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Renal and GI

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Why does body Na+ content determine ECF volume?
(1) most of the body Na+ is in the ECF

(2) when solute moves, H20 follows

(3) the amount of Na+ in the ECF determines the amount of water in the ECF, which is the ECF volume
what 4 factors stimulate renin secretion?
(1) dec perfusion pressure
(2) inc symp
(3) dec distal delivery of Na+
(4) prostaglandins
what 4 factors inhibit renin secretion?
(1) inc perfusion pressure
(2) dec symp
(3) inc distal delivery of Na+
(4) ANP
what factor causes stimulation of angiotensin II secretion?
inc renin
what factor causes inhibition of angiotensin II secretion?
ACE inhibitors
what 3 factors stimulate aldosterone secretion?
(1) inc angiotensin II
(2) dec Pa (via RAA)
(3) hyperkalemia
what 3 factors inhibit aldosterone secretion?
(1) dec angiotensin II
(2) inc Pa (via RAA)
(3) hypokalemia
regulation of body Na+
- what are the effects of symp activation of the kidney?
(1) constriction of afferent arterioles (dec GFR)
(2) stimulation of Na+ reabsorption in the proximal tubule
ANP
atrial natriuretic peptide

released from atria in response to stretch of "low-pressure" sensors
regulation of body Na+
- what are the effects of ANP on kidney?
(1) dilation of afferent arterioles and constriction of efferent arterioles --> inc GFR
(2) inhibition of Na+ reabsorption in late distal tubule & collecting ducts
BNP
brain natriuretic peptide (first _discovered_ in brain)

secreted by the ventricles in response to inc pressure; actions are the same as ANP but even stronger
urodilatin
structurally similar to ANP; secreted by and acts on the distal nephron, causes a local inhibition of Na+ reabsorption, leading to inc Na+ excretion
pressure natriuresis
inc in arterial P per se causes an inc Na+ excretion; "washout" of factors that normally promote Na+ reabsorption
osmoreceptors
- located where?
- fxn?
in the hypothalamus detect the inc in osmolarity and trigger drinking behavior
ADH
- fxn
- synth where?
- stored where?
major regulator of body fluid osmolarity, alters water reabsorption in late distal tubule and collecting ducts

ADH is a peptide hormone that is synthesized in the hypothalamic neurons, packaged in vesicles, and transported down the axons of those neurons to the posterior pituitary, where it is stored until there is a stimulus for its release
what is the major physiologic stimulus for ADH secretion from the posterior pituitary?
inc in plasma osmolarity, detected by osmoreceptive neurons in the hypothalamus
describe the ADH response to hypovolemia
dec in BV (hypovolemia) --> "low-pressure" sensors send info via vagus to ADH-secreting hypothalamic neurons
ADH secretion: response to hypovolemia vs. response to inc osmolarity
- compare sensitivity & power
response of ADH to hypovolemia is less sensitive than the response to increased osmolarity

BUT

hypovolemic stimulus is more powerful and will "override" the osmotic stimuli
Name 6 "other" stimuli for ADH secretion.
(1) pain
(2) nausea
(3) angiotensin II
(4) hypoglycemia
(5) nicotine
(6) opiates
name two "other" inhibitors of ADH secretion
(1) ethanol
(2) ANP
what are the two major actions of ADH? what receptor is involved?
(1) inc water permeability in principle cells of late distal tubule and collecting ducts via insertion of water channels in the luminal membrane (V2 receptor on principal cells)

(2) contraction of vascular smooth muscle (V1 receptor on blood vessels)
Law of the Intestine
peristaltic reflex results in contraction of circular muscle and relaxation of longitudinal muscle orad or above the site of stimulation and relaxation of circular muscle and contraction of longitudinal muscle caudad or below the site of stimulation
(intestinal) peristalsis
- contraction of muscle layers is mediated by what?
both muscle layers are mediated by excitatory motor neurons (ACh / tachykinin)
(intestinal) peristalsis
- relaxation of circular muscle layer is mediated by what?
inhibitory motor neurons (VIP/NOS)
(intestinal) peristalsis
- relaxation of longitudinal muscle layer is mediated by inhibition of what?
inhibition of cholinergic/tachykinin motor neuron
what cell feature allows electrical events and second messengers to spread rapidly from cell to cell in gut smooth muscle?
gap junctions between cells
what are the two types of electrical activity that can be identified in gut smooth muscle?
(1) spikes or muscle APs

