Biomedical subjects

P Holzer

Publications and source records attributed to P Holzer.

At least 19 recordsLinked to original sources

PubMed2005

Endogenous neuropeptide Y depresses the afferent signaling of gastric acid challenge to the mouse brainstem via neuropeptide Y type Y2 and Y4 receptors.

Vagal afferents signal gastric acid challenge to the nucleus tractus solitarii of the rat brainstem. This study investigated whether nucleus tractus solitarii neurons in the mouse also respond to gastric acid challenge and whether this chemonociceptive input is modified by neuropeptide Y acting via neuropeptide Y receptors of type Y2 or Y4. The gastric mucosa of female mice was exposed to different concentrations of HCl or saline, excitation of neurons in the nucleus tractus solitarii visualized by c-Fos immunohistochemistry, gastric emptying deduced from the gastric volume recovery, and gastric lesion formation evaluated by planimetry. Relative to saline, intragastric HCl (0.15-0.35 M) increased the number of c-Fos-expressing cells in the nucleus tractus solitarii in a concentration-dependent manner, inhibited gastric emptying but failed to cause significant hemorrhagic injury in the stomach. Mice in which the Y2 or Y4 receptor gene had been deleted responded to gastric acid challenge with a significantly higher expression of c-Fos in the nucleus tractus solitarii, the increases amounting to 39 and 31%, respectively. The HCl-induced inhibition of gastric emptying was not altered by deletion of the Y2 or Y4 receptor gene. BIIE0246 ((S)-N2-[[1-[2-[4-[(R,S)-5,11-dihydro-6(6H)-oxodibenz[b,e] azepin-11-yl]-1-piperazinyl]-2-oxoethyl]cyclopentyl] acetyl]-N-[2-[1,2-dihydro-3,5 (4H)-dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl]ethyl]-argininamide; 0.03 mmol/kg s.c.), a Y2 receptor antagonist which does not cross the blood-brain barrier, did not modify the c-Fos response to gastric acid challenge. The Y2 receptor agonist peptide YY-(3-36) (0.1 mg/kg intraperitoneally) likewise failed to alter the gastric HCl-evoked expression of c-Fos in the nucleus tractus solitarii. BIIE0246, however, prevented the effect of peptide YY-(3-36) to inhibit gastric acid secretion as deduced from measurement of intragastric pH. The current data indicate that gastric challenge with acid concentrations that do not induce overt injury but inhibit gastric emptying is signaled to the mouse nucleus tractus solitarii. Endogenous neuropeptide Y acting via Y2 and Y4 receptors depresses the afferent input to the nucleus tractus solitarii by a presumably central site of action.

Analysis of Variance↗

PubMed2005

Facilitation of gastric compliance and cardiovascular reaction by repeated isobaric distension of the rat stomach.

Gastric distension causes cardiovascular reactions and enhances gastric compliance. Here, we investigated how these responses are related to each other, whether they change upon repeated distension and which neural mechanisms are involved. Mean arterial blood pressure (MAP) in phenobarbital-anaesthetized rats was recorded from a carotid artery and gastric compliance determined with an electronic barostat. Runs of intermittent gastric distension were generated by stepwise increments (5 mmHg) of intragastric (IG) pressure. While gastric compliance peaked at IG pressures of 20 mmHg, the change in MAP (predominantly hypotension) was largest at IG pressures beyond 30 mmHg. Repeated distension enhanced the MAP response to IG pressures beyond 35 mmHg, whereas gastric compliance was facilitated primarily at IG pressures below 20 mmHg. This facilitation of gastric compliance depended on the magnitude of the preceding distension. The MAP response to distension was enhanced by nitric oxide synthase inhibition, inhibited by subdiaphragmatic vagotomy but hardly affected by coeliac ganglionectomy. The facilitation of gastric compliance was changed by vagotomy in a complex manner but left unaltered by the other interventions. These findings show that isobaric gastric distension elicits both MAP and gastric compliance responses whose characteristics, mechanisms and sensitization properties differ profoundly.

Air Pressure↗

PubMed2004

Vagal afferent input from the acid-challenged rat stomach to the brainstem: enhancement by interleukin-1beta.

