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Inhibitory neurotransmission in lower oesophagus

Ny, Lars (1996)
Abstract (Swedish)
Popular Abstract in Swedish

Regleringen av esofagus och den nedre esofagussfinkterns motilitet har rönt intresse på grund av dess betydelse vid vissa sjukdoms-tillstånd såsom gastroesofageal reflux och akalasi. Den nedre esofagussfinktern har vidare använts som modell för farmakologiska och fysiologiska studier av viss typ av autonom neurotransmission, s k icke-adrenerg, icke-kolinerg (NANC) neurotransmission.



Esofagus väsentliga funktion är att fungera som ett transportrör för föda från munhåla till magsäck. Transporten av födan medieras genom ett komplext samspel av kontraktioner och relaxationer i esofagus-muskulaturen. Esofagus motilitet står under en välutvecklad nervös kontroll. I de nedre, glatt... (More)
Popular Abstract in Swedish

Regleringen av esofagus och den nedre esofagussfinkterns motilitet har rönt intresse på grund av dess betydelse vid vissa sjukdoms-tillstånd såsom gastroesofageal reflux och akalasi. Den nedre esofagussfinktern har vidare använts som modell för farmakologiska och fysiologiska studier av viss typ av autonom neurotransmission, s k icke-adrenerg, icke-kolinerg (NANC) neurotransmission.



Esofagus väsentliga funktion är att fungera som ett transportrör för föda från munhåla till magsäck. Transporten av födan medieras genom ett komplext samspel av kontraktioner och relaxationer i esofagus-muskulaturen. Esofagus motilitet står under en välutvecklad nervös kontroll. I de nedre, glatt muskel försedda, delarna av esofagus anses intramuralt förlagda nervplexus i esofagus-väggen vara av huvudsaklig betydelse för motilitets-kontrollen. De nerver som styr kontraktion av den glatta muskulaturen använder sig av acetylkolin som signalsubstans. Den signalsubstans som används av de NANC-nerver som styr relaxation av glatt muskulatur har emellertid ej kunnat fastställas. Vissa neuropeptider, exempelvis vasoaktiv intestinal peptid (VIP), har framförts som möjliga kandidater. I slutet av 1980-talet kunde man visa att gasen kväveoxid sannolikt fungerar som signalsubstans i vissa experimentella modeller för studier av NANC neurotransmission.



I denna studie, på vävnad från människa och katt, har den inhibitoriska motilitets-kontrollen av esofagus undersökts med morfologiska, funktionella och biokemiska tekniker, i syfte att klarlägga de signalsubstanser och intracellulära signalöverföringsvägar som är involverade i den inhibitoriska regleringen av esofagus motilitet.



Med konventionell immunohistokemi och konfokal laser scanning mikroskopi kunde en riklig distribution av nervcellkroppar, lokaliserade i nervplexus, och enskilda nerver, påvisas. Den högsta nervtätheten observerades i området runt den nedre esofagussfinktern. De olika typerna av nervstrukturer innehöll ofta kväveoxidsyntas (kväveoxid producerande enzym), haem oxygenas-2 (kolmonoxid producerande enzym), VIP och pituitary adenylate cyclase activating peptide (PACAP; en peptid i VIP familjen). Ibland förekom kväveoxidsyntas, haem oxygenas-2, VIP och PACAP var för sig, ibland inom samma nervstruktur.



I funktionella experiment inducerade elektrisk nervstimulering en relaxation av den glatta muskulaturen, vilken kunde blockeras av kväveoxid-syntes hämmare och ånyo framkallas genom behandling med aminosyran L-arginin. Relaxationen av den glatta muskulaturen åtföljdes av en ökad koncentration av cykliskt GMP i vävnaden, men utan förändring av cykliskt AMP koncentrationen. Även en icke kväveoxid-medierad relaxation kunde demonstreras med elektrisk nervstimulering eller genom exponering för ett spindelgift, alpha-latrotoxin. Denna icke kväveoxid medierade relaxation medförde ej några förändringar av cykliskt GMP eller cykliskt AMP koncentrationerna i vävnaden, men kunde däremot hämmas genom att behandla vävnaden med VIP-antikroppar.