(2) slow waves also called basic electrical rhythm or control potentials
what does a gut slow wave consist of?
a rapid upstroke (depolarization), a partial repolarization, a sustained plateau lasting several seconds, and a complete repolarization to resting level
gut pacemaker cells
aka Interstitial Cell of Cajal

gut smooth muscle cells are coupled to these pacemaker cells which oscillate at a higher frequency than the intrinsic rate of smooth muscle cells; located at myenteric and submucosal jxns and have processes that contact both muscle cells and neurons
contraction of circular gut muscle above the site of distension is mediated by?
cholinergic neurons and tachykinin containing (substance P) neurons
relaxation below the site of distension is mediated by?
VIP/NO Synthase-containing neurons
tonic contraction
muscle in one area remains contracted over time; e.g. sphincters, proximal stomach, and gallbladder
segmental contraction
mixing contractions in local area which are not propagated; common in small intestine and colon
peristaltic contraction
propulsive, propagated contractions which move lumenal contents towards the anus; found throught the gut (except proximal stomach)
what are the initial events involved in swallowing?
(1) initial stimulus is mediated by activation of sensory nerve endings in the pharynx that respond to touch

(2) results in activation of swallowing center located in the lower pons and medulla

(3) once activated, swallowing begins by activation of cranial nerves and the vagal innervation of the esophagus
what are the three phases of the swallow?
(1) oral or voluntary phase
(2) pharyngeal phase
(3) esophageal phase
name the 4 steps of the pharyngeal phase of swallowing
(1) soft palate elevates to seal off the nasopharynx
(2) epiglottis closes over the larynx to close opening to trachea (respiration is inhibited)
(3) upper esophageal sphincter relaxes and the pharynx contracts to propel the bolus into the esophagus
(4) upper esophageal sphincter contracts behind the bolus
relaxation of LES is mediated by what?
release of vasoactive intestinal peptide and NO from myenteric neurons
what are the 4 anatomical regions of the stomach? give basic fxn of each
proximal (fundus and orad corpus) -- tonically contracted at rest, no slow waves, storage site for meal

corpus (mid and caudad) -- slow waves, mixes and stores food

antrum (distal stomach) -- very thick circular M and demonstrates slow waves with superimposed AP (spikes); very strong contractions serve to grind solid particles and propel food into small intestine
receptive relaxation of stomach
- involves which nerves?
involves vagal preganglionic nerves and myenteric relaxant nerves which contain VIP and NO synthase
which components of chyme slow gastric emptying and how?
acid -- release of secretin

lipid digestion products -- release of cholecystokinin and GIP from pancreatic islets

AAs -- release of CCK and gastrin

osmolarity -- both hypo and hyperosmolar solutions slow gastric emptying
what components of chyme are most effective at slowing gastric emptying?
lipid digestion products
what is the most likely physiological stimulus for intestinal peristalsis?
the mucosal reflex
mucosal reflex
IPAN activated indirectly --> serotonin released from enterochromaffin cells --> activates 5-HT4 receptor on IPAN --> release CGRP and P --> activates interneurons in the reflex arc
Axon Collateral Reflex
- aka
- what happens?
Distension Reflex

physical distension of gut activates an extrinsic afferent CGRP neuron originating in the dorsal root ganglion
Migrating Myoelectric Complex
- when occurs?
- three phases?
occurs during fasting

Phase 1 (Quiescence) 45-60 min
Phase 2 (Inc Contractile Activity)
Phase 3 (Muscle Contracting Intensely) 10 min
intestino-intestinal reflex
distension of one area of intestine results in inhibition of motility in other areas
gastro-ileal reflex
increase in activity in the stomach causes increased activity in the ileum to clear it of contents
ileocecal sphincter
- what two ways does it prevent movement from cecum --> ileum?
(1) has a fold or flap

