1
Q
GI System Physiology Two Major Functions:
A
(1) Digestion
(2) Absorption of Nutrients
2
Q
GI System Physiology Four Activities:
A
- Motility
- Secretions
- Digestion
- Absorption
3
Q
Motility -
Define
A
food propelled from mouth –> rectum
4
Q
Secretions -
Define
A
pancreatic, salivary and hepatic enzymes and electrolytes help with digestion/absorption
5
Q
Absorption -
Define
A
–> Blood - absorbed nutrients, electrolytes & water are transferred into the blood stream
6
Q
Mucosal Layer contains:
A
(Epithelium + Lamina Propria + Muscularis Mucosa)
7
Q
Mucosal Layer function:
A
- Epithelium specialized for absorption & secretion
* Contraction of muscularis mucosa = ΔShape & Surface Area of Epithelium
8
Q
Submucosal Layer contains:
A
(collagen, elastin, glands, blood vessels)
9
Q
Muscularis Mucosa layer:
A
Circular Muscle
Longitudinal Muscle
10
Q
Serosal Mucosa layer:
A
(Faces Blood)
11
Q
Nerve Plexuses
A
- Meissner’s Plexus:
2. Myenteric Plexus:
12
Q
Meissner’s Plexus:
A
Submucosal Plexus (Meissner’s Plexus): deep to submucosal layer
13
Q
Myenteric Plexus:
A
deep to circular muscle
14
Q
Enteric Nervous System (ENS):
A
Composed of the Meissner’s Plexus & Myenteric Plexus located on either side of the circular smooth muscle. They comprise the intrinsic innervation of the GI Tract.
15
Q
Innervation of the GI Tract -
A
Autonomic Nervous System Extrinsic & Enteric System Intrinsic
16
Q
Extrinsic Innervation include:
A
Parasympathetics & Sympathetics
17
Q
Parasympathetics Nerves:
A
- Vagus Nerve:
2. Pelvic Splanchnic Nerves:
18
Q
Vagus Nerve:
A
Striated muscle in ↑1/3 of Esophagus, Stomach, Small Intestine & Ascending Colon (= ↑GI Tract)
19
Q
Pelvic Splanchnic Nerves:
A
Transverse colon, descending + sigmoid colon, & striated muscle of anal canal (= ↓GI Tract)
20
Q
Parasympathetics have long?
A
Pre-ganglionic fibers that synapse in ganglion INSIDE the submucosal & myenteric plexus
21
Q
Parasympathetic post-ganglionic fibers relayed to
A
Smooth muscle, endocrine glands & secretory cells.
22
Q
Parasympathetic Neurotransmitters:
A
- Cholinergic Neurons: AcH
2. Peptidergic Neurons: Substance P, VIP, etc.
23
Q
Sympathetic Ganglia:
A
- Celiac
- Superior Mesenteric
- Inferior Mesenteric
- Hypogastric
24
Q
Sympathetics have short
A
Pre-ganglionic fibers that synapse with ganglion OUTSIDE the layers of the GI wall
25
Sympathetic post-ganglionic fibers travel to
Submucosal or myenteric ganglion, or directly innervate the smooth muscle, endocrine glands, & secretory cells.
26
Sympathetic Neurotransmitters:
Adrenergic Neurons: Norepinephrine
27
Enteric System
| Enteric Ganglion:
Located entirely in the submucosal or myenteric plexus on GI tract wall
28
Enteric System receives sensory information from
Mechanoreceptors & chemoreceptors in
| mucosa & directly relays to smooth muscle, secretory glands, & endocrine cells as well as other ganglion.
29
Enteric System receives input from
parasympathetic & sympathetic extrinsic systems.
30
Neurocrines
| AcH: location & function
from cholinergic neurons --> contraction of muscle wall + relaxation of sphincter + ↑all secretion
31
Neurocrines
| NE: location & function
from adrenergic neurons --> relaxation of muscle wall + contraction of sphincter + ↑secretion of saliva
32
From Neurons of Mucosa or Smooth Muscle
1. Vasoactive intestinal peptide (VIP)
2. Gastrin-related peptide (GRP)/Bombesin
3. Enkephalins (opiates)
4. Neuropeptide Y
33
Vasoactive intestinal peptide (VIP) -->
relaxation of muscle wall + ↑all secretion
34
Gastrin-related peptide (GRP)/Bombesin -->
↑Gastric Secretion
35
Enkephalins (opiates) -->
contraction of smooth muscle + ↓Intestinal Secretion
36
Neuropeptide Y -->
relaxation of smooth muscle + ↓Intestinal Secretion
37
Gastrointestinal Peptides =
Hormones + Paracrines + Neurocrines
38
Hormones Released from
endocrine cells; cells are dispersed throughout GI tract
39
Hormones Secreted into
portal circulation --> liver ---> blood stream --> systemic blood
40
Hormones Blood delivers to
Target cells in OR outside of the GI tract
41
Hormones Must meet following criteria:
1. Secreted from physiologic stimuli & carried via blood to distant site to fulfill physiologic response
2. Must act independent of neural activity
3. Must be isolated & chemically ID
42
Gastrin Hormones:
Gastrin-CCK Family
1. G17 (Little Gastrin):
2. G34 (Big Gastrin):
43
G17 (Little Gastrin):
↑secretions during/just after meals
44
2.G34 (Big Gastrin):
↑secretions at low levels in between meals
45
Gastrin Site of Secretion:
G (Gastrin) Cells in Stomach Antrum.
