Subtypes of Muscarinic Receptors in Pancreatic Exocrine Secretion in Anesthetized Dog

Iwatsuki, Kazuhiko; Horiuchi, Akira; Yonekura, Hiroaki; Homma, Norio; Haruta, Kouichi; Chiba, Shigetoshi

doi:10.1097/00006676-198906000-00011

Cited by 20 publications

(15 citation statements)

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“…Although five classes of muscarinic receptors in the brain have been cloned (3,4), the classification of these receptors has to date been largely based on the evaluation of the pharmacological effects of selective receptor antagonists. Although early reports classified the pancreatic acinar cell muscarinic receptor as the M2 type, later studies noted that cholinergic secretion was mediated by a 4-DAMP-sensitive M3 acinar cell receptor (11,12,28). Our present pharmacological studies are in agreement with previous reports in regard to the presence of a 4-DAMP-sensitive muscarinic receptor on the pancreatic acinar cell.…”

Section: Discussionsupporting

confidence: 91%

“…Muscarinic antagonists are most often used to establish the class of muscarinic receptors; based on the relative efficiency of these agents, the acinar cell receptor has been designated an M3 subtype (11,12,28), whereas more proximal cholinergic pathways that affect the pancreas appear to be regulated by M1 receptors (26). Multiple subtypes of muscarinic receptor may be present on a single cell (5) and may potentially couple to distinct signaling pathways.…”

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confidence: 99%

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Telenzepine-sensitive muscarinic receptors on rat pancreatic acinar cells

Schmid

Modlin

Tang

et al. 1998

American Journal of Physiology-Gastrointestinal and Liver Physi

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. Telenzepinesensitive muscarinic receptors on rat pancreatic acinar cells. Am. J. Physiol. 274 (Gastrointest. Liver Physiol. 37): G734-G741, 1998.-To identify the muscarinic subtype present on the rat pancreatic acinar cell, we examined the effects of different muscarinic receptor antagonists on amylase secretion and proteolytic zymogen processing in isolated rat pancreatic acini. Maximal zymogen processing required a concentration of carbachol 10-to 100-fold greater (10 Ϫ3 M) than that required for maximal amylase secretion (10 Ϫ5 M). Although both secretion and conversion were inhibited by the M3 antagonist 4-diphenylacetoxy-N-methyl-piperidine (4-DAMP) (50% inhibition ϳ6 ϫ 10 Ϫ7 M and 1 ϫ 10 Ϫ8 M, respectively), the most potent inhibitor was the M1 antagonist telenzepine (50% inhibition ϳ5 ϫ 10 Ϫ10 M and 1 ϫ 10 Ϫ11 M, respectively). Pirenzepine, another M1 antagonist, and the M2 antagonist methoctramine did not reduce amylase secretion or zymogen processing in concentrations up to 1 ϫ 10 Ϫ5 M. Analysis of acinar cell muscarinic receptor by PCR revealed expression of both m1 and m3 subtypes. The pancreatic acinar cell has a distinct pattern of muscarinic antagonist sensitivity (telenzepine : 4-DAMP Ͼ pirenzepine) with respect to both amylase secretion and zymogen conversion. muscarinic antagonist; 4-diphenylacetoxy-N-methyl-piperidine; carboxypeptidase A 1 ; secretion NEUROHUMORAL STIMULATION of the exocrine pancreas generates a number of physiological responses, including enhanced zymogen secretion. Recent studies suggest that cholinergic pathways may have a more important role in regulating pancreatic secretion than previously appreciated. Thus the primary action of CCK released by the intestinal nutrients may be to stimulate the cholinergic release of acetylcholine (ACh) (1, 16). The neurotransmitter then acts on muscarinic ACh receptors (mAChR) to stimulate acinar cell secretion. Cholinergic pathways may play a role in pathological processes such as the proteolytic processing of zymogens to active forms.Cholinergic stimulation may contribute to the pathogenesis of pancreatitis such as that induced by the bite of the Tityus serrulatus scorpion (22), alcohol-associated disease, and cholinesterase inhibitors (17). A key step for initiating many forms of pancreatitis appears to be the pathological intracellular activation of digestive zymogens (15). In vivo studies that use supramaximal concentrations (10-to 100-fold greater than that generating a maximal secretory response) of CCK or cholinergic agonists generate acute pancreatitis (9) and zymogen activation (18). Likewise, hyperstimulation of isolated pancreatic acini by CCK leads to the rapid activation of proteases and enhanced zymogen processing (15). The protease activation observed in isolated pancreatic acini may be relevant to the pathogenesis of acute pancreatitis.The identification of the muscarinic receptors on the pancreatic acinar cell is relevant to pancreatic physiology and pathology. Muscarinic antagonists are most often used to establish the...

