The presence of HCl in the stomach by W. Prout in secretagogues and anti-ulcer efficacy

Transcription

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3 #' The presence of HCl in the stomach by W. Prout in 1823 Vagus plays crucial role in gastric HCl secretion by I.P. Pavlov in 1895 Gastrin is gastric HCl stimulant by J.S. Edkins in 1902 '# Dictum; ; NO ACID NO ULCER by K. Schwartz in 1910 Histamine as gastric HCl secretagogue by L. Popielski in 1916 H 2 -receptor antagonists by J.W. Black in 1972 and proton pump inhibitors by G. Sachs in 1980 showing strong inhibition of HCl secretion stimulated by various secretagogues and anti-ulcer efficacy Helicobacter pylori and its role in gastritis and peptic peptic ulcer disease by B.J. Marshall & R.J. Warren in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

4 # Gastrin-cell Gastrin CCK 2 Gastrin Vagal nerve Ach M 3 Ca ++ camp CCK 2 Ach H2 M 1 Histamine SSTR 2 (-) Histamine ECL-cell SSTR 2 Somatostatin-cell M 2 (-) Ach Parietal cell Protein kinases H +, K + - ATPase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10 Mucus- Bicarbonate Barrier Epithelial Tigh Junctions #$ Gastric lumen Mucosal defence mechanism Mucus H + Pepsinogen HCO 3 - H + Mucosal defence mechanism Pepsin H + ph 1.5 ph 2.0 Mucus HCO H + H 2 O + CO 2 Neutralization ph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

11 #% A Gastric Distension Vagus Enteric Neurons Ach (-) D - Cell B Meal Somatostatin IV GRP Acid GRP Protein Digestion Products G - Cell (-) H + SS H+ Gastrin Gastrin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

12 #& IA?HAJHOF=JJAH HAIFIAIJJFE?=EHHEJ=JIIK?D=I0FOHE H =IFEHE=FFE?=JE=@"@AJAHE=JEBANFHAIIEB?.5EEJHEIE?=@ ANJHEIE?AKHIELLA@EJDAJH=IEIIEBCKJ>H=ECKJIEC=I!7IEC IK?DME@AIFA?JHKBFDOIECE?==@FD=H=?CE?=JIIALAH=HAIA=H?DAHI MAHA=>AJHALA=JD=JJDAC=IJH@K@A=K?I=EIAGKEFFA@MEJD=L=HEAJOB AKH=IAIHIJD=JHAIF@JJDA=?JEBKE=EHHEJ=JIIK?D=I0FOHE FH@K?A@?OJJNE?IK>IJ=?AIAIFA?E=O?OJJNE+=C)=@8=?)KE==?E@ AJD=L=HEKI@HKCIACIJAHE@==JEEB==JHO=CAJI5)1,HALA FDOIECE?=?D=CAIIK?D=I?DAE?=ECHA@EAJIBB@EJII=HEJO=@F0=I MA=IJEEJO=@JAIEBJDA/1JH=?JM=6DHKCD=?JEL=JEB?DA IA?D==@?EHA?AFJHIBC=IJH@K@A=K?I=JDA=BBAHAJAHLAI A@E=JEAIDHJ?=HEJH=KH==@CL=CL=C=HANJH=KH==N==@ IFE=H?AHA>H=HABANAIJHECCAHA@>OKE=0 H0FOHE =@=BBA?JEC=C JDAHI=IJDAK?KI0+! IA?HAJEJDAC=IJH@K@A=K?I=>=HHEAHI=@ A AUTONOMIC NERVOUS SYSTEM PARASYMPATHETIC DIVISION SACRAL SPINAL CORD BRAINSTEM EFFERENT NERVES PELVIC NERVES ENTERIC NERVOUS SYSTEM Myenteric plexus VAGUS NERVES Smooth muscle Secretory cells Submucosal plexus SYMPATHETIC DIVISION AFFERENT NERVES SYMPATHETIC GANGLIA PREGANGLIONIC FIBERS POSTGANGLIONIC FIBERS Blood vessels LUMBAR SPINAL CORD THORACIC SPINAL CORD B C Gut Lumen STIMULATION CHEMICAL MECHANICAL Normal Acid Mucosa Ascending (oral) pathway Sensory neuron (mechanical, chemical) THE ENTERIC NERVOUS SYSTEM FUNCTIONS AS A BRAIN-IN-THE-GUT Integrated Circuits 1. Program Library 2. Feedback Control 3. Reflexes 4. Information Processing Excitatory motor neurons (Ach,SP) Descending (oral) pathway Inhibitory motor neurons (VIP, NO, PACAP) Muscularis Contraction Sensory neuron (stretch) (-) (-) (-) (-) S T R E T C H Relaxation.EC% *H=ECKJ=NEI-JAHE?AKH=IOIJA-5EI?IE@AHA@=IEJJA>H=E?A?JA@>OJM F=JDM=OIMEJD+5*-5?IEIJIB=>KJEEBIAIHO=@JHAKHI=@ EJAHAKHIEIK>K?KI=@KI?K=HFANKIAI

