Biomedical subjects

Peter Holzer

Publications and source records attributed to Peter Holzer.

26 records · Page 2Linked to original sources

PubMed2003

Stomach-brain communication by vagal afferents in response to luminal acid backdiffusion, gastrin, and gastric acid secretion.

Vagal afferents play a role in gut-brain signaling of physiological and pathological stimuli. Here, we investigated how backdiffusion of luminal HCl or NH(4)OH and pentagastrin-stimulated acid secretion interact in the communication between rat stomach and brain stem. Rats were pretreated intraperitoneally with vehicle or appropriate doses of cimetidine, omeprazole, pentagastrin, dexloxiglumide (CCK(1) receptor antagonist), and itriglumide (CCK(2) receptor antagonist) before intragastric administration of saline or backdiffusing concentrations of HCl or NH(4)OH. Two hours later, neuronal activation in the nucleus of the solitary tract (NTS) and area postrema was visualized by c-Fos immunohistochemistry. Exposure of the rat gastric mucosa to HCl (0.15-0.5 M) or NH(4)OH (0.1-0.3 M) led to a concentration-dependent expression of c-Fos in the NTS, which was not related to gender, gastric mucosal injury, or gastropyloric motor alterations. The c-Fos response to HCl was diminished by cimetidine and omeprazole, enhanced by pentagastrin, and left unchanged by dexloxiglumide and itriglumide. Pentagastrin alone caused an omeprazole-resistant expression of c-fos, which in the NTS was attenuated by itriglumide and prevented by dexloxiglumide but in the area postrema was reduced by dexloxiglumide and abolished by itriglumide. We conclude that vagal afferents transmit physiological stimuli (gastrin) and pathological events (backdiffusion of luminal HCl or NH(4)OH) from the stomach to the brain stem. These communication modalities interact because, firstly, acid secretion enhances afferent signaling of gastric acid backdiffusion and, secondly, gastrin activates NTS neurons through stimulation of CCK(1) receptors on vagal afferents and of CCK(2) receptors on area postrema neurons projecting to the NTS.

Afferent Pathways↗

PubMed2003

Acid-sensitive ion channels in gastrointestinal function.

Deviations from the physiological values of extracellular pH are monitored by multiple acid sensors. Acid-sensing ion channels are activated by moderate acidification, whereas transient receptor potential cation channels, notably TRPV1, are gated by severe acidosis. In contrast, ionotropic purinoceptor (P2X) ion channels, particularly P2X(2), and two-pore domain background K(+) channels, such as TASK, do not directly signal acidification but rather modulate cell membrane excitability in response to acidosis. These acid sensors, which are expressed by afferent neurons, are most relevant to the regulation of acid secretion, foregut motility and mucosal protection, as well as to gastrointestinal disturbances associated with inflammation, ischaemia and stasis.

Abdominal Pain↗

PubMed2003

Evaluation of peristalsis in multiple segments of the guinea-pig isolated small intestine: optimisation of tissue use by refined in vitro methodology.

Peristalsis is the aboral movement by which the intestine propels its contents. Since pharmacological research requires an experimental model with which drug-induced modifications of peristalsis can be reliably quantified, we set out to develop and validate an in vitro method for studying peristalsis in multiple gut segments. In our arrangement, up to four 10cm segments isolated from the guinea-pig jejunum and ileum can be set up in parallel and their lumens perfused. Peristalsis was elicited by pressure-evoked wall distension, and the peristalsis-induced changes in the intraluminal pressure were evaluated with software that determined the peristaltic pressure threshold, the frequency, maximal acceleration and amplitude of the peristaltic waves, and the residual baseline pressure. Validation experiments showed that the peristalsis parameters at baseline and after modification by morphine (0.01-10microM) did not differ between segments from the jejunum and ileum, or between segments examined in a consecutive manner. In conclusion, our work succeeded in optimising the use of the guinea-pig jejunum and ileum for multiple recordings of peristalsis in vitro, and in refining the recording and evaluation of peristaltic motility. This system promises to be particularly useful in the pharmacological screening and testing of drugs which modify peristalsis.

