Biomedical subjects

P Holzer

Publications and source records attributed to P Holzer.

At least 19 recordsLinked to original sources

PubMed1996

Morphologic basis of the functional gastric acid barrier.

The gastric mucosa possesses a functional barrier that prevents intrusion of luminal acid. The aim of the present study was to elucidate the morphologic basis of this barrier by exploring the effect of acid challenge on the gastric mucosal epithelium, basal lamina, and microvasculature. The stomachs of urethane-anesthetized rats were perfused, for at least 45 minutes, with 0.05 M HCl or 0.15 M HCl in the absence or presence of the mucosal barrier breaker ethanol (15%) and examined by light, scanning, and transmission electron microscopy. Gastric perfusion with 0.05 M HCl alone caused superficial cell injury, the damaged surface cells loosing the surface membrane, whereas the junctional complex and basolateral membrane were preserved. Perfusion of 0.15 M HCl alone led to focal ablation of surface epithelial cells in the interfoveolar regions, and cells in the gastric pits remained grossly normal. Exposure to the barrier breaker ethanol (15%) in the presence of 0.05 M HCl caused extensive ablation of the surface epithelium. There were many focal areas in which the honeycomb structure of the lamina propria was exposed and the basal lamina was removed. Gastric mucosal damage progressed further when the luminal HCl concentration was raised to 0.15 M in the presence of ethanol (15%). In this instance, extensive areas with deep erosions and vast areas of deep-reaching ablation of the epithelium and basal lamina were observed. Ultrastructurally, there was extensive damage to the endothelium of capillaries lying underneath denuded areas of the gastric mucosa, the injured capillaries containing erythrocyte ghosts and thrombocyte aggregates. The data suggest that the integrity of the junctional complex, basolateral membrane, and basal lamina forms the morphologic basis of the functional gastric acid barrier. Once these structures are disrupted or ablated to an appreciable extent, damage forms in the mucosal microvasculature, and injury progresses to deeper layers of the mucosa.

Animals↗

PubMed1995

Visceral vasodilatation and somatic vasoconstriction evoked by acid challenge of the rat gastric mucosa: diversity of mechanisms.

1. Acid back-diffusion through a disrupted gastric mucosal barrier increases blood flow to the stomach without any change in systemic blood pressure. This study was undertaken to examine the gastric acid-evoked changes in blood flow in a number of visceral and somatic arterial beds and to elucidate the mechanisms which lead to the regionally diverse haemodynamic responses. 2. The gastric mucosa of urethane-anaesthetized rats was challenged with acid by perfusing the stomach with ethanol (15%, to disrupt the gastric mucosal barrier) in 0.15 M HCl. Blood flow was estimated by laser Doppler flowmetry, the hydrogen clearance method or the ultrasonic transit time shift technique. 3. Gastric acid challenge increased blood flow in the gastric mucosa and left gastric artery while blood flow in the femoral artery and skin declined. 4. Afferent nerve stimulation by intragastric administration of capsaicin enhanced blood flow in the left gastric artery but did not diminish blood flow in the femoral artery when compared with the vehicle. 5. The gastric acid-evoked dilatation of the left gastric artery was depressed by acute extrinsic denervation of the stomach, capsaicin-induced ablation of afferent neurones or hexamethonium-induced blockade of autonomic ganglionic transmission. 6. The gastric acid-induced constriction of the femoral artery was attenuated by acute extrinsic denervation of the stomach but left unaltered by capsaicin, hexamethonium, guanethidine, indomethacin, telmisartan (an angiotensin II antagonist), [d(CH2)5(1), Tyr(Me)2, Arg8]-vasopressin (a vasopressin antagonist), bosentan (an endothelin antagonist) and acute ligation of the blood vessels to the adrenal glands. 7. These data show that acid challenge of the gastric mucosa elicits visceral vasodilatation and somatic vasoconstriction via divergent mechanisms. The gastric hyperaemia is brought about by extrinsic vasodilator nerves, whereas the reduction of somatic blood flow seems to be mediated by non-neural, probably humoral, vasoconstrictor messengers that remain to be identified.

