGMP analog 8-(4-chlorophenylthio)-cGMP caused a concentration-dependent, tetrodotoxin-resistant relaxation of precontracted strips from rat small intestine. The inhibitory effect of both substances was completely blocked at lower concentrations and was significantly attenuated at higher concentrations by the selective cGMP-dependent protein kinase (cGK) antagonist KT-5823 (1 microM). cGK-I was identified by immunohistochemistry in circular and longitudinal muscle, lamina muscularis mucosae, and smooth muscle cells of the villi and in fibroblast-like cells of the small intestine. Additionally, there was staining of a subpopulation of myenteric and submucous plexus neurons. Double staining for neuronal NO synthase (nNOS) and cGK-I demonstrated a colocalization of these two enzymes. Western blot analysis of smooth muscle preparations and isolated nerve terminals demonstrated that these structures predominantly contain the cGK-Ibeta isoenzyme, whereas the cGK-Ialpha expression is about threefold less. The isoform cGK-II was entirely confined to mucosal epithelial cells. These results show that cGK-I is expressed in different muscular structures of the small intestine and participates in the NO-induced relaxation of gastrointestinal smooth muscle. The presence of cGK-I in NOS-positive enteric neurons further suggests a possible neuronal action site.

Alkaloids↗

PubMed1998

Characterization and splice variants of neuronal nitric oxide synthase in rat small intestine.

The aim of this study was to characterize neuronal nitric oxide synthase (nNOS) activity and 5'-end splice variants in rat small intestine. nNOS was predominantly expressed in the longitudinal muscle layer, with attached myenteric plexus (LM-MP). The biochemical properties of NOS activity in enriched nerve terminals resemble those of nNOS isolated from the brain. Western blot analysis of purified NOS protein with an nNOS antibody showed a single band in the particulate fraction and three bands in the soluble fraction. Rapid amplification of 5' cDNA ends-PCR revealed the presence of three different 5'-end splice variants of nNOS. Two variants encode for nNOSalpha, which has a specific domain for membrane association. The third variant encodes for nNOSbeta, which lacks the domain for membrane association and should therefore be soluble. nNOS is predominantly expressed in LM-MP and can be enriched in enteric nerve terminals. We present the first evidence that three 5'-end splice variants of nNOS encoding two different proteins are expressed in rat small intestine. These two nNOS enzymes exhibit different subcellular locations and might be implicated in different biological functions.

Alternative Splicing↗

PubMed1998

Regulation of gastrin, somatostatin and bombesin release from the isolated rat stomach by exogenous and endogenous gamma-aminobutyric acid.

BACKGROUND/AIMS AND METHODS: gamma-Aminobutyric acid (GABA) is localized in epithelial cells and intrinsic nerve fibers of the gastric mucosa raising the possibility of a regulatory role for this transmitter. Therefore, it was the aim of the present study to examine the effect of exogenous and endogenous GABA on the neuroendocrine functions of the isolated perfused rat stomach. RESULTS: Infusion of GABA (10(-8), 10(-6), 10(-4) M) caused a significant increase in gastrin release by 187 +/- 98, 328 +/- 43 and 493 +/- 84 pg/20 min and a significant decrease in somatostatin secretion by -540 +/- 203, -867 +/- 96 and -893 +/- 195 pg/20 min, respectively. Release of bombesin-like immunoreactivity (BLI) remained unchanged during infusion of GABA at the concentrations employed. The gastrin and somatostatin responses to 10(-4) M GABA were completely inhibited by the GABA(A) antagonist bicuculline (10(-5) M) and the cholinergic blocker atropine(l0(-7) M), whereas the GABAB antagonist CGP 35348 (5 x 10(-5) M) was ineffective. To evaluate the contribution of endogenous GABA in the vagal regulation of gastric neuroendocrine functions, gastrin, somatostatin and BLI responses to electrical stimulation of the vagal nerves were examined in the presence of bicuculline. Vagal stimulation (10 V, 10 Hz, 1 ms) induced a significant inhibition of somatostatin release by - 518 +/- 78 pg/10 min, which was attenuated to -259 +/- 143 pg/10 min (p < 0.05) in the presence of bicuculline. Atropine (10(-7) M) turned vagally induced inhibition of somatostatin release into a stimulation by 928 +/- 266 pg/10 min which was not altered by additionally infused bicuculline. Vagally stimulated gastrin release was reduced from 397 +/- 47 to 217 +/- 72 pg/10 min (p < 0.05) by bicuculline, while atropine had no effect. Vagally induced BLI release was not altered by bicuculline and atropine. Since the effect of bicuculline on vagally induced gastrin release was independent of cholinergic mechanisms, a potential direct effect of GABA on gastrin release was examined in isolated rabbit antral G cells. In this preparation carbachol (10(-4) M) and neuromedin C (10(-9) M) significantly stimulated gastrin release from 2.6 +/- 0.4 to 4.9 +/- 0.3 and 8.5 +/- 0.9% of the total cellular content, respectively, while GABA (10(-10)-10(-3) M) changed neither basal nor carbachol- and neuromedin C-stimulated gastrin release. CONCLUSION: The present data confirm that exogenous GABA stimulates gastrin release and inhibits somatostatin release from the isolated rat stomach via GABA(A) receptors by activating cholinergic neurotransmission. Furthermore, it was shown for the first time that endogenous GABA contributes to the vagal regulation of gastrin and somatostatin release from the rat stomach. Inhibition of somatostatin secretion by endogenous GABA is mediated by cholinergic mechanisms, whereas stimulation of gastrin release is mediated by pathways unrelated to the cholinergic system and bombesin peptides.

Animals↗