Animal Use Alternatives↗

PubMed2002

Involvement of mu- and kappa-, but not delta-, opioid receptors in the peristaltic motor depression caused by endogenous and exogenous opioids in the guinea-pig intestine.

Opiates inhibit gastrointestinal propulsion, but it is not clear which opioid receptor types are involved in this action. For this reason, the effect of opioid receptor - selective agonists and antagonists on intestinal peristalsis was studied. Peristalsis in isolated segments of the guinea-pig small intestine was triggered by a rise of the intraluminal pressure and recorded via the intraluminal pressure changes associated with the peristaltic waves. Mu-opioid receptor agonists (DAMGO, morphine), kappa-opioid receptor agonists (ICI-204,448 and BRL-52,537) and a delta-opioid receptor agonist (SNC-80) inhibited peristalsis in a concentration-related manner as deduced from a rise of the peristaltic pressure threshold (PPT) and a diminution of peristaltic effectiveness. Experiments with the delta-opioid receptor antagonists naltrindole (30 nM) and HS-378 (1 microM), the kappa-opioid receptor antagonist nor-binaltorphimine (30 nM) and the mu-opioid receptor antagonist cyprodime (10 microM) revealed that the antiperistaltic effect of ICI-204,448 and BRL-52,537 was mediated by kappa-opioid receptors and that of morphine and DAMGO by mu-opioid receptors. In contrast, the peristaltic motor inhibition caused by SNC-80 was unrelated to delta-opioid receptor activation. Cyprodime and nor-binaltorphimine, but not naltrindole and HS-378, were per se able to stimulate intestinal peristalsis as deduced from a decrease in PPT. The results show that the neural circuits controlling peristalsis in the guinea-pig small intestine are inhibited by endogenous and exogenous opioids acting via mu- and kappa-, but not delta-, opioid receptors.

Animals↗

PubMed2002

Differential peristaltic motor effects of prostanoid (DP, EP, IP, TP) and leukotriene receptor agonists in the guinea-pig isolated small intestine.

1. Since the role of prostanoid receptors in intestinal peristalsis is largely unknown, the peristaltic motor effects of some prostaglandin (DP, EP, IP), thromboxane (TP) and leukotriene (LT) receptor agonists and antagonists were investigated. 2. Propulsive peristalsis in fluid-perfused segments from the guinea-pig small intestine was triggered by a rise of the intraluminal pressure and recorded via the intraluminal pressure changes associated with the peristaltic waves. Alterations of distension sensitivity were deduced from alterations of the peristaltic pressure threshold and modifications of peristaltic performance were reflected by modifications of the amplitude, maximal acceleration and residual baseline pressure of the peristaltic waves. 3. Four categories of peristaltic motor effects became apparent: a decrease in distension sensitivity and peristaltic performance as induced by the EP1/EP3 receptor agonist sulprostone and the TP receptor agonist U-46619 (1-1000 nM); a decrease in distension sensitivity without a major change in peristaltic performance as induced by PGD(2) (3-300 nM) and LTD(4) (10-100 nM); a decrease in peristaltic performance without a major change in distension sensitivity as induced by PGE(1), PGE(2) (1-1000 nM) and the EP1/IP receptor agonist iloprost (1-100 nM); and a decrease in peristaltic performance associated with an increase in distension sensitivity as induced by the EP2 receptor agonist butaprost (1-1000 nM). The DP receptor agonist BW-245 C (1-1000 nM) was without effect. 4. The peristaltic motor action of sulprostone remained unchanged by the EP1 receptor antagonist SC-51089 (1 micro M) and the DP/EP1/EP2 receptor antagonist AH-6809 (30 micro M), whereas that of U-46619 and LTD(4) was prevented by the TP receptor antagonist SQ-29548 (10 micro M) and the cysteinyl-leukotriene(1) (cysLT(1)) receptor antagonist tomelukast (10 micro M), respectively. 5. These observations and their pharmacological analysis indicate that activation of EP2, EP3, IP, TP and cysLT(1) receptors, but not DP receptors, modulate intestinal peristalsis in a receptor-selective manner, whereas activation of EP1 seems to be without influence on propulsive peristalsis. In a wider perspective it appears as if the effect of prostanoid receptor agonists to induce diarrhoea is due to their prosecretory but not peristaltic motor action.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2002

Clonidine and dexmedetomidine potently inhibit peristalsis in the Guinea pig ileum in vitro.