Animals↗

PubMed1995

Activity of SR 142801 at peripheral tachykinin receptors.

The pharmacological profile of the novel tachykinin NK3 receptor antagonist SR 142801, ((S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl) piperidin-3-yl) propyl)-4-phenylpiperidin-4-yl)-N-methylacetamide), was studied at tachykinin NK1, NK2 and NK3 receptors, in several in vitro bioassays. In the guinea-pig isolated ileum longitudinal muscle preparation, SR 142801 (10 nM-1 microM) caused an insurmountable antagonism of tachykinin NK3 receptor-mediated contractions produced by senktide (apparent pKB = 9.27). The blockade induced by SR 142801 was essentially irreversible, since it was not removed by washout (up to 2 h) and was increased by prolonging the incubation from 15 to 120 min. SR 142801 showed similar antagonist potency at rat tachykinin NK3 receptors (portal vein) and rabbit tachykinin NK2 receptors (pulmonary artery) (pKB = 7.49 and 7.66, respectively), whereas it was distinctly less potent at hamster tachykinin NK2 receptors (trachea; pKB = 6.84) and inactive at guinea-pig tachykinin NK1 receptors (ileum, longitudinal muscle). In the guinea-pig whole ileum SR 142801 (100 nM) did not affect the contraction produced by capsaicin (1 microM). The combined SR 142801 pretreatment and tachyphylaxis of neuronal CGRP (calcitonin gene-related peptide) receptors produced a slight (about 25%), but significant reduction of the response to capsaicin, suggesting that tachykinin NK3 receptors play a minor role in capsaicin-induced neuronal excitation of afferent nerves in the guinea-pig ileum.

Analysis of Variance↗

PubMed1995

The non-peptide NK1 receptor antagonist SR140333 produces long-lasting inhibition of neurogenic inflammation, but does not influence acute chemo- or thermonociception in rats.

In anaesthetized rats, the neurokinin (NK)1 receptor antagonist SR140333 (10-1000 micrograms/kg) stereo-selectively inhibited mustard oil-induced plasma protein extravasation in the dorsal skin of the hind paw. After s.c. administration of SR140333, inhibition of plasma protein extravasation was maximal 3 h after injection. A dose of 0.1 mg/kg i.v. or 1.0 mg/kg s.c. produced long-lasting inhibition which was still significant 24 h after treatment. Since systemic administration of SR140333 has been shown to inhibit nociceptive responses in anaesthetized rats, we wanted to evaluate a possible effect of SR140333 on chemo- and thermonociception in conscious rats. SR140333 (100 micrograms/kg s.c.) did not reduce the behavioral response of rats to the irritant effect of capsaicin in the wiping test, nor did it affect the thermal nociceptive threshold in the plantar test. Furthermore, the decrease in thermal nociceptive threshold which was produced by intraplanter injection of PGE2, and which has been shown to be entirely dependent on capsaicin-sensitive afferents, was not affected by treatment with this NK1 receptor antagonist. These results show that systemic administration of SR140333, at doses which cause inhibition of neurogenic inflammation, has no detectable effect on acute chemo- or thermonociception in conscious rats.

Animals↗

PubMed1995

Mediation by CCKB receptors of the CCK-evoked hyperaemia in rat gastric mucosa.

1. Cholecystokinin octapeptide (CCK-8) and gastrin-17 augment gastric mucosal blood flow in the rat. The present study examined whether the gastric vasodilator effect of these peptides is mediated by CCKA or CCKB receptors. 2. Intravenous injection of CAM-1481 (1 mg kg-1), a dipeptoid antagonist of CCKA receptors, or CAM-1028, a dipeptoid CCKB receptor antagonist (1 mg kg-1), had no effect on basal gastric mucosal blood flow as determined by the clearance of hydrogen in urethane-anaesthetized rats. 3. Intravenous infusion of CCK-8 or gastrin-17 (8-200 pmol min-1) increased gastric mucosal blood flow in a dose-dependent fashion. The CCKB receptor antagonist, CAM-1028, significantly attenuated the hyperaemic response to CCK-8 and gastrin-17 whereas the CCKA receptor antagonist, CAM-1481, did not antagonize CCK-8 but caused a slight attenuation of the vasodilator response to gastrin-17. 4. The selectivity of the two antagonists was proved by the findings that CAM-1028, but not CAM-1481, inhibited gastric acid secretion evoked by CCK-8 or gastrin-17 (CCKB receptor assay) while CAM-1481, but not CAM-1028, inhibited the CCK-8-induced contraction of guinea-pig isolated gall bladder strips (CCKA receptor assay). 5. These data show that the actions of CCK-8 and gastrin-17 to increase mucosal blood flow in the rat stomach are primarily mediated by CCKB receptors.