Exposure of the gastric mucosa to back-diffusing concentrations of HCl (0.25 M, pH 0.51) stimulates vagal afferent input to the brainstem. Here we have examined whether pretreatment of rats with the proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha causes sensitization of vagal afferent pathways to HCl. Rats were pretreated i.p. with interleukin-1beta, tumor necrosis factor-alpha (10 microg/kg) or their vehicle (sterile saline) 24, 48 and 96 h before intragastric administration of HCl (0.25 M, 1 ml/100 g). Activation of neurons in the nucleus tractus solitarii was visualized by c-Fos immunohistochemistry 2 h after the HCl challenge. I.p. administration of interleukin-1beta and tumor necrosis factor-alpha alone induced c-Fos in the brainstem, an effect that was gone after 24 h. At this time, however, the effect of HCl to cause expression of c-Fos in the nucleus tractus solitarii was significantly enhanced by pretreatment with interleukin-1beta and tumor necrosis factor-alpha. The sensitizing effect of i.p.-administered interleukin-1beta was sustained for more than 48 h and prevented by the interleukin-1 receptor antagonist anakinra. Intracisternal administration of interleukin-1beta and tumor necrosis factor-alpha (100 ng) failed to amplify the HCl-evoked expression of c-Fos in the brainstem. These results show that peripheral administration of the proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha induces prolonged sensitization of vagal afferent pathways to gastric HCl challenge. This effect seems to arise from a peripheral action on vagal afferents and may be of relevance to gastric chemonociception.

Afferent Pathways↗

PubMed2004

[Innovative treatment of acute migraine pain with CGRP receptor antagonists].

Neurogenic inflammation caused by the release of vasoactive neuropeptides such as calcitonin gene-related peptide (CGRP) from nociceptive perivascular nerve fibres has been implicated in the development of acute migraine pain. It has recently been demonstrated that the CGRP receptor antagonist BIBN 4096 BS significantly reduces acute pain in migraine. This therapeutic efficacy provides further evidence for a critical role of CGRP in the pathophysiology of migraine. Given the apparent absence of vasoconstrictor activity both in meningeal and extracranial vessels, BIBN 4096 BS may provide an alternative for the treatment of migraine in those patients where triptans and ergotamine derivatives are contraindicated due to their side effects.

Calcitonin Gene-Related Peptide↗

PubMed2004

Endotoxin pretreatment modifies peristalsis and attenuates the antipropulsive action of adrenoceptor agonists in the guinea-pig small intestine.

The action of endotoxin to alter gastrointestinal motility in vivo may reflect a direct effect on the gut or result from vascular and other systemic manifestations of this sepsis model. Here we examined whether in vivo pretreatment of guinea-pigs with endotoxin modifies peristalsis in the isolated gut and influences the antipropulsive action of adrenoceptor agonists. Distension-induced peristalsis was recorded in fluid-perfused segments of the small intestine taken from animals pretreated intraperitoneally with endotoxin (1 mg kg(-1)Escherichia coli lipopolysaccharide) or vehicle 4 or 20 h before. Clonidine, adrenaline, noradrenaline, dopamine and dobutamine inhibited peristalsis with differential potency. Endotoxin pretreatment lowered the peristaltic pressure threshold and altered other parameters of baseline peristalsis in a time-related manner. The potency and efficacy of clonidine to inhibit peristalsis were markedly decreased after endotoxin administration, while the potency of the other test drugs was less attenuated. The antipropulsive action of clonidine in control segments was reduced by yohimbine and prazosin, whereas in segments from endotoxin-pretreated animals it was antagonized by yohimbine but not prazosin. We conclude that systemic endotoxin pretreatment of guinea-pigs modifies baseline peristalsis by an action on the gut and inhibits the antipropulsive action of adrenoceptor agonists through changes in adrenoceptor activity.

Adrenergic Agonists↗

PubMed2004

Gastric enteric neurones that respond to luminal injury.

