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P Holzer

Publications and source records attributed to P Holzer.

At least 37 records · Page 2Linked to original sources
PubMed2001

PACAP-(6-38) inhibits the effects of vasoactive intestinal polypeptide, but not PACAP, on the small intestinal circular muscle.

Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating peptide-(1-38) (PACAP) have been found to stimulate distension-induced peristaltic motility in the guinea-pig isolated small intestine. In this study, we tested whether the putative VIP/PACAP receptor antagonist PACAP-(6-38) counteracts the properistaltic effect of VIP and PACAP in isolated segments of the guinea-pig small intestine. VIP (100 nM) and PACAP (30 nM) had a stimulatory effect, i.e., lowered the peristaltic pressure threshold at which peristaltic waves were triggered and enhanced the frequency of peristaltic waves. PACAP-(6-38) (3 microM) was per se without effect on peristalsis but prevented or reversed the peristaltic motor stimulation caused by VIP, when it was given before or after the agonist, respectively. PACAP-(6-38), however, failed to antagonize the properistaltic effect of PACAP. In ileal circular strips treated with tetrodotoxin (1 microM) and indomethacin (3 microM), spontaneous myogenic activity was inhibited by VIP (5-30 nM). This effect was significantly reduced by a pretreatment with PACAP-(6-38) (3 microM). A similar inhibition by PACAP-(1-38) (10-500 nM) was not influenced by the antagonist. It is concluded that PACAP-(6-38) is a VIP receptor antagonist, both in the peristaltic motor pathways and at the level of the circular muscle of the guinea-pig small intestine. The lack of a motor effect of PACAP-(6-38) on its own indicates that VIP acting on PACAP-(6-38)-sensitive receptors (located on neurons and/or the smooth muscle) is unlikely to participate in peristaltic motor regulation.

Animals↗
PubMed2001

Gastrointestinal afferents as targets of novel drugs for the treatment of functional bowel disorders and visceral pain.

An intricate surveillance network consisting of enteroendocrine cells, immune cells and sensory nerve fibres monitors the luminal and interstitial environment in the alimentary canal. Functional bowel disorders are characterized by persistent alterations in digestive regulation and gastrointestinal discomfort and pain. Visceral hyperalgesia may arise from an exaggerated sensitivity of peripheral afferent nerve fibres and/or a distorted processing and representation of gut signals in the brain. Novel strategies to treat these sensory bowel disorders are therefore targeted at primary afferent nerve fibres. These neurons express a number of molecular traits including transmitters, receptors and ion channels that are specific to them and whose number and/or behaviour may be altered in chronic visceral pain. The targets under consideration comprise vanilloid receptor ion channels, acid-sensing ion channels, sensory neuron-specific Na(+) channels, P2X(3) purinoceptors, 5-hydroxytryptamine (5-HT), 5-HT(3) and 5-HT(4) receptors, cholecystokinin CCK(1) receptors, bradykinin and prostaglandin receptors, glutamate receptors, tachykinin and calcitonin gene-related peptide receptors as well as peripheral opioid and cannabinoid receptors. The utility of sensory neuron-targeting drugs in functional bowel disorders will critically depend on the compounds' selectivity of action for afferent versus enteric or central neurons.

Animals↗
PubMed2001

The gut as a neurological organ.

We refer to the gut as a neurological organ to emphasize the particular importance of the nervous system in the regulation of digestive functions, given that the gastrointestinal tract is innervated by five different classes of neurons: intrinsic enteric neurons, vagal afferents, spinal afferents, parasympathetic efferents and sympathetic efferents. Virtually each aspect of digestive activity is under the regulatory influence of neurons, among which the enteric nervous system (ENS) plays the most important part. The ENS acts like a brain in the gut that functions independently of the central nervous system, contains programmes for a variety of gastrointestinal behaviours and governs the activity of all gastrointestinal effector systems according to need. Intrinsic sensory neurons supply the ENS with the kind of information that this system requires for its autonomic control of digestion, whereas extrinsic afferents notify the brain about any data that are relevant to energy and fluid homeostasis and the sensation of discomfort and pain. Many diseases of the gut, particularly the functional bowel disorders, seem to be related to dysfunction of the ENS and other components of the gastrointestinal innervation. The ENS and extrinsic afferents are hence prime targets for the therapeutic management of gut diseases and for the relief of the pain and discomfort associated with these disorders.

