PNB Exam III Chemical Digestion & Absorption ∙ Typically “Paired” ∙ The next few slides describe the paired digestion and absorption of different TYPES of nutrients ∙ Certain things only get absorbed in certain places o Nutrient absorption woks through channels and transporters Pretty specific Except gases just go through DigesDon't forget about the age old question of What are examples of long term assets?
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tion: Carbohydrates ∙ Only SIMPLE carbohydrates (monosaccharides) can be absorbed! 1. Amylase Breaks to simpler forms (disaccharides) ∙ Lactose, sucrose, maltose 2. Brush border enzymes Breaks down into monomer, the simplest that can be absorbed Small intestine Glucose, fructose, and galactose Absorption: Carbohydrates ∙ Transporters Are Required for Carbohydrate Absorption o Absorption is going into blood Entirely through cell Assume everything that makes it into the cell also makes it into the extracellular fluid, anything there makes it to bloodstream ∙ Apical: o SGLT 1: 2° Active Transport Glucose (!!) & Galactose to intestinal epithelial cell Coupled with sodium o GLUT 5: Facilitated Diffusion Fructose to the bloodstream ∙ Has its own way in while glucose and galactose have a harder time due to them sharing a transporter ∙ Basolateral : o GLUT 2: Facilitated diffusion All Digestion: Proteins ∙ Don't need to be in simplest form to be digested ∙ Starts in stomach ∙ Endopeptidases o Attack peptide bonds to break protein into fragments in the middle o Stomach Secretions (e.g. Pepsin) o Pancreatic Secretions (e.g. Trypsin) o Small Intestine Peptidases∙ Exopeptidases o Release Single Amino Acids! o Mostly Pancreas (e.g. carboxypeptidase) o Cuts towards the end to get a long chain and amino acids Absorption: Proteins ∙ Absorbed In Many Forms o Amino Acids Na+ Symport Brought in in intestinal epithelial cell o Di/Tripeptides H+ Symport Different transporters o Large Peptides Transcytosis (Endocytosis) Can be toxins or pathogens, sometimes (like infants with passive immunity) we need the functional antibodies in our blood that come from them ∙ Peptide = most, large peptides more common in infants o Passive immunity from mom o Should breastfeed because milk gives antibodies ∙ Don't want to absorb the large peptide the food was eaten as because they are pathogens and would have an immune response to them Digestion: Fats ∙ Not water soluble (carbs and amino acids are) o Hydrophobic in water environment so they all want to come together Floating in aqueous, if you want to digest fat, only the surface can do that ∙ Would be very inefficient o In small intestine o Amylase/peptidase/brush border are typically soluble o Use motility, peristalsis, and segmentation to increase surface area to be more efficient ∙ EMULSIFICATION o Bile (From Liver) o Keeps fat droplets from reassembling Coat fat with bile salts Keeps SA maximized Keeps lipases coming in to attach to molecule and start digestion o Big fat dropletsmaller fat droplets coated with bile salts Still non-polar, lipid soluble, hydrophobic ∙ DIGESTION o Lipases (From Pancreas) Digests triglycerides into monoglycerides, free fatty acids Some cross brush border through diffusion o Breaks bonds ∙ MICELLES: in lumen o Hydrophobic wants to be with hydrophobic o Tiny fat droplet sticks togethero Free fatty acids form fat cell As they move towards plasma membrane and villi of small intestine, some fatty acids move off micelle and migrate across apical membrane into the cell ∙ Membrane is made of lipids o In aqueous environment, exist as a particle, but as you get closer to the membrane they pull off and diffuse across Cholesterol also gets absorbed here because of the bile salts ∙ Move free fatty acid into the cell ∙ Alli drug o Weight loss Not absorbing fatty components o Side effect: oily discharge from rectum Digestive system is an external environment ∙ In lumen, stay in lumen until absorbed or excreted as waste o Blocks ability to absorb fats If you don't absorb fats, you get undigested lipids straight through your system 1. Bile salts from liver coat fat droplets 2. Pancreatic lipase and colipase break down fats into monoglycerides and fatty acids stored in micelles 3. Monoglyceride acids move stuff out and enter cells 4. Cholesterol is transported into cells Absorption: Fats ∙ Now you have hydrophobic molecule on side of the cytoplasm that is inside an aqueous environment, doesn't like that o Wrap them in a vesicle (chylomicron): in the cell (already absorbed) ∙ Apical Membrane o Monoglycerides & FA -> Diffusion o Cholesterol Transporter ∙ Inside Cells o Chylomicrons Form to get exocytosed from the cell Ends up in extracellular fluid To big to absorb in capillaries and directly in blood stream Has to go to lymphatic system: good at picking up big particles (proteins/fatty chylomicrons) ∙ End up back in circulation after draining into vena cava ∙ Doesn't happen with carbs or proteins (epithelial cell to blood) ∙ Basolateral Membrane o Exocytosis ∙ Lipases are water soluble, so only have access to what is on the surface The Hepatic Portal System 1. Nutrient rich blood from gut 2. Portal vein 3. Liver 4. Hepatic vein to vena cava ∙ Tend to ingest things that are toxic and can damage fragile places in body, liver helps detox this with enzymes to modify and detoxifyo Frustrating because effective drugs end up in the portal vein, go to liver, and gets modified/killed/inactivated o Need to design so this doesn't get modified, or so that the modification is what makes them active o Careful about what you ingest or you can damage the liver ∙ LIVER METABOLISM: o Carbs o Amino Acids o Lipids o Detoxification ∙ Liver determines nutrient balance because it is the first thing to see everything you ingest o Everything except fats o First pass metabolism ∙ Capillary network: anywhere exchange happens ∙ Regardless of what is absorbed (besides fats) ends up in hepatic portal vein to send to liver Be Good To Your Liver… ∙ Alcohol absorption happens mostly in the stomach ∙ Alcohol Dehydrogenase enzyme in liver o Converts EtOH to Acetylaldehyde o Acetylaldehyde- gives side effects of drinking Toxic (Headaches, Vomiting, Carcinogenic) ∙ Leads to the transformation ∙ Damage caused by acetylaldahyde floating in body Makes you feel miserable after drinking ∙ Acetylaldehyde Dehydrogenase & Glutathione (detoxifies other compounds)- another enzyme in liver o Break down Acetaldehyde into something harmless (like vinegar) o We only have so much of these enzymes available Used to detoxify other compounds in body ∙ Drinking later and feel like crap so don't take Tylenol ∙ If you are drinking and taking Tylenol, you’re just going to break down Tylenol with flutathione instead of the acetylaldehyde which is damaging tissues in body o Don’t want to take anything that goes through the hepatic portal vein or this problem will occur ∙ Vietnamese-American friend got three haircuts, and saw how long it took to grow back o Had champagne and got red o Asians are susceptible to Asian flush syndrome o Overactive dehydrogenase that converts all ethanol to nasty acetaldehyde o Small amountsbig effects ∙ Can get cancers from drinking because can’t detox fast enough o Men go through process faster o Alcohol affects women more Phases of Integrated Meal Response-Digestion of food 1. Cephalic Phaseo Mouth and esophagus 2. Gastric Phase o Food is modified in stomach 3. Intestinal Phase o Small intestine 4. Colonic Phase o Large intestine ∙ We have a one way digestive system because it is more efficient because we are big o Can’t ingest more until you finish processing everything else, takes 18 hours Cephalic Phase Secretions: Saliva ∙ FUNCTIONS o Mechanical WWII Idea: If we chew, we can make digestion more efficient ∙ Thought that we needed teeth to increase surface area on food for digestive enzymes to work ∙ Patriotic duty to chew 100x per bite to extract more nutrients from less meal ∙ Not true, chewing doesn't really change anything in stool sample ∙ More mechanical digestion happens in other places o Stomach, small intestine o Enough to break food molecules ∙ Chew to stimulate saliva production and to avoid choking, not increasing surface area o Digestive in mouth Salivary Amylase ∙ Break down carbs into disaccharides Salivary Lipase ∙ Breast milk is fatty so this is good Chemical digestion begins in the mouth, usually just some carb digestion Antimicrobial o Protective Lysozyme ∙ Break down cell walls of bacteria Fluoride HCO3- ∙ Protect teeth from acid ∙ Secreted in ducts Not all secreted from same part of salivary gland o Secreted by Parotid, Sublingual, and Submandibular Glands (Autonomic Regulation!) Endocrine glands are not ducted, secrete into the bloodstream Exocrine glands are ducted: has secretory epithelial cells ∙ Secretions end up in duct that drains into larger ductsoral cavityo Enzymes come from bulb portion in salivary glands and pancreas (also has ducts) Cephalic Phase: Swallowing ∙ Motility ∙ Sphincter muscle o Smooth muscle arranged as a circle o Contracting decreases radius (esophagus) ∙ Upper Esophageal Sphincter o Skeletal so you