Challenge of the rat gastric mucosa with HCl stimulates intrinsic neurones in the myenteric plexus of the stomach as demonstrated by immunohistochemical detection of c-Fos. In multiple labelling experiments of whole-mounts and sections of the gastric corpus we determined the chemical code of the stimulated neurones and investigated further whether neural pathways involving capsaicin-sensitive afferents, cholinergic neurones or the vagal system contribute to the stimulation of these neurones. Intragastric (IG) administration of 0.5 m HCl caused c-Fos expression in 12% of myenteric neurones, whereas IG saline failed to induce c-Fos. All stimulated neurones stained for nitric oxide synthase (NOS), vasoactive intestinal polypeptide (VIP) and neuropeptide Y (NPY), but not for choline acetyltransferase (ChAT). Fibres coexpressing NOS/VIP/NPY were found predominantly in the external muscle layer and the muscularis mucosae of the stomach wall. Pretreatment with capsaicin or hexamethonium, combination of both pretreatments or vagotomy reduced HCl-induced c-Fos expression by 54%, 66%, 63% and 68%, respectively. The data indicate that mucosal acid challenge of the stomach stimulates inhibitory motor neurones in the myenteric plexus and that capsaicin-sensitive afferents as well as cholinergic neurones participate in the neuronal stimulation probably via a vago-vagal reflex.

Animals↗

PubMed2004

Chemical nociception in the jejunum induced by capsaicin.

BACKGROUND AND AIMS: Chemonociception in the human small intestine has not been studied extensively. Although capsaicin can cause intestinal sensations, it is not known if this is due to stimulation of chemoreceptors or to motor changes. Our aims were to evaluate motor activity during capsaicin induced nociception and to compare qualities of jejunal nociception induced by capsaicin and mechanical distension. METHODS: Twenty nine healthy subjects swallowed a tube with a perfusion site at the ligament of Treitz and, 7 cm distally, a barostat balloon. Phasic motor activity was measured around the perfusion site and the balloon. Capsaicin solutions (40, 200, and 400 microg/ml) 2.5 ml/min were perfused for 60 minutes or until severe discomfort occurred. A graded questionnaire for seven different sensations was completed every 10 minutes and after capsaicin perfusion was replaced by saline perfusion because of severe discomfort. Sensations arising from pressure controlled distensions were assessed before and after capsaicin perfusion when sensations had stopped (n = 19), or during capsaicin administration when no discomfort was reported (n = 5). RESULTS: Capsaicin perfusion induced feelings of pressure, cramps, pain, and warmth. The quality and abdominal location of these sensations were similar to those induced by distension, except for warmth (p<0.01) and pressure (p<0.05). Seven of 12 subjects receiving 40 microg/ml capsaicin and all subjects receiving higher capsaicin concentrations developed discomfort. Perfusion had to be stopped after 55 (3.3), 15 (5.7), and 10 (2.2) minutes with 40, 200, and 400 microg/ml capsaicin, respectively, whereafter the sensations disappeared within 10 minutes. Repeated capsaicin (200 microg/ml) applications significantly reduced the time until discomfort occurred (p = 0.01). Jejunal tone was not altered by capsaicin but phasic activity proximal to the perfusion site was reduced during capsaicin induced discomfort (p<0.001). Pain thresholds during distensions were not different before and after capsaicin perfusion. CONCLUSION: Despite the similarities in abdominal localisation and perceptional quality of capsaicin and distension induced sensations, our results rule out the fact that abdominal discomfort evoked by capsaicin involves sensitisation of mechanoreceptors or an increase in phasic and tonic motor activity. Capsaicin evokes abdominal sensations by stimulation of chemoreceptors which proves the existence of chemonociception in the human small intestine.

Abdomen↗

PubMed2003

Actions of endothelin and corticotropin releasing factor in the guinea-pig ileum: no evidence for an interaction with capsaicin-sensitive neurons.

