İleal fren mekanizmasında endojen GLP-1'in rolü ve otonom sinir sistemi ile CCK-A reseptörlerinin bu mekanizmaya katılımı
The Role of endogenous GLP-1 in the ileal brake mechanism and the participitation of the autonomic nervous system and CCK-A receptor in this mechanism
Yazar: AYHAN BOZKURT
Danışman: PROF.DR. BERRAK Ç. YEĞEN
Marmara Üniversitesi / Sağlık Bilimleri Enstitüsü / Fizyoloji Ana Bilim Dalı
Derece: Doktora, 2001
Konu: Fizyoloji = Physiology

Özet:
1. ÖZET ILEAL FREN MEKANİZMASINDA ENDOJEN GLP-1 'İN ROLÜ VE OTONOM SİNİR SİSTEMİ İLE CCK-A RESEPTÖRLERİNİN BU MEKANİZMAYA KATILIMLARI Karbonhidrat ve yağ içeren yiyecek alımını takiben distal ince barsaktaki L hücrelerinden salman bir inkretin hormon olan GLP-l'in ileal fren mekanizmasını düzenleyen mediyatörlerden biri olduğu iddia edilmektedir. Bu çalışmanın amacı, intraluminal olarak perfüze edilen glikoz ile indüklenen ileal fren mekanizmasını aydınlatmak ve bu mekanizmaya endojen GLP-1 ve CCK'in muhtemel katılımını göstermektir. Anestezi altında sıçanlara ileal ve intravenöz kateterler yerleştirildi. İyileşme döneminin ardından 18 saat açlık sonrası 40 dakikalık intravenöz ya da ileal perfüzyon sürelerinin son 30 dakikasında mide boşalma deneyleri yapıldı. Fizyolojik tuzlu su ya da distile su içinde hazırlanmış glikoz solüsyonlarının ileal perfüzyonunun mide boşalmasını konsantrasyona bağımlı şekilde yavaşlattığı, ancak fizyolojik tuzlu su içinde hazırlanmış glikoz solüsyonunun mide boşalmasını yavaşlatıcı etkisinin daha kuvvetli olduğu bulundu. Fizyolojik tuzlu su içinde hazırlanan ileal glikoz (%10) ile oluşan mide boşalması inhibisyonu, GLP-1 reseptör antagonisti (eksendin) ve CCK-A reseptör antagonisti (SR27897) ile engellenirken, vagal afferent denervasyon ile azaldı. İleuma glikoz uygulanmasından önce bretilyum tosilat ile yapılan adrenerjik reseptör blokajı ve atropin ile yapılan kolinerjik blokaj etkisiz olarak bulundu. GLP-1 ve CCK-8s'in eksojen uygulanması mide boşalmasını doza bağlı şekilde inhibe etti. SR27897, CCK-8s'in (50 pmol/ kg/dak; iv) inhibitor etkisini tamamen engellerken GLP-l'in (10 pmol/kg/dak;iv) inhibitor etkisini anlamlı şekilde azalttı. Diğer taraftan eksendin GLP-l'in inhibitor etkisini engelledi ancak CCK-8s'in inhibitor etkisini değiştirmedi. Sonuçlarımız, ileumda bulunan glikozun mide boşalması üzerine etkili ileal fren mekanizmasını başlattığını, lümendeki Na+'un bu etkiyi artırdığını ve bu mekanizmada GLP-1 ve CCK-A reseptörleri ile vagal afferent sinirlerin yer aldığını göstermektedir. Ayrıca sonuçlarımıza göre, eksojen GLP-l'in mide boşalması üzerine inhibitor etkisi kısmen CCK-A reseptörleri aracılığıyla gerçekleşmektedir.2- SUMMARY THE ROLE OF ENDOGENOUS GLP-1 IN THE ILEAL BRAKE MECHANISM AND THE PARTICIPATION OF THE AUTONOMIC NERVOUS SYSTEM AND CCK-A RECEPTORS IN THIS MECHANISM GLP-1, which is an incretin hormone secreted from L cells of the distal small intestine in response to carbohydrate and lipid containing meal ingestion, is suggested to be one of the mediators of the ileal brake. The aim of this study is to investigate the ileal brake mechanism induced by intraluminally perfused glucose and the possible participation of endogenous GLP-1 and CCK in this mechanism. Under anesthesia, rats were fitted with ileal and intravenous catheters. After the recovery period rats were fasted for 1 8 h and the gastric emptying experiments were commenced during the last 30 min of 40-min intravenous or ileal perfusion periods. Ileal perfusion of glucose prepared either in distilled water or saline inhibited gastric emptying rate in a