13 #' K?I=EJACHEJO=IMA=IK?I=E?H?EH?K=JE!.EC%6DAIF=?A 0FOHE K?I=EJACHEJO""1DK=IMEJD0FOHE EC=IJHE?K?I=>O0FOHE =NEIIJ=HJECMEJDJDAEHHEJ=JEBK?I=?DAHA?AFJHI>ONEKI?DAE?=I FOHE FHJA?JELADKH=IIK?D=I2/C=IJHEI=JIJ=JECDHAEAFJEAJ?JD=J=O MEJD>H=ECKJ=NEI"#"$ -7404)4-/7)61./)5641+)+1, )+6 ),02; ,56)+0 F=OEC=HFHJA?JELAHAE=EJ=EECBC=IJHE?K?I=EJACHEJOJDAHAEI

14 # DEIJ=EA?FAJIHAIKJECEJDAAN?EJ=JEBNOJE??AIEJDA BMECIJAFIJDA=?JEL=JE>OIA?HAJ=CCKAIBF=HEAJ=?AHA?AFJHIIK?D =I0 4! 4++ JDABH=JEBEJH=?AK=HIJEK=JHO E?HFH=JEB=?JELA?OJF=IE?FHJFKFIEJJDAA>H=A?LAHEC )62=IAH E ANJHAAODECD??AJH=JEEJJDAC=IJHE?KA'"$.EC& 6DAA?D=EIB0 EILEHJK=OJDAI=A@KHEC=JDHAAFD=IAI>KJJDA?JHE>KJEBAKH=L=C= =@JDAFD=IABIA?HAJE BHDEI]ID=BA@^@CIMEJDFAA@AIFD=CA=BEIJK=J=LE@JDAIM=MA@ Cholinergic neuron Parietal cells Intracellular cannaliculi Acetylcholine M 3 -R Ca 2+ Gastric lumen ECL-cell Histamine H 2 -R ATP Adenylyl cyklase campprotein kinase K+ H + -K + -ATPase H + H + -K + -ATPase G-cell Circulation Gastrin CCK 2 -R Ca 2+.EC& -@CAKIIJEK=JIBF=HEAJ=?AI=@JDAEHEJH=?AK=HA@E=JHI

15 # =HA=MEJDBKL=C=EAHL=JEJ]EHHH^JDAIA?HAJHO=?JELEJOBEJ=?J IA?HAJE ]+JEKEC^JDAHECE=2=LLIAHLEI IA?HAJEHA=?DEC=>KJ#$BFAJ=C=IJHE=NEK5ALAH=EJAHAIJEC

16 # HA?AFJHIBH++++ @ANO, L=C=?DEAHCE??FAJF=OI=IJEFHJ=JHAE?AFD=E? H+ (mmol/30 min) GASTRIC SECRETION 0 * * * Sham-feeding Insulin 2-DG Control Atropine L-364,718 S-0509 Vagus (Sham-feeding, insulin or 2-DG) Gastrin H + Histam. Ach G-c GRP S-S D-c Ach Gastrin.EC' /=IJHE?=?E@HAIF?AJL=C=IJEK=JEE@K?A@>OID=BAA@ECEIKEDOFCO?AE= =FFE?=JEB=JHFEA #CC!$"%&++ HA?AFJH>?AHCCH5#'# CC++ HA?AFJH>?AHKFK>EIDA@@=J=

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21 # % Divergent Responses to H. pylori Infection Chronic H. pylori Infection 10-15% ~80% 2-5% Antral predominant Gastritis Acid & Gastrin, little or no atrophy low risk of gastric Ca Mild Mixed Gastritis Corpus predominant Gastritis MAG, Acid, Gastrin high risk of gastric carcinoma Normal Acid Duodenal ulcer Gastric Carcinoma disease No significant disease? Bacterial? Environment? Host.EC 0FOHE EBA?JEHAIKJIEC=IJHEJEIE=IK>A?JI>KJEIABJDA#?=KIAI C=IJHE?@K@A=K?AHI,7HC=IJHE??=?AH+= H. pylori and gastric pathology Pro-inflammatory cytokines gene polymorphisms IL-1B-511*T IL-1-RN*2*2 IL-10 ATA haplotype TNF-A-308*A IL-8-251*A Hypergastrinemia Atrophy Innate immune response gene polymorphisms TLR4+896*G Bacteria promoted factors CagA, VacA Endotoxins (LPS) Growth factors, gastrins, COX-2-Prostaglandins Reactive oxygen species Environmental factors Smoking Dietary factors Abuse of stimulants.ec 0FOHEEBA?JE=O>A=IHAIFIE>ABHC=IJHE??=?AHCAAIEIJD=JBMIANFHAIIE =@=?JEC=IJHE?K?I=B?OJJNEI+=C)=@8=?)FHEB==JHO?OJEAI=@C=IJHEI

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