Animals↗

PubMed1995

Mediation by prostaglandins of the nitric oxide-induced neurogenic vasodilatation in rat skin.

1. Intraplantar administration of the nitric oxide (NO) donor, sodium nitroprusside (SNP), induces hyperaemia in the rat paw skin, which is in part due to release of calcitonin gene-related peptide (CGRP) from afferent nerve fibres. The present study examined whether prostaglandins or other inflammatory mediators participate in the neurogenic vasodilatation caused by SNP. Blood flow in the plantar hindpaw skin of urethane-anaesthetized rats was measured by laser Doppler flowmetry. 2. The hyperaemic responses to intraplantar administration of the NO donors SNP (150 pmol) and 3-morpholino-sydnonimine (SIN-1, 15 nmol) were attenuated by 45% and 61%, respectively, after injection of the CGRP antagonist, CGRP8-37 (50 nmol kg-1, i.v.) which did not significantly change baseline blood flow. 3. The NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 15 mg kg-1, i.v.), the bradykinin antagonist Hoc-140 (100 nmol kg-1, i.v.) and the histamine antagonists, pyrilamine (2 mg kg-1, i.v.) plus cimetidine (10 mg kg-1, i.p.) were without effect on baseline blood flow and the vasodilatation caused by SNP. 4. The cyclo-oxygenase inhibitors, indomethacin (10 mg kg-1, i.p.) and flurbiprofen (5 mg kg-1, i.p.) depressed the SNP-induced hyperaemia by 65% and 42%, respectively, without altering baseline blood flow. The ability of CGRP8-37 to inhibit the vasodilator response to SNP was lost in indomethacin-treated rats. 5. Intraplantar administration of prostaglandin E2 (PGE2, 15 pmol) evoked cutaneous vasodilatation which was attenuated by 66% after administration of CGRP8-37 but remained unaltered by indomethacin or L-NAME. 6. These data indicate that the neurogenic hyperaemia which in rat skin is induced by intraplantar administration of NO donors involves the formation of prostaglandins which in turn cause release of the vasodilator peptide, CGRP, from perivascular afferent nerve fibres.

Animals↗

PubMed1995

Chemosensitive afferent nerves in the regulation of gastric blood flow and protection.

The experimental use of capsaicin has made possible the discovery that chemosensitive neurons participate in the activation of endogenous mechanisms of protection in the face of pending injury to the gastric mucosa. At present, the pathophysiological potential of this neural emergency system is best reflected by the gastric hyperemic response to acid back-diffusion, a response which is signalled to a large degree by peptidergic afferent neurons. There is good evidence that CGRP released from perivascular afferent nerve endings is an important mediator of the acid-induced hyperemia in the rat gastric mucosa. The vasodilator action of CGRP depends on the formation of NO which functions as a second intercellular messenger of the CGRP- induced vasodilatation. The resulting hyperemia acts to limit acid damage to the superficial part of the mucosa. The hyperemic and protective roles of peptidergic sensory neurons have been studied in most detail in the stomach but there is evidence that they play a similar role in the esophagus, duodenum and colon. Further elucidation of this neural emergency system in the digestive system represents an important area for studies into the pathophysiology and management of gastrointestinal mucosal damage.

Afferent Pathways↗

PubMed1995

Substance P stimulates and inhibits intestinal peristalsis via distinct receptors.

