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ABSTRACT: Functional innervation of the human small intestine may be different from that of experimental animals. These experiments set out to assess the mediating roles of P(2) purinoceptors in the non-adrenergic, non-cholinergic (NANC) relaxation of the human ileum longitudinal and circular muscles.
In organ bath experiments NANC relaxations were evoked by electrical field stimulation (EFS). The relaxant effects of ATP and sodium nitroprusside were also examined.
In the longitudinal muscle, relaxation in response to EFS (2 or 10 Hz for 30 s) or the relaxant effect of exogenous ATP were strongly inhibited or abolished, respectively, by the P(2) purinoceptor antagonist MRS 2179 (10 microM). MRS 2179 had a smaller effect at 3 microM. The NANC relaxation was also inhibited by apamin (3 microM), but not by N(G)-nitro-L-arginine (100 microM), an inhibitor of nitric oxide synthesis. Both apamin (3 microM) and MRS 2179 (3 microM, a concentration below the effective range if administered alone) strongly inhibited the NANC response in preparations pretreated with the nitric oxide synthase inhibitor. NANC relaxations of the circular muscle were also inhibited by MRS 2179 (3-10 microM).
MRS 2179-sensitive P(2) purinoceptors play a mediating role the NANC relaxation in the ileal longitudinal and circular muscle. There seems to be a supra-additive relationship between the purinergic and nitrergic mechanisms in the longitudinal muscle.
Life sciences 05/2009; 84(25-26):871-5. · 2.56 Impact Factor
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ABSTRACT: There has been no direct functional evidence for a purinergic innervation of the human intestinal muscle. In the present study, the relaxant effects of electrical field stimulation (1 or 10 Hz for 20s), ATP, and isoprenaline were studied in organ bath experiments on precontracted circular muscle strips of the human ileum. Non-adrenergic, non-cholinergic relaxations in response to electrical field stimulation in the presence of a nitric oxide synthase inhibitor were significantly reduced by the P(2) purinoceptor antagonists pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS; 50 microM) or suramin (100 microM). A combination of the two antagonists yielded an approximately 70% inhibition at 1 Hz. The relaxant effect of exogenous ATP, but not that of isoprenaline, was inhibited by PPADS+suramin. It is concluded that purinergic nerves (through P(2) purinoceptors) play a mediating role in the non-nitrergic relaxation in the human ileum.
Brain Research Bulletin 01/2007; 71(1-3):242-4. · 2.82 Impact Factor
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ABSTRACT: The transmitters involved in the non-nitrergic component of the non-adrenergic, non-cholinergic (NANC) inhibitory response of the rat small intestinal longitudinal muscle to electrical field stimulation of its nerves is a matter of controversy. The present study is the first one to utilise a combination of a nitric oxide synthase inhibitor and a P(2) purinoceptor antagonist for studying this response. We found that the P(2) purinoceptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS; 5x10(-5) M) abolished the non-nitrergic NANC relaxation to electrical field stimulation (10 Hz). PPADS alone provided a significant, moderate inhibitory action. PPADS specifically inhibited relaxations due to exogenous adenosine 5'-triphosphate (ATP) or alpha,beta-methylene ATP. The guanylate cyclase blocker 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 10(-6) M) did not add to the inhibitory action of N(G)-nitro-L-arginine on field stimulation-induced relaxation. ODQ abolished the relaxant effect of the nitric oxide donors nitroglycerin or sodium nitroprusside. These data indicate that: (1) nitric oxide and ATP fully account for the field stimulation-induced relaxation in the rat ileal strip under the experimental conditions of this study, and (2) no ODQ-sensitive guanylate cyclase-mediated mechanism is involved in the non-nitrergic component of the NANC relaxation.
