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Peter Holzer

Publications and source records attributed to Peter Holzer.

At least 19 recordsLinked to original sources
PubMed2006

Involvement of endothelial NO in the dilator effect of VIP on rat isolated pulmonary artery.

The endothelium and its interaction with smooth muscle play a central role in the local control of the pulmonary vasculature, and endothelial dysfunction is thought to contribute to pulmonary hypertension and chronic obstructive pulmonary disease. Vasoactive intestinal peptide (VIP), a 28-amino acid neuropeptide, relaxes the rat pulmonary artery, but there is controversy as to whether or not this action of VIP depends on the endothelium. The aim of this study, therefore, was to investigate the role of the endothelium and nitric oxide (NO), the major endothelium-derived relaxing factor, in the dilator action of VIP on the rat isolated pulmonary artery. Pulmonary artery preparations pre-contracted by the alpha(1)-adrenoceptor agonist L-phenylephrine were relaxed by VIP (0.003-1 microM) and acetylcholine (0.003-10 microM) in a concentration-dependent manner. Mechanical removal of the endothelium reduced the maximal response to VIP by about 50% and practically abolished the response to acetylcholine. Inhibition of NO synthesis by N(omega)-nitro-L-arginine methyl ester (0.5 mM) had a similar effect, abolishing the vasorelaxation caused by acetylcholine and attenuating the vasorelaxation caused by VIP by about 50%. From these data it is concluded that the relaxant action of VIP on the rat isolated pulmonary artery depends in part on the presence of the endothelium and that this part is mediated by endothelial NO.

Acetylcholine↗
PubMed2006

Taste receptors in the gastrointestinal tract. V. Acid sensing in the gastrointestinal tract.

Luminal acidity is a physiological challenge in the foregut, and acidosis can occur throughout the gastrointestinal tract as a result of inflammation or ischemia. These conditions are surveyed by an elaborate network of acid-governed mechanisms to maintain homeostasis. Deviations from physiological values of extracellular pH are monitored by multiple acid sensors expressed by epithelial cells and sensory neurons. Acid-sensing ion channels are activated by moderate acidification, whereas transient receptor potential ion channels of the vanilloid subtype are gated by severe acidosis. Some ionotropic purinoceptor ion channels and two-pore domain background K(+) channels are also sensitive to alterations of extracellular pH.

Acid Sensing Ion Channels↗
PubMed2006

Intestinal motility disturbances in intensive care patients pathogenesis and clinical impact.

BACKGROUND: Gastrointestinal motility disturbances in critically ill patients are frequent in the ICU setting, causing considerable discomfort and are associated with increased rates of morbidity and mortality. This review focuses on the pathophysiological basis of intestinal motility, the major patterns of pathological motility alterations, the impact on patient outcome, and current therapeutic options. DISCUSSION: Intestinal motility is controlled by the enteric nervous system, modulated by hormones and extrinsic afferent and efferent neurons. Pathological motility disturbances can affect the stomach, small bowel, and colon separately or in combination. Changes in esophageal motor activity contribute to the aspiration of gastric juice, whereas early enteral feeding most frequently fails due to gastric intolerance. Disturbances in digestive and interdigestive motility patterns and the inability to switch motor activity from the interdigestive to the digestive pattern also contribute to feeding disability and thus to increased morbidity and mortality as well. CONCLUSIONS: The therapeutic options for motility disturbances in critically ill patients include the adjustment of electrolyte imbalances, tailored fluid management, early enteral feeding, appropriate management of catecholamines and drugs used for analgosedation, and prokinetic drugs. Unfortunately, the therapeutic options for treating motility disturbances in ICU patients are still limited. This situation requires careful assessment of ICU patients with respect to gut motility disturbances and their pathophysiological mechanisms and an individually tailored treatment to prevent further aggravation of existing motility disturbances.

Critical Care↗
PubMed2006

Efferent-like roles of afferent neurons in the gut: Blood flow regulation and tissue protection.