The tachykinins substance P (SP) and neurokinin A participate in the neural control of intestinal peristalsis. This study aimed at elucidating the types of tachykinin receptors involved in SP's ability first to stimulate and then to inhibit propulsive activity. Peristalsis in the guinea pig isolated ileum was triggered by fluid-induced distension of the intestinal wall. Unlike SP, the neurokinin (NK)-1 receptor-selective agonist SP methyl ester (1-100 nM) failed to facilitate peristalsis but caused a delayed inhibition of peristaltic activity. In contrast, the NK-2 receptor-selective agonist [beta-Ala8]-NKA-(4-10) (BANKA, 1-100 nM) stimulated, but did not inhibit, peristalsis. The NK-3 receptor-selective agonist succinyl-[Asp6,N-MePhe8]-substance P-(6-11) (SENKTIDE, 0.1-10 nM) was most potent in facilitating propulsive activity, and only with 10 nM SENKTIDE was a delayed inhibition of peristalsis seen. The receptors responsible for the tachykinin-evoked stimulation and inhibition of peristaltic activity were further characterized by use of the NK-1 receptor-selective antagonist (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994, 300 nM) and the NK-2 selective antagonist (-)-N-methyl-N[4-acetylamino-4-phenyl-piperidino-2 (3,4 dichlorophenyl)butyl]-benzamide (SR-48,968, 100 nM). CP-99,994 antagonized the inhibitory effects of SP (100 nM) and SP methyl ester (100 nM) on peristalsis but did not alter the facilitation of propulsive motility brought about by SP or BANKA (100 nM). Conversely, SR-48,968 (100 nM) suppressed the ability of SP and BANKA to stimulate persitaltic activity but did not attenuate the inhibitory motor effects of SP and SP methyl ester.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Vascular bed-dependent roles of the peptide CGRP and nitric oxide in acid-evoked hyperaemia of the rat stomach.

1. Acid back-diffusion through a disrupted gastric mucosal barrier is known to increase gastric mucosal blood flow via a neural mechanism. The present study examined how the acid-evoked change in the gastric microcirculation compares with blood flow changes in the left gastric artery, one of the major arteries supplying the stomach, and whether the dilator mediators in the left gastric artery are identical to those in the gastric mucosa. 2. The experiments were performed on rats anaesthetized with urethane. Blood flow in the left gastric artery was measured by the ultrasonic transit time shift technique, and blood flow in the gastric mucosa was assessed by the hydrogen gas clearance method. 3. Gastric acid back-diffusion evoked by perfusion of the stomach with 15% ethanol in 0.15 M HCl increased blood flow in the left gastric artery by a factor of 4.7, which was significantly larger than the 2.9-fold increase in blood flow through the gastric mucosa. Blood pressure and heart rate were not altered appreciably. 4. The acid-evoked hyperaemia in the left gastric artery was left unaltered by atropine and the substance P receptor antagonist RP-67580. 5. The calcitonin gene-related peptide (CGRP) antagonist CGRP (8-37) had no effect on gastric blood flow but prevented the dilator action of CGRP and inhibited the acid-evoked hyperaemia in the gastric mucosa to a larger degree than the hyperaemia in the left gastric artery. 6. Blockade of nitric oxide synthesis by N omega-nitro-L-arginine methyl ester (L-NAME) caused constriction of the left gastric artery and the gastric mucosal microvessels. The acid-evoked vasodilatation in the gastric mucosa was blocked by L-NAME, whereas the dilator response in the left gastric artery was not significantly depressed. 7. The data show that the gastric hyperaemic response to acid back-diffusion results from dilatation of mucosal microvessels and extramural arteries. The dilator mechanisms, however, differ between the two vascular beds. CGRP and nitric oxide are important vasodilator mediators in the gastric mucosa but are of less relevance in the left gastric artery.

Animals↗

PubMed1994

Nitric oxide mediates the amplification by interleukin-1 beta of neurogenic vasodilatation in the rat skin.