Archiv für Experimentelle Pathologie und Pharmakologie 08/2006; 373(4):319-24. · 2.65 Impact Factor
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ABSTRACT: Adenosine 5'-triphosphate (ATP) may be an important neurotransmitter in the gastrointestinal tract. The present study examined the motor effects of exogenous ATP on longitudinally-oriented preparations of the guinea-pig isolated ileum and the influence of drugs on the ATP-induced responses. High micromolar concentrations of ATP caused two types of contraction, a phasic, cholinergic response and a tonic, tetrodotoxin-resistant contraction. The phasic contraction was reduced by hexamethonium (5x10(-5) M), but left uninfluenced by capsaicin tachyphylaxis or tachyphylaxis to alpha,beta-methylene ATP. The tonic response was resistant to atropine, hexamethonium, capsaicin, omega-conotoxin GVIA, or pretreatment with alpha,beta-methylene ATP. Both types of ATP-induced contraction were diminished or abolished by the P2 purinoceptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS, 3x10(-6) and 3x10(-5) M, respectively). In the precontracted, atropine-treated ileum ATP (10(-6)-10(-4) M) caused guanethidine-resistant relaxation. This response was not influenced by tetrodotoxin, omega-conotoxin GVIA, or NG-nitro-L-arginine, but was abolished by apamin (10(-7) M), and inhibited by PPADS (3x10(-5) M) or reactive blue 2 (10(-5) M), in a surmountable manner. A high degree of tachyphylaxis was observed with the relaxant effect of ATP (10(-5)-10(-4) M). A high concentration (3x10(-4) M) of PPADS failed to influence ileum contractions to exogenous acetylcholine or histamine. It is concluded that, in addition to its direct contractile action in the guinea-pig ileum, ATP can activate (partly preganglionic) cholinergic neurones, an effect whose mechanism is largely different from that of alpha,beta-methylene ATP. ATP also causes relaxation by a direct, probably P2Y-receptor-mediated effect on the smooth muscle. All motor effects of ATP are inhibited by the antagonist PPADS.
Basic & Clinical Pharmacology & Toxicology 06/2006; 98(5):488-95. · 2.18 Impact Factor
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ABSTRACT: It has been well established that visceral hyperesthesia plays a role in the development of irritable bowel syndrome (IBS).
1. to detect the possible changes of visceral perception in different subtypes of IBS patients, 2. to analyze the difference of visceral hyperaesthesia in different subtypes of IBS, 3. to examine whether distension protocols (e.g. phasic or ramp distension) has any influence on sensory thresholds, 4. to analyze the differences of perception thresholds produced by phasic or ramp distension in different subtypes of IBS.
10 patients having colorectal polypectomy (control group) and 40 IBS patients were studied. The diagnosis was based on the Rome-II criteria. Diarrhoea-predominant, alternating and constipation-predominant subtypes were determined by the Talley bowel habit questionnaire. Sensory thresholds were detected by semi random ascending phasic and ramp rectosigmoid distension. Rectal dynamic compliance was calculated by using the dV/dP ratio.
1. The pain thresholds determined by phasic distension were significantly lower in all subtypes of IBS. 2. Increased thresholds for pain were found in almost half of constipation-predominant IBS patient determined by ramp distension. Thus two distinct subgroups could be found based on the findings of ramp distension: a normosensitive and a hyposensitive group. 3. Rectal dynamic compliance was significantly higher both in the constipation-predominant and alternating subtype of IBS patients.
Visceral hyperesthesia can be detected in all types of IBS. Tolerance to physiologic stimuli could be observed in constipating IBS patients that is not related to the increase of rectal compliance.
Orvosi Hetilap 04/2006; 147(9):421-6.
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ABSTRACT: The aim of the present study was to assess the acute motility effects and desensitizing activity of the stable ATP analogue and P(2X) purinoceptor agonist alpha,beta-methylene ATP (alpha,beta-meATP) and the effect of alpha,beta-meATP desensitization on nerve-mediated cholinergic responses in the guinea-pig ileum in vitro. It was confirmed that alpha,beta-meATP (1-30 microM) causes neurally-mediated, cholinergic (tetrodotoxin- and atropine-sensitive) longitudinal contractions. These responses were not influenced by the ganglionic blocking drug hexamethonium (50 microM), or a combination of the adrenergic neurone blocking drug guanethidine (3 microM), the opioid receptor antagonist naloxone (0.5 microM) and the nitric oxide synthase inhibitor N(G)-nitro-L-arginine (L-NOARG; 100 microM), but were strongly reduced or abolished by the P2 purinoceptor antagonist PPADS (30 microM) or by tachyphylaxis evoked by 10 microM alpha,beta-meATP. The contractile effect of alpha,beta-meATP (3 microM) was moderately inhibited by 10 microM and strongly suppressed by 30 microM of NF 279, an antagonist predominantly affecting P2X1 purinoceptors, but left uninfluenced by the P2X(5,7) receptor antagonist Brilliant blue G. No relaxant effect of alpha,beta-meATP was detected in the concentration range of 1-30 microM. Tachyphylaxis to alpha,beta-meATP (1-10 microM) caused a moderate inhibition of the cholinergic (atropine-sensitive) contractile response of the ileum to electrical field stimulation (5 Hz for 5 sec.). This reduction was unaltered in the presence of guanethidine, naloxone and L-NOARG. Responses to nicotine (1 or 2 microM) were not reduced by alpha,beta-meATP tachyphylaxis. It is suggested that alpha,beta-meATP-sensitive P(2X) purinoceptors are involved in the prejunctional modulation of cholinergic neurotransmission between the myenteric plexus and longitudinal smooth muscle in the guinea-pig small intestine.