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Section: Discussionsupporting

confidence: 91%

mentioning

confidence: 99%

Telenzepine-sensitive muscarinic receptors on rat pancreatic acinar cells

Schmid

Modlin

Tang

et al. 1998

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…It has been suggested, primarily on the basis of pharmacological studies using muscarinic antagonists of limited receptor subtype selectivity, that muscarinic stimulation of exocrine pancreas function is virtually exclusively controlled by the M 3 receptor subtype (Louie and Owyang, 1986;Korc et al, 1987;Iwatsuki et al, 1989;van Zwam et al, 1990;Kato et al, 1992;Love et al, 1999). However, in the present study we provide unambiguous evidence that cholinergic activation of pancreatic digestive enzyme (amylase) secretion is mediated by a mixture of M 1 and M 3 mAChRs, at least in the mouse.…”

Section: Discussionmentioning

confidence: 99%

“…In the past, several groups have reported that ACh (muscarinic agonist)-induced stimulation of exocrine pancreas secretion is mediated by the M 3 receptor subtype (Louie and Owyang, 1986;Korc et al, 1987;Iwatsuki et al, 1989;van Zwam et al, 1990;Kato et al, 1992;Love et al, 1999). This conclusion was based on radioligand binding and functional studies using several subtype-preferring muscarinic antagonists, such as pirenzepine (preferentially binds to M 1 receptors), AF-DX 116 (methoctramine, preferentially binds to M 2 and M 4 receptors), and 4-DAMP (ϳ10 higher affinity for M 1 , M 3 , M 4 , and M 5 receptors than for M 2 receptors) (Dörje et al, 1991;Wess, 1996;Caulfield and Birdsall, 1998).…”

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confidence: 99%

Cholinergic Stimulation of Amylase Secretion from Pancreatic Acinar Cells Studied with Muscarinic Acetylcholine Receptor Mutant Mice

Gautam¹,

Han²,

Heard³

et al. 2005

J Pharmacol Exp Ther

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Muscarinic acetylcholine receptors (mAChRs) expressed by pancreatic acinar cells play an important role in mediating acetylcholine-dependent stimulation of digestive enzyme secretion. To examine the potential roles of M 1 and M 3 mAChRs in this activity, we used M 1 and M 3 receptor single knockout (KO) and M 1 /M 3 receptor double KO mice as novel experimental tools. Specifically, we examined the ability of the muscarinic agonist carbachol to stimulate amylase secretion in vitro, using dispersed pancreatic acini prepared from wild-type and mAChR mutant mice. Quantitative reverse transcription-polymerase chain reaction studies using RNA prepared from mouse pancreatic acini showed that deletion of the M 1 or M 3 mAChR genes did not lead to significantly altered mRNA levels of the remaining mAChR subtypes. Moreover, immunoprecipitation studies with M 1 and M 3 mAChR-selective antisera demonstrated that both mAChR subtypes are expressed by mouse pancreatic acini. Strikingly, carbachol-induced stimulation of amylase secretion was significantly impaired in acinar preparations from both M 1 and M 3 receptor single KO mice and abolished in acinar preparations from M 1 /M 3 receptor double KO mice. However, another pancreatic secretagogue, bombesin, retained its ability to fully stimulate amylase secretion in acinar preparations from M 1 /M 3 receptor double KO mice. Together, these studies support the concept that cholinergic stimulation of pancreatic amylase secretion is mediated by a mixture of M 1 and M 3 mAChRs and that other mAChR subtypes do not make a significant contribution to this activity. These findings clarify the long-standing question regarding the molecular nature of the mAChR subtypes mediating the secretion of digestive enzymes from the exocrine pancreas.