Abdominal Pain↗
PubMed2001

Estimation of acute flurbiprofen and ketoprofen toxicity in rat gastric mucosa at therapy-relevant doses.

OBJECTIVE: Since assessment of the acute gastrotoxicity of nonsteroidal antiinflammatory drugs (NSAIDs) in rats requires high doses of the drugs, we sought to establish an experimental model with which this adverse NSAID effect can be estimated at therapy-relevant doses. METHODS: The study was performed with racemic flurbiprofen-trometamol (R/S-FBP), its pure enantiomers S-FBP and R-FBP, and racemic ketoprofen-trometamol (R/S-KP). Two hours after administration of FBP or KP to Sprague-Dawley rats, HCl (0.5 M, 10 ml/kg) was given intragastrically (IG), and the haemorrhagic lesion area in the gastric mucosa quantified 1 h post-HCI. RESULTS: FBP amplified gastric acid injury in a dose-related manner, the rank order of potency being S-FBP > R/S-FBP >> R-FBP. While less than 1 micromol/kg S-FBP and R/S-FBP aggravated acid injury, doses up to 50 micromol/kg failed to cause appreciable damage without subsequent HCl challenge. Similar observations were made with R/S-KP which at doses of > or = 1 micromol/kg aggravated gastric acid injury. There was no significant difference in the gastrotoxicity of FBP when the drug was administered subcutaneously or IG, whereas subcutaneously injected R/S-KP was slightly more toxic than IG R/S-KP. CONCLUSIONS: These data show that FBP- and KP-induced amplification of acid injury in the rat gastric mucosa is a sensitive assay whereby, with single drug dosing, the gastrotoxic potential of these and other NSAIDs may be estimated at therapy-relevant doses that in humans threaten mucosal integrity only following chronic use.

Animals↗
PubMed2001

Cooperation of NMDA and tachykinin NK(1) and NK(2) receptors in the medullary transmission of vagal afferent input from the acid-threatened rat stomach.

Noxious challenge of the rat gastric mucosa by hydrochloric acid (HCl) is signaled to the nucleus tractus solitarii (NTS) and area postrema (AP). This study examined the participation of glutamate and tachykinins in the medullary transmission process. Activation of neurons was visualized by in situ hybridization autoradiography of c-fos messenger RNA (mRNA) 45 min after intragastric (IG) administration of 0.5 M HCl or saline. IG HCl caused many neurons in the NTS and some neurons in the AP to express c-fos mRNA. The NMDA glutamate receptor antagonist MK-801 (2 mg/kg), the NK(1) tachykinin receptor antagonist GR-205,171 (3 mg/kg) and the NK(2) receptor antagonist SR-144,190 (0.1 mg/kg) failed to significantly reduce the NTS response to IG HCl, whereas the triple combination of MK-801, GR-205,171 and SR-144,190 inhibited it by 45--50%. Only in rats that had been preexposed IG to HCl 48 h before the experiment was MK-801 alone able to depress the NTS response to IG HCl. In contrast, the c-fos mRNA response in the AP was significantly augmented by MK-801, an action that was prevented by coadministration of GR-205,171 plus SR-144,190. Inhibition of neuronal nitric oxide synthase with 7-nitroindazole (45 mg/kg) was without effect on the IG HCl-evoked c-fos mRNA expression in the NTS and AP. Our data show that glutamate acting via NMDA receptors and tachykinins acting via NK(1) and NK(2) receptors cooperate in the vagal afferent input from the acid-threatened stomach to the NTS and participate in the processing of afferent input to the AP in a different and complex manner. These opposing interactions in the AP and NTS and the increase in NMDA receptor function in the NTS after a gastric acid insult are likely to have a bearing on the neuropharmacology of dyspepsia.

Animals↗
PubMed2001

Vagal afferent signaling of a gastric mucosal acid insult to medullary, pontine, thalamic, hypothalamic and limbic, but not cortical, nuclei of the rat brain.