BACKGROUND: Inhibition of intestinal peristalsis is a major side effect of drugs used for anesthesia or for analgesia and sedation of patients in the intensive care unit. This in vitro study examined the effect of clonidine and dexmedetomidine on intestinal peristalsis and analyzed some of their mechanisms of action. METHODS: In isolated segments of the guinea pig small intestine, peristalsis was triggered by a perfusion-induced rise of the intraluminal pressure. The peristaltic pressure threshold to elicit a peristaltic wave was used to quantify drug effects on peristalsis. Vehicle (Tyrode's solution), clonidine (10 nM-100 microm), or dexmedetomidine (0.1-100 nM) were added extraserosally to the organ bath. In other series of experiments, clonidine or dexmedetomidine was administered after pretreatment with yohimbine, prazosin, apamin, naloxone, or vehicle. Clonidine was also tested after blockade of NO synthase with L-NAME and in the presence of the inactive enantiomer D-NAME. RESULTS: Clonidine and dexmedetomidine concentration-dependently increased peristaltic pressure threshold and inhibited peristalsis (clonidine: EC50 = 19.6 microm; dexmedetomidine: EC50 = 12.0 nM). The inhibition caused by clonidine could be prevented by pretreatment with yohimbine, naloxone, and apamin, but not by prazosin, L-NAME, or D-NAME. Inhibition caused by dexmedetomidine was prevented by yohimbine only.(50) (50) CONCLUSIONS: The results reveal that clonidine and, much more potently, dexmedetomidine inhibit peristalsis of the guinea pig ileum. The inhibition is caused by interaction with alpha2 adrenoceptors and, in the case of clonidine, also involves activation of small conductance Ca2+ -activated potassium channels and endogenous opioidergic pathways.

Adrenergic alpha-Agonists↗

PubMed2002

Inhibition by female sex steroids of peristalsis in the guinea pig small intestine.

AIMS: The effects of steroid hormones on propulsive peristalsis in the intestine were investigated in order to compare their adverse effect profile on this clinically most important motor pattern. METHODS: Peristalsis in isolated segments of the guinea pig small intestine was triggered by luminal distension and recorded via the peristalsis-associated changes of the intraluminal pressure. Drug effects on muscular activity were investigated in a circular muscle preparation of the ileum. RESULTS: Estradiol and progesterone, but not testosterone, hydrocortisone or cholesterol (each at 3-30 microM), caused a prompt and concentration-related increase in the peristaltic pressure threshold at which propulsive muscle contractions were elicited. Mifepristone (RU-486; 30 microM) did not prevent the inhibitory effect of progesterone, but blocked peristalsis per se. Pharmacological blockade of inhibitory neural pathways with N(G)-nitro-L-arginine methyl ester (nitric oxide synthase inhibitor), naloxone (opioid receptor antagonist), apamin or suramin plus pyridoxal phosphate-6-azophenyl-2',4'-disulphonic acid (P2 purinoceptor blockers) counteracted the inhibitory effect of submaximally (10 microM), but not maximally (30 microM), effective concentrations of progesterone. Estradiol and progesterone depressed circular muscle contractions evoked by cholecystokinin octapeptide to a larger degree than responses to the tachykinin NK(1) receptor agonist GR-73,632. CONCLUSION: The peristaltic motor inhibition caused by sex steroids at micromolar concentrations arises primarily from a depressant action on intestinal muscle activity and may be particularly relevant for high-dose regimens of mifepristone.

Animals↗

PubMed1999

Visceral Afferent Neurons: Role in Gastric Mucosal Protection.

Gastric mucosal homeostasis requires rapid alarm of protective mechanisms in the face of pending injury. This article summarizes the evidence that spinal afferent neurons monitor insults to the gastric mucosa and activate local mechanisms of defense and repair through release of transmitter peptides from their endings in the stomach.

Journal Article↗