The maintenance of gastrointestinal mucosal integrity depends on the rapid alarm of protective mechanisms in the face of pending injury. To this end, the gastric mucosa is innervated by intrinsic sensory neurons and two populations of extrinsic sensory neurons: vagal and spinal afferents. Extrinsic afferent neurons constitute an emergency system that is called into operation when the gastrointestinal mucosa is endangered by noxious chemicals. The function of these chemoceptive afferents can selectively be manipulated and explored with the use of capsaicin which acts via a cation channel termed TRPV1. Many of the homeostatic actions of spinal afferents are brought about by transmitter release from their peripheral endings. When stimulated by noxious chemicals, these afferents enhance gastrointestinal blood flow and activate hyperaemia-dependent and hyperaemia-independent mechanisms of protection and repair. In the rodent foregut these local regulatory roles of sensory neurons are mediated by calcitonin gene-related peptide and nitric oxide. The pathophysiological potential of the neural emergency system is best portrayed by the gastric hyperaemic response to acid back-diffusion, which is governed by spinal afferent nerve fibres. This mechanism limits damage to the surface of the mucosa and creates favourable conditions for rapid restitution and healing of the wounded mucosa. Other extrinsic afferent neurons, particularly in the vagus nerve, subserve gastrointestinal homeostasis by signalling noxious events in the foregut to the central nervous system and eliciting autonomic, emotional-affective and neuroendocrine reactions. Under conditions of inflammation and injury, chemoceptive afferents are sensitized to peripheral stimuli and in this functional state contribute to the hyperalgesia associated with functional dyspepsia and irritable bowel syndrome. Thus, if GI pain is to be treated by sensory neuron-directed drugs it needs to be considered that these drugs do not inhibit nociception at the expense of GI mucosal vulnerability.

Animals↗
PubMed2005

Selective increase of dark phase water intake in neuropeptide-Y Y2 and Y4 receptor knockout mice.

Neuropeptide-Y (NPY) is involved in the regulation of ingestive behaviour and energy homeostasis. Since deletion of the NPY Y2 and Y4 receptor gene increases and decreases food intake, respectively, we examined whether water intake during the light and dark phases is altered in Y2 and Y4 receptor knockout mice. The water consumption of mice staying in their home cages was measured by weighing the water bottles at the beginning and end of the light phase during 4 consecutive days. Control, Y2 and Y4 receptor knockout mice did not differ in their water intake during the light phase. However, during the dark phase Y2 and Y4 receptor knockout mice drank significantly more (46-63%, P<0.05) water than the control mice. The total daily water intake over 24 h was also enhanced. The enhanced water intake during the dark phase was not altered by the beta-adrenoceptor antagonist propranolol or the angiotensin AT1 receptor antagonist telmisartan (each injected intraperitoneally at 10 mg/kg). These data indicate that NPY acting via Y2 and Y4 receptors plays a distinctive role in the regulation of nocturnal water consumption. While beta-adrenoceptors and angiotensin AT1 receptors do not seem to be involved, water intake in Y2 and Y4 receptor knockout mice may be enhanced because presynaptic autoinhibition of NPY release and inhibition of orexin neurons in the central nervous system are prevented.

Adrenergic beta-Antagonists↗
PubMed2005

Differential effects of intragastric acid and capsaicin on gastric emptying and afferent input to the rat spinal cord and brainstem.