46
Gastrin Stimuli for/against Secretion:
Anything to do with Eating
1. Peptides + Amino Acids: most potent are AA phenylalanine & tryptophan
2. Distention of Stomach
3. Vagal Stimulation: occurs via neurocrine GRP acting on G cells
4. Somatostatin: inhibits secretion
5. ↓pH: inhibits secretion
47
Gastrin Action
1. ↑H+ Release by gastric parietal cells
| 2. ↑Growth of Gastric Mucosa (trophic effect)
48
Cholecytokinin (CCK) Hormones:
Gastrin-CCK Family Act on Two Receptors
1. CCKA:
2. CCKB:
49
CCKA: selective for
CCK
50
CCKB: sensitive for
CCK & Gastrin
51
Cholecytokinin (CCK) Site of Secretion:
I Cells in Duodenum & Jejunum
52
Cholecytokinin (CCK) Stimuli for/against Secretion:
Basically the Fat & Protein in a Meal
1. Monoglycerides + Fatty Acids (NOT TGs)
2. Small Peptides + AAs
53
Cholecytokinin (CCK) Action:
Functions contribute to Fat, Protein, & CHO Digestion
54
Cholecytokinin (CCK) cause: Contraction of Gallbladder + Relaxation of Sphincter of Odi:
↑Bile into SI
55
Cholecytokinin (CCK) cause: Secretion of Pancreatic Enzymes:
lipases (FA/MG), amylase (CHO), protease
56
Cholecytokinin (CCK) cause: Secretion of Pancreatic
HCO3-
57
Cholecytokinin (CCK) cause: ↑Growth of Exocrine Pancreas + Gallbladder:
tropic effects where CCK acts
58
Cholecytokinin (CCK) cause: ↓Gastric Emptying = ↑Gastric Emptying Time:
↓chyme from stomach --> SI
59
Secretin Hormones:
Secretin-Glucagon Family
60
Secretin Site of Secretion:
S (Secretin Cells) in Duodenum
61
Secretin Stimuli for/against Secretion:
Acidity in Duodenum (pH < 4.5)
1. ↑H+ In duodenum
2. ↑FA in duodenum
62
Secretin Action:
Neutralize H+ in Duodenum = protects acid-sensitive pancreatic lipase
1. ↑Pancreatic HCO3- Secretion
2. ↑Biliary HCO3- Secretion
3. ↓Gastrin Effects = ↓H+ secretion from G cells; ↓tropic effects
63
Glucose-Dependent Insulinotropic Peptide (GIP)
| Hormones:
Secretin-Glucagon Family
64
Glucose-Dependent Insulinotropic Peptide (GIP) Site of Secretion:
K Cells in Duodenum & Jejunum
65
Glucose-Dependent Insulinotropic Peptide (GIP) Stimuli for/against Secretion:
Only hormone stimulated by all 3 nutrient types
1. AA
2. Fatty Acids
3. Oral Glucose (ORAL ONLY)
66
Glucose-Dependent Insulinotropic Peptide (GIP) Action:
1. Stimulates Insulin Secretion from Pancreatic β Cells
| 2. ↓Gastric H+ Secretion
67
Paracrines Hormones: secreted & act:
* Secreted by endocrine cells
* Diffuse short distances via ISF or carried via capillaries
* Act locally within same tissue that secretes them
68
Paracrines Hormones GI tract:
Somatostatin & Histamine
69
Somatostatin Site of Secretion:
D Endocrine + Paracrine Cells
70
Somatostatin Stimuli for/against Secretion:
↓Luminal pH
71
Somatostatin Action:
1. ↓Secretion of other GI hormones
| 2. ↓Gastric H+ Secretion
72
Histamine Site of Secretion:
Endocrine-Cells in H+ Secreting Region of Stomach
73
Histamine Stimuli for/against Secretion:
many
74
Histamine Action:
↑Gastric H+ Secretion by Gastric Parietal cells
75
Neurocrines secreted & act:
* Made by neurons in GI tract
* Released after action potential
* Diffuse across synapse to act on target
76
All contractile muscle is smooth muscle EXCEPT:
a) Pharynx
b) ↑1/3 of Esophagus
c) External Anal Sphincter
77
GI Smooth Muscle =
Unitary Smooth Muscle
78
Cells in Unitary Smooth Muscle are electrically
Coupled via gap-junctions that are ↓resistance pathways = fast AP
79
Unitary Smooth Muscle Fast spread of AP =
coordinated + fast muscle contractions
80
Circular vs. Longitudinal Muscle
a) Circular Muscle: contraction shortens a ring of smooth muscle = ↓diameter at a certain segment
b) Longitudinal Muscle: contraction shortens a length of smooth muscle = ↓length of a certain segment
81
Phasic vs. Tonic Contraction
a) Phasic: period contraction then relaxation; found in esophagus, gastric antrum, small intestine = mixing/propelling tissues
b) Tonic: constant low-level contraction without relaxation; found in upper/orad stomach & sphincters (↓esophageal, ileocecal, internal anal sphincter)
82
orad define:
toward the mouth or oral region
83
Slow Waves:
Oscillating Depolarization & Repolarization of Membrane Potential in Gastric Smooth Muscle Cells
84
Slow Waves: Depolarization Phase:
Membrane potential becomes less negative & approaches threshold
a) If depolarization achieves threshold --> burst of APs on top of the slow wave
b) Mechanical response (contraction/tension) lags behind the electrical activity
85
Slow Waves: Repoalrization Phase:
Membrane potential becomes more negative away from threshold
86
Characteristics of Slow Waves Frequency:
Frequency of slow waves determines ==> frequency of APs ==> frequency of contraction
(1) Stomach has slowest frequency (3 slow waves/min)
(2) Duodenum has highest frequency (12 slow waves/min)
(3) Neural input or hormonal input DO NOT affect frequency of slow waves, but DO affect frequency of action potentials
87
Characteristics of Slow Waves Origin:
Interstitial Cells of Cajal
(1) “Pacemaker of GI Smooth Muscle”
(2) Found in myenteric plexus; transmits cyclic depolarization/repolarization to smooth muscle via ↓resistance gap junctions
88
Characteristics of Slow Waves Mechanism of Slow Wave:
(1) Depolarization: Ca++ Channels Open ==> ↑Influx of Ca++ ==> Depolarization
(2) Repolarization: K+ Channels Open ==> ↑Efflux of K+ ==> Repolarization
89
Characteristics of Slow Waves & Contraction
(1) Even the cyclic depolarizations that do not achieve threshold result in weak tonic contraction
(2) Depolarizations that achieve threshold result in phasic contraction
(a) The ↑#APs on top of depolarization ==> ↑Duration of Phasic Contraction
90
Chewing - Three Functions
1. Mixes food with saliva = wets & lubricates food to allow swallowing
2. ↓Size of food particles
3. Mixes CHO with salivary amylase = kicks off CHO digestion
91
Voluntary vs. Involuntary Chewing
1. Involuntary: sensory information via mechanoreceptors goes to brainstem --> reflex oscillatory chewing