Although gastric acid is a factor in upper abdominal pain, the signaling and processing of a gastric mucosal acid insult within the brain are not known. This study examined which nuclei in the rat brain respond to challenge of the gastric mucosa by a noxious concentration of hydrochloric acid (HCl) and whether the central input is carried by vagal afferent neurons. Activation of neurons in the brain was mapped by in situ hybridization autoradiography of messenger ribonucleic acid (mRNA) for the immediate early gene c-fos 45 min after intragastric administration of saline or HCl. Following intragastric HCl (0.5 M) challenge, many neurons in the nucleus tractus solitarii, lateral parabrachial nucleus, thalamic and hypothalamic paraventricular nucleus, supraoptic nucleus, central amygdala and medial/lateral habenula expressed c-fos mRNA as compared to intragastric treatment with saline (0.15 M). However, c-fos transcription in the insular cortex was not enhanced by the gastric acid insult. Hypertonic saline (0.5 M) caused only a minor expression of c-fos mRNA in the hypothalamus and amygdala. The acid-evoked c-fos induction in subcortical nuclei was depressed by at least 80% five days after bilateral subdiaphragmatic vagotomy. Collectively, these observations indicate that vagal afferent input from the acid-threatened gastric mucosa does not reach the insular cortex but leads to activation of subcortical brain nuclei that are involved in emotional, behavioral, neuroendocrine, autonomic and antinociceptive reactions to a noxious stimulus.

Animals↗
PubMed2001

Tachykinin receptors in the gut: physiological and pathological implications.

The tachykinins substance P and neurokinin A participate in the regulation of gastrointestinal motility, secretion, vascular permeability and pain sensitivity. Advances made during the past two years corroborate a causal involvement of tachykinins in inflammation-induced disturbances of gut function, such as dysmotility, secretory diarrhoea, oedema and hyperalgesia. It would therefore appear that tachykinin receptors, which in the digestive system are expressed in a cell-specific manner, represent attractive targets for novel therapeutics in gastroenterology.

Animals↗
PubMed2001

Disturbance of peristalsis in the guinea-pig isolated small intestine by indomethacin, but not cyclo-oxygenase isoform-selective inhibitors.

1. Since the cyclo-oxygenase (COX) isoform-nonselective inhibitor indomethacin is known to modify intestinal motility, we analysed the effects of COX-1 and COX-2 inhibition on intestinal peristalsis. 2. Peristalsis in isolated segments of the guinea-pig small intestine was triggered by a rise of the intraluminal pressure and recorded via the pressure changes associated with peristalsis. 3. The COX-1 inhibitor SC-560, the COX-2 inhibitor NS-398 (both at 0.1 -- 1 microM) and the isoform-nonselective inhibitors flurbiprofen (0.01 - 10 microM) and piroxicam (0.1 - 50 microM) were without major influence on peristalsis, whereas indomethacin and etodolac (0.1 -- 10 microM) disturbed the regularity of peristalsis by causing nonpropulsive circular muscle contractions. 4. Radioimmunoassay measurements showed that SC-560, NS-398, indomethacin and etodolac (each at 1 microM) suppressed the release of 6-keto-prostaglandin F(1 alpha) (6-keto-PGF(1 alpha)) from the intestinal segments. 5. Reverse transcription - polymerase chain reaction tests revealed that, relative to glyceraldehyde-3 phosphate dehydrogenase ribonucleic acid, the expression of COX-1 mRNA increased by a factor of 2.0 whereas that of COX-2 mRNA rose by a factor of 7.9 during the 2 h experimental period. 6. Pharmacological experiments indicated that the action of indomethacin to disturb intestinal peristalsis was unrelated to inhibition of L-type calcium channels, adenosine triphosphate-sensitive potassium channels or phosphodiesterase type IV. 7. These results show that selective inhibition of COX-1 and COX-2 does not grossly alter peristaltic motor activity in the guinea-pig isolated small intestine and that the effect of indomethacin to disturb the regular pattern of propulsive motility in this species is unrelated to COX inhibition.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2001

Gastroduodenal mucosal defense: coordination by a network of messengers and mediators.

