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Stimulatory Effect of Β-Adrenergic Agonists on Ileal L Cell Secretion

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Stimulatory Effect of Β-Adrenergic Agonists on Ileal L Cell Secretion 271 Stimulatory effect of â-adrenergic agonists on ileal L cell secretion and modulation by á-adrenergic activation J Claustre, S Brechet, P Plaisancie, J A Chayvialle and J C Cuber U 45 INSERM, Hoˆ pital Edouard Herriot, Pavillon H bis, 69437 Lyon Cedex 3, France (Requests for offprints should be addressed to J Claustre ) Abstract Postprandial release of peptide YY (PYY) and glucagon- (10"5 M) induced significant GLP-1 and PYY se- like peptide-1 (GLP-1) from L cells results from both cretions (135&30 and 305&39 fmol/8 min respect- nutrient transit in the ileal lumen and neural drive of ively), isoproterenol-induced secretions are suggested to endocrine cells. The adrenosympathetic system and its result mainly from stimulation of the â2-isoreceptor type. effectors have been shown to induce secretion of L cells In contrast, the á1-agonist phenylephrine (10"7 M) did in vivo or in vitro. Because these transmitters act through not stimulate peptide release. When co-infused with three receptors, â, á1, á2, coupled to different intra- 10"6 Mor10"7 M isoproterenol, 10"7 M phenylephrine cellular pathways, we evaluated the responses of L cells to raised GLP-1 release to 174&53 and 108&28 fmol/ specific agonists, using the model of isolated vascularly 8 min respectively (vs 38&16 and 35&10 fmol/8 min perfused rat ileum. General stimulation of adrenergic for isoproterenol alone, P<0·05) whereas PYY secretion receptors with epinephrine (10"7 M) induced significant was not significantly increased. Clonidine (10"7 M), an GLP-1 and PYY secretions (94&38 and 257&59 fmol/ á2-agonist, induced a moderate and delayed increase of 8 min respectively) which were abolished upon pro- GLP-1 and PYY but abolished the isoproterenol-induced pranolol (10"7 M) pretreatment and strongly decreased peptide secretion. Our results showed that general stimu- upon infusion with 10"8 M prazosin. Blockade of lation of adrenergic receptors stimulates the secretory á2-receptors with idazoxan (10"8 M) did not alter activity of ileal endocrine L cells. The net peptide secre- epinephrine-induced peptide secretion. The â-adrenergic tion results from the activation of the â2-isoreceptor type. agonist isoproterenol (10"6 M) infused for 30 min induced Additionally, GLP-1 and PYY secretions are positively a transient release of GLP-1 and PYY (integrated release modulated by á1-receptor stimulation and inhibited by over the 8 min of the peak secretion: 38&16 and á2-receptor activation upon â-receptor occupation. 214&69 fmol for GLP-1 and PYY respectively, P<0·05). Journal of Endocrinology (1999) 162, 271–278 Because terbutaline but not dobutamine or BRL 37,344 Introduction Whereas the effects of nutrients on PYY and GLP-1 secretions have been extensively studied in vivo and in vitro Intestinal endocrine cell secretion is under the control of (Fu-Cheng et al. 1995, Wen et al. 1995), the modulation nutrients in the lumen, and of nervous or endocrine of these endocrine secretions by the nervous system has mediators acting at the basolateral side (Walsh 1994). In been poorly investigated. The sympathetic nervous system the ileum, endocrine cells are primarily accounted for by is known to control mucosal functions (Cooke 1986), and enterochromaffin cells, and L cells that secrete peptide mucosal glands are surrounded by putative noradrenergic YY (PYY) and several pro-glucagon-derived peptides processes (Newson et al. 1979). Electrical stimulation of (Sjo¨lund et al. 1983, Walsh 1994). Pro-glucagon-derived the splanchnic nerves induced PYY release in anaesthe- peptides are glucagon-like peptide-1 (GLP-1), GLP-2, tized dogs and pigs (Sheikh et al. 1989, Zhang et al. 1993). oxyntomodulin, and glicentin. GLP-1 is a potent Epinephrine was shown to induce GLP-1 release in the insulinotropic hormone (Holst & Orskov 1994). PYY, isolated vascularly perfused rat ileum (Herrmann-Rinke which is co-stored with GLP-1 in L cells, induces vaso- et al. 1995), and to stimulate the release of PYY and constriction, inhibits intestinal motility and secretion, and enteroglucagon from enteric endocrine cells in primary inhibits pancreatic and gastric secretions (Walsh 1994). short-term culture (Barber et al. 1987, Aponte et al. 1988, PYY has thus been proposed to participate in the ileal Buchan et al. 1987). In agreement with these results, brake (Wen et al. 1995). isoproterenol, a â-adrenergic agonist, was shown to Journal of Endocrinology (1999) 162, 271–278 Online version via http://www.endocrinology.org 0022–0795/99/0162–271 1999 Society for Endocrinology Printed in Great Britain Downloaded from Bioscientifica.com at 09/26/2021 06:26:10AM via free access 272 J CLAUSTRE and others · Adrenergic control of ileal L cells stimulate the release of the two peptides from the isolated the mesenteric artery and the portal vein respectively. rat ileum (Dumoulin et