can do it on command Voluntary Exception because usually smooth muscle o Closed when not swallowing to protect digestive structures before you are ready ∙ Lower Esophageal Sphincter o Smooth muscle Contracts to generate sufficient pressure o Between esophagus and stomach 1. Tongue makes food into a ball and pushes bolus against soft palate and back of mouth to the uvula, triggering swallowing reflex o Either you swallow, or choose not to swallow 2. Upper esophageal sphincter relaxes while epiglottis closes to keep swallowed material out of the airways o Also have airway here, need to send to esophagus, not lungs o Airlungs, foodesophagus depending on epiglottis o Epiglottis goes more superior to go to esophagus o Now open sphincter muscle 3. Food moves downward into the esophagus, propelled by peristaltic waves and aided by gravity Gastroesophageal Junction ∙ Bolus Movement Is Due to Pressure Changes o Always movement going on ∙ Not gravity, just muscle contraction o Pressure gradient comes from contractions (peristalsis in small intestine) Peristalsis contracts behind and relaxes in front High pressure behind bolus, low in front for forward contraction all the way down o Astronauts and keg stands can still swallow, just uncomfortable ∙ Esophageal Pressure Reduced By: o Caffeine o Alcohol o Cigarettes o Chocolate ∙ Why Is Low Pressure Bad? o Makes it hard to swallow and can become lower than pressure in stomach Always move from highlow o When lower sphincter opens, things can back up from stomach and come back to esophagus (GERD) o Can’t swallow∙ Gastroesophageal Reflux: o Open LES (Relaxed SM) ∙ Achalasia: can’t open lower sphincter o Contracted=closed so nothing moves from esophagus to stomach With this disease, can’t open lower sphincter o Sphincters are very important o High pressure in bottom of esophagus Can’t swallow Hard to generate high pressure further up o Higher baseline pressure to create pressure gradient The Gastric Phase: Stomach ∙ Anatomy Division o Cardia o Fundus o Body Biggest part of the stomach o Antrum Connects to duodenum Gastric emptying into small intestine o Pyloric sphincter Closes small intestine from gastric secretion ∙ Functional Division o Proximal Reservoir Stores food Cardia, fundus, body Has to be expandable to fit your food o Distal Pump, Grinder Closer to small intestine Smooth layer ∙ Specializations: o Rugae Ridges Like a waistband Flattens to allow stomach to increase in volume o Oblique Layer Extra layer of smooth muscle Helps to have more forceful contractions to mix food with juices, and to send to small intestine Gastric Secretion by Cell Type∙ Chief Cells: o Pepsinogen Pepsin precursor A type of zymogen ∙ Inactivated until necessary ∙ Parietal Cells: o HCl pH, catalyst o Intrinsic Factor B12 absorption ∙ Mucus Cells: o Mucus ∙ G-Cells: o Gastrin ∙ D-Cells: o Somatostatin ∙ ECL Cells: o Histamine Regulation of Proton Pump ∙ All on basolateral membrane because it is facing the blood stream ∙ Activating o Gq, increased calcium, PKC, phosphorylation o Histamine: Increase cAMP o ACh & Gaastrin : Increase Ca2+ Muscarinic o Histamine and ACh don’t always have the same effects with each other in other systems Smooth muscle is different because of a different receptor and mechanism o HCl is a catalyst in this reaction ∙ Inhibitory o Gs, increases cAMP, PKA, more H+ out, more acid secretion o Somatostatin (PGE2) Works though GI Decrease cAMP, stop phosphorylation, stop secretion ∙ Direct Vagal Stimulation∙ Local activation ∙ Negative feedback o Somatostatin inhibits gastrin (has the negative sign over it) o Works on G cells as well as the parietal cell Review Question ∙ All of the following occur when food enters the stomach EXCEPT: o Increased HCl formation (no, you need this to digest and activate G cells) o Increased exopeptidase activity o Increased cAMP production within parietal cells (no, always stimulatory, also has negative feedback which also increases somatostatin) o Increased somatostatin production (no, negative feedback loop) Motor Functions of the Stomach ∙ Varies by stomach regiono Storage Occurs in FUNDUS & BODY ∙ Receptive Relaxation Food in Esophagus (Pre-emptive) ∙ Adaptive Relaxation ∙ Before food is even in stomach Food in Stomach ∙ More relaxation because stretch receptors are activated to cause smooth muscle relaxation o Mixing Peristalsis ∙ Strong contractions in distal stomach because of smooth muscle layer Occurs in Antrum ∙ Needs to contract and expand Gastric Motility ∙ Mechanical Stimuli o Movements Are Under Neural Control (Vagovagal Reflexes) o Stomach starts to stretch, starts process of contraction and send things towards small intestine o Receptive and adaptive relaxation and contraction ∙ Chemical Stimuli o Digestive Products Present (PROTEINS!) ∙ Proximal stomach is different than distal stomach o Proximal contracts first, then distal, then to the small intestine Things spend time in the stomach o Distal: more forceful peristaltic contractions o Pyloric sphincter is closed, churning motion against a closed door causing mixing o Peristalsis has some mixing even though segmentation is known for that too ***Smooth muscle is not parietal cells (mucosal cells) o Use similar signals and chemicals but how the cell responds is different because of the receptors o Ca stimulates one cell that contracts, and one that secretes HCl Absorption in Stomach ∙ Secretions of stomach promote gastric motility o Gastrin regulates acid secretion o Stimulates parietal and exocromin cell o Gastric emptying o Not much absorbed in the stomach Typically happens through transporters and channels None of those, can’t get nutrients in NO VILLI ∙ Give us more membrane space to bring things in ∙ Not very efficient when you don’t have them Still absorbed ∙ Alcohol, drugs (aspirin)∙ Stomach Wall is Not Specialized For Absorption (What’s missing?) o Aspirin o Alcohols Protection of the Stomach Wall ∙ Alkaline mucus protects against HCl o Epithelial cells can be easily destructed o Mucous secreting cells Top of gastric pit and in mucosal layer Creates a mucous barrier of HCO3 ∙ Buffer, not perfect, still damage o The epithelial is rapidly dividing so it’s okay ∙ Rapid Replacement of Gastric Epithelia via Mitosis ∙ Chemotherapy? o Chemo drugs are nonspecific o Target rapidly dividing cells DNA replication and repair Side effect is on GI tract ∙ Cells in mucosal layer are rapidly dividing in the GI tract so it attacks them o B blood has a similar antigen so it can be attacked Gastric Ulcers ∙ Death and destruction of cells that make up mucosal layer of stomach o Death of cells creates necrosis and space ∙ Caused by Infection with Helicobacter Pylori o Most of us have H. pylori but not a lot get an ulcer Changes mucous production to decrease buffer and keep acid production the same to destroy more cells o Found bacteria in stomach, crazy because its acidic so sounds impossible Antibiotics made it go away o Drank H. pylori to prove and got an ulcer, treated with antibiotics that proved bacteria caused ulcers Not stress or spice, interplay of bacteria with immune systemmost ulcers ∙ Always thought ulcers were excess gas formation, spicy foods, and stress o Took antacids and relieve symptoms, but they would return Intestinal Phase Gastric Emptying ∙ Strong peristaltic waves (where?) o More active, promotes movement into small intestine o Distal stomach ∙ Increased tone in gastric reservoir o Proximal stomach ∙ Opening of the Pylorus (Pyloric Valve, Pyloric Sphincter) o Closed door for churning and mixing o Want to empty, open the sphincter muscle Need to relax sphincter while you contract stomach ∙ Use different signals to have this difference in both smooth muscleso VIP relaxes sphincter muscles for gastric emptying (opens them) o Contractions in small intestine would inhibit gastric emptying Relax smooth muscle in sphincter but also contract smooth muscle in stomach ∙ Inhibition of Duodenal Segmental Contractions Regulation of Gastric Emptying ∙ Increased By: o Gastric Volume & Content (Liquid, High Protein) o Neural Control (On Pyloric Sphincter) o Gastrin ∙ Secretions are active, inhibits gastric motility ∙ Small intestine increases what it is doing, stomach shuts down Gastric Emptying (INHIBITION) ∙ Factors Decreasing Gastric Motility o Inhibit gastric motility and emptying o Balance Don't want to move things too fast out of the stomach because we need to absorb protein or else we get dumping syndrome ∙ Enterogastrones o Secretin = pH ∙ Stimulus is acidic pH Neutralizes pH Gastric juice is acidic Duodenum is at low pH, releases secretin o Cholecystokinin (CCK) = fat ∙ Stimulus is fats Helps with fat digestion Stimulates release of CCK Need bile to absorb fat so CCK stimulates that o Gastric Inhibitory Peptide (GIP) = carbs ∙ Stimulus is carbs in duodenum Helps absorb carbs into tissue and release insulin Still contains carbs when it goes to small intestine, which gives you GIP Need to figure out how to absorb into cells∙ Released due to a particular thing in small intestine and has a particular effect on other tissues o If you don't have one of them, you still have two