Gastroduodenal mucosal defense is composed of structural features of the mucosa, cellular monitors of pending or actual injury, and a web of effector cells that protect the mucosa from damage and govern its recovery from injury. By virtue of these systems, the gastroduodenal mucosa can cope with the harmful ingredients of ingested food and the potentially deleterious effects of gastric acid and pepsin. It is increasingly appreciated that a network of chemical messengers coordinates the alarm, defensive, and healing mechanisms. This article highlights some of the advances from the past year that have furthered our understanding of the regulatory systems that govern gastroduodenal mucosal homeostasis. Particular emphasis is given to control of the mucous and epithelial phospholipid barriers, the mucosal microcirculation, and the epithelial, neural, immune, and inflammatory mediators of the mucosal repair mechanisms.

Journal Article↗
PubMed2001

Differential effects of clonidine, dopamine, dobutamine, and dopexamine on basal and acid-stimulated mucosal blood flow in the rat stomach.

OBJECTIVE: To analyze the effects of clonidine, dopamine, dobutamine, and dopexamine on gastric mucosal blood flow (GMBF) at baseline and after stimulation by acid back diffusion through a disrupted gastric mucosal barrier. DESIGN: Prospective, randomized, unblinded study. SETTING: University research laboratory. SUBJECTS: Adult Sprague-Dawley rats. INTERVENTIONS: Mean arterial blood pressure (MAP) and heart rate (HR) were recorded from a carotid artery of the phenobarbital-anesthetized animals. A jugular vein was cannulated for continuous infusion of saline and intravenous drug administration. The stomach was prepared for luminal perfusion and for recording GMBF with the hydrogen gas clearance technique. Gastric mucosal vascular conductance (GMVC) was calculated as GMBF divided by MAP. MEASUREMENTS AND MAIN RESULTS: Clonidine (37.5 and 112.5 nmol x kg(-1)) lowered MAP and HR and caused gastric vasodilation as shown by a rise of GMVC. The 2.5-fold increase in GMVC elicited by gastric perfusion with HCl (0.15 M) plus ethanol (25%) was depressed by clonidine. All cardiovascular effects of clonidine were prevented by the alpha2-adrenoceptor antagonist idazoxan (2 micromol x kg(-1)). Infusion of dopamine (15 and 45 micromol x kg(-1) x hr(-1)), dobutamine, or dopexamine (each at 5 and 15 micromol x kg(-1) x hr(-1)) caused tachycardia. GMVC at baseline was attenuated by the higher dose of dopamine and dopexamine, but not dobutamine. In contrast, the acid-induced vasodilation in the gastric mucosa was depressed by dobutamine and dopexamine, but not dopamine. CONCLUSIONS: Clonidine, dobutamine, and dopexamine at high dosage suppress the gastric mucosal vasodilator response to acid back diffusion, which is an important defense mechanism. Although the dose equivalence between rats and humans is not known, the antivasodilator effects highlight an adverse action whereby large doses of dobutamine, dopexamine, and clonidine may compromise gastric mucosal homeostasis and facilitate stress ulcer formation. Dopamine lacks this detrimental activity.

Adrenergic alpha-Agonists↗
PubMed2001

Mucosal acid challenge activates nitrergic neurons in myenteric plexus of rat stomach.

We tested the hypothesis that intrinsic neurons of the rat gastric myenteric plexus can be activated by an acid (HCl) challenge of the mucosa. Activated neurons were visualized by immunohistochemical detection of c-Fos, a marker for neuronal excitation. The neurochemical identity of the neurons activated by the HCl challenge was determined by colocalizing c-Fos with a marker for excitatory pathways, choline acetyltransferase (ChAT), and a marker for inhibitory pathways, nitric oxide synthase (NOS). Two hours after intragastric administration of HCl or saline, stomachs were removed and immunofluorescence triple labeling of myenteric neurons was carried out on whole mount preparations. Treatment with 0.35, 0.5, and 0.7 M HCl induced c-Fos in 8%, 56%, and 64%, respectively, of NOS-positive but not ChAT-positive neurons. c-Fos was also seen in glial cells of HCl-treated rats, whereas in saline-treated animals c-Fos was absent from the myenteric plexus. HCl treatment did not change the proportion of ChAT- and NOS-immunoreactive neurons in the myenteric ganglia. It is concluded that gastric acid challenge concentration-dependently stimulates a subpopulation of nitrergic, but not cholinergic, myenteric plexus neurons, which may play a role in muscle relaxation, vasodilatation, and/or secretion.