Both endothelins and corticotropin releasing factor (CRF) appear in capsaicin-sensitive neurons. We have investigated the effects of human endothelin-1 (ET-1) and CRF in the guinea-pig ileum longitudinal and circular preparations and sought for ways of specific antagonism. With the aid of tachyphylaxis to capsaicin (i.e., rendering capsaicin-sensitive neurons functionally impaired) it was tested if these neurons played a mediating role in the effects of ET-1 or CRF. We also tried to find out whether endogenous endothelin or CRF plays a role in the excitatory and inhibitory effects of capsaicin in the ileum. In preparations at basal tone, both exogenous ET-1 (1-100 nM) and CRF (3-100 nM) caused contraction. These responses were not influenced by capsaicin tachyphylaxis. The contractile effect of ET-1 was not affected by tetrodotoxin (1 microM), atropine (1 microM), methysergide (100 nM), chloropyramine (100 nM) or SR140333 (100 nM) but was significantly inhibited or even abolished by the receptor antagonist BQ123 (3 microM) or BQ788 (3 microM). CRF caused contraction that was fully sensitive to tetrodotoxin (1 microM), tachyphylaxis to CRF or to atropine (1 microM) plus the tachykinin NK1 receptor antagonist SR140333 (200 nM). Atropine alone had a weak inhibitory effect on the contractile action of CRF. Neither the antagonist BQ123 (3 microM) nor CRF tachyphylaxis inhibited the contractile action of capsaicin (2 microM), even in the presence of a mixture of GR82334 (3 microM) and SR142801 (100 nM), for blocking tachykinin NK1 and NK3 receptors, respectively--a treatment that by itself significantly reduced the effect of capsaicin. Exogenous ET-1 (0.3-5 nM), but not CRF (30-100 nM), caused relaxation of the atropine-treated, histamine-precontracted ileum. This effect of ET-1 was significantly inhibited or abolished by BQ123 (10 microM), or BQ788 (3 microM), but was not influenced by capsaicin tachyphylaxis. Likewise, relaxation of the atropine-treated, histamine-precontracted ileum in response to capsaicin was not influenced by the endothelin receptor antagonist BQ788 (3 microM) or BQ788 (3 microM) plus BQ123 (3 microM). Apamin (300 nM) was also without effect on the capsaicin-induced relaxation. In circular muscle strips ET-1 inhibited the indomethacin-induced spontaneous activity. This effect was abolished by BQ123 (3 microM) or BQ788 (3 microM). CRF caused a stimulation of the circular muscle. This stimulatory effect was not influenced by atropine (1 microM) alone, but was inhibited by atropine plus tachykinin NK1 and NK2 receptor antagonists (SR140333 (200 nM) and SR48968 (200 nM)) and also by tetrodotoxin (1 microM). It is concluded that capsaicin-sensitive neurons do not play a role in the effects of exogenous ET-1 or CRF in the guinea-pig ileum. ET-1 can both contract and relax the ileal longitudinal smooth muscle directly, probably via both ETA and ETB receptors. CRF acts by specifically stimulating excitatory (but not inhibitory) neurons of the myenteric plexus. Neither endogenous ET-1 nor CRF seems to play a role in the excitatory or inhibitory effects of capsaicin.

Animals↗

PubMed2003

Acid challenge delays gastric pressure adaptation, blocks gastric emptying and stimulates gastric fluid secretion in the rat.

Functional dyspepsia can be associated with impaired gastric relaxation in response to food intake and delayed gastric emptying. In this study, we investigated whether luminal hydrochloric acid (HCl) may reproduce these motor alterations in phenobarbital-anaesthetized rats via activation of extrinsic neural pathways. Intragastric pressure (IGP) changes induced by a 2-mL fluid bolus were recorded with an oesophageal catheter, and gastric emptying was determined via the fluid volume recovered from the stomach 30-min post-bolus. Experiments involving acute nerve transections or pharmacological blockade of nitric oxide synthesis revealed that the initial increase of IGP after a 0.35 mol L(-1) HCl bolus is dampened by duodenogastric and gastrogastric relaxation reflexes depending on vagal and splanchnic pathways as well as nitric oxide. Compared with saline, HCl (0.15-0.5 mol L(-1)) delayed the subsequent decrease (adaptation) of IGP, inhibited gastric emptying and stimulated gastric fluid secretion as seen in stomachs with ligated pylorus. The acid-evoked delay in IGP adaptation and inhibition of gastric emptying involved duodenogastric and duodenopyloric extrinsic nerve reflexes, whereas the gastric fluid secretion was independent of the extrinsic innervation. It is proposed that the gastropyloric motor changes induced by luminal acid challenge have a bearing on the motor disturbances underlying functional dyspepsia.

Animals↗

PubMed2003

Capsaicin-sensitive extrinsic afferents are involved in acid-induced activation of distinct myenteric neurons in the rat stomach.