others Dumping Syndrome ∙ Gastric Emptying Occurs (Too) Quickly o Didn't finish absorbing yet o Gastric bypass surgery: reduce size of stomach to treat obesity, but the stretching is needed for emptying then it stretches faster Send things to small intestine faster impacting absorption because it is not complete yet Get bloating and cramps because more solutes so more water is attracted Things are sitting in small intestine longer, water sits there and bloating occurs ∙ Loss of Feedback Control ∙ Excess Simple (Refined) Sugars lead to Water Retention (Distension) ∙ Pain, Cramping, Malabsorbtion Review Question: ∙ What would the following stimuli do to the rate of gastric emptying? o Increased peristaltic waves in Antrum Increase Antrum in stomach, motility is needed to move things to small intestine o Increased tonic contraction in gastric reservoir Increase Proximal stomach, sends things to small intestine o Increased action of VIP in the pyloric sphincter Increase Relaxes sphincter muscle muscles, opening the door o Increased H+ in duodenum Decrease pH decreased, more acidic Enterogastrone (secretin) released, inhibit gastric emptying ∙ Inhibitory A genetically modified "knockout" mouse lacks the hormone secretin. In comparison to a normal mouse you would expect to see: ∙ Increased ductal pH ∙ Increased volume of pancreatic secretions ∙ Decreased pH in duodenum o Stay acidic o Stomach acid in small intestine ∙ Lack of nutrient absorption o Don't have negative feedback=dumping syndrome, but still have CCK and GIP so SOME negative feedback even without secretinWhich of the following is true about the region labeled "A" ? ∙ Secretin can stimulate secretions from this region o Secretes HCO3 o Exocrine gland ∙ Gastrin leads to phosphorylation of a pump on the apical surface of this region ∙ Secretions from this region inhibit gastric motility o HCO3 doesn't change motility ∙ CCK stimulates secretions from this region Small Intestine Anatomy ∙ Regions: o Duodenum Mixing & Digestion! ∙ Food first enters Secretions from accessory organs Shortest segment of the small intestine o Jejunum Digestion (!) & Absorption (!) ∙ Most absorption is here because the villi are the longest ∙ Major site of absorption Longer segment of small intestine Brush border enzymes o Ileum Iliocecal Valve (to LI) Mostly Absorption ∙ Not much digestion anymore Specialization of Small Intestine ∙ Villi o Smooth muscle is found in muscularis layer (peristalsis and segmentation) o Muscularis mucosa (shape of lumen) ∙ Lacteal o Fats go to lymphatic system and the vessel is called lacteal Don't go to blood because too big o Carbs, proteins, and drugs go to blood from hepatic system Motility in Small Intestine ∙ Primarily Segmentation Contractions o Mixing Proximal and distal contraction at the same time o SLOW Propulsion (Frequency Gradient) Create baseline in electrolyte activity, you can change the baseline ∙ Contract smooth muscle faster in one place than another If you change gradient, you can still produce forward movement Back and forth movement in peristalsis Segmentation gives slight forward movement in small intestine ∙ Not very efficient alone ∙ Infrequent Peristalsis o Migrating Motor Complex (MMC) Stimulation: Motilin (Fasting) ∙ Very strong peristalsis to keep it moving forward ∙ Empty small intestine so it is moving air Inhibition: Feeding o Stomach growling Hear the peristalsis inside small intestine as it starts to empty out ∙ Emptying secretes motilin which activates peristalsis to pick up extra stuff Secretions into SI: Pancreas ∙ Regions o Pancreatic Acini (Acinus) - EXOCRINE enzymes, resembles salivary glands Enzymes! Amylase ∙ Breaks starch into sugars Lipase ∙ Help with bad digestion ∙ From CCK helping digest HCO3- ∙ Pancreas is endocrine too ∙ Ductal cell produces bicarbonate o Comes in to neutralize acid o Makes small intestine kind of alkaline ∙ Secretin stimulates cells in ducts with different receptors o Most come from bulbs, but this comes from duct Precursors (Trypsinogen, Chymotrypsinogen, Procarboxypeptidase) ∙ Through pancreatic duct (common bile duct) o Pancreatic Islet – ENDOCRINE Hormones Glucagon and endopeptidase ∙ Can’t live without o Both GI and metabolic Control of Pancreas ∙ Hormonal o Secretin (Works At Duct): Stimulus = low (acidic) pH Secretes HCO3 to neutralize Increases pH o CCK (Works at Acinus): Bulb part Stimulus = Fatty Acids Stimulates acinus to secrete other enzymes like lipase o Enzyme Release Zymogens: have to be activated in duodenum, not tissue producing (pancreas) ∙ Can cause necrosis/cell death if activated here ∙ Local activation is very important ∙ Nervouso Vagus Stimulus = Parasympathetic Almost always regulates secretions ∙ Ductal cells, other cells Compared with a normal animal, a genetically modified mouse lacks the hormone secretin, which of the following would be expected to be increased in the mutant mouse? ∙ pH of pancreatic ductular secretion ∙ Volume of pancreatic secretion ∙ pH of duodenal contents ∙ Susceptibility to duodenal erosions and ulcerations Pancreatitis ∙ Autodigestion of Pancreatic Tissues ∙ Causes o Gallstone lodges in duct blocking lumen and aggravating pancreas ∙ Bacterial infection, alcohol, blockage (ischemia) ∙ We have zymogens, sometimes get activated in pancreas and autodigest Secretions into SI: Bile (Liver) ∙ Synthesized in the Liver by Hepatocytes o Fat digestion: emulsify (coat) the fat droplets o Made in liver, comes to duodenum o Gallbladder stores bile ∙ Composition: o Bile Salts (Cholesterol) If they crystalize, lodge in duct, cause pancreatitis o Bilirubin (RBC Catabolism) o Lecithin Non-stick cooking spray: emulsifies fat o HCO3- Secretions into SI: Liver ∙ BILE o Production stimulated by Secretin (SI) Low pH in duodenum Can stimulate to produce bile Not QUITE cause and affect like all the other ones o Release (via Gallbladder) stimulated by CCK (SI) & Vagus Always with fats, secreted from small intestine Stimulates production of lipase in pancreas Here, the stimulus to release bile from gallbladder ∙ Very important for fat digestion o From small intestine: enterogastrones o Into small intestine: pancreatic juices and bile ∙ Hepatic Duct to Gallbladder ∙ Common Bile Duct to Duodenum o This is where we are worried about blocking because it is shared with pancreas Colonic PhaseLarge Intestine Anatomy 1. Cecum 2. Colon a. Four Regions Ascending Transverse Descending Sigmoid loop b. Enterocytes c. Goblet Cells 3. Rectum ∙ Specializations: o Thin Wall o Teniae Coli (Haustra) Muscularis externa layer Ribbon looking in length (longitudinal) ∙ Smooth muscle Elastic waistband vibes Relax: causes colon to scrunch up ∙ Transition From Smooth Muscle To Skeletal Muscle ∙ Does not really absorb except some water and vitamins o Important for diarrhea Due to changes in water reabsorption in large intestine and how long it takes o Doesn't absorb everything else Motility: Haustra and Defecation ∙ Defecation reflex o Temporary Storage of Waste in Rectum Leads to Stretching (Mechanoreceptor Activation) Afferent signals relayed to CNS ∙ Get efferent signals back ∙ Signals the sphincter Motor signals back through enteric nervous system to large intestine ∙ Stimulates motility (contraction, peristalsis) at distal portions o Parasympathetic Output Is Increased in Colon o Parasympathetic Output is Decreased in Rectum (Internal Anal Sphincter) Smooth muscle Feel the urge to go Not completely involuntary because you have external o Voluntary Relaxation of External Anal Sphincter Skeletal muscle Teach children to hold it by controlling this area 1. Stretch, afferent signalsperistalsis 2. Internal sphincter 3. Relax external sphincter ∙ Peristalsis a few times in the dayo Mass movements a few times a day where it descends o Picks up what is moving through and move it towards sigmoid colon and rectum o Stretch sigmoid colon: start of defecation reflex o Other parts of digestive system stretches out and distends, signal detected Renal Physiology I: Basic Renal Process Introduction to the Renal System ∙ Kidneys filter 180 lit/day o ~45 mins, your entire plasma volume is filtered ∙ Urine output ~1-2 lit/day o Don't want to pee plasma, so you need to reabsorb ∙ 99% of filtrate volume is reabsorbed o Filtrate is plasma without proteins ∙ Functions of kidneys o Excretion of wastes and foreign chemicals o Regulation of water and ion (salt) balance (homeostasis) pH regulation o Secretion of hormones Anatomy ∙ Gross external o Kidneys o Ureters Carry to bladder o Bladder Storage Can be held voluntarily ∙ Skeletal muscle ∙ Internal o Renal cortex: two parts of medulla Outer cortical region Inner juxtamedullary region o Renal medulla Pyramids o Renal pelvis Feeds into ureter o There is an osmotic gradient from the outer cortex to the inner medulla Outer cortex: 300 mOsm Inner medulla: 1200 mOsm ∙ Increased osmolarity/particle concentration ∙ Nephron: Functional Unit of Kidney o Vascular component Glomerular capillaries in glomerulus ∙ Filter fluid from blood to beginning of kidney (nephron) Fenestrated capillaries o Bowman’s capsule o Proximal convoluted tubule Beginning Convoluted (twisty) o Loop of Henle Descending and ascending o Distal convoluted tubule In contact with afferent arteriole ∙ Adjusts blood flow if needed o Collecting duct Deep in medulla Distal tubule of many nephrons connect here to turn substance into urine by adjusting water content o Deliver to minor calysmajor all the way out ∙ Blood supply o Renal artery o Afferent arteriole Takes blood from renal artery Delivers to glomerulus o Glomerulus Tuft of capillaries ∙ Fenestrated Site of filtration Blood side of renal corpuscle If blood doesn't drain here, deliver to efferent o Efferent arteriole Carries blood away from glomerular capillaries to peritubular capillaries o Peritubular capillaries Vasa recta ∙ Special class of nephron o Juxtamedullary Long loops of Henle (15% of nephrons) Around the tubule ∙ The rest of the nephron ∙ All exchange occurs in and out of these capillaries Collecting duct can access these capillaries Material reabsorbed from tubule are reabsorbed INTO peritubular capillaries Materials secreted into tubule move FROM peritubular capillaries into tubule o Renal vein Now back to heart and systemic system Nephron ∙ Two types of nephrons o Cortical (85%) Short loops of Henle A little bit into medulla o Juxtamedullary (15%) Loops of Henle are deep into capillary region (deepest) Interstitial fluid is saltier and saltier ∙ Gradient Role in urine concentrating mechanism ∙ Orientation o Afferent arteriole adjacent to distal tubule Renal Corpuscle ∙ Renal corpuscle=site of filtration o Glomerular capillaries Fenestrated capillaries More permeable than typical capillaries More course o Bowman’s capsule Podocytes ∙ Visceral layer ∙ Interlace together ∙ Foot cells with foot processes ∙ Wrap around fenestrated capillaries ∙ Filtration process occurs between two membranes (capillary epithelium and podocytes) Juxtaglomerular Apparatus ∙ Afferent arteriole comes in contact with distal tubule o Intermixing o Controlling diameter in AA controls how much blood delivered to glomerulus and how fast we filter Ideally 7.5 ∙ Juxtaglomerular apparatus (JGA) o Macula densa cells Densa=sensa Osmoreceptors in distal tubule Sense particle concentration o Juxtaglomerular (JG) cells of afferent arteriole Secrete renin ∙ Enzymatic hormone o Next to glomerulus apparatus Basic Renal Processes Defined: Making Urine ∙ Filtration o Bulk flow of protein-free plasma from glomerular capillaries into nephron Plasma=nutrients, glucose, amino acids, ions, electrolytes, Na+ ∙ Don’t want to pee out, reabsorb back into blood ∙ Want to adjust electrolytes, but don't want to excrete o Reabsorb selectively o Everything else ends up in Bowman’s Nutrients, things you want back, don’t separate out o Filtrate=protein free plasma ∙ Reabsorption o Back into blood (peritubular capillaries)- materials to be retained Stick in kidney, now want back in the blood Bloodkidneyblood o Not ABsorption, that is in small intestine ∙ Secretion o Transport of materials into tubule for excretion If you secrete to tubule, that will be excreted o Add more substances are excreted o Don't want toxins in blood, send to tubule and excrete Functional Anatomy Overview ∙ Cortex o Renal corpuscles: glomerular filtration o Convoluted tubules: secretion and reabsorption Distal and proximal ∙ Medulla o Longer loops of Henle: create osmotic gradient Juxtamedullary: long loops ∙ Make gradient in the first place ∙ Make salty medulla o Collecting ducts: adjust final urine composition Drain into the renal pelvis and ureter Watery, or conserving water can make a concentrated urine Urinary Bladder ∙ Bladder wall o Detrusor muscle Smooth muscle of bladder Can stretch to hold more o Transitional epithelium Layered epithelium subtype that is able to withstand stretch, by changing cell’s shape ∙ Internal and external urethral sphincters o Internal = involuntary smooth muscle o Eternal = skeletal muscle fibers, controlled by somatic nervous system Want to control this so you can hold your pee Relax the sphincter to open it Micturition Reflex ∙ Reflex mediated by parasympathetic nervous system ∙ Voluntary control through descending input form higher centers Basic Renal Processes ∙ Amount excreted= amount filtered+amount secreted-amount reabsorbed o Renal artery is afferent delivers to glomerulus Leaves glomerulus efferent to leave Vasa recta vein with juxtamedullary o Add filtrate to nephron Add other products via secretion, additional products separate from the filtrate o We filter substances to the proportion in our blood, but then we get rid of it ∙ Not all processes apply to all substances! o Don't always reabsorb everything o Substance X: excrete completely after filteringo Substance Y: reabsorb and secrete o Substance Z: reabsorb all of it Glucose/amino acids ∙ Different substances may be filtered, secreted and/or reabsorbed to different degrees Filtration ∙ Bulk flow, governed by blood (hydrostatic) pressure o Across filtration membrane o Trying to equalize the pressure ∙ Filtration membrane o Fenestrated capillary epithelium Pores allow even plasma proteins through, but NOT cells o Basement membrane (AKA lamina densa) – restricts large plasma proteins, allows small ones o Podocytes Epithelial cells of Bowman’s capsule ∙ Filtration slits between pedicels (foot processes) ∙ Slits are small enough to prevent the passage of proteins into Bowman’s space ∙ Fluid is now called glomerular filtrate o Contains all the substances, EXCEPT proteins; that are present in the plasma; and in the same proportions ∙ Afferent and efferent arterioles o Afferent arteriole is bigger in diameter ∙ Filtrate: protein-free plasma o Dialysis? ∙ Resulting filtrate=protein-free diasylate of plasma ∙ Forces favoring filtration o Glomerular capillary blood (hydrostatic) pressure (Pgc) Glomerular capillary BPP=driving force for filtration o Capsular COP-normally zero-ignore If present, would favor filtration ∙ Force opposing filtration o Fluid pressure in Bowman’s Space (Pbs)=hydrostatic pressure of fluid in Bowman’s Capsule o Blood colloid osmotic pressure (πgc): osmotic force due to protein in plasma ∙ To calculate net glomerular filtration pressure o NFP=Pgc-Pbs- πgc o Example=60-15-29=16 mmHg Look at your diagram. If we DILATE the AFFERENT arteriole, then ___________ ∙ PGC will increase ∙ PGC will decrease ∙ PBS will decrease∙ NFP will increase ∙ NFP will decrease ∙ Both A and D Glomerular Filtration Rate (GFR) ∙ GFR is volume of fluid filtered from glomeruli into Bowman’s capsule per unit time ∙ Normal GFR: 7.5 lit/hr ∙ Driving force=blood pressure ∙ Regulation of diameter of afferent+efferent arterioles Changing GFR ∙ Increase GFR o Decrease Pgc o Constrict afferent arteriole o Dilate efferent arteriole o Decrease glomerular capillary BP ∙ Decrease GFR o Increase Pgc o Dilate afferent arteriole o Constrict efferent arteriole o Increase glomerular capillary BP ∙ Vasodilation and vasoconstriction of the afferent and efferent arterioles alter the blood flow through the glomerular capillaries, causing corresponding alterations in the glomerular filtration rate (GFR) Regulation of GFR ∙ Renal autoregulation o Local control whose purpose is to keep GFR within normal limits (7.5 li/hr) o Keep this homeostatically normal ∙ Myogenic mechanism o Stimulus: increase renal BP Response: constrict afferent arteriole (AA) decrease GFR (flow) o Stimulus: decrease renal BP Response: dilate AA increase GFR (flow) ∙ JGA: juxtaglomerular apparatus o Afferent arteriole and distal tubule come in contact here ∙ Tubuloglomerular feedback mechanism o Stimulus: increase osmolarity (of filtered fluid) and/or increase flow rate (sensed by macula densa)constrict AA decrease GFR o Opposite response to decreased osmolarity/flow rate ∙ Due to autoregulation, GFR stays relatively constant over a range of systemic blood pressures ∙ Other extrinsic (nervous, hormonal) regulatory mechanisms covered later Reabsorption ∙ Occurs in renal tubules from lumen through 3 membranes o Luminal Facing tubule fluid o Basolateral Facing interstitial fluid Access to blood Access to hormones to stimulate change o Endothelium (of peritubular capillaries) To reach the blood What is Reabsorbed? ∙ These substances are the most completely reabsorbed o Water, glucose, Na, amino acids ∙ Substances are partially reabsorbed o K+ o Urea, phosphates ∙ Some substances are not reabsorbed at all o Creatinine, sulfates Sites of Reabsorption ∙ Proximal convoluted tubule o Water 70% of reabsorption of renal fluid Moves across following every solute o Glucose 100% of reabsorption glucose and all nutrients Fat soluble proteins need transporters so they can’t get across the membrane o Na+ o K+ o Amino acids o HCO3- ∙ Loop of Henle: descending limb o Water permeable o From cortexdeep medulla, osmolarity gets higher o Urea is essential to this gradient When you move from cortex with 300 osmolaritydeep medulla 1200 osmolarity Reabsorb all the way down so the juxtamedullary loop is 400 ∙ Loop of Henle: ascending limb o NaCl ∙ Distal convoluted tubule o Acts like a collecting duct, variable permeability to water Has regulation Hormones are likely to operate here o HCO3= o Na+ o In