BACKGROUND: Hydrochloric acid (HCl) is a potential threat to the integrity of the gastric mucosa and is known to contribute to upper abdominal pain. We have previously found that gastric mucosal challenge with excess HCl is signalled to the rat brainstem, but not spinal cord, as visualized by expression of c-fos messenger ribonucleic acid (mRNA), a surrogate marker of neuronal excitation. This study examined whether gastric mucosal exposure to capsaicin, a stimulant of nociceptive afferents that does not damage the gastric mucosa, is signalled to both brainstem and spinal cord and whether differences in the afferent signalling of gastric HCl and capsaicin challenge are related to different effects on gastric emptying. RESULTS: Rats were treated intragastrically with vehicle, HCl or capsaicin, activation of neurons in the brainstem and spinal cord was visualized by in situ hybridization autoradiography for c-fos mRNA, and gastric emptying deduced from the retention of intragastrically administered fluid. Relative to vehicle, HCl (0.5 M) and capsaicin (3.2 mM) increased c-fos transcription in the nucleus tractus solitarii by factors of 7.0 and 2.1, respectively. Capsaicin also caused a 5.2-fold rise of c-fos mRNA expression in lamina I of the caudal thoracic spinal cord, although the number of c-fos mRNA-positive cells in this lamina was very small. Thus, on average only 0.13 and 0.68 c-fos mRNA-positive cells were counted in 0.01 mm sections of the unilateral lamina I following intragastric administration of vehicle and capsaicin, respectively. In contrast, intragastric HCl failed to induce c-fos mRNA in the spinal cord. Measurement of gastric fluid retention revealed that HCl suppressed gastric emptying while capsaicin did not. CONCLUSION: The findings of this study show that gastric mucosal exposure to HCl and capsaicin is differentially transmitted to the brainstem and spinal cord. Since only HCl blocks gastric emptying, it is hypothesized that the two stimuli are transduced by different afferent pathways. We infer that HCl is exclusively signalled by gastric vagal afferents whereas capsaicin is processed both by gastric vagal and intestinal spinal afferents.

Afferent Pathways↗
PubMed2005

Peristalsis in the Guinea pig small intestine in vitro is impaired by acetaminophen but not aspirin and dipyrone.

Inhibition of intestinal peristalsis is a major side effect of opioid analgesics. It is unknown whether non-opioid analgesics, such as acetaminophen, acetylsalicylic acid, and dipyrone, exert any effect on intestinal motility. In the current in vitro study we examined the effect of these analgesics on intestinal peristalsis and analyzed some of their mechanisms of action. In isolated segments of the guinea pig small intestine peristalsis was triggered by a perfusion-induced increase of the intraluminal pressure. The peristaltic pressure threshold (PPT) at which peristaltic waves were elicited was used to quantify drug effects on peristalsis. Vehicle (Tyrode's solution), acetaminophen (0.01-100 microM), acetylsalicylic acid (100-300 microM), and dipyrone (10-100 microM) were added extraserosally to the organ bath. Acetaminophen concentration-dependently increased PPT and abolished peristalsis in four of six segments at the concentration of 10 microM and in all segments tested at 100 microM (EC50=6.0 microM). The increase in PPT resulting from 3 microM acetaminophen was reduced by naloxone and apamin but not changed by L-nitro-arginine methylester (L-NAME), its inactive enantiomer D-NAME, acetylsalicylic acid, methysergide, or tropisetron. Acetylsalicylic acid and dipyrone did not affect peristalsis. The results reveal, for the first time, that acetaminophen concentration-dependently impairs intestinal peristalsis, whereas acetylsalicylic acid and dipyrone lacked such an effect. The inhibition caused by acetaminophen involves transmitters acting via small conductance Ca2+-activated potassium channels, endogenous opioidergic pathways, and presumably inhibition of cyclooxygenase-3.

Acetaminophen↗
PubMed2004

Effects of capsaicin on visceral smooth muscle: a valuable tool for sensory neurotransmitter identification.