Exogent tillfört kväveoxid eller kolmonoxid inducerade koncentrations-beroende relaxationer, vilka ökade cykliskt GMP koncentrationen i vävnaden. VIP och PACAP, inducerade koncentrations-beroende relaxationer, vilka ökade cykliskt AMP koncentrationen. I glatt muskulatur från esofagus reducerade kväveoxid-syntes hämmare latensperioden och ökade amplituden hos kontraktioner erhållna vid elektriskt nervstimulering. Kväveoxid-syntes hämmare blockerade också relaxationer inducerade genom elektrisk nervstimulering i kontraherade preparat av glatt muskulatur från esofagus. Kväveoxid, VIP och alpha-latrotoxin producerade alla en hyperpolarisation av celler från glatt muskulatur i esofagus. I kattvävnad kunde kväveoxidsyntas och haem oxygenas aktivitet demonstreras. I kattvävnad var VIP koncentrationerna 50-faldigt högre än PACAP, i human vävnad var den 10-faldigt högre.



Dessa resultat påvisar en viktig roll för kväveoxid-systemet i motilitets-regleringen av esofagus och dess nedre sfinkter hos människa och katt. Även en signalöverföringsväg icke medierad av kväveoxid är närvarande, vilken möjligen involverar kolmonoxid, VIP och/eller PACAP. (Less)
Abstract
The inhibitory neuromuscular control of the human and cat lower oesophagus was investigated by morphological, functional, and biochemical methods. A supply of nerve fibres and myenteric cell bodies, containing nitric oxide synthase (NOS), haem oxygenase (HO)-2, vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase activating peptide (PACAP) was observed. The highest density of nerves was seen at the oesophagogastric junction area with an abundace in the circular muscle layer. As judged by confocal microscopy, NOS, HO-2, VIP and PACAP were frequently colocalized within the same nerve structures.



In circular smooth muscle strips from the lower oesophageal sphincter (LOS), electrical field stimulation (EFS)... (More)
The inhibitory neuromuscular control of the human and cat lower oesophagus was investigated by morphological, functional, and biochemical methods. A supply of nerve fibres and myenteric cell bodies, containing nitric oxide synthase (NOS), haem oxygenase (HO)-2, vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase activating peptide (PACAP) was observed. The highest density of nerves was seen at the oesophagogastric junction area with an abundace in the circular muscle layer. As judged by confocal microscopy, NOS, HO-2, VIP and PACAP were frequently colocalized within the same nerve structures.



In circular smooth muscle strips from the lower oesophageal sphincter (LOS), electrical field stimulation (EFS) induced nerve-mediated relaxations that were abolished by the nitric oxide (NO) synthesis inhibitor NG-nitro-L-arginine (L-NOARG). The response was prevented and partially restored by L-arginine, but not by D-arginine. The relaxation was associated with an increase in cyclic GMP levels. A L-NOARG resistant relaxation could be induced, electrically or by the spider venom alpha-latrotoxin, which was not associated with changes in cyclic GMP or cyclic AMP levels, but inhibited by VIP-antiserum. The HO inhibitors, zinc protoporphyrin-IX or tin protoporphyrin-IX did not affect EFS induced relaxations. NO and carbon monoxide (CO) induced concentration-dependent relaxations associated with an increase of cyclic GMP levels, whereas VIP and PACAP induced concentration-dependent relaxations associated with an increase in cyclic AMP levels.



In circular smooth muscle stips from the oesophageal body (OB), L-NOARG reduced the latency period and increased the amplitude in EFS-evoked contractions, and in carbachol-contracted strips, EFS induced relaxations that was abolished by L-NOARG. NO, VIP and alpha-latrotoxin all produced a hyperpolarization of oesophageal smooth muscle. In cat tissue, activities of NOS and HO could be demonstrated. In LOS tissue of the cat, VIP concentrations were 50-fold higher than PACAP concentrations; in human tissue they were 10-fold higher.



