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Ernest Starling perfused the renal tubule with cyanide and found that the amount of NaCl in the urine increased. This means A) NaCl is actively reabsorbed into the blood from the tubules. B) NaCl reabsorption requires cellular respiration. C) NaCl reabsorption depends on a functioning Krebs cycle. D) NaCl reabsorption depends on ATP. E) all of the above. Where are we?
Last time I talked about... How the kidney refreshes the blood through the processes of filtration, reabsorption, secretion and excretion. Today I will talk about... Homeostasis: Maintaining a stable internal milieu and Allostasis: Maintaining a metastable internal milieu in times of stress. Are we water creatures?
We usually think of ourselves living in an environment surrounded by air; but that is only half of the truth. Each one of our cells surrounds itself with a thin layer of fluid that has a chemical composition that is not that far from the chemical composition of the sea in which our ancestors lived. Internal Milieu
This primordial sea water, which we carry inside our body, is called the interstitial fluid. Claude Bernard called this fluid, along with the lymph and blood plasma, "The Internal Milieu." The body goes to great lengths to keep the physical properties and chemical composition of the fluid that bathes our cells constant. Internal Milieu
The interstitial fluid is separated from the blood in the rapidly moving circulatory system by the epithelial walls of the capillaries. The similarity between the interstitial fluid in a given organ and the blood plasma depends on the permeability of the epithelial walls in the organ in question. The Capillaries that Carry the Circulating Blood Are Immersed in the Interstitial Fluid The Lymphatic Capillaries Remove Waste from the Interstitial Fluid The interstitial fluid is also in communication with the lymph in the lymphatic capillaries of the lymphatic system. The lymphatic system returns substances from the interstitial fluid to the circulatory system. (The lymphatic system is also involved in fighting infection). The Lymphatic System PhysicoChemical Properties of the Internal Milieu pH about 7.4 (buffered in part by a bicarbonate buffer system and by a balance of bicarbonate reabsorption and proton secretion in the kidney). Osmotic pressure of about 300 mOsm/L. Internal temperature of about 37 C (98.6 F) Calcium concentration is 10 mg/100 ml. Glucose concentration is 90 mg/100 ml. The Internal Milieu is Regulated by Hormones Produced by the Endocrine Glands Endocrine Glands
The endocrine glands, including the pineal, hypothalamus, pituitary, thyroid, parathyroid, thymus, adrenal, pancreas, ovary and testes maintain homeostasis by secreting hormones into the blood stream. Osmoregulation: Homeostatic Balance of Water and Salt Dehydration causes the salt concentration of the blood to rise. The posterior pituitary gland secretes antidiuretic hormone (ADH), which places more water channels in the collecting tube so that more water is reabsorbed by the kidney and the osmotic pressure of the blood returns to normal. When the osmotic pressure gets too low due to drinking too much water too quickly, ADH secretion decreases and the water channels are removed so that more water gets diverted to the ureter to be expelled in the urine. Thermoregulation Due to Vasoconstriction or Vasodilation When it is cold, we reduce the flow of blood to the skin so that we reduce the amount of heat loss by the surface of the body. We get "cold feet", but keep the temperature of our core constant. By increasing the flow of blood to the skin when it is hot, we increase the amount of heat lost by the surface of the body. The heat loss is augmented by sweating, since sweating uses up heat to evaporate the sweat. This keeps the temperature of our core constant. Other Processes that Help Keep Us Warm An iodinecontaining hormone from the thyroid increases the rate of cellular respiration, which generates body heat. produced as a byproduct of muscle contraction and shivering. Body heat is also Thermal Insulation
