Intestinal Transport of Electrolytes and Water PDF

Section 9: Intestinal Transport of Electrolytes and Water I. Enterosystemic fluid balance: = movement of electrolytes and water between lumen of the GI tract and the ECF A. Absorptive processes balance digestiv...

Section 9: Intestinal Transport of Electrolytes and Water I. Enterosystemic fluid balance: = movement of electrolytes and water between lumen of the GI tract and the ECF A. Absorptive processes balance digestive secretions 1. Most fluid entering GI tract is from endogenous secretions 2. Small and large intestine recovers 98% of fluid Where does the extra fluid go? Urine Fig. 32 Enterosystemic fluid balance in 70 kg human (in ml/24 hr) Sweat 2 Liters Insensible losses (e.g., respiration) [hard to measure] 7 liters Fluid absorbed wth nutrients during a meal fluid absorbed by Total: 9 L of liquid in GI tract NaCl - couple absorption between meals 0.2 L lost in stool - 98% reabsorbed into system II. Functional morphology of the intestine A. Absorption Villus - Small intestine Surface epithelium - Large intestine B. Secretion Crypt - Both small and large intestine Fig. 33 Villus: differentiated epithelium digestion by brush border enzymes absorb nutrients, electrolytes, and water Enterocyte = absorbative cell Crypt: undifferentiated (stem cells, transit-amplifying cells) proliferation secrete electrolytes and water 56  III. Small intestine: Electrolyte and water absorption A. Na+-coupled nutrient absorption 1. Na+ absorbed with nutrient substrate (S) Fig. 34. Small intestine: Na+- coupled nutrient transport Typically, 1 Na+ : 1 substrate (e.g., glucose) Lumen Blood Most transporter are nutrent-specific; driven by Na+ gradient Absorbs vs. concentration gradient Substrate Na+ 2. Little neuroendocrine control Facilitated Diffusion Ex.: SGLT1 Depends on nutrient availabilty Substrates: Na+ Hexoses K+ L- Amino acids B-Vitamins Bile salts 3. Oral rehydration solutions Cl- Ex: Pedialyte (Na, K, Cl, Mg, Citrate, Glucose) Why is glucose added? its not for energy supplementation! NaCl NaCl NaCl NaCl NaCl NaCl Glucose increase Na+ absorption via Na+ - coupled glucose transport > H2O Cl- follows via eletrical gradient > H20 follows via osmotic gradient = increase NaCl + H2O absorption B. H+-coupled nutrient absorption 1. Driven by outside to inside cell pH gradient Cell surface: < pH 7.0 (due to Na+/H+ exchange) Result: H+ gradient Cell interior: > pH 7.0 2. H+-di-/tri-peptide transporter, Pept1 – Main pathway for amino acid absorption Transports digested peptides of 2- or 3- amino acid length Driven by H+ gradient Fig. 35. Small intestine: H+-coupled Entering H+ recycled by Na+/H+ exchange nutrient transport Lumen Peptides Able to transport ~400 dipeptides and ~8,000 tripeptides H+ Peptide Transport Peptidases Pept1 Transports some drugs (ACE inhibitors, cephalosporin Di-/Tri- Peptides Amino Acids antibotics) H+ AA Transport 3. H+-amino acid transporter, PAT1 Amino PAT1 Acids Only transports a few amino acids H+ Na+ K+ Similar mechanism to Pept1, but for single AA (mainly proline) NHE Na+ Blood 57  C. Electroneutral NaCl absorption Small Intestine 1. Coupling of Na+/H+ and Cl-/HCO3- exchangers Fig. 36. Small intestine: Electroneutral NaCl absorbed in exchange for H+ + HCO33- = H2O +CO2 NaCl absorption  1Na+ exchanged for 1H+ (same for Cl-/HCO3- Lumen Blood exchange) Na+  Exchangers coupled by action of carbonic NHE anhydrase + uncatalyzed hydration of CO2 H2O H+ Na+ Cl- + CO2 K+ HCO3- CBE  NaCl absorbed and water follows osmotic Cl- H2CO3 gradient Carbonic Anhydrase