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“…It seems that muscarinic receptors are the key participants in the regulation of exocrine pancreatic function. Iwatsuki et al (1989), in a study on anaesthetised dogs, have shown that bethanechol-stimulated pancreatic secretion is mediated by the M3 type of muscarinic receptors. The study of Kato et al (1992) on rat pancreatic acini also suggests that M3 muscarinic receptors play an important role in pancreatic exocrine secretion.…”

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confidence: 99%

The Role of Cholinergic and Peptidergic Pathways in the Regulation of Pancreatic Exocrine Function During Postnatal Development in Pigs

Leśniewska

Gregard

Weström

et al. 2001

Experimental Physiology

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The aim of this study was to investigate the role of the parasympathetic (cholinergic and peptidergic) nervous system in the regulation of exocrine pancreas function in piglets during their early postnatal development. The cholinergic and peptidergic regulatory pathways of exocrine pancreatic function were tested by the specific muscarinic receptor blocker 4-diphenylacetoxy-N-methylpiperidine-methiodide (4-DAMP) and bombesin, respectively. At the age of 2 weeks, piglets were surgically fitted with a chronic pancreatic duct catheter, a duodenal re-entrant cannula and a jugular vein catheter. The experiments comprised a pre-weaning period, and a post-weaning period that commenced at the beginning of the 5th week of age. Intravenous infusion of 4-DAMP (100 pmol kg _1 h _1 ) reduced the outflow of pancreatic juice, the output of total protein and the activity of trypsin, chymotrypsin, carboxyl ester hydrolase and amylase during preprandial and postprandial pancreatic secretion, in both the pre-and post-weaning periods. However, the inhibitory effect of 4-DAMP during postprandial secretion was significantly greater (P < 0.05) in suckling piglets. The infusion of bombesin (10, 100 and 1000 pmol kg _1 h _1) stimulated exocrine pancreatic secretion in a dose-dependent manner during both the pre-and post-weaning periods. However, the stimulatory effect of 1000 pmol kg _1 h _1 bombesin on total protein output and the activities of trypsin, chymotrypsin and amylase were significantly higher (P < 0.05) in suckling piglets. In summary, our study showed that cholinergic and peptidergic mechanisms are involved in the regulation of exocrine pancreas function in piglets in both the pre-and post-weaning stages. 4-DAMP had a greater inhibitory effect on exocrine pancreatic secretion in piglets during the pre-weaning period. Thus, these observations suggest that the parasympathetic nervous system plays a dominant role in the functioning of the exocrine pancreas at this time. The action of bombesin suggests that it is a potent secretagogue for the exocrine pancreas in pigs during their postnatal development. Experimental Physiology (2001) 86.3, 399-409. 2151

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Subtypes of Muscarinic Receptors in Pancreatic Exocrine Secretion in Anesthetized Dog

Cited by 20 publications

References 0 publications

Telenzepine-sensitive muscarinic receptors on rat pancreatic acinar cells

Telenzepine-sensitive muscarinic receptors on rat pancreatic acinar cells

Cholinergic Stimulation of Amylase Secretion from Pancreatic Acinar Cells Studied with Muscarinic Acetylcholine Receptor Mutant Mice

The Role of Cholinergic and Peptidergic Pathways in the Regulation of Pancreatic Exocrine Function During Postnatal Development in Pigs

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