Blood flow in the plantar hindpaw skin of anaesthetized rats was measured by laser Doppler flowmetry. Intraplantar injection of interleukin-1 beta (50 pg) significantly enhanced the hyperaemic response to intraplantar capsaicin (0.3 microgram). Pretreatment with a neurotoxic dose of capsaicin reduced the capsaicin-evoked hyperaemia and prevented the facilitatory effect of interleukin-1 beta. Blockade of nitric oxide formation by NG-nitro-L-arginine methyl ester failed to affect the capsaicin-evoked vasodilatation but abolished its amplification by interleukin-1 beta. These data indicate that the enhancement by interleukin-1 beta of the capsaicin-induced hyperaemia involves thin afferent nerve fibres and depends on nitric oxide as essential intermediate.

Animals↗

PubMed1994

Pharmacological profile of selective muscarinic receptor antagonists on guinea-pig ileal smooth muscle.

The present study examined the effects of a series of tricyclic muscarinic receptor antagonists on muscarinic receptors present in the guinea-pig ileum, both in vitro and in vivo. The selectivity profiles of these antagonists and that of atropine were determined by their affinity for cortical muscarinic M1, cardiac M2 and submandibular M3 receptors and for m4 receptors expressed in CHO cells. The compounds pirenzepine, UH-AH 37, AQ-RA 391 and AQ-RA 618 possessed high affinity (pKi 7.94-8.22) for muscarinic M1 receptors. Pirenzepine exhibited the most pronounced muscarinic M1 selectivity. AF-DX 384 and AQ-RA 741 possessed an approximately 10-fold higher affinity for the cardiac muscarinic M2 receptor than AF-DX 116. However, both compounds also exhibited high affinity for muscarinic m4 receptors. High affinity for muscarinic M3 and m4 receptors was observed for UH-AH 37, AQ-RA 391 and AQ-RA 681. The antagonists were then tested for their interaction with the muscarinic receptors which are responsible for the methacholine-induced contraction of longitudinal muscle in vitro, circular muscle in vivo and muscarinic receptors which mediate the distension-evoked ascending reflex contraction of circular muscle in vitro. Compounds showing high affinity for muscarinic M3 receptors (e.g. AQ-RA 618) were the most potent antagonists in the functional experiments. Comparison of the binding displacement data with the functional results indicates that the effects of methacholine on the longitudinal and circular muscle of the guinea-pig ileum were predominantly mediated by muscarinic M3-type receptors. In contrast, the correlation between muscarinic M2 receptor affinity and antagonism of muscarinic receptors in the ileum was very weak.

Animals↗

PubMed1994

Synergistic role of muscarinic acetylcholine and tachykinin NK-2 receptors in intestinal peristalsis.

It is known that tachykinins (substance P, neurokinin A) participate in the excitatory neural pathways subserving peristaltic motor activity in the intestine. The aim of the present study was to elucidate the types of tachykinin receptor (NK-1 or NK-2) involved in peristalsis by the use of receptor subtype-selective antagonists. Peristaltic motility in isolated segments of the guinea-pig ileum was induced by pumping fluid into the oral end of the intestinal segment. By way of the intraluminal pressure the compliance of the intestinal wall during the preparatory phase and the pressure threshold to trigger the emptying phase of peristalsis were recorded. The tachykinin antagonists were used at concentrations that were at least 30 times in excess of the equilibrium dissociation constants which had previously been evaluated with receptor subtype-selective agonists on the guinea-pig ileum circular muscle. The NK-1 selective antagonist CP-96,345 (0.3 microM) had a slight stimulant influence on peristalsis, whereas the NK-2 selective antagonists MEN-10,376 (10 microM), GR-94,800 (0.3 microM) and SR-48,968 (0.1 microM) led to a small inhibition of motor activity. However, when given after exposure of the ileum to a threshold concentration of atropine (5-20 nM) causing little depression of peristalsis, the tachykinin NK-2 receptor antagonists invariably abolished peristalsis. This synergistic interaction was not seen when SR-48,968 was administered after the ileal segments had been exposed to concentrations of hexamethonium, isoproterenol or calcitonin gene-related peptide that by themselves caused a slight inhibition of peristalsis only.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Effect of omega-conotoxin on cholinergic and tachykininergic excitatory neurotransmission to the circular muscle of the guinea-pig colon.