(2) neural reflexes exist such that increase in intracecal pressure results in an increase in the sphincteric pressure
colon
- tenia coli
- haustra
longitudinal muscle gathers into three bands called tenia coli

circular muscle forms pouches called haustra
colono-colonic reflex
insures that distension of one region of the colon causes relaxation of other regions and is mediated by the S.N.S.
gastrocolonic reflex
distension of the stomach causes increased motility in the colon and increases the frequency of mass movements in order to prepare the way for material to arrive in the colon
defecation reflex
rectum distended --> activates stretch receptors --> reflex is intitiated through enteric and pelvic nerves to smooth muscle and pudendal nerves to the skeletal muscle (external anal sphincter) --> rectum contracts, internal anal sphincter relaxes and external anal sphincter contracts --> if neural inputs are inhibited --> defecation
list and describe the three major components of the juxtaglomerular apparatus
(1) juxtaglomerular cells surround the afferent arterioles and secrete renin

(2) macula densa is a specialized region of the early distal tubule that comes in close contact with its own glomerulus

(3) mesangial cells line the glomerulus and afferent and efferent arterioles
what are the two important fxns of juxtaglomerular apparatus?
(1) secrete renin

(2) tubuloglomerular feedback
what does it mean if the clearance ratio < 1.0
the substance is either not freely filtered or is filtered and subsequently reabsorbed
what are the two mechanisms that can be used to explain autoregulation of RBF and GFR?
(1) myogenic hypothesis -- afferent arterioles stretch and then contract, leading to increased resistance

(2) tubuloglomerular feedback -- inc RBF inc GFR --> inc flow to macula densa --> adenosine --> vasoconstriction of afferent arterioles --> dec RBF dec GFR
list and briefy describe the three layers of the glomerular capillary barrier
(1) endothelial layer of 70-100 angstroms, which has filtration pores

(2) a basement membrane

(3) an epithelial cell layer with podocytes that attach to the basement membrane by foot processes, interspersed with narrow filtration slits
sieving coefficient
expresses the ability of a particular solute to be filtered across the glomerular capillary barrier

1.0 means there is no restriction
what are the two major factors that determine filterability?
(1) MW (<5500 freely filtered)

(2) charge (neg charge restricted)
effects of sympathetic nervous system (alpha 1 receptors) on kidney
vasoconstriction of afferent and efferent
more alpha 1 receptors on afferent
dec RBF
dec GFR
effects of A-II on kidney
vasoconstriction of afferent and efferent
efferent more sensitive
dec RBF
inc or maintains GFR
effects of ANP on kidney
vasodilation of afferent
vasoconstriction of efferent
inc RBF
inc GFR
effects of NO on kidney
vasodilation of afferent and efferent
inc RBF
effects of prostaglandins on kidney
vasodilation of afferent and efferent

released locally (in kidney) in high vasoconstrictor states

modulate, or offset, vasoconstriction by sympathetic and A-II

protect RBF and GFR
effects of dopamine (low dose) on kidney
vasodilation of afferent and efferent
what is the cellular mechanism for glucose reabsorption in the kidney?
Na+-glucose cotransporter in luminal membrane of early proximal tubule
Tm
transporters saturated
threshold
e.g. glucose first starts appearing in urine
splay
threshold occurs before Tm
how can pregnancy lead to glucosuria?
inc GFR leads to inc filtered load of glucose
renal glucosuria
dec Tm due to dec # or affinity of the Na+-glucose cotransporter
parietal cells
secrete H+, needed for conversion of pepsinogen to pepsin, optimal pH, prevent bacteria

also secrete intrinsic factor (needed for vit B12 absorp in ileum)
chief cells
secrete pepsinogen, gastric lipase
histamine
released from enterochromaffin-like cells in lamina propria in response to vagal stimulation, activate H2 receptors on parietal cell --> inc HCl secretion
somatostatin
released from paracrine cells in mucosa, inhibit parietal cell HCl secretion
what are the three phases of gastric acid secretion?
(1) cephalic phase

(2) gastric phase

(3) intestinal phase
gastric acid section:
cephalic phase
sight or smell of food activates vagal reflex resulting in stimulation of the parietal cell directly as well as inducing the release of gastrin from the G-cell
gastric acid section:
gastric phase
presence of meal in stomach causes max stimulation of acid secretion; neural (local and vagal) mech directly stim parietal; G-cell release of gastrin stim by distension, protein digestion products, and neural activity
gastric acid section:
intestinal phase
presence of chyme in intestine and acid in antrum begin to inhibit acid secretion