2. Voluntary: overrides involuntary reflex chewing at any time
92
Swallowing:
Voluntary ---> Involuntary
93
Initiation of swallowing is
voluntary in the mouth, then involuntary in the pharynx & beyond
94
Swallowing Regulated by the
swallowing center in the medulla
95
Sensory information (food in mouth) sensed via
somatosensory receptors in pharynx
96
Information carried to medulla swallowing center via
CN IX and X
97
Medulla sends efferent innervation to
striated muscle in the pharynx & ↑1/3 of esophagus
98
Three Phases of Swallowing:
1. Oral Phase:
2. Pharyngeal Phase:
3. Esophageal Phase:
99
Swallowing Oral Phase:
tongue pushes bolus to pharynx, where there are ↑↑↑somatosnesory receptors
100
Swallowing Pharyngeal Phase:
propel food through pharynx to esophagus in the following order:
• Soft palate pulls upward to prevent reflux into nasopharynx
• Epiglottis close opening of larynx (∴breathing inhibited during pharyngeal phase)
• Upper esophageal sphincter relaxes creating an opening for food into esophagus
• Peristaltic wave is initiated
101
Swallowing Esophageal Phase:
overlaps with esophageal motility
102
Esophageal Motility: Upper esophageal sphincter opens during
the pharyngeal phase of swallowing
• Bolus of food moves from pharynx to esophagus
• Upper esophageal sphincter closes to prevent reflux into pharynx
103
Esophageal Motility Primary Peristaltic Contraction:
mediated by swallowing reflex
| • Series of coordinated sequential contractions that generate pressure just behind bolus, pushing it along
104
Esophageal Motility Food Approaches Lower Esophageal Sphincter - Three Things Happen
* Lower esophageal sphincter opens from vagal nerve release of VIP (Vasovagal Reflex)
* Orad region of stomach relaxes; ↓P_orad allows bolus in stomach (“Receptive Relaxation”)
* Lower esophageal sphincter closes P_Sphincter > P_Orad or P_Esophageal
105
Esophageal Motility Secondary Peristaltic Contraction -
back up to primary peristaltic contraction via enteric system
• If primary peristaltic contraction doesn’t clear food, secondary peristaltic contraction begins
106
Esophageal Motility Pressure & the Esophagus:
* Recall, P_intrathoracic is negative ===> P_Esophageal is also negative
* P_abdomen > P_Esophagus
107
Esophageal Motility: Two consequences of negative intra-esophageal pressure, explaining purpose of esophageal sphincters
1. Air can enter the esophagus ==> Upper Esophageal Sphincter prevents this
2. Gastric contents can enter the esophagus ==> Lower Esophageal sphincter prevents this
* ***In obesity or pregnancy, P_abdomen > P_Lower_Esophageal_Sphincter = GERD
108
Gastric Motility Muscles of Stomach:
outer longitudinal layer --> middle circular layer --> inner oblique layer
• ↑Thickness of muscle wall from proximal to distal end of stomach
109
Gastric Motility Structural Organization:
Fundus + Body + Antrum
110
Gastric Motility Orad =
fundus + proximal portion of body --> thin walled for weaker contractions
111
Gastric Motility Caudad =
distal body + antrum --> thick walled for stronger contractions to mix & propel food
112
Gastric Motility Innervation
* Extrinsic Parasympathetic + Sympathetic Innervation
| * Intrinsic Enteric Innervation from Myenteric & Submucosal Plexuses
113
Gastric Motility Three Phases:
1. Receptive Relaxation
2. Mixing & Digestion
3. Gastric Emptying
114
Gastric Motility Receptive Relaxation -
Orad Territory
• Function of orad region is receive bolus by relaxing when lower esophageal sphincter distends
• Relaxation of orad region = ↓P_Orad = ↑V_Orad = bolus can enter stomach
115
Gastric Motility Mixing & Digestion -
Caudad Territory
• Contractions around mid-/distal-body break down bolus (chyme), mix gastric contents, & propel food
• ↑Strength of contractions distally also close pylorus ---> chyme pushed back into stomach (“Retropulsion”)
116
Gastric Motility Parasympathetic stimulation & gastrin/motilin =
↑frequency of APs & contraction force (x slow waves)
117
Gastric Motility Sympathetic stimulation & secretin/GIP =
↓frequency of APs & contraction force (not slow waves)
118
Gastric Motility Gastric Emptying -
Monitored to ensure appropriate size ( slows gastric emptying --> ↑time for absorption of fatty gastric contents
• ↑H+ = ↑enteric reflex --> myenteric plexus slows gastric emptying --> ↑time for HCO3- neutralization
119
Throughout stomach & small intestine, migrating myoelectric complexes are
Mediated by motilin. These are periodic contractions (every 90 mins) during fasting that clear stomach & SI of residual food/chyme contents.
120
Small Intestine Motility
| Innervation:
1. Parasympathetic Innervation (Vagus Nerve): ↑contraction of intestinal smooth muscle
2. Sympathetic Innervation (Celiac + Superior Mesenteric Ganglion): ↓contraction of intestinal smooth muscle
121
Small Intestine Motility Segmentation & Peristaltic Contractions ~ Coordinated by
Enteric System
122
Small Intestine Motility Segmentation Contractions =
MIX CHYME
• Contraction occurs within a bolus of chyme
• Bolus of chyme is split, some sent in the orad direction & in the caudad direction
• Back/forth movement mixes chyme, no propulsion
123
Small Intestine Motility Peristaltic Contractions =
PROPEL CHYME
• Contraction occurs behind bolus of chyme & relaxation occurs in front of bolus of chyme
• Chyme is propelled forward
• Simultaneous contraction/relaxation is regulated by parasympathetic/sympathetic innervation respectively
124
Small Intestine Motility Vomiting ~ Regulated by
Vomiting Center in Medulla
125
Small Intestine Motility Vomiting Sensory innervation:
Vestibular system, back of throat, GI tract, & chemoreceptors in 4th ventricle
126
Small Intestine Motility Vomiting Motor innervation:
↑reverse peristalsis beginning at SI --> relaxation of stomach & lower esophageal
sphincter --> inspiration to generate ↑P_Abdominal --> YAK!