Challenge of the rat gastric mucosa with 0.5 mol L(-1) HCl activates nitrergic neurons in the myenteric plexus as visualized by c-Fos immunohistochemistry. In the present study, we characterized the activated neurons more extensively by their chemical coding and investigated whether a neural pathway that involves capsaicin-sensitive extrinsic afferents and/or cholinergic neurons transmitting via nicotinic receptors contributes to the activation of myenteric neurons. In multiple labelling experiments, c-Fos was examined for co-localization with nitric oxide synthase (NOS), vasoactive intestinal peptide (VIP), neuropeptide Y (NPY), enkephalin (ENK), gastrin-releasing peptide (GRP), substance P (SP), calbindin D-28k (CALB) and neurofilament 145 (NF 145). All c-Fos-positive neurons were immunoreactive for NOS, VIP, NPY and NF 145, but not for SP, ENK, GRP and CALB. Nerve fibres co-expressing NOS, VIP and NPY were predominantly found in the external muscle layer and in the muscularis mucosae but rarely in the mucosa. Pre-treatment with capsaicin or hexamethonium or a combination of both pre-treatments reduced HCl-induced c-Fos expression by 54, 66 and 63%, respectively. Acid challenge of the stomach, therefore, leads to activation of presumably inhibitory motor neurons responsible for muscle relaxation. Activation of these neurons is partly mediated by capsaicin-sensitive afferents and involves ganglionic transmission via nicotinic receptors.

Animals↗

PubMed2003

Afferent signalling of gastric acid challenge.

Gastric acid is a factor in the pain associated with peptic ulcer and other acid-related disorders including functional dyspepsia, given that antisecretory treatment is a mainstay in the treatment of upper abdominal pain. However, the molecular sensors, afferent pathways and central processing systems of gastric chemonociception are little known. This article reviews emerging evidence that vagal afferent pathways play a pivotal role in gastric chemonociception. Exposure of the rat gastric mucosa to backdiffusing concentrations of luminal acid is signalled to the brainstem, but not spinal cord, as visualized by functional neuroanatomy based on the rapid expression of c-fos. This observation is complemented by the finding that the visceromotor response to gastric acid challenge is suppressed by vagotomy, but not splanchnectomy. The gastric acid-induced expression of c-fos in the brainstem is reduced by inhibition of gastric acid secretion and enhanced by pentagastrin-evoked stimulation of gastric acid secretion. These data indicate that endogenous acid modulates the sensory gain of acid-sensitive vagal afferents. Further consistent with a role of these neurons in gastric nociception is the finding that exposure to proinflammatory cytokines and the induction of experimental gastritis or gastric ulceration sensitizes vagal afferent pathways to gastric acid. Taken together, these observations are of relevance to the understanding and treatment of gastric hyperalgesia and dyspeptic pain.

Afferent Pathways↗

PubMed2002

[Why are substance P(NK1)-receptor antagonists ineffective in pain treatment?].

The undecapeptide substance P is expressed by primary afferent neurons where it is considered to be a cotransmitter of other peptides and glutamate. Since it is predominantly found in sensory neurons with unmyelinated fibres (C-fibres), substance P has long been thought to be a "pain transmitter". Following stimulation of nociceptive afferents, substance P is released in the spinal cord and substance P-mediated transmission is primarily brought about by tachykinin NK1 receptors. To inhibit this process, a considerable number of non-peptide, highly potent, highly selective and brain penetrant NK1 receptor antagonists have been developed during the past decade. Experimental studies have proved that NK1 receptor antagonists are indeed able to blunt pain in sensitized states and thus to reverse hyperalgesia, whereas acute pain is left fairly unchanged. The hyperalgesic role of substance P has been corroborated by the sensory deficits seen in substance P and NK1 receptor knockout mice. However, the concept that NK1 receptor antagonists would represent a novel class of analgesic drugs, as suggested by the preclinical studies, has not been borne out by the clinical trials that have been reported thus far. This article offers an overview of those hyperalgesic conditions in which NK1 receptor antagonists may be of therapeutic value and discusses possible reasons for the discrepancies between preclinical and clinical trials with NK1 receptor antagonists.

Analgesics↗

PubMed2002

Sensory neurone responses to mucosal noxae in the upper gut: relevance to mucosal integrity and gastrointestinal pain.