LATE distal tubule, WATER Early DCT is impermeable to water If ADH is present ∙ Cortical collecting duct o Na+ o WATER ∙ Papillary collecting duct o Urea o WATERo If ADH is present Determines water permeability Present: water permeable Absent: water impermeable o Papillary region: as deep as you can be Empties into the end parts of forming urine Osmolarity 400 If ADH is present you can reabsorb Mechanisms of Tubular Reabsorption ∙ Passive transport o Water following Na+ o Osmosis ∙ Active transport mechanisms o Many coupled to Na+ o Glucose is absorbed by secondary active transport driven by Na+ Pumps are on the basolateral (blood) side ∙ Physiological control: Only certain substances are reabsorbed in a regulated fashion o Organic nutrients: usually not regulated by kidney o Water and ions: reabsorption may be regulated Transport Maxima ∙ For active reabsorptive systems, there will be a transport maximum o Rate at which transporters are saturated o When saturated, carrier is full and binding/unbinding as fast as it can Can’t go any faster ∙ Renal threshold for glucose is about 180 – 200 mg/dl (Note – dl = deciliter or 100 ml) o Proximal tubule doesn’t control, it just reabsorbs everything uncontrollably o Inside is higher ∙ Tm for glucose: ~380 mg/DL or ~320 mg/min ∙ Filtration: bulk flow o Filtrate: protein free plasma ∙ Reabsorption and secretion turns plasma into urine ∙ As soon as the blue and orange separate, starts spilling into urine (threshold) o Green starts there because glucose secretion increases with urine excretion o Some carriers start getting saturated, so the rate can’t increase anymore o As blood glucose levels get higher, can’t keep up with filtration and reaches maximum The renal threshold for glucose is at a blood glucose concentration at which: ∙ All glucose carriers are saturated ∙ The rate of glucose reabsorption levels off ∙ Glucose first spills into the urine ∙ A and B ∙ All of the aboveWhat is Secreted? ∙ Most important o H+ o K+ o NH2+ o Organic ions Including acids o Metabolites o Foreign chemicals Get completely out of blood ∙ Proximal tubule is primary site of secretion ∙ Distal tubule secretion: more likely to be regulated o Regulation is really important for secretion ∙ Sites of tubular secretion include active transport systems in proximal and distal tubules o While proximal tubule secretes MORE substances; secretion in distal tubule are more likely to be REGULATED o Note importance of secretion mechanisms to rid the body of toxins / poisons! Histology of Nephron ∙ Compare epithelia of proximal and distal convoluted tubules ∙ Proximal o More mitochondria o Microvilli for brush border for reabsorption/secretion 70% of filtered fluid is reabsorbed here ∙ Distal Renal Physiology II: Renal Clearance Urine Concentrating Mechanism Renal Clearance ∙ Definition: for Substance S o Calculation value representing volume of plasma from which S is completely cleared per unit time o Clear things in your body out into urine Cleaning blood o Get an exact GFR ∙ Cs=(Us*V)/Ps o Cs= clearance of substance S o Us= S in urine o V= urine volume/unit time (a flow rate) o Ps= S in plasma ∙ Understand formula, don't use it Example: Inulin ∙ Inulin is a biologically inert polysaccharide that is freely filtered, but is not reabsorbed OR secreted o Recall clearance formula o Can infuse by IV Not changed by liver Not metabolized Removed by urine∙ Given Uin=125, V=1, Pin=1 o Cin=(125*1)/1=125 The renal clearance of glucose should be _________ . ∙ Greater than that of inulin ∙ Equal to the GFR ∙ Somewhat less than the GFR ∙ Zero o Don't want to excrete glucose, want to reabsorb it We Can Determine how Nephron Handles a Substance by Comparing its Clearance to That of Inulin ∙ Since inulin ONLY appears in urine due to filtration o Isn’t removed by reabsorption, nor is more added by secretion o We can use inulin clearance to determine GFR Rate at which your unit is removed from plasma Normal=7.5 ∙ Can also determine how nephron handles other substances by comparing their clearances to that of inulin o If clearance of substance X is < Cinulin, we conclude substance X is filtered and reabsorbed 5.5<7.5, put back in blood, don’t clear, reabsorb o If clearance of substance Y is >Cinulin, we conclude substance Y is filtered and secreted 8.5>7.5, get rid of it, secretion ∙ Example o Creatinine You make in your metabolism already Freely filtered, not reabsorbed, a little secreted Similar to inulin, but Creatinine is a little secreted Can use to estimate GFR The renal clearance of glucose should be _________ ∙ Greater than that of inulin ∙ Equal to the GFR ∙ Somewhat less than the GFR ∙ Zero o Always assume normal, want to reabsorb all the glucose, but not hypoglycemic o Need to be VERY hyperglycemic to show in pee, works hard to always be absorbed The clearance rate for creatinine, a metabolite that is freely filtered and slightly secreted, can be used to provide a/an ___________ estimate of the GFR ∙ Exact ∙ Slight under ∙ Slight over o Secretion adds materials for excretion Water Concentration ∙ Terrestrial animals generally need ways to conserve water o Different animals have differing abilities to do this Recall, Water Reabsorption is Coupled to the Reabsorption of Na (and other solutes)∙ When membranes are permeable to water, it follows the movement of Na+ ions pumped across membrane by the ion pumps o Aquaporins determine water permeability of membranes Some aquaporins are regulated by hormones ∙ Aquaporins are permanent in PCT Water channel proteins Can be sensitive to ADH or not ∙ ADH absent: late distal tubule and collecting duct not permeable to water o Need ADH to stick here for water to freely diffuse by osmosis o Permeability varies in different regions of renal tubule ∙ Water can also diffuse through adjacent tubule cells Water Permeability Varies in Different Regions of Renal Tubule ∙ The collecting ducts and late DCTs permeability to water is regulated by ADH How Urine is Concentrated ∙ Medullary osmotic gradient o 300 in juxtamedullary o 1200 in medulla ∙ Collecting ducts can exploit this gradient to form a concentrated urine ∙ Osmotic gradient established by juxtamedullary nephrons and maintained by vasa recta Countercurrent Anatomy ∙ Use pumps to make a gradient o Each pump does a 200 difference Entire gradient does 300-1200 ∙ Examples o Heat exchangers o Loop of henle (ascending and descending limb) o Loop+vasa recta ∙ Can be artery vs vein o Move from one condition to another in both places, in opposite directions Like hotcold, and coldhot ∙ Flow in opposite directions ∙ Ducks have countercurrent flow of blood in feet so they don't get hypothermia in cold water o Veins come back and pick up heat from arteries for heat exchange ∙ In humans o Flow of urine and flow of blood o Ascending and descending limb are always a countercurrent Can exchange salt between o Countercurrent between each limb in the vasa recta Serving the limb causes countercurrent o Also between limbs and vasa recta** Note Permeability Characteristics of Each Segment of Tubule, and Follow Changes in Osmolarity of Tubular Fluid It Takes 2 Transporters to Move Na from LumenBlood in Ascending Limb Epithelial Cells∙ NKCC2 Na-K-2Cl cotransporter o From lumen through apical membrane Apical means lumen side, with pee Basolateral=blood o Sodium has to go through the lumen side too Active transport because it can’t just diffuse o Loop diuretic blocks this transporter ∙ Na/K/ATPase (active transport pump) o From cell through basolateral membrane to blood Countercurrent Mechanism 1. Descending limb (loop of henle) is permeable to water, impermeable to solutes ∙ As fluid descends, water moves out of descending limb, following osmotic gradient ∙ As fluid descends, water moves out of descending limb, following osmotic gradient ∙ Very efficient exchange ∙ Works with ascending limb o Ascending brings in NaCl, descending brings in water 2. Ascending limb actively transports NaCl and is impermeable to water ∙ Otherwise it would all flow out ∙ Drives the descending limb ∙ EDT acts like ascending limb o LDT acts as collecting duct 3. Collecting ducts permeable to urea (contributes to gradient) ∙ Urea is reabsorbed in the deepest part of collecting duct ∙ Doubles the gradient 4. Water permeability (and urine concentration) determined by ADH at the collecting duct 5. Vasa recta act as a countercurrent exchanger ∙ Maintains osmotic gradient while delivering blood to medulla Countercurrent Additional Notes ∙ Cortical nephron bottom of loop=400 ∙ Juxtamedullary nephron at bottom of loop=1200 o These ones make the gradient ∙ The longer the loop, the more pumps, the more you can multiply the benefit for each one o More salt, more gradient Loop of Henle and Countercurrent Multiplication ∙ Longer the loop of Henle, the greater the multiplication effect! o Multiply 200 ∙ Urea recycling is crucial to achieve the full osmotic gradient The kangaroo rat is a desert mammal that does not need to drink at all. You would expect its urine concentration to be ____________ mOsm ∙ Always greater than 1200 ∙ Sometimes greater than 1200 ∙ Always less than 1200∙ Zero Beavers are mammals that create their own freshwater ponds by building dams. 1) Do they need to make urine as concentrated as humans? 