Basic & Clinical Pharmacology & Toxicology 01/2006; 97(6):369-73. · 2.18 Impact Factor
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ABSTRACT: Moderate concentrations of the sensory stimulant drug capsaicin caused relaxation in human and animal intestinal circular muscle preparations (guinea-pig proximal, mouse distal colon, human small intestine and appendix) in vitro. With the exception of the guinea-pig colon, the nitric oxide (NO) synthase inhibitor N(G)-nitro-L-arginine (L-NOARG; 10(-4) M) strongly inhibited the relaxant effect of capsaicin. Tetrodotoxin, an inhibitor of voltage-sensitive Na+ channels failed to significantly reduce the inhibitory effect of capsaicin in the guinea-pig colon, human ileum and appendix; it caused an approximately 50% reduction in the mouse colon. The relaxant effect of capsaicin was strongly reduced in colonic preparations from transient receptor potential vanilloid type (TRPV1) receptor knockout mice as compared to their wildtype controls. It is concluded that nitric oxide, possibly of sensory origin, is involved in the relaxant action of capsaicin in the circular muscle of the mouse and human intestine.
Life Sciences 05/2005; 76(24):2773-82. · 2.53 Impact Factor
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Lorand Barthó,
Rita Benkó,
Riccardo Patacchini,
Gabor Pethö,
Ulrike Holzer-Petsche,
Peter Holzer,
Zsofia Lázár, Sarolta Undi,
Laszlo Illényi,
Andras Antal,
Ors-Peter Horváth
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ABSTRACT: 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.
European Journal of Pharmacology 11/2004; 500(1-3):143-57. · 2.52 Impact Factor
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ABSTRACT: A vállalt munka fő céljai: Izolált szervi kísérletekben megismerni a zsigerek mozgásválaszainak mechanizmusait, az állatokon kapott eredményeket humán preparátumokkal összevetve. Szenzoros és más eredetű nem-adrenerg, nem-kolinerg (NANC) transzmitterek azonosítása (funkcionális vizsgálatok és a transzmitter-felszabadulás mérése). Kóros zsigeri működések modellezése. (Egyes irányokban komplett, másokban tájékozódó kísérletek). Közölt eredmények: Új humán adatok közlése mellett összefoglaltuk a kapszaicin zsigeri hatásaival, transzmittereivel kapcsolatos jelentősebb eredményeket. Alappal fölvetettük annak lehetőségét, hogy emberben?és bizonyos állatfajokban is?az NO szenzoros transzmitter (Barthó et al. 2004?Eur J Pharmac; Benkó et al. 2005?Life Sci). Mind állati, mind (világelsőként) humán GI preparátumokban bizonyítottuk az ATP közvetítő szerepét NANC válaszokban (Undi et al. 2005?Bas Clin Pharmac; 2006?Brain Res Bull; Benkó et al 2006?NS Arch Pharmac, 2007?Neurosci). Nem találtunk bizonyítékot VIP szerepére emberi bél kapszaicinnel kiváltott gátló válaszában, a CO szerepére perisztaltikus reflexben (kongresszusi közlés), ill a CO szerepére a NANC gátló válaszban állati és humán GI preparátumokon (ld. fenti közlemények). Közlésre vár: P-anyag és CGRP-IR felszabadulás bélből; szenzoros izgató mustárolaj és H2S hatásmechanizmusa; a passzív szenzibilizáció/antigén-expozíció hatásainak elemzése állati és emberi GI és légúti simaizomzaton stb. | Aims of the project Experiments on isolated tissues for elucidating the mechanisms behind some evoked movements of viscera of animals and man. Identifying sensory and other non-adrenergic, non-cholinergic (NANC) transmitters. Measuring neurotransmitter release. Modelling pathophysiological processes of viscera. (Planned were complete series of experiments in some and pilot experiments in other directions.) Published results Review, containing original results, on visceral effects of capsaicin and the transmitters thereof. Providing indirect evidence that NO is a sensory neurotransmitter (Bartho et al. 2004?Eur J Pharmac; Benko et al. 2005?Life Sci). Proving the presence of purinergic innervation of human (Undi et al. 2006?Brain Res Bull; Benko et al. 2007?Neurosci) and rat intestine (Benko et al. 2006?NS Arch Pharmac). No evidence for a mediating role of VIP in the inhibitory effect of capsaicin in the human gut, a role of CO in the peristaltic reflex (congress presentations) or in the evoked NANC relaxation in animal or human GI preparations (papers as above). To be published Release of substance P- or CGRP-like IR from the gut; mechanisms of action of the sensory stimulants mustard oil and H2S; effects of passive sensitization/antigen exposure on GI and respiratory smooth muscles of animals and man, etc.