The aim of this study was to compare the stimulus-response characteristics of the cholinergic and tachykininergic excitatory transmission to the circular muscle of the guinea-pig proximal colon and their susceptibility to inhibition by the N-type calcium channel blocker omega-conotoxin (CTX). All experiments were performed in the presence of guanethidine (3 microM), indomethacin (10 microM), L-nitroarginine (L-NOARG, 30 microM) and apamin (0.1 microM). In the presence of the tachykinin receptor antagonists, FK 888 (10 microM0 and GR 94,800 (3 microM), to block NK1 and NK2 receptors, respectively, electrical field stimulation (EFS) produced frequency-dependent atropine- (1 microM) sensitive contractions. In the presence of atropine (1 microM), EFS produced tachykininergic contractions which were abolished by the combined administration of FK 888 (10 microM) and GR 94,800 (3 microM). The maximal responses produced by cholinergic and tachykininergic neurotransmission ranged between 80 and 100% of the maximal contractile response to 80 mM KCl. The frequency of stimulation, pulse width and voltage required to produce 50% of the maximal cholinergic and tachykininergic contraction were not different from each other, although cholinergic transmission appeared more efficient in producing twitch contractions in response to single pulse EFS. Furthermore, cholinergic transmission was more efficient than tachykininergic transmission in producing contraction in response to short periods of EFS. CTX (0.1 microM for 30 min) produced a large and comparable rightward shift of the cholinergic and tachykininergic frequency-response curve (19 and 17 fold increase in the frequency of stimulation producing 50% of the maximal response, respectively) and markedly depressed (51 and 43% inhibition, respectively) the maximal concentrations response.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1994

Tachykinin NK1 and NK2 receptor antagonists and atropine-resistant ascending excitatory reflex to the circular muscle of the guinea-pig ileum.

1. The aim of this study was to investigate the effect of various antagonists, selective for the tachykinin NK1 or NK2 receptor, on the atropine-resistant ascending excitatory reflex (AER) to the circular muscle of the guinea-pig ileum elicited by radial stretch (balloon distension) or electrical field stimulation. 2. Submaximal and maximal atropine- (1 microM) resistant AER elicited by balloon distension averaged about 40-50% and 70-90% of maximal circular spasm to 80 mM KCl, respectively. The NK1 receptor antagonist, (+/)-CP 96,345 (1 microM) inhibited both maximal and submaximal AER. FK 888 (1-3 microM) inhibited submaximal AER only. RP 67,580 (1 microM) was ineffective. The NK2 receptor antagonist, GR 94,800, inhibited both maximal and submaximal AER at all concentrations tested (0.1-3.0 microM), while SR 48,968 was effective only at 1.0 microM. The NK2 receptor antagonists, MEN 10,376 and MEN 10,573 inhibited both submaximal and maximal AER at 10 and 1.0 microM, respectively. 3. In other experiments, an NK1 receptor antagonist, (+/-)-CP 96,345 or FK 888 (1.0 microM in each case) was administered first and the effect of GR 94,800 (1.0 microM) on the residual AER response was determined; or GR 94,800 was administered first and the effect of (+/-)-CP 96,345 or FK 888 was determined. The results of these experiments indicated an additive effect produced by the combined treatment with NK1 and NK2 receptor antagonists. 4. Electrical field stimulation (10 Hz for 0.5 s, 10-20 V, 0.15-0.3 ms pulse width) with electrodes placed at 1.4-1.8 cm anal to the recording site, produced ascending contractions which were almost abolished by 10 MicroM hexamethonium (electrically-evoked AER). In the presence of apamin (0.1 MicroM) and N0-nitro-L-arginine (30 MicroM) these contractions were reproducible over 10 consecutive stimulation cycles.GR 94,800 (1 MicroM) and FK 888 (1 MicroM) both produced a partial inhibition of the electrically-evoked AER and their combined administration produced an inhibitory effect which was larger than that induced by each antagonist alone.5. FK 888 (1-3 MicroM), GR 94,800 (1-3 MicroM), MEN 10,573 (1 MicroM) and MEN 10,376 (10 MicroM) did not significantly affect the atropine-sensitive twitch contractions produced by electrical field stimulation of the guinea-pig ileum longitudinal muscle-myenteric plexus preparation, which were abolished by 10-30 MicroM procaine, 1 MicroM tetrodotoxin or 1 MicroM atropine. (+/-)-CP 96,345 (1 MicroM) and SR 48,968 (1 ILM)produced 12% and 27% inhibition of cholinergic twitches in the longitudinal muscle of the ileum,respectively.6. We conclude that both NK1 and NK2 receptors mediate the atropine-resistant AER to the circular muscle of the ileum. NK2 receptor activation plays a more important role than NK1 receptor activation in the AER evoked by radial stretch. Since a consistent fraction of the distension- and electrically evoked atropine-resistant AER persists in the presence of combined NK1 and NK2 receptor blockade,the existence of a third excitatory transmitter to the circular muscle of the ileum, in addition to acetylcholine and tachykinins, is suggested.