127
Large Intestine Motility Overview:
* Material not absorbed in SI is sent to LI, where it is called feces
* SI contents pass through the ileocecal valve, followed by contraction of the ileocececal sphincter
* Prevents reflux into SI
128
Large Intestine Motility Segmentation Contractions:
1. As in SI, segmentation contractions occur in the middle of a bolus of feces to mix contents
2. Mediated by haustra
129
Large Intestine Motility Mass Movements:
~ 1-3/day
1. Function to move contents of LI over long distances
2. As mass movements occur, water absorption occurs in the distal colon; contents become more difficult to move as feces approaches rectum
130
Large Intestine Motility: Defecation: As rectum enlarges with entering feces
smooth muscle of rectum contracts & internal anal sphincter relaxes (“Rectosphincteric Reflex”)
131
Large Intestine Motility Defecation: Defecation requires that the
external anal sphincter also relaxes; this occurs when rectum is 25% full
132
Large Intestine Motility Defecation: When appropriate, external anal sphincter relaxes & smooth muscle in anal canal contracts =
defecation
133
Large Intestine Motility Gastrocolic Reflex: Distention of stomach by food =
↑Motility of Colon + ↑Frequency of Mass Movements
134
Large Intestine Motility Gastrocolic Reflex:
| Afferent limb:
mediated by parasympathetics in stomach
135
Large Intestine Motility Gastrocolic Reflex:
| Efferent limb:
mediated by hormones CCK & gastrin
136
Salivary Secretions ~
1 Liter/Day
137
Structure of Parotid Glands:
serous cells secreting aqueous fluid (=water, ions & enzymes)
138
Structure of Submandibular & Sublingual Glands:
serous AND mucous cells secreting aqueous
| fluid AND mucin glycoproteins
139
Acinus:
Cluster of Grapes of Glands = Cluster of Acinus
140
Acinus: blind end of duct lined with
acinar cells where saliva is produced
141
Saliva from acinus through
short intercalated duct lined with myoepithelial cells
142
Myoepithelial cells neuronal stimulation -->
contraction / ejection of saliva
143
Saliva then passes through striated duct lined with
ductal cells
144
Ductal cells alter the
electrolyte composition of the saliva
145
Both parasympathetic & sympathetic stimulation =
↑Saliva Production (Parasympathetic > Sympathetic)
146
Effect of Flow Rate on Saliva Composition:
| ↑Flow Rate =
↓Contact time original saliva has with ductal cells =
| ↓absorption / ↓secretion = isotonic saliva ~ plasma
147
Effect of Flow Rate on Saliva Composition
| ↓Flow Rate =
↑Contact time original saliva has with ductal cells =
| ↑absorption / ↑secretion = hypotonic saliva
148
Effect of Flow Rate on Saliva Composition
| EXCEPTION =
HCO3-
(1) Bicarbonate: ↑concentration should follow ↓flow rate
(2) Bicarbonate secretion is selectively stimulated only when saliva production is stimulated; it is more dependent on para/sympa innervation for saliva production than flow
(3) ∴↑[Bicarbonate] in saliva with ↑Flow Rate
149
Regulation of Salivary Secretion is
Salivary secretion is only neuronal control; no hormonal control
150
Regulation of Salivary Secretion Parasympathetic Input:
CNVII & CN IX
(1) Postganglionic fibers release AcH which bind to M-receptors gland cell
(2) M-Receptor activation = ↑IP3/Ca++
(3) ↑IP3/Ca++ = ↑Secretion
(4) ↑Para stimulation with conditioning, food, smell, nausea
(5) ↓Para stimulation with dehydration, fever, sleep
151
Regulation of Salivary Secretion Sympathetic Input:
T1-T3 & Superior Cervical Ganglion
(1) Postganglionic fibers release NE; bind to β-receptors
(2) ↑β-Receptor activation = ↑cAMP = ↑Secretion
152
Regulation of Salivary Secretion Net Effect of Parasympathetic & Sympathetic Input
(1) ↑Saliva Production
(2) ↑HCO3- Secretion (Selectively Secreted!)
(3) ↑Enzyme Secretion
(4) Contraction of Myoepithelial Cells
153
Gastric Juice ~
HCl, Pepsinogen, Intrinsic Factor & Mucus
154
Body: Cell Types
```
Parietal Cells (Oxyntic)
Chief Cells (Peptic)
```
155
Antrum: Cell Types
G Cells
| Mucosal Neck Cells
156
Parietal Cells (Oxyntic) Secretions:
HCl + Intrinsic Factor
157
Chief Cells (Peptic) Secretions
Pepsinogen
158
G Cells Secretions
Gastrin
159
Mucosal Neck Cells Secretions
Mucus, HCO3-, Pepsinogen
160
HCl Secretion ~
Parietal Cell’s Function to Acidify Gastric Contents to pH ~ 1-2
161
↓pH functions to convert inactive
pepsinogen (made by chief cells in body of stomach) --> active pepsin (protease for proteins)
162
Gastric parietal cells’ cellular mechanism based on structure of
luminal/apical & basolateral membranes
(1) Luminal Membrane: H+/K+ ATPase + Cl- Channel
(2) Basolateral Membrane: Na+/K+ ATPase + Cl-/HCO3- Exchanger
(3) Cell contains carbonic anhydrase
163
Cellular Mechanism ~ Net HCl secretion + HCO3- absorption
(1)CO2 produced by aerobic metabolism combines with H2O --> H2CO3 --> H+ + HCO3-
(2)H+ is secreted into the lumen against its’ gradient via the apical membrane H+/K+ ATPase
(a)H+/K+ ATPase or H+ secretion is the target of PPI (Omeprazole)
(3)Cl- follows H+ via diffusion through Cl- channel ==> HCl secretion into lumen is complete
(4)HCO3- is absorbed into blood stream via basolateral Cl-/HCO3- exchanger ==> HCO3-
absorption is complete
(a)↑pH just after meal occurs because of the ↑HCO3- absorption
164
Regulation of HCl Secretion
(1) AcH = Neurocrine
(2) Histamine = Paracrine
(3) Gastrin = Hormone
165
Regulation of HCl Secretion
| AcH = Neurocrine
(a) ↑AcH --> ↑M3 Activation on Parietal Cells --> ↑DAG + IP3 --> ↑Ca++ --> ↑H+ Secretion by Parietal Cells
(b) Blocked by atropine
166
Regulation of HCl Secretion
| Histamine = Paracrine
(a)↑Histamine from Enterochromaffin Like Cells (ELC) --> ↑H2
Receptors --> ↑Gs-PCR --> ↑cAMP --> ↑H+ Secretion
(b)Blocked by cimetidine
167
Regulation of HCl Secretion
| Gastrin = Hormone
(a)↑Gastrin from G Cells in Antrum --> ↑Gastrin in Systemic Blood --> ↑Gastrin to CCKB --> ↑IP3/Ca++ --> ↑H+
168
Regulation of HCl Secretion
| Interaction of AcH, Histamine & Gastrin
(i) Rate of H+ secretion is regulated by each but also from their interactions = “Potentiation”
(ii) ↑H+ Secretion b/c the stimulants act on different receptors & in some cases via different 2nd messengers
(iii) ↑H+ Secretion b/c atropine & gastrin activate ECL cells --> ↑Histamine Release via 2nd mechanism
169
Stimulation of H+ Secretion:
| Vagus nerve innervates gastric parietal cells & G cells in antrum of stomach directly, but
by different nuerotransmitters
170
Stimulation of H+ Secretion:
| Vagus nerve --> parietal cells -->
AcH release --> HCl Secretion
171
Stimulation of H+ Secretion:
| Vagus nerve --> G cells -->
GRP release --> Gastrin Secretion --> Blood -->
| Parietal Cells --> H+ Secretion
172
Stimulation of H+ Secretion:
| Consequence of Atropine?