H2O + CO2 2. Euvolemia (healthy state of ECF): Process is inhibited by parasympath. n.s. and mediators acting NaCl NaCl NaCl NaCl NaCl NaCl through intracellular messengers (cyclic nucleotides, Ca2+) H2O  NaCl absorption via this process is held in check during digestion/absorption resumes after digestion to recover NaCl and water  Process strongly inhibited by bacterial enterotoxins Increase cAMP and cGMP > diarrhea 3. Hypovolemia: Sympathetic n.s. and/or enkephalinergic interneurons blocks inhibition by digestive neuroendocrine control to allow copius absorption of salt and water Rapid NaCl and water absorption D. "Uncoupled" Na/H and Cl/HCO3 exchanger activity regional -Provides adjustment of luminal pH in specific intestinal regions 1. Upper jejunum: recovers luminal HCO3 (bicarbonate) Na+/H+ exchangers >> Cl-/HCO3- exchangers Net H+ secretion neutralizes any excess HCO3- from pancreas bicarb - makes carbonic acid 2. Ileum: Cl-/HCO3- exchange alkalizes ileal effluent Cl-/HCO3- exchangers >> Na+/H+ exchangers Net HCO3- secretion enters large intestine to buffer VFA ileal effluent is alkaline and has a low [Cl-] buffers VFA like saliva in ruminants 58  IV. Large intestine: Salt and water absorption A. Proximal Large Intestine: Electroneutral NaCl absorption 1. Same transporters as small intestine low [Cl-] due to ileal Cl-/HCO3- exchagne Cl-/HCO3- exchange is less in the healthy colon Fig. 37. Proximal large intestine: VFA and Na+/H+ exchange. Lumen Blood 2. Site of fermentation - Na+/H+ "uncouples" to HAc Main VFAs: recycle protons for VFA absorption and absorb Na+ Acitate H+ Butarate VFA is the main anion in the colon (vs. Cl-) Ac- + H+ + Ac- Facilitated Diffusion Propinatate Acetate, butyrate, and propionate NHE Na+ Na+ K+ e.g., acetic acid CBE HCO3- HAc = Ac- + H+ Cl- Na+ and Ac- Hac is lipid soluble > enter cells > H+ recylced to th elumen and absorbed, and Ac- transported via ficilitated diffusion to the blood NaAc NaAc water follows the NaAc NaAc NaAc NaAc osmotic gradient H2O B. Distal Large Intestine: Electrogenic Na+ absorption generating net charge across barrier Somewhat species specific (doesnt occur in rodents) 1. "Na+scavenging": Na+ channels absorb Na+ against a large concentration gradient Fig. 38. Distal large intestine: -Same process as distal tubule of kidney Electrogenic Na+ absorption/K+ secretion. ENaC absorbs Na+ down to 5mM in the lumen Lumen Blood Specific for Na+ (electrogenic) K+ Cl- follows eletrical gradient, water follows osmotic gradient, and K+ secretion maintain membrane potentail Na+ EN aC Na+ K+ K+ 2. Regulated by plasma aldosterone concentration Aldosterone: Increase ENac expression Cl- Increase Na+/K+ ATPase activity Increase K+ channels NaCl NaCl NaCl NaCl NaCl NaCl Fecal electrolytes relative to plasma? Na - decrease H2O Cl - decrease K - increase 59 V. Intestinal Crypts: Salt and water secretion (small intestine and colon) A. Electrogenic Cl- and HCO3- secretion Fig.39 Function: dilution, hydration of mucus, buffering, cleans surface Lumen Blood 1. Mechanism of secretion for small and large intestine Cl- 2Cl- NKCC1 K+ CFTR Na+ 2 HCO3- Cl- HCO3- 2. In the epithelial cell, Cl- accumulates via the NBC Na+ HCO3- Na/K/2Cl- cotransporter (NKCC1) and HCO3- accumulates via the NaHCO3 cotransporter (NBC) Na+ K+ from the basolateral (blood) side of epithelium. Carbonic Anhydrase NaCl NaCl NaCl NaCl Na+ H2O. 3. Cl- and HCO3- secreted via anion channel (CFTR) and Cl-/HCO3- exchanger CFTR: 4 Cl- : 1 HcO3- CFTR couples with Cl-/HCO3- exchangers to recycle Cl- and increase bicarbonate