- presence of food and acid in duodenum causes release of hormonones (GIP, CCK, secretin, entrogastrone) which inhibit acid secretion
7 ingested material alterations:
(1) emulsification of fat/lipid material
(2) initial conversion of triglyceride to FFA and diglyceride
(3) initial digestion of protein to oligo/polypeptides and few AAs
(4) initial digestion of large carbs and staches to produce some oligosaccharides
(5) some absorption of water and ions
(6) acidification of chyme
(7) large increase in osmolarity of chyme
zymogen granules
membrane bound vesicles in which all pancreatic enzymes are stored
what is the [TF/P]inulin ratio used to measure?
used to measure water reabsorption since inulin, once filtered, is "inert" (i.e. neither reabsorbed or secreted)
glomerulotubular balance
regulatory feature of the proximal tubule; says that glomerular filtration of Na+ (and solute and water) are balanced by reabsorption resulting in constant fractional reabsorption of 67%
where does the vast majority of GI absorption take place?
intestine
lacteals
part of villus, extensive network of lacteals removes lipids rapidly to maintain gradient for lipid absorption
starch
polymer of glucose mocecules linked by alpha-1-4-linkages and by alpha-1-6-linkages at branch points
sucrose
fructose and glucose
lactose
glucose and galactose
cellulose
glucose polymer of beta-1,4-linkages
glucose absorption in intestine
SGLT1 (Sodium-Glucose Linked Transport Protein 1) is carrier protein of mature epithelial cells (upper villus). Na+ is actively pumped out on basolateral membrane by a Na/K ATPase pump. Glucose is removed at basal membrane by facilitated transport using a carrier protein termed GLUT2 and removed by diffusion into capillaries of villus.
galactose absorption in intestine
SGLT1 & GLUT2 (same as glucose)
fructose absorption in intestine
enters epithelial cell by facilitated diffusion which uses different carrier (GLUT5) than glucose/galactose and which is not coupled to Na+. Once in cell, fructose leaves the basal side by facilitated diffusion using GLUT2.
pepsin
initial digestion of protein is by pepsin in stomach

optimal pH acidic, inactive at neutral pH

converts large peptides into smaller peptones and polypeptides
GIP
glucose-dependent insulinotrophic factor

released into blood by presence of glucose in the duodenal lumen, GIP acts on pancreatic endocrine cells to secrete insulin which then acts to inc uptake of nutrient glucose from blood
bile
- composed of
bile acids, water and electrolytes, cholesterol, phospholipids, proteins and wastes intended for excretion (bilirubin, drug metabolites)
where are bile salts reabsorbed? how?
in terminal ileum; enterocytes of the terminal ileum have sodium-linked carrier mechanisms for the reabsorption of bile salts; also reabsorbed passively
primary bile acids
- definition
- examples
synth by hepatocytes from cholesterol

e.g. cholic acid and chenodeoxycholic acid
secondary bile acids
- definition
- examples
primary bile acids modified in intestine by bacteria which dehydroxylate them

e.g.

cholic acid --> deoxycholic acid

chenodeoxycholic acid --> lithocholic acid
bile acids conjugated to what?
to either taurine or glycine
most lipid is ingested in the form of . . .
triglycerides
where does most lipid digestion occur? enzymes?
intestine; pancreatic lipase and co-lipase
intestinal absorption of lipids
absorption across the lumenal membrane of the intestinal epithelial cell is by passive diffusion
what factors increase the absorption of Ca2+ in the intestine?
parathyroid hormone and vit D
absorption of vit B12 requires?
intrinsic factor secreted by oxyntic cells of stomach
where is most of the body's K+ localized?
in the ICF
hyperkalemia
inc ECF or blood [K+]
hypokalemia
dec ECF or blood [K+]
what agents shift K+ into cells?
insulin and Beta Agonists
what agents / conditions shift K+ out of cells?
cell lysis, exercise, hyperosmolarity, lack of insulin
where in nephron does the K+ regulation occur?
distal tubule and collecting duct
what is the mechanism of K+ reabsorption in alpha-intercalated cells?
H+-K+ ATPase
what is the driving force governing the magnitude of K+ secretion from the principal cells?
the K+ electrochemical gradient
what four main factors alter K+ secretion?
diet, aldosterone, acid-base, flow rate
explain the mechanism of action of aldosterone on principal cells with regards to K+ secretion
inc aldosterone --> inc synth Na+ channels --> inc Na+ entry --> inc Na+ extrusion by Na+ - K+ ATPase --> inc K+ entry by Na+ - K+ ATPase --> inc electrochemical gradient --> inc K+ secretion