Animals↗

PubMed1994

Cutaneous vasodilatation induced by nitric oxide-evoked stimulation of afferent nerves in the rat.

1. The site of action at which nitric oxide (NO) may contribute to neurogenic vasodilatation in the hindpaw skin of urethane-anaesthetized rats was examined by the use of NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase. 2. Skin blood flow was measured by laser Doppler flowmetry, and neurogenic vasodilatation was evoked either by topical application of mustard oil (5%) or antidromic electrical stimulation of the saphenous nerve (antidromic vasodilatation). 3. L-NAME (60 mumol kg-1, i.v.) attenuated the hyperaemia evoked by mustard oil in an enantiomer-specific manner but failed to reduce antidromic vasodilatation and the vasodilatation due to i.v. injected calcitonin gene-related peptide (CGRP) and substance P (0.1-1 nmol kg-1 each), two proposed mediators of neurogenic vasodilatation. 4. Pretreatment of rats with capsaicin (125 mg kg-1, s.c. 2 weeks beforehand), to defunctionalize afferent neurones, reduced the hyperaemic response to mustard oil and prevented L-NAME from further decreasing the vasodilatation evoked by mustard oil. 5. Intraplantar infusion of sodium nitroprusside (SNP, 0.15 nmol in 1 min), a donor of NO, induced hyperaemia which was significantly diminished by the CGRP antagonist CGRP8-37 (50 nmol kg-1, i.v.) and by capsaicin pretreatment. The ability of CGRP8-37 to inhibit the vasodilator response to SNP was lost in capsaicin-pretreated rats. 6. Taken together, these data indicate that NO does not play a vasorelaxant messenger role in neurogenic vasodilatation but can contribute to activation of, and/or transmitter release from, afferent nerve fibres in response to irritant chemicals.

Animals↗

PubMed1994

Interleukin-1 beta enhances capsaicin-induced neurogenic vasodilatation in the rat skin.

1. This study examined the effect of interleukin-1 beta (IL-1 beta) on the capsaicin-induced increase in cutaneous blood flow of anaesthetized rats as measured by laser Doppler flowmetry. 2. The substances were administered by intraplantar subcutaneous injection of 10 microliters-volumes, saline being injected into one hindpaw and IL-1 beta into the other. 3. IL-1 beta (0.5-500 pg) was without effect on blood flow on its own but dose-dependently enhanced the hyperaemic response to intraplantar capsaicin (0.3 microgram) up to 180% (P < 0.05) of the response seen in saline-treated paws. 4. Il-1 beta-(163-171), a fragment devoid of proinflammatory activity, failed to enhance capsaicin-induced hyperaemia when given at a dose of 50 pg. 5. Indomethacin (10 mg kg-1, i.p.) did not alter the capsaicin-induced vasodilatation but prevented IL-1 beta (50 pg) from augmenting the hyperaemic response to capsaicin. 6. The hyperaemia evoked by intraplantar calcitonin gene-related peptide (0.038-3.8 ng) was not altered by IL-1 beta (50 pg). 7. These data indicate that IL-1 beta enhances the cutaneous hyperaemic response to afferent nerve stimulation with capsaicin in a prostaglandin-dependent manner. This proinflammatory action of the cytokine appears to arise from sensitization of afferent nerve endings.