2) What kind of nephrons do they have? ∙ Yes, mostly juxtamedullary ∙ No, mostly juxtamedullar ∙ Yes, mostly cortical ∙ No, mostly cortical o Juxtamedullary makes the gradient o He has bigger loop in proportion to himself, more multiplication, more gradient Renal Physiology III: Regulation: Water Balance +Hormonal Regulation of the Kidney Renal Regulation of MAP Regulation of Ion and Water Balance ∙ Sources of water gain+loss o Water in via beverages, food, metabolism o Water out: Urine, sweat, “insensible loss” = via lungs, skin, etc. Can be severe water loss with vomiting or diarrhea ∙ Sources of NaCl gain and loss o Input via food o Output via sweat, feces, urine Severe sweating, vomiting, or diarrhea can lead to excess loss of NaCl ∙ HemorrhageNaCl+ water loss ∙ Normal regulation o NaCl+water loss=NaCl+water gain Hormonal Regulation of Kidneys: ADH ∙ Function: antidiuresis o Controls water reabsorption by collecting duct and late distal tubule Distal tubule is pretty small ∙ Early ∙ Late o Secreted hypothalamus; released by posterior pituitary o Secreted in response to increased osmolarity of ECF sensed by osmoreceptors Stimulus Increasestoo concentrationdehydratedturn on ADHreabsorb water o Target is late distal tubule and collecting duct ∙ Key point o To conserve water in the body by reabsorption, the late DCT and collecting duct must be permeable to water o ADHincreased permeabilitydecreased urine ∙ In presence of ADH o Collecting duct is permeable to H2O which then follows osmotic gradient out of (into interstitial fluid and then blood) o Also have aquaporins on basolateral side o Follows osmotic gradient out (into interstitial fluid and then blood)o Urine volume is small, and hyperosmotic (concentrated) ∙ Mechanism: AH, through cAMP, induces insertion water channel proteins into collecting duct epitheliumincreased water permeability of collecting duct o These ADH-sensitive aquaporins are called AQP2. o AQP3 and AQP4, also found in the collecting duct; are not ADH sensitive, nor are the AQP 1 water channel proteins found elsewhere in the nephron ∙ Note: ability of ADH to conserve H2O depends on osmotic gradient Mechanism of ADH (vasopressin) action upon late DCT and Collecting Duct cells ∙ V2 vasopressin receptor o Gs-coupled, activates adenyl cyclasecAMPPKA o If you retain fluid, higher BP Vasopressin=ADH o On the blood side ADH works on the late distal tubule or collecting duct Don't put hormone in pee then reabsorb, come from BLOOD o ADH binds to receptor, activate second messenger system: intr ∙ Activates synthesis and export of AQP2 aquaporins to luminal membrane o Aquaporin type 2 is the one that response to ADH o Take away aquaporin 2: less permeable to water ∙ Basolateral membrane has non-ADH-sensitive aquaporins Regulation: ADH ∙ Osmoreceptors o Increased osmolarity (particle concentration)increased firing of osmoreceptors (hypothalamus)increase in ADH production (need to conserve water) o Decreased in ADH production when osmoreceptors signal decreased ECF osmolarity o Increase in ADH production when osmoreceptors signal increased ECF osmolarity o Decrease in ADH production when osmoreceptors signal decreased ECF osmolarity Without ADH, DCT/collecting duct do not reabsorb water; water stays in urine – large volume and dilute ∙ Baroreceptors o Decreased MAPdecreased firing of baroreceptorsincreased ADH production o Conversely, increased MAP increased firing of baroreceptors decreased ADH production o Other name for ADH is vasopressin Reabsorption of Na+ by the DCT and Cortical Collecting Duct is Regulated by Aldosterone ∙ Stimulus for aldosterone release o Increase in plasma K o Decrease in plasma volume, through AII Angiotensin II activates RAAS o Aldosterone is a steroid hormone Don't need receptors Can get into cells by themselves∙ Effect o Increase Na+ reabsorption and K secretion o Aldosterone stimulates production and activation of the NCC transporter ∙ The WHOLE DCT is sensitive to Aldosterone, late DCT is better at it (and can also reabsorb water) It Takes 2 Transporters in DCT Epithelial Cells to Move NaCl from LumenBlood ∙ NCC co-transporter o From lumen through apical membrane o Then pump moves Na into blood ∙ NA/K/ATPase o From cell through basolateral membrane, out of the cell and into blood Renal Regulation of Na and H2O ∙ Recall o Na reabsorption-the primary active transport process in all nephron segments o Water reabsorption is coupled to Na reabsorption ∙ Responses controlling Na excretion are initiated primarily by: o Cardiovascular baroreceptors o Sensors in kidney that monitor filtered load of Na By looking to see how much is in the distal tubule DCT makes contact with afferent arteriole feeding blood into the system ∙ Should be hypotonic ∙ Can’t control proximal segment, only distal RAAS: Renin-Angiotesin Aldosterone System ∙ Three signals increase Renin from JG cells of afferent arteriole (all of these happen when hemorrhaging) o Sympathetic stimulation Renal sympathetic nerves o Decreased MAP o Decreased NaCl (in distal tubule) sensed by macula densa Osmolarity is not changed in hemorrhaging ∙ No osmotic signal, losing isotonic fluid o *A decrease in blood volume results in all three signals ∙ Renin o Enzymatic hormone secreted by renal JGA in kidney released into the blood o Catalyzes formation of AI from antiotensinogen Angiotensinogenangiotensin 1 ∙ Doesn't stimulate anything, has to circulate to get to lungs ∙ Angiotensin circulates cortex to release aldosteronedistal tubule and collecting ductincrease sodium reabsorption o Upregulates the NaK pump and transporter on the other side o Angiotensin converting enzyme (ACE) catalyzes formation of AII from AI A1A2 ∙ Angiotensin II o Vasoconstrictor: increase TPRo Stimulates secretion of aldosterone Sodium reabsorption and potassium secretion o Constricts afferent arteriole: decrease GFR o Increases ADH secretion ∙ Aldosterone o Secreted by adrenal cortex Reduces aldosterone A2 receptors Circulates to LDT and collecting duct o Major control of Na+ reabsorption o EFFECT: increased Na reabsorption and K secretion ACE Inhibitors block Angiotensin Converting Enzyme. These drugs _________ blood pressure, by ____________ . ∙ Lower, preventing production of Angiotensin II ∙ Lower, decreasing aldosterone induced Na reabsorption Angiotensin II Receptor Blockers (ARBs) are a separate blood pressure drug acting on RAAS. What effects would you expect? ∙ Decreased reabsorption of Na and water by collecting duct Atrial Natriuretic Peptide (ANP) ∙ Abnormal increase in blood volumedistends atriasecretion of ANP o Salt from atrium to urine ∙ ANP increases GFR, and inhibits sodium reabsorption in the distal tubulenatriuresis (increased Na in urine), which increases urine volume as it decreases blood volume ∙ Problem is too much volume? o An abnormal increase in blood volume “stretches out” the atria, stimulating secretion of ANP (atrial natriuretic peptide) o ANP promotes vasodilation, thus increasing GFR, and inhibits sodium reabsorption in the distal tubule, leading to natriuresis (increased levels of sodium in urine) Increases urine volume as it decreases blood volume o RECALL! Relationship between arterial blood VOLUME and blood PRESSURE o “Blood volume is the major long-term determinant of blood pressure” ∙ Problem: too little volume o Abnormal decrease in blood volume and pressure activates baroreceptor neurons in the aorta and carotid sinuses, leading to increased secretion of vasopressin, AKA ADH Increases water permeability in the collecting ducts, which decreases the volume of excreted urine ∙ Problem: hypoosmotic fluid load o Drinking too much water causes an abnormal decrease in fluid osmolarity o Decreases firing of hypothalamic osmoreceptors o Reduces activity of ADH neurons o Leads to decreased secretion of ADH o Water permeability in the collecting ducts is reduces o Thus increasing the volume of excreted urine (diuresis) Renal Regulation of Potassium ∙ K is filtered from the glomerular capillaries∙ Relative rates of K reabsorption and secretion are determined by the law of mass action and by aldosterone ∙ Increases sodium reabsorption at the expense of increased K secretion Aldosterone and K+ ∙ A simple reflex loop regulates aldosterone production in response to plasma (K) ∙ Increased plasma (K)increased aldosteroneincreased tubular secretion of K (in exchange for Na) ∙ Recall that decreased blood volume also leads to Aldosterone secretion, via RAAS o Decreased blood volume and ingesting too much potassium both stimulate aldosterone secretion from the adrenal cortex o Aldosterone increases sodium reabsorption (at the “expense” of increased potassium secretion) Other Renal Hormones ∙ EPO o Secreted in response to hypoxia o Target: bone marrow o Effect: erythropoiesis ∙ Vitamin D o Vitamin D3 (dietary or UV light on skin precursor) is converted to active vitamin D in kidney Hypertension ∙ BP>140/90 ∙ Can lead to o Enlarged heartHF o Aneurysms o Hardening of arteries MI Stroke Kidney Failure o