Atropine will block the direct effects of AcH on parietal cells, but will not block the indirect effects of vagus nerve on G cells, as this neurotransmitter is different (GRP)
173
Three Phases of Gastric HCl Secretion:
Cephalic, Gastric & Intestinal
174
Phases of Gastric HCl Secretion:
| Cephalic (30%) Stimuli:
1. Smell
2. Taste
3. Conditioning
175
Phases of Gastric HCl Secretion:
| Cephalic (30%) Mechanism:
1. Vagus Nerve --> Direct Innervation of Parietal Cells (AcH)--> HCl Secretion
2. Vagus Nerve --> Direct Innervation of G Cells (GRP)--> Gastrin --> Indirect HCl Secretion
176
Phases of Gastric HCl Secretion:
| Gastric (60%) Stimuli: Distention of Stomach
Mechanism:
1. Vagus Nerve --> Direct Innervation of Parietal Cells (AcH)--> HCl Secretion
2. Vagus Nerve --> Direct Innervation of G Cells (GRP)--> Gastrin --> Indirect HCl Secretion
177
Phases of Gastric HCl Secretion:
| Gastric (60%) Stimuli: Distention of Antrum
Mechanism:
| Distention of antrum --> local reflex stimulation of gastrin --> indirect HCl secretion
178
Phases of Gastric HCl Secretion:
Gastric (60%) Stimuli:
1. AA & Small Peptides
2. Caffeine/Alcohol
Mechanism:
| Direct AA & Small Peptide stimulation of gastrin --> indirect HCl secretion
179
Phases of Gastric HCl Secretion:
| Intestinal (10%) Stimuli/Mechanism:
Products of protein digestion
180
Inhibition of H+ Secretion:
| Movement of Chyme Into SI (↓pH)
(a) When chyme moves to SI, pepsinogen activation via ↓pH is no longer needed; HCl secretion needs to be inhibited
(b) Loss of foodstuffs/chyme = loss of H+ buffer = relative excess of H+ = ↓pH
(c) ↓pH --> ↓gastrin release --> indirect ↓parietal cell H+ secretion
181
Inhibition of H+ Secretion:
| Somatostatin
(a) Direct Pathway: somatostatin + Gi-PCR Parietal Cell Receptors --> ↓AC --> ↓cAMP --> ↓H+ Secretions
(b) Indirect Pathway: somatostatin --> ↓ECL Histamine Release + ↓G Cell Gastrin Release --> ↓H+ Secretions
182
Inhibition of H+ Secretion:
| Prostaglandins
PGs --> ↓Gi-PCR Parietal Cell Receptors -->
| ↓AC --> ↓cAMP --> ↓H+ Secretions
183
Review of Protective Mechanisms to prevent Peptic Ulcer Disease (PUD)
1. Mucus: secreted by mucous neck glands,
forming protective gel like layer
2. HCO3-: secreted by parietal cells, trapped
in mucous, neutralizes H+ & pepsin (requires ↓pH for activity)
3. PGs: inhibit release of H+ by antagonizing
cAMP (histamine) pathway
4. Growth Factors / Blood Flow
184
Review of Potentially Damaging Mechanisms Peptic Ulcer Disease (PUD)
Review of Potentially Damaging Mechanisms
1. Excess H+
2. Pepsin
3. Helicobacter Pylori Infection
4. NSAIDS (anti-PGs)
5. Stress, Smoking, Alcohol
185
Gastric Ulcers
| Defect:
Mucosal Barrier
| H+ & pepsin can digest protective mucosa
186
Gastric Ulcers
| Etiology & Pathogenesis
1. H. Pylori colonizes gastric mucosa because it
secretes urease which ↑pH surrounding pH
2. H. Pylori attaches to parietal cells --> ↑cytokines
3. ↑Cytokines --> Damage to Parietal Cells
187
Gastric Ulcers
| H+ & Gastrin Secretions
1. ↓H+ Secretion b/c H+ gets in damages mucosa
| 2. ↑Gastrin Secretion b/c ↓H+ Secretion
188
Gastric Ulcers
| Diagnosed:
```
Diagnosed with CO2 breath test post-ingestion
of urea (converted to CO2+NH3 via urease)
```
189
Duodenal Ulcers
| Defect:
↑H+ Secretions
190
Duodenal Ulcers
| Etiology and Pathogenesis:
1.H. Pylori colonizes gastric mucosa & indirect effect is ↓somatostatin secretion
2. ↓Somatostatin = ↓inhibition of G cells --> ↑Gastrin Secretion --> ↑H+ secretion to inhibit excess Gastrin
3.H. Pylori spreads to duodenum --> ↓HCO3- from
pancreatic secretions
4.Overall, ↑H+ of Duodenum & ↑Mass of Parietal Cells (Trophic Effects)
191
Duodenal Ulcers
| H+ & Gastrin Secretions
1. ↑Gastrin Secretion
| 2. ↑H+ Secretions
192
Zollinger-Ellison Syndrome (Gastrinoma)
| Defect:
↑↑↑Gastrin Secretions (Pancreatic Tumor)
193
Zollinger-Ellison Syndrome (Gastrinoma)
| Etiology & Pathogenesis:
1. Pancreatic tumor secretes excess gastrin
2. ↑Gastrin --> ↑H+ and ↑Parietal Mass
3. ↑Gastrin --> ↓pH of duodenum --> ulcer +
inactivation of pancreatic lipases
4. ↓Lipase activity --> steatorrhea
5.Gastrin not feedback inhibited (neoplasia)
194
Zollinger-Ellison Syndrome (Gastrinoma)
| H+ & Gastrin Secretions:
1. ↑Gastrin Secretion
| 2. ↑H+ Secretions
195
Gastric Ulcers, Duodenal Ulcers, & Zollinger-Ellison Syndrome (Gastrinoma):
Treatment:
Tx w/Cimetidine and Omeprazole
196
Pepsinogen Secretion
Recall, pepsinogen is secreted by chief cells & mucous cells in oxyntic glands & is activated by ↓pH to digest proteins
197
Pepsinogen Secretion
| Stimuli for Pepsinogen Secretion:
(1) Vagal Stimulation
(2) H+ Secretion --> ↑Local Reflex --> ↑Chief Cell Stimulation --> ↑Pepsin Release
This ensures that pepsinogen will only be secreted when the pH is low enough to activate it to pepsin
198
Intrinsic Factor Secretion