Also, aldosterone --> inc synth of K+ channels --> inc K+ secretion
acidemia affect on K+ secretion
inc H+ in blood --> inc H+ into cell / K+ out of cell --> dec [K+] --> dec K+ secretion
effect of flow rate on K+ secretion?
inc flow rate --> dilute [K+] in lumen --> inc K+ electrochemical gradient --> inc K+ secretion
describe how body brings plasma osmolarity back toward normal following deprivation of H2O
deprive H2O --> inc plasma osmolarity --> stimulates osmoreceptors in anterior hypothalamus --> inc ADH secretion from posterior pituitary --> inc H2O permeability in late distal tubule and collecting duct --> inc H2O reabsorption --> inc urine osmolarity and dec urine volume --> dec plasma osmolarity towards normal

Also stimulates osmoreceptors in anterior hypothalamus --> inc thirst
what effect does alcohol have on ADH secretion?
alcohol --> inhibits ADH secretion --> water diuresis
corticopapillary osmotic gradient
large osmotic gradient created in loop of Henle from outermost part of kidney (cortex) to innermost part (papilla)
what are the essential components in the formation of hyperosmotic urine?
(1) establishment of the corticopapillary gradient by loops of Henle

(2) vasa recta helps maintain gradient

(3) ADH
where does ADH increase urea permeability?
in the inner medullary collecting ducts
vasa recta
the capillaries which supply the medulla and papilla of the kidney with oxygen and nutrients necessary for active transport; also remove the water by the desc limbs of henle and the collecting ducts
show mechanism of action of ADH on principal cells
ADH binds to V2 receptor (basolateral) --> via Gs protein activates adenylate cyclase --> inc cAMP --> activates protein kinases --> phosphorylation --> insertion of AQP2 water channels luminal membrane
diabetes insipidus
absence of ADH or resistance of principal cells to ADH; large volumes of dilute urine excreted
free water clearance
the amount of water which must be subtracted from or added to urine to make it isosmotic with plasma
what is the expected effect of low ADH on the corticopapillary gradient?
decreased b/c ADH stimulates both countercurrent multiplication and recycling
what is required for production of hyperosmotic urine?
corticopapillary gradient and ADH
what is required for production of hyposmotic urine?
requies that diluting segments (TALH and early distal) be diluting and no or low ADH
central diabetes insipidus
absence of ADH (central diabetes insipidus)
nephrogenic diabetes insipidus
resistance of the principal cells to ADH (nephrogenic diabetes insipidus)
what three things cause the parietal cells to secrete acid?
gastrin, histamine, and ACh (Vagal)
Antral G cells secrete gastrin when?
in response to AA, FFA, and Vagal Stimulation
How does H. Pylori promote ulceration?
(1) induces local inflammation and damage to mucosal barrier

(2) inhibits somatostatin secretion --> remove negative feedback mechanism in fundus and antrum --> high HCl levels
ZE Syndrome
extremely high levels of gastrin due to presence of gastrin secreting tumor, No pylori present
what can urea breath test identify?
presence of H. pylori
proton pump inhibitor
e.g.
omeprazole
clearance eqn
Cx = UxV/Px
why is inulin a "glomerular marker"
inulin is filter, but is neither reabsorbed or secreted
GFR eqn
GFR = [U]inu x V / [P]inu
"Effective" RPF
[U]PAH x V / [P]PAH
"True" RPF
[U]PAH x V / [RA]PAH - [RV]PAH
RBF
RBF = RPF / (1-Hct)
Filtration fraction
- eqn
- approx value
FF = GFR / RPF
20%
filtered load
GFR x [P]x
excretion rate
[U]x x V

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