Damage to eyes ∙ Afterload effect o CO=HR*SV SV=EDV-ESV ∙ ESV increased from elevated MAP o Must be overcome by cardiac contraction to eject blood from ventricles ∙ SV is decreased with increased ESV o Heart must work harder to accomplish ejection Antihypertensive Meds ∙ Earlier in the semester we considered some ways to address hypertension by addressing FAST controls o Ca channel blockers and beta (adrenergic) receptor blockers to decrease contractility and heart rate ∙ Now we will look at meds that address RENAL side Blood Volume=Major Long-Term Determinant of Blood Pressure ∙ We can address fluid volume with diuretics o Thiazides, Loop diuretics, K+ sparing diuretics∙ Can also interrupt the RAAS to lower the MAP o ACE inhibitors o ARBs Angiotensin II receptor blockers Acid Base Balance Homeostasis of H+ in the Body ∙ Why is pH homeostasis important? o Acidosis vs alkalosis o Blood: 7.35-7.45 pH PCO2 ∙ High=high and low pH Sources of Hydrogen Ion Gain or Loss ∙ Gain o Generation of H+ from CO2 o Production of nonvolatile acids from the metabolism of proteins and other organic molecules o Gain of H+ due to loss of HCO3 in diarrhea or other nongastric GI fluids o Gain of H+ due to loss of HCO3 in the urine ∙ Loss o Utilization of H+ in the metabolism of various organic anions o Loss of H+ in vomitus o Loss of H+ in the urine o Hyperventilation Regulation of H+ in the Body: Buffers ∙ Effective for short term pH regulation only o Temporary regulation ∙ Reversibly bind H+ ions (protons) o HBufferBuffer-+H+ ∙ Immediate response to altered H+ ∙ Buffers in the body o Primary extracellular buffer CO2-HCO3 system CO2+H2OH2CO3HCO3+H Bicarb is a buffer o Intracellular buffers Phosphates Proteins Hb can buffer for you ∙ Examples of buffers: Hb in cells, bicarbonate in blood o Pick up temporarily to help things o Can be from cause of pH change o Blowing out CO2 can make your blood more alkaline Regulation of H+ in the Body: Respiratory System ∙ The respiratory system also responds, rapidly, to altered plasma H+ concentrations o Can keep blood levels under control until the kidneys eliminate the imbalanceo Changes take 1 – 3 minutes ∙ Rapid (1 – 3 min) reflex response to altered [H+] (if source of change in H+ is non-respiratory!) o In response to METABOLIC acidosis By increasing ventilation possible to decrease [H+] (increase pH) o In response to METABOLIC alkalosis By decreasing ventilation possible to increase [H+] (decrease pH) ∙ Recall: Changes in ventilation rate/depth can be solution to pH problem or cause of pH problem! ∙ Hyperventilation causes respiratory alkalosis ∙ Hypoventilation causes respiratory acidosis Regulation of H+ in the Body: Renal System ∙ Kidneys are the ultimate balancers of H+ and pH o Slowly-acting mechanisms can eliminate any imbalance in H+ levels ∙ Changes take hours days ∙ In alkalosis, rate of proton pumping is decreased o Filtered HCO3 not replaced o HCO2 excreted o Cells pump protons into blood for excretion ∙ Response to alkalosis o Lowered plasma [H+] or increased pH o Kidneys excrete large quantities of HCO3 (bicarbonate) in the urine o Maintaining normal pH and correcting alkalosis: Reabsorption of filtered HCO3 Reabsorption is coupled to H+ ion secretion ∙ H+ ions are produced by dissociation of carbonic acid in tubular cells ∙ HCO3 produced as a result enters blood from the cell Secreted H+ ions combine with the filtered HCO3- ∙ Net result: maintenance of blood pH o Unless there is alkalosis Rate of H+ secretion is inadequate to reabsorb all the filtered HCO3 Large quantities of HCO3- can be excreted Net result: decrease in plasma HCO3- concentration Filtered bicarbonate ions can be reabsorbed (replaced) by generation of new HCO3 ions in the tubule cells Maintains normal pH o Slowing down pump=slowing down production of bicarb Less replacement bicarb, less proton secretion Some bicarbs don't combine at all, just get excreted Respiratory Acidosis ∙ Most common challenge to acid base equilibrium o Takes a long time ∙ Example: Diabetic Ketoacidosis (metabolic acidosis)å o With insulin deficiency Shift to fat metabolism Hyperglycemia induced diuresis ∙ Hypotensioncirculatory shock ∙ Regulation of H+ in the Kidneys o In acidosis, additional buffering is gained with new bicarbonate ions, synthesized in the tubule cells As long as sink for hydrogen ions is available New bicarbonate ions can also be synthesized from catalysis of the amino acid glutamine o Response to acidosis Raised plasma [H+] or decreased pH Kidney tubular cells conserve HCO3- Produce new bicarbonate, and add it to the plasma ∙ Protons are higher than normal in blood ∙ Bicarb is lower than normal in blood o Less in filtrate o Some in tubular lumen, not as much as usual ∙ Use phosphate to buffer o All these protons are excreted o Reabsorbed bicarb is not replacing a filtered bicarb, it is additional ∙ If acidic, turn on proton pump to secrete protons o Turn on pump with more protons o Increase rate of HCO3 formation in tubular epithelial cells by having more protons (acidosis) Additional Information******* ∙ Tubule cells (luminal membranes) are impermeable to HCO3- o Must conserve HCO3- by using carbonic acid reaction ∙ Reabsorption of HCO3- requires secretion of H+ o New HCO3- generated by tubule cell can cross basolateral membrane to enter interstitial fluid Reabsorbed ∙ Can work to maintain normal pH (by conserving/ “reabsorbing” bicarbonate) o If you generate rate of proton pumping for the pH of your blood, you will generate a proton and bicarb for every filtered bicarb Pump will turn on enough to secrete a proton into urine and make a bicarb to reabsorb ∙ Replace each filtered bicarb to maintain pH Buffer H ion with bicarbcarbonic aciddissociate into CO2 and H2O ∙ Pee out, haven’t altered bicarb ∙ Turned it into something else ∙ Can correct alkalosis (by excreting excess bicarbonate) Review ∙ Describe rate of o Proton pumping In alkalosis: decreases In acidosis: increase o H2CO3 formation In alkalosis: decreases In acidosis: add more to the blood o Protons in tubule are buffered by _________ Normal pH: bicarb ∙ Excreted in urine but replaced by the one you made with carbonic acid High pH: bicarb ∙ Higher in filtrate, reflects blood bicarb level Low pH: phosphates o What happens to filtered HCO3? Reproductive System Introduction ∙ Primary reproductive organs o Ovaries and testes o Functions Gametogenesis ∙ Production of sperm and oocytes Secretion of sex steroids ∙ Testes: testosterone ∙ Ovaries: estrogen and progesterone ∙ Accessory reproductive organs o Duct systems o Glands opening into ducts o Female breast tissue Hormonal Control ∙ Hypothalamic releasing hormones o GnRH ∙ Anterior pituitary tropic hormones o FSH, LH ∙ Gonadal hormones o Testosterone, estrogen, progesterone Male Reproductive Physiology ∙ Testis o Seminiferous Tubules Meiotically active cells (producing gametes) Supporting Sertoli cells also within the seminiferous tubules Where spermatogenesis occurs ∙ Spermatidspermatozoa ∙ Stem cells = spermatogonia Spermiogenesis: Spermatid Spermatozoa ∙ Remove excess “cytoplasmic baggage”, form head, acrosome, midpiece and tail ∙ Sperm “Anatomy” o Head Nuclear material: 23 chromosomes Acrosome∙ Enzymes necessary to access oocyte membrane for fertilization o Midpiece Mitochondria – ATP to power the flagella (to swim) o Tail Flagellum o Sertoli (Sustentacular) Cells Required for spermatogenesis to occur In response to FSH and testosterone, the sertoli cells support spermatogenesis Blood Testis Barrier ∙ Tight junctions between Sertoli cells; divides seminiferous tubules into two compartments: o Basal compartment Spermatogonia, can receive hormonal influence o Adluminal compartment Next to the lumen ∙ Where cells going through spermatogenesis are located Meiotically active cells lumen of seminiferous tubules Prevents sperm antigens from getting into the blood where they would be recognized as foreign by the immune system ∙ This would cause sterility Nourish developing sperm Secrete ABP (Androgen Binding Protein) and luminal fluid Respond to stimulation by testosterone and FSH to stimulate secretion of paracrine (local signal) agents that then stimulate sperm proliferation and differentiation Secrete Inhibin (decreases FSH production from the pituitary) Phagocytosis of defective sperm Secrete (during embryonic life) Mullerian Inhibiting Hormone (MIH; aka MIS) o Interstitial (Leydig) cells In “interstitium” (outside seminiferous tubules); these cells secrete Testosterone In response to LH, the leydig cells produce steroids (testosterone) ∙ Duct system o Epididymis Sperm stored Maturation (sperm acquire motility) o Vas Deferens o Ejaculatory Duct o Urethra ∙ Accessory glands o Seminal Vesicles Secrete alkaline, viscous fluid that makes up approximately 60% of semen Includes nutrients (fructose) Prostaglandins (decrease viscosity of cervical mucus and increase uterine contractions) o Prostate Gland Secretes fluid (33% of semen) with enzymes to activate sperm ∙ Acid phosphatase; fibrinolysin o Bulbourethral Gland Secretions neutralize acidic traces of urine in urethra ∙ Penis: erectile tissue o Corpus spongiosum