al. 1995).The effects of Upon catheterization, the ileum was vascularly perfused á-adrenergic agonists on GLP-1 secretion have been (2·5 ml/min) with a medium consisting of washed bovine studied in cell cultures only (Buchan et al. 1987). Because erythrocytes (25%), BSA (3%), glucose (5 mM), amino â- and á-adrenoceptors are coupled to different intra- acid solution (1%) in Krebs–Henseleit buffer oxygenated cellular transduction pathways (Summers & McMartin with gaseous O2:CO2 (95:5%). The perfused ileum was 1993), we assessed the effects of epinephrine in the transferred to a bath at 37 )C and luminally perfused with presence of specific adrenergic blockers and of â-, á1- and isotonic saline (250 µl/min). á2-adrenergic agonists alone or associated on L endocrine cell secretions. Infusion protocol Isoproterenol, as epinephrine, binds the three types of â-adrenergic isoreceptors (Giacobino 1995), and effects of After equilibration (5 min), venous effluents were col- catecholamines on the gastrointestinal tract have been lected on EDTA (final concentration: 10 mM) every attributed both to â2- and â3-adrenergic stimulation 2 min and rapidly centrifuged. Supernatants were stored (Coruzzi et al. 1997, Levasseur et al. 1997). â-adrenergic frozen at "20 )C until assay. Drugs were infused (250 µl/ receptors are coupled to the cAMP pathway (Emorine min in isotonic saline containing 3% BSA) through a et al. 1989) but â3-, unlike â2-adrenoceptors, are not catheter connected close to the arterial input. Infusion of subject to desensitization (Nantel et al. 1993), which adrenergic agonists consisted of a 20-min control period, may have consequences on the pattern of response to 30-min drug infusion, and a 10-min post-infusion control catecholamine stimulation. We thus wished to study the period. Blockers were infused 2 min before and during effects of specific â-adrenergic agonists on GLP-1 and agonist infusion (i.e. after an 18-min control period). PYY secretion. This study was conducted in a model of isolated vascularly perfused rat ileum (Cuber et al. 1990). RIA GLP-1 and PYY were assayed directly in the supernatant from venous effluents, as previously described (Plaisancie´ Materials and Methods et al. 1994, 1995). The 199D anti-GLP-1 antibody was used at a 1:250 000 dilution. This antibody reacts 100% Reagents with GLP-1-(7–36) amide, 84% with GLP-1-(1–36) Chemical reagents were purchased from Merck amide, and less than 0·1% with GLP-1-(1–37), GLP-1- (Darmstadt, Germany). Bovine serum albumin (BSA) was (7–37), GLP-2, and glucagon. The detection limit obtained from Biovalori (Cassen, France) and the amino and ID50 (half maximal inhibitory dose) were 0·4 and acid mixture hyperamine 25 (25·6 g nitrogen/l) from 4 fmol/tube. PYY was assayed with the A4D anti-porcine Braun Medical (Boulogne, France). The following re- PYY antiserum at a 1:800 000 dilution. This antibody agents were from Sigma (St Louis, MO, USA): clonidine, cross-reacts less than 1% with bovine pancreatic poly- dobutamine, idazoxan, isoproterenol, phenylephrine, peptide and neuropeptide Y. Sensitivity and ID50 were prazosin, terbutaline, yohimbine, and GLP-1-(7–36) 1 and 7 fmol/tube respectively. amide. PYY (porcine) was purchased from Peninsula Laboratories (St Helens, Merseyside, UK). BRL 37,344 Statistical methods was a kind gift from SmithKline Beecham Pharmaceuticals Results are expressed as means&... obtained in five to (Welwyn Garden City, Herts, UK). eight experiments. Integrated responses were calculated for each animal from the sum of discharges measured during peak secretion (from the second to the ninth Surgical procedure minute of infusion) minus the mean value of the 20-min The dissection of the ileum and controls of viability in control period. Comparisons were performed with ex vivo conditions have been described previously (Cuber Student’s t-test for paired or unpaired data as appropriate. et al. 1990). Briefly, male 250–300 g Wistar rats (De´pre´, Differences reaching the P<0·05 level were considered Saint Doulchard, France) were anaesthetized with i.p. significant. pentobarbitone (75 mg/kg), the abdomen was opened with a midline incision, viscera were exteriorized and, after ligation of vessels, the colon was removed. A first Results cannula was inserted 10 cm proximal to the ileo-colic junction and after emptying and rinsing the intestine a Effects of epinephrine alone or with specific blockers on GLP-1 second one was inserted at the ileo-colic junction. After and PYY secretion ligating its supplying vessels, the foregut was pulled apart, Epinephrine infusion (10"7 M) induced GLP-1 and PYY and steel and silicone elastomer cannulas were inserted in secretions (Fig. 1, n=6, P<0·05) to maximal secretion rates Journal of Endocrinology (1999) 162, 271–278 Downloaded from Bioscientifica.com at 09/26/2021 06:26:10AM via free access Adrenergic control of ileal L cells · J CLAUSTRE and others 273 When prazosin (10"8 M) was co-infused with 10"7 M epinephrine the resulting GLP-1 secretion was decreased (Fig.
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