Studying the visceral effects of the sensory stimulant capsaicin is a useful and relatively simple tool of neurotransmitter identification and has been used for this purpose for approximately 25 years in the authors' and other laboratories. We believe that conclusions drawn from experiments on visceral preparations may have an impact on studies dealing with the central endings of primary afferent neurons, i.e. research on nociception at the spinal level. The present review concentrates on the effects of capsaicin--through the transient receptor potential vanilloid receptor type 1 (TRPV1) receptor--on innervated gastrointestinal, respiratory and genitourinary smooth muscle preparations. Tachykinins and calcitonin gene-related peptide (CGRP) are the most widely accepted transmitters to mediate "local efferent" effects of capsaicin-sensitive nerves in tissues taken from animals. Studies more and more frequently indicate a supra-additive interaction of various types of tachykinin receptors (tachykinin NK(1), NK(2), NK(3) receptors) in the excitatory effects of capsaicin. There is also evidence for a mediating role of ATP, acting on P(2) purinoceptors. Non-specific inhibitory actions of capsaicin-like drugs have to be taken into consideration while designing experiments with these drugs. Results obtained on human tissues may be sharply different from those of animal preparations. Capsaicin potently inhibits tone and movements of human intestinal preparations, an effect mediated by nitric oxide (NO) and/or vasoactive intestinal polypeptide.

Animals↗
PubMed2004

TRPV1 and the gut: from a tasty receptor for a painful vanilloid to a key player in hyperalgesia.

Capsaicin, the pungent ingredient in red pepper, has been used since ancient times as a spice, despite the burning sensation associated with its intake. More than 50 years ago, Nikolaus Jancso discovered that capsaicin can selectively stimulate nociceptive primary afferent neurons. The ensuing research established that the neuropharmacological properties of capsaicin are due to its activation of the transient receptor potential ion channel of the vanilloid type 1 (TRPV1). Expressed by primary afferent neurons innervating the gut and other organs, TRPV1 is gated not only by vanilloids such as capsaicin, but also by noxious heat, acidosis and intracellular lipid mediators such as anandamide and lipoxygenase products. Importantly, TRPV1 can be sensitized by acidosis and activation of various pro-algesic pathways. Upregulation of TRPV1 in inflammatory bowel disease and the beneficial effect of TRPV1 downregulation in functional dyspepsia and irritable bladder make this polymodal nociceptor an attractive target of novel therapies for chronic abdominal pain.

Animals↗
PubMed2004

Differential reversal of drug-induced small bowel paralysis by cerulein and neostigmine.

OBJECTIVE: Cerulein and neostigmine are prokinetic drugs whose potency and effective dose range are barely known. The aim of this study was to assess their benefit for normal and compromised peristalsis. DESIGN: In vitro, isolated segments of guinea pig small intestine. Setting : University laboratory. INTERVENTIONS: Small bowel segments were mounted in tissue baths and luminally perfused with Tyrode solution. Test drugs (prokinetic: cerulein, neostigmine; inhibitory: atropine, hexamethonium, epinephrine, sufentanil) were added to the tissue bath. MEASUREMENTS AND RESULTS: Peristalsis was quantified via changes in the peristaltic pressure threshold. One-way and two-way analysis of variance (ANOVA) were used for statistical analysis. Cerulein (0.03-100 nM) stimulated normal peristalsis in a concentration-dependent manner and reversed paralysis of peristalsis induced by all inhibitory test drugs to a similar extent. The properistaltic effect of neostigmine was limited to a narrow concentration range (0.03-0.1 micro M), whereas concentrations >0.3 micro M inhibited peristalsis. Neostigmine more effectively counteracted blockage of peristalsis caused by atropine than that caused by hexamethonium. The inhibitory effects of epinephrine and sufentanil on peristalsis were reversed only at the concentration range of 0.1-0.3 micro M neostigmine. CONCLUSIONS: Cerulein stimulates normal peristalsis in vitro at a wide concentration range and reverses blockage of peristalsis caused by drugs with a site of action either on the enteric nervous system or intestinal smooth muscle. Neostigmine's prokinetic effect, to the contrary, is limited to a small concentration range and best seen when peristalsis is depressed by blockage of cholinergic muscle activation.

Adjuvants, Anesthesia↗
PubMed2004

Opioids and opioid receptors in the enteric nervous system: from a problem in opioid analgesia to a possible new prokinetic therapy in humans.