dose dependent manner; however, the inhibitory effect of glucose in saline was found to be more potent. The inhibition of gastric emptying induced by ileal perfusion of glucose (10 %) in saline was abolished by GLP-1 receptor antagonist (exendin) and CCK-A receptor antagonist (SR27897), while it was reduced significantly by vagal afferent denervation. Either adrenergic receptor blockade using bretylium tosylate or muscarinic receptor blockade with atropin before the administration of ileal glucose was found to be ineffective. Exogenous administration of GLP-1 or CCK-8s inhibited the gastric emptying in a dose dependent manner. SR27897B abolished the inhibitory effect of CCK-8s (50 pmol/kg/min; iv) while the inhibitory effect of GLP-1 (10 pmol/kg/min) on gastric emptying was significantly reduced. On the other hand, exendin abolished the inhibitory effect of GLP-1 but did not affect the inhibition induced by CCK-8s. Our results suggest that glucose in ileum activates an inhibitory ileal brake mechanism that delays gastric emptying, while luminal Na+ enhances this effect and this mechanism involves the participitation of GLP-1 and CCK-A receptors and the vagal afferent fibres. Our results also suggest that the inhibitory effect of exogenous GLP-1 on gastric emptying is dependent, in part, upon CCK-A receptors.

Abstract:
2- SUMMARY THE ROLE OF ENDOGENOUS GLP-1 IN THE ILEAL BRAKE MECHANISM AND THE PARTICIPATION OF THE AUTONOMIC NERVOUS SYSTEM AND CCK-A RECEPTORS IN THIS MECHANISM GLP-1, which is an incretin hormone secreted from L cells of the distal small intestine in response to carbohydrate and lipid containing meal ingestion, is suggested to be one of the mediators of the ileal brake. The aim of this study is to investigate the ileal brake mechanism induced by intraluminally perfused glucose and the possible participation of endogenous GLP-1 and CCK in this mechanism. Under anesthesia, rats were fitted with ileal and intravenous catheters. After the recovery period rats were fasted for 1 8 h and the gastric emptying experiments were commenced during the last 30 min of 40-min intravenous or ileal perfusion periods. Ileal perfusion of glucose prepared either in distilled water or saline inhibited gastric emptying rate in a dose dependent manner; however, the inhibitory effect of glucose in saline was found to be more potent. The inhibition of gastric emptying induced by ileal perfusion of glucose (10 %) in saline was abolished by GLP-1 receptor antagonist (exendin) and CCK-A receptor antagonist (SR27897), while it was reduced significantly by vagal afferent denervation. Either adrenergic receptor blockade using bretylium tosylate or muscarinic receptor blockade with atropin before the administration of ileal glucose was found to be ineffective. Exogenous administration of GLP-1 or CCK-8s inhibited the gastric emptying in a dose dependent manner. SR27897B abolished the inhibitory effect of CCK-8s (50 pmol/kg/min; iv) while the inhibitory effect of GLP-1 (10 pmol/kg/min) on gastric emptying was significantly reduced. On the other hand, exendin abolished the inhibitory effect of GLP-1 but did not affect the inhibition induced by CCK-8s. Our results suggest that glucose in ileum activates an inhibitory ileal brake mechanism that delays gastric emptying, while luminal Na+ enhances this effect and this mechanism involves the participitation of GLP-1 and CCK-A receptors and the vagal afferent fibres. Our results also suggest that the inhibitory effect of exogenous GLP-1 on gastric emptying is dependent, in part, upon CCK-A receptors.