These results suggest that the L-arginine/NO system plays an important role in the inhibitory neuronal control of oesophageal motility in cat and man. Also NO independent inhibitory pathways are present, involving other mediators of which VIP, PACAP, and CO are putative candidates. The L-arginine/NO system seems to act in concert with the NO-independent mechanisms to produce relaxant effects. (Less)
Please use this url to cite or link to this publication:
author
opponent
  • Lundberg, Jan, Department of Physiology and Pharmacology, Karolinska Institutet, S-171 77 Stockholm, Sweden
publishing date
type
Thesis
publication status
published
subject
keywords
toxikologi, farmaci, Farmakologi, farmakognosi, toxicology, pharmacy, pharmacognosy, pituitary adenylate cyclase activating peptide, vasoactive intestinal peptide, Pharmacological sciences, oesophagus, nonadrenergic noncholinergic, nitric oxide, lower oesophageal sphincter, haem oxygenase, cyclic GMP, carbon monoxide, cyclic AMP
pages
156 pages
publisher
Divison of Clinical Chemistry and Pharmacology
defense location
N/A
defense date
1996-01-26 10:15
external identifiers
  • Other:ISRN: LUMEDW/(MECF-1031) 1-156 (1996)
ISBN
91-628-1862-7
language
English
LU publication?
no
id
e1d9f84f-5395-4774-b523-99941bf7046a (old id 28165)
date added to LUP
2007-06-08 14:40:19
date last changed
2016-09-19 08:45:12
@misc{e1d9f84f-5395-4774-b523-99941bf7046a,
  abstract     = {The inhibitory neuromuscular control of the human and cat lower oesophagus was investigated by morphological, functional, and biochemical methods. A supply of nerve fibres and myenteric cell bodies, containing nitric oxide synthase (NOS), haem oxygenase (HO)-2, vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase activating peptide (PACAP) was observed. The highest density of nerves was seen at the oesophagogastric junction area with an abundace in the circular muscle layer. As judged by confocal microscopy, NOS, HO-2, VIP and PACAP were frequently colocalized within the same nerve structures.<br/><br>
<br/><br>
In circular smooth muscle strips from the lower oesophageal sphincter (LOS), electrical field stimulation (EFS) induced nerve-mediated relaxations that were abolished by the nitric oxide (NO) synthesis inhibitor NG-nitro-L-arginine (L-NOARG). The response was prevented and partially restored by L-arginine, but not by D-arginine. The relaxation was associated with an increase in cyclic GMP levels. A L-NOARG resistant relaxation could be induced, electrically or by the spider venom alpha-latrotoxin, which was not associated with changes in cyclic GMP or cyclic AMP levels, but inhibited by VIP-antiserum. The HO inhibitors, zinc protoporphyrin-IX or tin protoporphyrin-IX did not affect EFS induced relaxations. NO and carbon monoxide (CO) induced concentration-dependent relaxations associated with an increase of cyclic GMP levels, whereas VIP and PACAP induced concentration-dependent relaxations associated with an increase in cyclic AMP levels.<br/><br>
<br/><br>
In circular smooth muscle stips from the oesophageal body (OB), L-NOARG reduced the latency period and increased the amplitude in EFS-evoked contractions, and in carbachol-contracted strips, EFS induced relaxations that was abolished by L-NOARG. NO, VIP and alpha-latrotoxin all produced a hyperpolarization of oesophageal smooth muscle. In cat tissue, activities of NOS and HO could be demonstrated. In LOS tissue of the cat, VIP concentrations were 50-fold higher than PACAP concentrations; in human tissue they were 10-fold higher.<br/><br>
<br/><br>
These results suggest that the L-arginine/NO system plays an important role in the inhibitory neuronal control of oesophageal motility in cat and man. Also NO independent inhibitory pathways are present, involving other mediators of which VIP, PACAP, and CO are putative candidates. The L-arginine/NO system seems to act in concert with the NO-independent mechanisms to produce relaxant effects.},
  author       = {Ny, Lars},
  isbn         = {91-628-1862-7},
  keyword      = {toxikologi,farmaci,Farmakologi,farmakognosi,toxicology,pharmacy,pharmacognosy,pituitary adenylate cyclase activating peptide,vasoactive intestinal peptide,Pharmacological sciences,oesophagus,nonadrenergic noncholinergic,nitric oxide,lower oesophageal sphincter,haem oxygenase,cyclic GMP,carbon monoxide,cyclic AMP},
  language     = {eng},
  pages        = {156},
  publisher    = {ARRAY(0x97cf838)},
  title        = {Inhibitory neurotransmission in lower oesophagus},
  year         = {1996},
}