The gut is a neurological organ, which implies that many neuroactive drugs such as opioid analgesics can seriously disturb gastrointestinal function, because many of the transmitters and transmitter receptors present in the brain are also found in the enteric nervous system. One of the most common manifestations of opioid-induced bowel dysfunction is constipation which results from blockade of peristalsis and intestinal fluid secretion. The discovery of opioid receptor antagonists with a peripherally restricted site of action, such as N-methylnaltrexone and alvimopan, makes it possible to normalize bowel function in opiate-treated patients without compromising central opioid analgesia. There is emerging evidence that opioid receptor antagonists may also have prokinetic actions, reversing pathological states of gastrointestinal hypomotility that are due to overactivity of the enteric opioid system.

Analgesics, Opioid↗
PubMed2004

Newly discovered tachykinins raise new questions about their peripheral roles and the tachykinin nomenclature.

The tachykinin family has recently been extended by the discovery of a third tachykinin gene encoding previously unknown mammalian tachykinins (hemokinin 1, endokinin A and endokinin B) that have a widespread peripheral distribution and a tachykinin NK(1) receptor selectivity. This and the identification of other tachykinin-like peptides such as C14TKL-1 and virokinin raise many questions about the roles played by tachykinins in peripheral tissues and render terms such as 'neurokinins' and 'SP receptor' inappropriate.

Animals↗
PubMed2004

Immunocytochemical characterization of rat brainstem neurons with vagal afferent input from the stomach challenged by acid or ammonia.

Exposure of the gastric mucosa to backdiffusing acid is signalled to the brainstem via vagal afferents. This study examined whether exposure of the Sprague-Dawley rat stomach to hydrochloric acid (HCl) or ammonium hydroxide (NH4OH), a noxious chemical produced by Helicobacter pylori, activates different vagal afferent pathways as reflected by different circuitries in the medullary brainstem. Two hours after intragastric treatment with HCl or NH4OH the activation of neurons in the nucleus tractus solitarii at the rostrocaudal extension of the area postrema (NTSAP) was visualized by c-Fos immunohistochemistry and their chemical coding characterized by double-labelling immunohistochemistry. Exposure of the rat gastric mucosa to HCl (0.15-0.5 M) or NH4OH (0.1-0.3 M) led to a concentration-dependent expression of c-Fos in the NTSAP. The number and distribution of NTSAP neurons activated by 0.35 M HCl and 0.3 M NH4OH were similar; the highest number of activated neurons occurring in the medial part of the NTSAP. Some 60% of the NTSAP neurons activated by intragastric HCl and NH4OH stained for the high affinity glutamate transporter EAAC1, while some 30% contained calbindin or neuropeptide Y. Glutamate receptors of the N-methyl-D-aspartate type were found on approximately 50% of the c-Fos-positive cells in the NTSAP, whereas tachykinin NK1, NK2 and NK3 receptors were present on 5-10% of the activated neurons. The similar number and distribution of c-Fos-expressing neurons within the NTSAP and their identical chemical coding indicate that exposure of the rat stomach to backdiffusing concentrations of HCl and NH4OH activates the same vagal afferent-NTSAP pathway.

Amino Acid Transport System X-AG↗
PubMed2004

Increased expression of TRPV1 receptor in dorsal root ganglia by acid insult of the rat gastric mucosa.