The digestive tract is supplied by extrinsic and intrinsic sensory neurones that, together with endocrine and immune cells, form a surveillance network that is essential to gut function. This article focuses on the responses of extrinsic afferent neurones to chemical insults of the gastrointestinal mucosa and their pathophysiological relevance to mucosal integrity and abdominal pain. Within the gastroduodenal region, spinal afferents subserve an emergency function because, in case of alarm by influxing acid, they stimulate mechanisms of mucosal protection via an efferent-like release of transmitters. Other sensory neurones signal chemical noxae to the brain, a task that is not confined to spinal afferents because vagal afferents communicate gastric acid and peripheral immune challenges to the brainstem and in this way elicit autonomic, endocrine, affective and behavioural reactions. Emerging evidence indicates that hypersensitivity of extrinsic afferent pathways to mechanical and chemical stimuli makes an important contribution to the abdominal hyperalgesia seen in functional dyspepsia and irritable bowel syndrome. Sensitization may be brought about by inflammatory processes that lead to up-regulation and functional alterations of receptors and ion channels on sensory neurones. Such sensory neurone-specific molecules, which include vanilloid (capsaicin) receptors, may represent important targets for novel drugs to treat abdominal pain.

Animals↗

PubMed2002

[Neurogenic inflammation. I. Basic mechanisms, physiology and pharmacology].

Activation of sensory unmyelinated neurons by noxious stimuli evokes the release of neuropeptides, such as substance P and calcitonin gene-related peptide (CGRP) from peripheral nerve endings. These neuropeptides and subsequently released mediators cause a local oedema, hyperaemia and an erythema which extends beyond the site of stimulation (so-called flare response). Since these inflammatory signs depend on the function and integrity of peripheral sensory nervous systems, the response has been termed neurogenic inflammation. Due to the fact that nearly all tissues in mammals including humans are innervated by afferent sensory neurons, this neurogenic inflammation can occur ubiquitously throughout the body. Albeit first evidence showing that sensory neurons contribute to the inflammatory signs, described as antidromic vasodilatation, axon reflex, triple response, neurogenic inflammation, elicited at the level of tissue that they innervate was first obtained more than one hundred years ago, it was in the last two decades that inflammation caused by the release of neuropeptides from afferent nerve endings was recognised as a physiologically and pathologically relevant process. A large number of exogenous and endogenous substances and autacoids may stimulate or sensitise sensory nerve endings, thus simultaneously producing pain and nociceptive responses, as well as neurogenic inflammation. On the basis of recent research a variety of pharmacological substances and antagonists of putative mediators have been identified to modulate or suppress neurogenic inflammation, thus providing a rationale for therapeutical strategies for various diseases in which neurogenic inflammation is suggested to be involved. Among them, capsaicin and other newly developed agonists and antagonists at the vanilloid receptor have attracted particular attention, since they were found to be capable of desensitizing nociceptive nerve structures and thus of preventing development of neurogenic inflammation or even of abolishing an ongoing inflammatory process.

Animals↗

PubMed2002

[Neurogenic inflammation. II. pathophysiology and clinical implications].

Neurogenic inflammation is elicited by activation of unmyelinated sensory neurons through noxious stimuli and subsequent release of neuropeptides such as substance P and calcitonin gene-related peptide (CGRP) from peripheral nerve endings. The nerve-mediated inflammatory responses in the tissue consist of hyperaemia and oedema which under some circumstances may be accompanied by pain. Neurogenic inflammation has been implicated in the pathophysiology of various human diseases with uncertain etiology. Signs of inflammation and hyperalgesia associated with chronic pain syndromes such as migraine, arthritis and complex regional pain syndrome resemble the characteristics of neurogenic inflammation. By extrapolation of convincing evidence obtained in rodent models, neurogenic inflammation is assumed to contribute to diseases of the respiratory system, gastrointestinal tract, urogenital tract, and skin in humans. Since, however, highly selective substance P receptor antagonists, found to be effective against inflammation in rodents, failed to inhibit inflammatory processes in clinical trials, the hypothesis of an involvement of neurogenic inflammation in human diseases is discussed critically in this review. Beyond its primarily inflammatory character neurogenic inflammation can be regarded as a mechanism that activates protective responses, thus bringing about a first line of defence to maintain the integrity of the tissue and to contribute to tissue repair.

Animals↗

PubMed2002

[Thio- and oxybarbiturates inhibit peristalsis in the Guinea-pig ileum in vitro].