Animals↗

PubMed1994

Role of bradykinin in the hyperaemia following acid challenge of the rat gastric mucosa.

1. This study examined whether the hyperaemia following acid challenge of the rat gastric mucosa involves bradykinin, a peptide formed in response to tissue injury. 2. Gastric mucosal blood flow in urethane-anaesthetized rats was assessed by the hydrogen gas clearance method. Infusion of a bradykinin solution (10 microM) into the gastric wall augmented gastric mucosal blood flow by a factor of 2.3, an effect that was prevented by the bradykinin B2 antagonist Hoe-140 (icatibant; 100 mumol kg-1, i.v.). 3. I.V. injection of bradykinin (20-60 nmol kg-1) caused a 2.3-3.5 fold increase in blood flow through the left gastric artery as measured by the ultrasonic transit time shift technique. The hyperaemic effect of bradykinin in this gastric artery was also prevented by Hoe-140 (100 mumol kg-1, i.v.). 4. Gastric acid back diffusion was evoked by perfusing the stomach with 15% ethanol, to break the gastric mucosal barrier, in the presence of luminal acid. Depending on the concentration of acid (0.05 and 0.15 M HCl), this procedure increased gastric mucosal blood flow by a factor of 1.6-2.8 and caused formation of gross damage in 1.5-3% of the glandular mucosa. Hoe-140 (100 mumol kg-1, i.v.) failed to alter the moderate vasodilatation seen in the presence of 0.05 M HCl but significantly (P < 0.05) attenuated the marked hyperaemia and enhanced the gross mucosal damage observed in the presence of 0.15 M HCl. 5. These data show that bradykinin is able to enhance gastric mucosal blood flow via activation of B2 receptors. It appears as if this kinin is formed during severe acid challenge of the rat gastric mucosa and participates in the hyperaemic reaction to gastric acid back diffusion.

Animals↗

PubMed1994

Reduced endogenous nitric oxide in the exhaled air of smokers and hypertensives.

We wanted to determine whether the production of endogenous nitric oxide (NO) is affected by cigarette smoking and various pathological conditions. Endogenously produced NO was measured by chemiluminescence in the exhaled air of 81 healthy volunteers (21 nonsmoking females (NSF), 12 smoking females (SF), 24 nonsmoking males (NSM) and 24 smoking males (SM)) and 38 patients (10 with hypertension, 10 intra- and 10 postoperative, 5 with renal failure and 3 with sepsis) entered the protocol. Subjects inspired from a NO-free air supply, which was also used to calibrate the NO-analyser. Endogenous NO production of volunteers was 18 +/- 8 per billion (ppb) depending on smoking habits. In exhaled air of NSF, NO concentration was 21 +/- 7 ppb, in SF 16 +/- 6 ppb, in NSM 19 +/- 8 ppb and in SM 15 +/- 6 ppb. Differences between smokers and nonsmokers were significant. Increased diastolic blood pressure was noted in SM compared to NSM (86 +/- 7 versus 78 +/- 7 mmHg). Patients with documented and treated hypertension (systolic and diastolic blood pressure: 141 +/- 18 and 82 +/- 9 mmHg) exhaled 13.7 +/- 5.3 ppb NO; hypertensive males 10 +/- 2 ppb NO and females 17 +/- 5 ppb NO. In patients with renal failure NO concentration in exhaled air was 20.2 +/- 6.8 ppb before and 19.8 +/- 6.4 ppb one hour after the onset of dialysis. In patients undergoing major surgery NO concentration was 5.6 +/- 2.5 ppb intra- and 10.3 +/- 3.5 ppb postoperatively. In three mechanically ventilated patients with documented septic syndrome, exhaled NO was 29.3 +/- 24 ppb.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