1. Mucoprotein secreted by gastric parietal cells require for B12 absorption in the ileum
2. Deficiency of IF --> Pernicious Anemia
199
Pancreatic Secretions:
~ HCO3- & Enzymatic Components
200
Structure of Pancreatic Exocrine Glands:
| Acinus:
Blind end branching duct lined with acinar cells responsible for the enzymatic component of pancreatic secretions
201
Structure of Pancreatic Exocrine Glands:
| Ductal Cells:
Epithelium that line the ducts; has specialized extension into acinus called centroacinar cells
202
Structure of Pancreatic Exocrine Glands:
| Centroacinar Cells:
Responsible for the HCO3- component of pancreatic secretions
203
Innervation of Exocrine Pancreas
| Sympathetic Innervation =
↓Pancreatic Secretion
| (1) Sympathetic innervation from post-ganglionic nerves from celiac & superior mesenteric plexues
204
Innervation of Exocrine Pancreas
| Parasympathetic Innervation =
↑Pancreatic Secretion
(1) Parasympathetic innervation from vagus nerve preganglionic --> synapse in enteric system --> synapse in exocrine tissue
205
```
Formation of Pancreatic Secretion
Enzymatic Component (Acinar Cells):
```
(1) Enzymatic components includes amylases & lipases (secreted as active enzymes) or proteases (need activation)
(2) Made in the RER of Acinar Cells --> Golgi Apparatus --> Packaged as Zymogens --> Stored Until Stimulus Arrives
206
Formation of Pancreatic Secretion
HCO3- Aqueous Component
(Centroacinar / Ductal Cells)
Centroacinar
(1) Aqueous component is isotonic solution of Na+, Cl-, K+ & HCO3-
(2) Centroacinar cells secrete initial isotonic component & ductal cell transporters modify component
(a) Apical Transporters: Cl-/HCO3- Exchanger
(b) Basolateral Membrane: Na+/K+ ATPase & Na+/H+ Exchangers
207
Formation of Pancreatic Secretion
HCO3- Aqueous Component
(Centroacinar / Ductal Cells)
Ductal Cells
(1) Ductal cell Carbonic Anhydrase combines CO2 + H2O --> H2CO3 --> H+ + HCO3-
(a) HCO3- is secreted into pancreatic juice (lumen) via apical transporter & H+ is absorbed into the blood
(2) Net Result: HCO3- secreted into pancreatic ductal juice & H+ acidifies pancreatic venous blood
(a) Note how this is opposite (balances!) the HCl secreting parietal cells of the stomach
208
Δ Pancreatic Flow Rates yield changes in
ΔPancreatic Flow Rates yield changes in HCO3- & Cl concentrations, but not Na+ and K+
209
Δ Pancreatic Flow Rates Unlike the relationship for the salivary glands
(a)↓Flow Rate = ↓HCO3- and ↓Cl-
(b)↑Flow Rate = ↑HCO3- and ↑Cl-
Explanation:
(a)At ↓rates of secretion, secretion is Na+ & Cl-
(b)At ↑rates of secretion, secretion is Na+ & HCO3-
210
Regulation of Pancreatic Secretion
Acinar Cells ~ Enzymatic Secretion
CCK From I-Cells
1. Stimulated by AA, peptides & FA in SI lumen
• AA phenylalanine, methionine & tryptophan
are most potent stimuli for CCK secretion
2. CCK acts via IP3/Ca++ signaling pathway -->
↑Secretions
211
Regulation of Pancreatic Secretion
Acinar Cells ~ Enzymatic Secretion
AcH
1. Stimulates AcH muscarinic receptors on the
pancreatic acinar cells
2. Potentiates CCK action via vasovagal reflex
212
Regulation of Pancreatic Secretion
Ductal Cells ~ Aqueous Secretion
Secretin From Duodenal S-Cells
1. Secreted in response to ↑H+ in chyme from
stomach (=↓pH)
2. Stimulates ↑HCO3- secretion from pancreas
3. Ensures activity of ↑pH-requiring pancreatic
lipases
213
Regulation of Pancreatic Secretion
Ductal Cells ~ Aqueous Secretion
CCK
Potentiates secretin effects
214
Regulation of Pancreatic Secretion
Ductal Cells ~ Aqueous Secretion
AcH
Potentiates secretin effects
215
Three Phases of Pancreatic Secretion
1. Cephalic Phase:
2. Gastric Phase:
3. Intestinal Phase:
216
Pancreatic Secretion
| Cephalic Phase:
Initiated by smell, taste & conditioning via Vagus Nerve; enzymatic component
217
Pancreatic Secretion
| Gastric Phase:
Initiated by distention of stomach via Vagus Nerve; enzymatic component
218
Pancreatic Secretion
| Intestinal Phase:
Important (80% of secretion); enzymatic & aqueous components are secreted
219
Circuit of Biliary System Step 1:
Hepatocytes constantly synthesize & secrete bile
220
Circuit of Biliary System Step 2:
Bile flows from liver via bile ducts to fill gallbladder, where it is stored
• Gallbladder concentrates bile via H2O & ion absorption
221
Circuit of Biliary System Step 3:
Stored bile flows into lumen of duodenum
• Chyme in duodenum --> ↑CCK release --> contraction of gallbladder + relaxation of
sphincter of ODI
• Bile emulsifies & solubilizes the water-insoluble dietary lipids
222
Circuit of Biliary System Step 4:
Post-lipid absorption, bile is recycled via enterohepatic circulation (portal blood)
• Ileum: Na+/Bile Salt cotransporter reabsorbs bile into the portal blood; important this occurs in ileum; bile salts around for lipid metabolism for entire length of SI!