o Corpora cavernosum Transport of Sperm ∙ Starting in seminiferous tubule lumen to… ∙ Rete Testis: tubular network; seminiferous tubules open into it ∙ Efferent Ductules: leave testis ∙ Epididymis: sperm maturation completed; storage o Like a cap on testis o Long coiled tube ∙ Vas Deferens: to urethra ∙ Ejaculatory Duct: formed from vas deferens and duct from seminiferous tubules ∙ Urethra Side Note ∙ Capacitation in female trip: sperm swim properly with purpose, vigorously, can fertilize Hormonal Regulation ∙ Hypothalamic Releasing Hormone o GnRH (Gonadotropin Releasing Hormone) ∙ Anterior Pituitary Tropic Hormones (Gonadotropins): o FSH: Follicle Stimulating Hormone Stimulates spermatogenesis in the testes indirectly by stimulating Sertoli cells to release androgen binding protein (ABP) Causes spermatogenic cells to bind and concentrate Testosterone FSH and Testosterone also cause Sertoli cells to release the local signals (paracrine agents) that stimulate spermatogenesis o LH: Binds to interstitial cells (of Leydig) to stimulate them to secrete Testosterone∙ Gonadal Steroid: Testosterone o Effector hormone Effects of Testosterone in Male ∙ Required for spermatogenesis; acts via Sertoli cells ∙ Decreases GnRH secretion via negative feedback on hypothalamus ∙ Decreases LH secretion via negative feedback on anterior pituitary ∙ Induces and maintains differentiation of male accessory reproductive organs; maintains function ∙ Induces male secondary sex characteristics ∙ Stimulates protein anabolism, bone growth, and cessation of bone growth o More build up than break down o Increase body protein ∙ Maintenance of sex drive; may enhance aggressive behavior ∙ Stimulates erythropoietin release by kidney Mechanism of Action: Testosterone ∙ Steroid mechanism o Activate genes for specific protein synthesis o Matures the male brain Sexual dimorphism when there are brain difference between women, gay men, and straight men Estrogen can not cross blood brain barrier ∙ Testosterone must convert to o DHT for some effects (including development of penis) o An estrogen to masculinize the fetal brain Female Reproductive Physiology Anatomy ∙ Ovary (gonad) o Anchored to uterine and pelvic wall by ligaments o Contains ovarian follicles, each of which consists of an oocyte and surrounding cells. ∙ Duct System o Uterine (Fallopian) tubes Fimbriae: “Fingerlike” projections which have cilia o Uterus: Body, fundus and cervix o Vagina Histology of Ovarian Follicle ∙ Surrounds the oocyte o Supporting cell ∙ Primordial Follicle o Primary oocyte + 1 layer follicle cells ∙ Primary Follicle o 2 or more layers of granulosa cells surround oocyte o Development of thecal cells Make androgens L reminds you of leydig cells ∙ Secondary Follicle o Antrum begins to form∙ Graafian (vesicular) Follicle o Mature follicle o Oocyte on stalk of granulosa cells, ready for ovulation ∙ Day 1: menstrual period o Beginning of cycle Uterine, ovarian, hormonal cycles ∙ LH is made for corpus luteum (yellow) Histology of Uterine Wall ∙ Perimetrium o Outermost, serous layer ∙ Myometrium o Middle, smooth muscle layer o Strongest in the body when going through contractions ∙ Endometrium o Mucosal lining; contains uterine glands o Stratum basalis – “regenerative” layer Not shed with menstrual flow Cells proliferate to restore functional layer of endometrium after menstruation o Stratum functionalis – “functional” layer; undergoes cyclic changes in response to ovarian hormones This layer is shed with menstrual flow Vascular Supply ∙ Uterine Arteries ∙ Radial branches ∙ Straight arteries o To Stratum Basalis ∙ Spiral Arteries o To Stratum Functionalis o Degenerate and regenerate each menstrual cycle o Shed with every period Spermatogonia are present in males ________________ and oogonia are present in females ________________ . ∙ Throughout life; only before birth Oogenesis∙ Begins in fetal ovaries ∙ Born with ~ 400K primary oocytes o Meiosis I arrested in prophase o Do not make any new oocytes, abandon oogonia ∙ After puberty, one (usually) primary oocyte completes Meiosis I each cycle o Only one is typically ovulated ∙ Meiosis II completed only with fertilization o Only happens if secondary oocyte was fertilized o Fertilization triggers meiosis II o Ovum hangs on to everything and polar body is ejected Ovarian Cycle ∙ The ovarian cycle of changes in steroid production drives the rest of the changes that characterize the menstrual cycle of adult females ∙ Two phases: (Numbers assume a “normal” 28-day menstrual cycle.) o Follicular phase: period of follicle growth: from day 1 (1st day of menstrual period) - day 14 (ovulation) of menstrual cycle Increasing levels of estrogens LH surge causes ovulation, meiosis 1secondary oocyte o Luteal phase: period of corpus luteum activity: day 14 - 28; (from ovulation to the end of the cycle) Increased progesterone levels o If not fertilized, it dies ∙ Note: menstrual cycles vary from 21 - 40 days in length ∙ Ovulation occurs fourteen days before the end of the cycle; i.e., luteal phase remains constant ∙ The ovarian cycle of changes in steroid production drives the res of the changes that characterize the menstrual cycle of adult females o Follicular phase marked by increasing levels of estrogens o Luteal phase is one of increased progesterone o Transition between the two is ovulationReview: Sites of Secretion in Ovarian Hormones (Non-Pregnant) ∙ Estrogen o Made by granulosa cells (Follicular phase): Requires thecal cells’ cooperation* LH stimulates thecal cells to synthesize androgens, which diffuse to granulosa cells Thecal cells also make androgenestrogen in presence of granulosa cells Under influence of FSH, granulose cells convert androgens to estrogen o Corpus luteum (Luteal phase) ∙ Progesterone: o Corpus luteum (Luteal phase) is major source To do uterine endometrium changes to support a baby o (Very small amounts from granulose/thecal cells just prior to ovulation) ∙ Inhibin: o Granulosa cells Ovarian Events and Hormonal Control o Ovulation provoked by surge in LH, marks transition to luteal phase of cycle (high levels of progesterone) o 14-15: decrease in LHluteolysis and the withdrawal of steroid support for thick, active uterus o Small increase in secretion of gonadotropens (FSH and LH) lead to follicular maturation o FSH makes follicles develop With help of LH, but mostly FSH Primordial: primary oocyte with 1 layer of cells Primary: 2 layers of cells in follicle (granulosa and thecal)o Including increase in synthesis and secretion of ovarian steroid hormones o Released from inhibition and FSH and LH start to rise at the end As we remove sex steroids o No replacement of LH, starts to die, causes next period o Ready for pregnancy, but didn't get pregnant ∙ High concentrations of Progesterone + Estrogen together feedback inhibition of GnRH and thus FSH/LH Summary of the Hormonal Control of Ovarian Function During… ∙ Early and Follicular Phase o Formation of estrogen o Androgen to estrogen o Estrogen feedback with pituitary and hypothalamus Good at eliminating LF o Inhibin eliminates FSH ∙ Hormonal control of ovarian function during late phase o Switch to positive feedback elicits large, ovulatory surge in LH o Inhibin controls FSH, tiny surge ∙ Luteal phase o After ovulation, corpus luteum releases inhibin, progesterone, and estrogen to inhibit release of gonadotropins o After surge, back to typical regulation o High levels of sex steroids, back to hypothalamus, keep estrogen levels low Don't want to pregnancies at two different times Uterine (Endometrial) Cycle ∙ Relationship between ovarian and uterine changes during the menstrual cycle ∙ Thick endometrium and spiral arteries are lost when period starts o 5 day ∙ Proliferate endometrium with estrogen ∙ Pregnancy: placenta doesn't develop fully for 3 months Summary: Feedback Effects ∙ Estrogen in low to moderate concentrations: inhibits FSH/LH production. ∙ Inhibin acts to inhibit FSH secretion ∙ Estrogen, when increasing dramatically, has positive feedback effect to increase LH secretion (and, lesser degree, FSH) in response to GnRH Review: Effects of LH Surge ∙ Meiosis I completed Secondary oocyte ∙ Increase in antrum size and blood flow to follicle ∙ Granulosa cells release some progesterone and decrease amount of estrogen release ∙ Ovulation ∙ Formation of corpus luteum estrogen + progesterone secretory endometrium. Review: Functions of Granulosa Cells ∙ Nourish oocyte ∙ Secrete chemical messengers that influence oocyte + theca cells ∙ Secrete antral fluid ∙ Produce Estrogen (in cooperation with thecal cells) ∙ Produce Inhibin Review: Effects of Female Sex Steroids ∙ Estrogen o Anabolic steroid o Secondary sex characteristics (puberty) o Proliferation of endometrium o Production of progesterone receptors o “Hospitable” cervical mucus ∙ Progesterone o Secretory endometrium o Quiets myometrium (decreased contractility) o “Inhospitable” cervical mucus Compare and Contrast Granuloma Cells and Sertoli Cells ∙ Similar o Both nourish developing gametes o Secrete paracrine (local) signals to influence androgen producing cells (thecal and leydig) and gamete development