INTRODUCTION: Inhibition of gastrointestinal motility by drugs used for anaesthesia or sedation in critically ill patients in the ICU is a major problem leading to various complications. Thus this study examines whether the thio- and oxybarbiturates thiopentone and pentobarbitone exert an inhibitory effect on intestinal peristalsis. METHODS: Peristalsis in isolated segments of the guinea-pig small intestine was elicited by distension of the gut wall through a rise of intraluminal pressure and recorded via the intraluminal pressure changes associated with the aborally moving peristaltic contractions. Thiopentone and pentobarbitone (0.1 - 300 microM)-induced inhibition of peristalsis was reflected by an increase of the peristaltic pressure threshold (PPT). RESULTS: Thiopentone (EC50 = 19,8 microM) and pentobarbitone (EC50 = 99.7 micro M) concentration-dependently increased the PPT. While the vehicle (saline) and 0.1 - 10 micro M thiopentone and pentobarbitone were without any effect on the PPT, 100 micro M caused a significant increase in PPT, and complete abolition of peristalsis occurred after 300 micro M thiopentone or pentobarbitone in all segments tested. Inhibition was reversed by changing the bath solution. CONCLUSIONS: Thio- and oxybarbiturates inhibit intestinal peristalsis in the guinea-pig ileum. It is assumed that thiopentone and pentobarbitone affect propulsive peristalsis also in the human small intestine.

Animals↗

PubMed2001

Role of tachykinin receptors in the central processing of afferent input from the acid-threatened rat stomach.

Noxious challenge of the rat gastric mucosa by hydrochloric acid (HCl) is signalled via vagal afferent neurons to several brain nuclei in which tachykinins and tachykinin receptors are present. Therefore, we tested whether tachykinin receptor antagonists would modify the central transmission of input from the acid-threatened stomach. Neuronal excitation was visualized by in situ hybridization autoradiography (ISH) of c-fos messenger ribonucleic acid (mRNA) 45 min after intragastric (IG) administration of HCl (0.5 M; 10 ml/kg). This stimulus has previously been shown to cause neurons in the nucleus tractus solitarii (NTS), lateral parabrachial nucleus (LPB), paraventricular (Pa) nuclei, supraoptic (SO) nucleus, central amygdala (CeA), area postrema (AP), subfornical organ (SFO) and habenula (Hb) to express c-fos mRNA. Intraperitoneal (IP) pretreatment with the NK1 receptor antagonist GR-205,171 (3 mg/kg) attenuated the acid-induced transcription of c-fos mRNA in NTS and augmented it in SFO. The NK2 receptor antagonist SR-144,190 (0.1 mg/kg, IP) had no effect. Subcutaneous administration of the NK3 receptor antagonist SB-222,200 (20 mg/kg) reduced the c-fos mRNA response in AP and SFO and enhanced it in Hb. These data show that the transmission of input from the acid-threatened stomach in distinct brain nuclei involves tachykinins acting at NK1 and NK3 receptors, but not NK2 receptors.

Afferent Pathways↗

PubMed2001

Sufentanil potentiates the inhibitory effect of epinephrine on intestinal motility.

OBJECTIVE: The aim of our study was to evaluate the effect of the combination of different catecholamines and sufentanil on peristalsis of the isolated guinea pig small bowel in vitro. DESIGN: In vitro study on excised guinea pig small-bowel segments (8-10 segments per substance tested). SETTING: Laboratory for experimental studies at the University. SUBJECTS: Isolated guinea pig small-bowel segments. INTERVENTIONS: Excised segments of guinea pig small bowel were mounted in a tissue bath (37 degrees C) in Tyrode's solution and bubbled with carbogen (95% O2/5% CO2). The lumina were perfused with Tyrode's solution at 0.5 ml/min. The test drugs (epinephrine, norepinephrine, dobutamine, sufentanil, and a combination of these catecholamines with sufentanil) were added to the tissue bath and peristalsis recorded via changes in the intraluminal pressure. One-way and two-way ANOVA were used for statistical analysis. MEASUREMENTS AND RESULTS: All the tested substances, both individually and in combination, inhibited intestinal peristalsis in a dose-dependent manner. High doses resulted in a complete blockade of peristalsis. Preexposure of the segments to sufentanil at 0.1 nM barely influenced the effects of the catecholamines on peristalsis. However, sufentanil at 0.3 nM enhanced the antiperistaltic activity of epinephrine in a supraadditive manner, whereas the effect on norepinephrine and dobutamine was less pronounced. CONCLUSIONS: Our experimental data suggest that the combination of epinephrine and sufentanil might be the worst choice for the intensive care setting. This is due to its pronounced inhibitory effect on peristalsis in vitro at moderate and higher concentrations.

Adrenergic Agents↗