• Portal blood takes bile salts back to hepatocytes for extraction
223
Circuit of Biliary System Step 5:
Bile from the portal circulation is extracted by the hepatocytes
• Only small amount of bile salts are excreted in the feces (600 mg/day of 2.5 g total)
• Enzyme for bile (cholesterol 7α-Hydroxylase) is inhibited by bile salts coming back
• ↑Bile salts from portal --> ↑Biliary Secretion of Bile Salts (“Choleretic Effect)
224
Composition of Bile ~
Bile Salts (50%) + Phospholipids (40%) + Cholesterol (4%) + Bilirubin (2%) + Ions/Water
225
Bile Salts: Represent Modification of Two Primary Bile Acids
Primary Bile Acids:
| Cholic Acid + Chenodeoxycholic Acid
226
Bile Salts: Secondary Bile Acids:
Deoxycholic Acid + Lithocholic Acid
227
Secondary bile acids are converted from primary bile acids via
intestinal bacteria post-release into SI
228
Bile Salts: Liver conjugates bile acids (cholic, deoxycholic, chenodeoxycholic & lithocholic acids) with taurine or glycine to form
eight distinct bile salts
229
Pre-conjugation, the pK of these bile salts
~7
230
Duodenal pH ~ 3-5, thus pre-conjugation bile acids (primary or secondary) would be in the
non-ionized (and therefore insoluble) form
231
Post-conjugation, the pK of these bile salts ~1-4; now they can exist in
ionized form in the duodenum & succesfully
| emulsify lipids for absorption & digestion as micelles (+ due to amphipathic properties)
232
Phospholipids & Cholesterol - included in micelles & (the phospholipids) help package
lipids in micelles
233
Bilirubin
~ Yellow-colored Pigment
234
RES metabolizes hemoglobin -->
bilirubin --> liver metabolizes bilirubin via glucuronidation --> bilirubin glucuronide
235
Bilirubin Glucuronide =
Conjugated Bilirubin = Yellow Pigment
236
Conjugated Bilirubin -->
secreted into intestine --> converted to urobilinogen via intestinal bacteria
237
Urobilinogen -->
Urobilin & Sterobilin (Dark Color in Stool)
238
Absorption (villi-mediated) can occur by two mechanisms:
cellular (substance crosses both apical & basolateral membranes) OR paracellular
(substance cross tight junctions in between cells into blood)
239
Everything is absorbed in the small intestine except
Vitamin B12 & Bile Salts, which are absorbed in the ileum
240
All CHO broken down into
glucose, galactose, fructose
241
Disaccharides
```
1. Trehalose-->2xGlucose
• Enzyme: Trehalase
2. Lactose-->Glucose+Galactose
• Enzyme: Lactase
3. Sucrose-->Glucose+Fructose
• Enzyme: Sucrase
```
242
Sucrase:
the hydrolysis of sucrose to fructose & glucose
243
α-Amylase:
linear α(1,4) glycosidic linkages, makes maltose
244
α-Dextrinsase:
Hydrolysis of (1->6)-alpha-D-glucosidic linkages
245
Maltase:
only alpha form of the maltose to glucose.
246
Glucose & Galactose
| Apical Membrane:
* Absorbed via Na+/Glucose SGLT1 Cotransporter
| * Occurs against electrochemical gradient, driven by basolateral Na+/K+ ATPase
247
Glucose & Galactose
| Basolateral Membrane:
Facilitated diffusion via GLUT2
248
Fructose
| Apical Membrane:
Absorbed via GLUT5,
249
Fructose
| Basolateral Membrane:
Facilitated diffusion via GLUT2
250
Lactose Intolerance
* Failure to break down lactose into monosaccharides from lactase deficiency
* Lactose is non-absorbable & holds water in the lumen --> osmotic diarrhea
251
All protein broken down into
AA, dipeptides & tripeptides via proteases in stomach & SI
252
Stomach: Pepsin activated from pepsinogen by
↓pH; inactivated in duodenum by pancreatic aqueous (HCO3-) secretions
253
SI Enterokinase (BB enzyme) activates
trypsinogen-->trypsin
254
SI Trypsin activates the others:
- Chymotrypsinogen->Chymotrypsin
- Proelastase->Elastase
- Procarboxypeptidase A/B -> Carboxypeptidase A/B
- Auto-activates more of itself: Trypsinogen->Trypsin
255
Unlike CHO, protein can be
absorbed as larger molecules
256
L-Amino Acids
| Apical Membrane:
* Absorbed via Na+/AA Cotransporter
| * Powered via Na+/K+ ATPase
257
L-Amino Acids
| Basolateral Membrane:
* Facilitated diffusion
| * On both apical/basolateral side there are separate transporters for acidic, basic, neutral, imino AA
258
Dipeptides & Tripeptides
| Apical Membrane:
* Absorbed via H+/Di-Tripeptide Cotransporter
* Powered by Na+/H+ apical cotransporter
* Majority hydrolyzed by peptidase
259
Dipeptides & Tripeptides
| Basolateral Membrane:
* AA via facilitate diffusion
| * Peptides absorbed unchanged
260
Chronic Pancreatitis / CF proteins:
* Deficiency of all pancreatic enzymes (more than proteases)
* Even if trypsin alone was lost, all proteases would be inactive
* Recall that role of pepsin in protein digestion (stomach) is not required
261
Cystinuria proteins:
* Genetic deficiency in apical transporter for cystine, ornithine, arginine, lysine in SI & kidney
* Excess cystine excreted in urine (cystinuria) & feces
262
Lipids Stomach start digestion:
• Lingual & gastric lipases start lipid digestion
-> MG + 2xFA
• CCK-mediated slowing of gastric emptying; ↑pancreatic digestion