Animals↗
PubMed2001

Surveillance of the gastrointestinal mucosa by sensory neurons.

A dense network of extrinsic and intrinsic sensory neurons supplies the gastrointestinal tract. Intrinsic sensory neurons provide the enteric nervous system with the kind of information that this brain of the gut requires for its autonomic control of digestion, whereas extrinsic afferents notify the brain about processes that are relevant to energy and fluid homeostasis and the sensation of discomfort and pain. The sensory repertoire of afferent neurons is extended by their responsiveness to mediators released from enteroendocrine and immune cells, which act like "taste buds" of the gut and serve as interface between the gastrointestinal lumen and the sensory nerve terminals in the lamina propria of the mucosa. Functional bowel disorders such as non-ulcer dyspepsia and irritable bowel syndrome are characterized by abdominal discomfort or pain in the absence of an identifiable organic cause. It is hypothesized with good reason that infection, inflammation or trauma causes sensory pathways to undergo profound phenotypic and functional alterations that outlast the acute insult. The pertinent changes involve an exaggerated sensitivity of the peripheral afferent nerve fibres as well as a distorted processing and representation of the incoming information in the brain. This concept identifies a number of receptors and ion channels that are selectively expressed by primary afferent neurons as important molecular targets at which to aim novel therapies for functional bowel disorders.

Colonic Diseases, Functional↗
PubMed2000

A Supramolecular Enzyme Mimic That Catalyzes the 15,15' Double Bond Scission of beta,beta-Carotene This research was supported by the Swiss National Science Foundation, Novartis International AG, and F. Hoffmann-La Roche AG. We are grateful to F. Hoffmann-La Roche AG for the generous gift of carotenoids, and we also thank Prof. Dr. Jakob Wirz, Insitut für Physikalische Chemie der Universität Basel, for the calculation of the binding constant K(a) of 1 to the receptor 3.

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Journal Article↗
PubMed2000

Differences in circular muscle contraction and peristaltic motor inhibition caused by tachykinin NK1 receptor agonists in the guinea-pig small intestine.

The tachykinin NK1 receptor agonist substance P methyl ester (SPOME) impedes intestinal peristalsis by releasing nitric oxide (NO) from inhibitory motor neurones. Since NK1 receptor agonists differ in their receptor interaction, we set out to compare a range of NK1 receptor agonists including SPOME, septide and GR-73 632 in their effects on propulsive peristalsis and circular muscle activity in the guinea-pig isolated small intestine. SPOME (100-300 nM) inhibited peristalsis by a rise of the pressure threshold at which peristaltic waves were triggered, whereas septide and GR-73 632 (30-300 nM) interrupted peristalsis by causing circular muscle spasms. Separate experiments showed that all three NK1 receptor agonists caused contraction of the circular muscle, which was enhanced by the NO synthase inhibitor NG-nitro-L-arginine methyl ester (300 mM) and the P2X purinoceptor antagonist suramin (300 mM). In contrast, tetrodotoxin (300 nM) augmented the contractile effect of septide and GR-73 632 but not that of SPOME. It is concluded that the motor response to NK1 receptor agonists involves release of NO and adenosine triphosphate from inhibitory motor neurones. However, the NK1 receptor agonists differ in the mechanism by which they cause inhibitory transmitter release, which corresponds to differences in their antiperistaltic action.

Adenosine Triphosphate↗
PubMed2000

Regulation of guinea pig intestinal peristalsis by endogenous endothelin acting at ET(B) receptors.