It is still unknown which receptors of peripheral sensory pathways encode and integrate an acid-induced nociceptive event in the gastric mucosa. The transient receptor potential vanilloid receptor 1 (TRPV1) and the acid-sensing ion channel 3 (ASIC3) are two nociception-related receptors. Here we investigated (i) to what extent these receptors are distributed in stomach-innervating neurons of dorsal root and nodose ganglia, using immunohistochemistry and retrograde tracing, and (ii) whether their expression is altered in response to a noxious acid challenge of the stomach. We also explored the presence of TRPV1 in the gastric enteric nervous system because of its possible expression by intrinsic sensory neurons. Most stomach-innervating neurons in nodose ganglia were immunoreactive for TRPV1 (80%) and ASIC3 (75%), these results being similar in the dorsal root ganglia (71 and 82%). RT-PCR and Western blotting were performed up to 6 h after oral application of 0.5 m HCl to conscious rats. TRPV1 protein was increased in dorsal root but not in nodose ganglia whereas TRPV1 and ASIC3 mRNAs remained unchanged. TRPV1 mRNA was detected in longitudinal muscle-myenteric plexus preparations of control stomachs and was not altered by the acid challenge. Combined vagotomy and ganglionectomy abolished expression of TRPV1, indicating that it may derive from an extrinsic source. In summary, noxious acid challenge of the stomach increased TRPV1 protein in spinal but not vagal or intrinsic sensory afferents. The TRPV1 receptor may be a key molecule in the transduction of acid-induced nociception of the gastric mucosa and a mediator of visceral hypersensitivity.

Acid Sensing Ion Channels↗
PubMed2004

Inhibition of guinea pig intestinal peristalsis by the flavonoids quercetin, naringenin, apigenin and genistein.

Flavonoids are known to relax precontracted intestinal smooth muscle and to delay intestinal transit. We therefore investigated the effects of quercetin, naringenin, apigenin and genistein on intestinal peristalsis in vitro. Peristalsis in fluid-perfused segments of the guinea pig small intestine was recorded through the intraluminal pressure changes associated with the peristaltic waves. Alterations of distension sensitivity were reflected by changes in the peristaltic pressure threshold and alterations of peristaltic performance by changes in the maximal acceleration, amplitude and residual baseline pressure of the peristaltic waves. Quercetin, naringenin, apigenin and genistein (10-300 micromol/l) depressed intestinal peristalsis in a structure- and concentration-dependent manner. The flavonoid-evoked changes in peristalsis parameters made it possible to distinguish between two patterns of peristaltic motor inhibition: a decrease in distension sensitivity and peristaltic performance (apigenin and genistein) and a decrease in distension sensitivity without a major change in peristaltic performance (quercetin and naringenin). The antiperistaltic effect of quercetin was partially prevented by apamin (0.5 micromol/l), N-nitro-L-arginine methylester (100 micromol/l) and naloxone (0.5 micromol/l), whereas the effect of genistein was hardly affected by these drugs. Peristaltic motor activity suppressed by quercetin (300 micromol/l), but not genistein (100 micromol/l), was partially restored by apamin. In contrast, neostigmine (0.3 micromol/l) caused a significant recovery of peristalsis from blockade by genistein but failed to reverse peristaltic motor blockade due to quercetin. These observations suggest that naringenin and quercetin inhibit peristalsis by facilitating inhibitory enteric pathways, whereas apigenin and genistein interfere with muscle excitation or excitation-contraction coupling.

Animals↗
PubMed2004

Gastrointestinal pain in functional bowel disorders: sensory neurons as novel drug targets.

Functional bowel disorders (FBDs) are defined by symptoms of gastrointestinal (GI) dysfunction, discomfort and pain in the absence of a demonstrable organic cause. Since the prevalence of FBDs, particularly functional dyspepsia and irritable bowel syndrome, can be as high as 20%, FBDs represent a significant burden in terms of direct healthcare and productivity costs. There is emerging evidence that the discomfort and pain experienced by many FBD patients is due to persistent hypersensitivity of primary afferent neurons, which may develop in response to infection, inflammation or other insults. This concept identifies vagal and spinal sensory neurons as important targets for novel therapies of GI hyperalgesia. Sensory neuron-specific targets can be grouped into three categories: receptors and sensors at the peripheral nerve terminals, ion channels relevant to nerve excitability and conduction and transmitter receptors. Particular therapeutic potential is attributed to targets that are selectively expressed by afferent neurons, such as the transient receptor potential channel TRPV1, acid-sensing ion channels and tetrodotoxin-resistant Na + channels.

Analgesics↗