• Lipids emulsified here by dietary protein (no bile salts in stomach)
263
Lipids Small Intestine digestion:
1. Bile salts emulsify lipids
2. Pancreatic enzymes:
• Pancreatic Lipase: MG + 2xFA
• Cholesterol Ester Hydrolase:
Cholesterol + FAs
• PLA2: Lysolecithin + FA
• Colipase: prevents bile-salt inactivation of pancreatic lipase
264
Lipids Products of Digestion
1.MGs + FAs - insoluble
2.Cholesterol - insoluble
3. Lysolecithin - insoluble
4.Glycerol - soluble
• Thus, micelles are needed to solubilize products for transport
265
Lipids Disorders
| Pancreatic Insufficiency
• ↓Lipid digesting enzymes
• ↓HCO3- secreted by pancreas;
lipid digesting enzymes inactivated at ↓pH
266
Lipids Disorders
| Acidity of Duodenum:
↑H+ (ZE Syndrome) inactivates lipid digesting enzymes
267
Lipids Disorders
| Deficiency of Bile Salts:
No solubilizing lipids; liver failure of ileal resection
268
Lipids Disorders
| Bacterial Overgrowth:
Bacteria convert bile salts -> bile acids (non-ionized form)
269
Lipids Disorders
| Decreased Intestinal Cells:
Tropical sprue: ↓Surface Area
270
Lipids Disorders
| Abetalipoproteineima
↓ApoB
271
Vitamins Fat Soluble
(A, D, E and K)
272
Vitamins Water Soluble
(B1, B2, B6, C, Biotin, Folic Acid, Nicotinic Acid,
| Pantothenic Acid)
273
Vitamin B12 Cleaved from
food in stomach by actions of pepsin
274
Vitamins Absorption Fat Soluble:
same as lipids
275
Vitamins Absorption Water Soluble:
Na+-Cotransporter
276
Vitamins Absorption Vitamin B12:
1. Cleaved B12 (stomach) binds RProteins made in saliva
2. SI: pancreatic lipases degrade RProtein, allowing B12 to bind IF secreted by parietal cells
3. Absorbed in ileum
277
Vitamins Disorder
| Pernicious Anemia
May follow gastrectomy (loss of IF) or ileal resection
278
Calcium Digestion
Cleaved from food in stomach & Small Intestine
279
Calcium Absorption
* Absorption mediated by 1-25 Dihydroxycholecalficerol (Vit D)
* Vit D --> ↑calbindin D-28K = Cabinding protein in SI
* Vit D synthesized in liver & renal tubules (1α-Hydroxylase)
280
Calcium Disorders
| Rickets & Osteomalacia:
Can occur with renal failure --> ↓1α-Hydroxylase --> ↓Vit D --> ↓Calbinding D-28K --> ↓Ca++
281
Fluids & Volumes in the GI Tract
| Total Volume of Fluid:
~ 9L = 2L Dietary Fluids + 7L GI Secretions
282
Fluids & Volumes in the GI Tract
| Majority is absorbed by
epithelial cells; 100-200 mL is excreted in feces
283
Fluids & Volumes in the GI Tract
| Disruption of absorption -->
Diarrhea
284
Fluids & Volumes in the GI Tract:
| In addition to absorbed fluid, the epithelial cells also
secrete some fluid
285
Fluids & Volumes in the GI Tract:
| Both absorption & secretion can occur
transcellularly or paracellularly; depends on presence or °leakiness of tight junctions
286
Villi-mediated absorption is always
isoosmotic; solute & water absorption occur simultaneously
287
Absorption Jejunum ~
Net Absorption of NaHCO3
288
Absorption Jejunum
| Apical Membrane:
Na+ absorbed via Na-Coupled Transporters (Na/Glucose; Na/AA; Na/H)
289
Absorption Jejunum
| Basolateral Membrane:
Na+/K+ ATPase (also involved in nutrient absorption) completes absorption
290
Jejunum Note H+ & HCO3- for Na/H apical cotransporter come from
H2O+CO2; H+ secreted via Na/H; HCO3- absorbed into blood --> ∴Net NaHCO3 absorption
291
Ileum ~
Net Absorption of NaCl
• HCO3- from CA-mediated action (in jejunum) is absorbed in the blood
• In Ileum, it is secreted into lumen by Cl-/HCO3- apical transporter --> ∴ Net NaCl absorption
292
Colon ~
Na Absorption & K Secretion
• Aldosterone mediated synthesis of Na+ channels --> ↑Na Absorption
• ↑Na+ entry into epithelial cell --> ↑activity of basolateral Na/K ATPase --> ↑K+ into cell -->
↑K Secretion
• K+ secretion is flow-rate dependent; ↑intestinal flow rate = ↑K+ Secretion = Hypokalemia
293
Epithelium lining crypts secrete fluid & electrolytes; different from
villi which mainly absorb
294
Cholera Mechanism:
* Normally, ions & H2O secreted by crypts are reabsorbed by the villi
* Cholera toxin A subunit detaches & catalyzes ADP ribosylation of α subunit of Gs protein coupled to AC
* ADP ribosylation inhibits GTPase activity of α subunit, inhibiting GTP --> GDP conversion --> ↑↑↑AC
* ↑↑↑AC --> ↑↑↑cAMP --> Excessive Secretion --> Secretory Diarrhea
295
Diarrhea Compensation Mechanism:
* Diarrhea --> ↓ECF --> ↓Arterial Pressure --> RAAS will attempt to correct
* Diarrhea --> ↓HCO3- (b/c intestinal fluid has ↑HCO3-) --> hyperchloremic metabolic acidosis
* Diarrhea --> ↓K+ (because flow rate dependent secretion of K+) --> hypokalemia
296
Disorder Diarrhea
| ↓Surface Area for Absorption ~
Inflammation and Infection of Small Intestine
297
Disorder Diarrhea
| Osmotic Diarrhea ~
↑Non-absorbable solutes in lumen (example: Lactase Deficiency)
298
Disorder Diarrhea
| Secretory Diarrhea ~
↑Secretion from Crypt Cells (example: Cholera)
299
Findings in Diarrhea
1. ↓Mean Arterial Pressure
2. Metabolic Acidosis
3. Hypokalemia
GI Liver
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