BACKGROUND & AIMS: Endothelins are expressed in many enteric neurons of the gut. Because activation of endothelin ET(A) and ET(B) receptors is known to alter intestinal muscle activity, the effect of ET(A) and ET(B) receptor agonists and antagonists on propulsive peristalsis was examined. METHODS: Repetitive peristalsis in fluid-perfused segments of the guinea pig isolated small intestine was elicited by a rise of the intraluminal pressure and recorded via the pressure changes generated by the peristaltic waves. RESULTS: Endothelin 1 (0.3-10 nmol/L added to the organ bath) stimulated peristalsis as shown by a decrease in the pressure threshold at which peristaltic waves were triggered, whereas the endothelin analog sarafotoxin 6c (0.3-10 nmol/L) inhibited peristalsis as reflected by an increase in the pressure threshold. The ET(A) receptor antagonist BQ-123 (3 micromol/L) converted the properistaltic action of endothelin 1 to an antiperistaltic action, whereas the ET(B) receptor antagonist BQ-788 (3 micromol/L) prevented the antiperistaltic action of sarafotoxin 6c. BQ-788, but not BQ-123, facilitated peristalsis on its own. Additional experiments indicated that the properistaltic action of endothelin 1 is mediated by enteric neurons, whereas the peristaltic motor effects of sarafotoxin 6c and BQ-788 are caused by a direct action on the muscle. CONCLUSIONS: ET(A) receptor activation stimulates, whereas ET(B) receptor activation inhibits, intestinal peristalsis. The ability of BQ-788 to facilitate peristalsis per se points to a physiologic role of ET(B) receptors in peristaltic motor regulation.

Animals↗
PubMed2000

Gastroduodenal mucosal defense.

The gastroduodenal mucosa is a model system of defense with several structural levels and biologic strategies that are closely interrelated with each other to cope with the harmful ingredients of ingested food and the potentially deleterious effects of gastric acid and pepsin. Experimental and clinical research carried out during the review period added to the understanding of each component of the multiple mechanisms of gastroduodenal mucosal protection. In the first place, mucosal integrity is defended by the mucus gel barrier, the epithelial cell barrier, and the immune barrier. The properties of these barriers are maintained by adequate regulation of mucus production, bicarbonate secretion, mucosal microcirculation, and motor activity. These regulatory systems are alarmed by nociceptive neurons and the mucosal immune system which includes chemokine-secreting epithelial cells. The ultimate defense system is rapid repair of the injured mucosa under the control of several growth factors. Progressing insight into the network of mucosal defense not only will improve existing therapies of inflammation and ulceration but also will provide new leads for the management of functional diseases in the gastroduodenal region.

Journal Article↗
PubMed2000

Low potential of dobutamine and dopexamine to block intestinal peristalsis as compared with other catecholamines.

OBJECTIVE: Catecholamines are frequently used in critically ill patients to restore stable hemodynamics and to improve organ perfusion. One effect of short-term or long-term administration of catecholamines may be inhibition of propulsive motility in the intestine. We therefore analyzed the effect of dopexamine, dobutamine, and dopamine on ileal peristalsis and compared their action with that of epinephrine and norepinephrine, which have long been known to suppress intestinal peristalsis. DESIGN: In vitro study on excised guinea pig ileum segments. SETTING: Laboratory for experimental studies at the University. SUBJECTS: Isolated guinea pig ileum. INTERVENTIONS: Segments of ileum excised from guinea pigs were mounted in a tissue bath in Krebs-Henseleit solution and bubbled with 95% oxygen/5% CO2. Luminal perfusion with the same solution was performed at a rate of 0.35 mL/min. The bath temperature was kept at 36.5 degrees C. Peristalsis was recorded via changes in the intraluminal pressure. The drugs under investigation (dopamine, epinephrine, norepinephrine, dobutamine, and dopexamine) were added to the tissue bath. MEASUREMENTS AND MAIN RESULTS: Low concentrations of each catecholamine, except epinephrine, caused a decrease in the pressure threshold, which reflects a stimulatory effect on peristalsis. Higher catecholamine concentrations caused a concentration-related increase in the threshold, cumulating in a complete block of peristalsis. The rank order of inhibitory potency was epinephrine > norepinephrine > dopamine > dobutamine approximately dopexamine. Dobutamine and dopexamine were about 500-fold less active than epinephrine in suppressing peristalsis. CONCLUSIONS: This study shows that dobutamine and dopexamine have the least potential to block propulsive motility in the intestine, whereas epinephrine demonstrates the most adverse inhibitory effect. Because at low concentrations dobutamine and dopexamine even stimulate peristalsis, these drugs appear to be superior compared with other catecholamines with regard to their direct effects on intestinal motility.

Adrenergic beta-Agonists↗