secretion (e.g., pancreatic duct) 4. Na+ and water follow between cells Na+: eletrical gradient > lumen H2O: osmotic gradient > lumen 5. Euvolemia: Tonic activation by parasympathetic nerv. system and endocrine agents acting through intracellular messengers (cyclic nucleotides, Ca2+) Cl- and HCO3- (and thus, Na+ and H2O) secretion from crypts provides bufered fluid for digestion Bacterisl enterotoxins INCREASE cAMP or cGMP > sectretory diarrhea Cystic fibrosis: mutation of CFTR. Compromises the composistion and volume of secreted luminal fluid > thick, stick mucus builds up in the lungs, pancreas and GI tract 60 VI. Neuroendocrine regulation of intestinal fluid secretion/antiabsorption *Note: Nutrient absorption not directly regulated by the autonomic nervous system A. Summary of neural regulation of electrolyte and water transport 1. Parasympathetic n.s. and enteric neural effector neurons - Stimulate fluid secretion at crypts increase CFTR activity Net fluid - Inhibit fluid absorption at villi/surface decrease NaCl absorption absorption 2. Sympathetic n.s. and enteric enkephalinergic interneurons - Inhibit enteric effector neurons to permit: Increased fluid absorption at villi/surface increase NaCl absorption Decreased fluid secretion at crypts decrease CFTR activity Net Fluid in Gut Lumen Anion Secretion Electroneutral NaCl Absorption B. Bacterial enterotoxins activate intracellular cyclic nucleotides Stimulate fluid secretion at crypts Inhibit fluid absorption at villi/surface enteric nervous system (ENS) B. Bacterial enterotoxins activate intracellular cyclic nucleotides 61 B. Bacterial enterotoxins activate intracellular cyclic nucleotides Stimulate fluid secretion at crypts Most bind irreversibly to adenylate/ guanylate cyclase and acivate. Must shed affeced cells! Inhibit fluid absorption at villi/surface Fig. 41 Intracellular Stimulus Type Cl Secretion + messinger Decrease NaCl Absorp. cyclic AMP VIP Neurotransmittor YES Enteroendocrine Prostaglandins Paracrine YES physiological Inflammatory mediator Cholera toxin Bact. Enterotoxin YES E. coli Bact. Enterotoxin YES Heat labile toxin Campylobacter spp. Bact. Enterotoxin YES pathological (secretory diarrhea) Pseudomonas spp. Bact. Enterotoxin YES cyclic GMP Guanylin Enteroendocrine YES Physiology E. coli Bact. Enterotoxin YES Heat stable toxin pathological Yersinia spp. Bact. Enterotoxin YES (secretory diarrhea) 2+ Ca /PKC Acetylcholine Neurotransmittor YES Serotonin Neurotransmittor YES mostly physiological Enterendocrine (except salmonella inection) Objectives: 1. Relate the enterosystemic fluid cycle to the fluid loss of diarrhea. 2. Understand the functional morphology of the small intestine. 3. Know what ion transport mechanisms operate in the small intestine. 4. Compare ion transport between the jejunum and ileum with regard to acid-base regulation of the luminal environment. 5. Know what ion transport mechanisms operate in the large intestine. 62 6. Know how Na+ is absorbed in the proximal colon and its relationship to VFA absorption. 7. Know how Na+ is absorbed in the distal colon and how it relates to K+ balance. 8. Describe the mechanism of salt and water secretion in the intestine. 9. Understand how net fluid movement into the intestinal lumen is regulated by the neural system. 10. Know the mechanism of enterotoxin-induced secretory diarrhea. Related Questions: 1. What would be the intestinal consequences of a genetic defect in the Cl- channel protein, CFTR? 2. How does the drug, loperamide (an opiate agonist), act to inhibit diarrhea? 63