Hair keeps the warmth in by insulating us. Even though we don't have much fur to raise, cold still induces the hair raising response in humans, which is seen as goose bumps. Calcium Homeostasis When the calcium concentration in the blood is too high, the thyroid gland releases calcitonin, which stimulates calcium uptake into the bone and inhibits the reabsorption of calcium by the kidney. When the calcium concentration in the blood is too low, the parathyroid gland releases parathyroid hormone, which promotes calcium absorption by the intestines, stimulates calcium reabsorption by the kidney and stimulates calcium release from the bone. Glucose Homeostasis Eating candy results in too much glucose in the blood. High blood sugar stimulates the pancreas to secrete insulin which flows to the liver where the excess glucose is polymerized into glycogen (animal starch). Insulin also lowers the blood glucose level by stimulating body cells to take up more glucose from the blood. Skipping a meal results in not enough glucose in the blood. Low blood sugar stimulates the pancreas to secrete glucagon which flows to the liver where the glycogen is depolymerized into glucose. Diabetes mellitus is a disease in which the Malfunction in Glucose Homeostasis body is unable to reduce the level of glucose in the blood. Type 1 diabetes is an autoimmune disease in which the body destroys the insulinproducing cells of the pancreas. It is treated by injecting insulin. Type 2 diabetes is a disease associated with obesity. In Type 2 diabetes, the insulin receptors are relatively insensitive to the normal levels produced by the pancreas. It can be managed with a healthy diet and regular exercise, and, if necessary, injections of high doses of insulin. GeneticallyEngineered Human Insulin Walter Cannon, who coined the Mechanisms to Prevent Disaster term homeostasis, realized that maintaining the constancy of the internal environment, not only required the kinds of mechanisms we have been talking about that respond to moderate changes in the environment; but also required additional devices that functioned to prevent disaster. These additional devices are called allostatic mechanisms. Allostasis or other state comes from the Greek for other (allo) and state (stasis). Homeostasis and Allostasis The body switches out of the typical relaxed "rest and digest" state in times of stress to a state that is prepared to deal with the stress. Note that stress can be good stress (e.g. skydiving that gives you an adrenaline rush) or distress (e.g. plane crash). Both the nervous system and the endocrine system are involved in switching between the relaxed homeostatic state and the stressed allostatic state. Hans Selye: Stress in Moderation Too much stress (hyperstress) is when your body exceeds the limits of its ability to adapt and begins to breakdown. Too little stress (hypostress) leads to a life of boredom, sensory deprivation, physical immobility, mental stimulation and neither motivation nor goals. Find a balance between the equally destructive forces of hyperstress and hypostress. In so doing, maximize good stress (eustress) and minimize distress. Optimal Stress Levels Help You Focus and Do Better on Exams! Crisis: Danger and Opportunity The Physiology of Stress Our body adapts to stress by means of the autonomic nervous system and the endocrine system. Two systems I will discuss today. Later in the semester, I will discuss the role the brain plays in adapting to stress as well as creating stress. We can use our knowledge of the physiology of stress to our advantage and use "the wisdom of our body" when we are faced with good stress and distress. Each person has a different stress optimum and may be his/her own best physician when it comes to solving stressrelated problems in the pursuit of happiness. To Each His/Her Own Autonomic Nervous System Walter Gaskell and John Langley were interested in the "involuntary" or "autonomic nervous system." Through making histological sections, they traced the nerves that went to each of the visceral organs of the body. different systems of nerves (what we now call the sympathetic and parasympathetic systems). Each visceral organ is innervated by two Test Plant Extracts on Nervous System John Langley (1890) systematically tested the effect of various plant (e.g. nicotine) and fungal (e.g. muscarine) extracts on nervous responses. First he would electrically stimulate a given nerve and observe the response of a given organ. Then he painted the drugs with a fine brush on a particular nerve and again watched the response of the organ. He noticed that some drugs specifically affected the sympathetic and others the parasympathetic nervous system. Sympathetic/Parasympathetic Nervous System Dilates/constricts pupils Inhibits/stimulates saliva production Dilates/constricts bronchi Accelerates/slows heart Stimulates adrenaline and noradrenaline release Stimulates glucose release from liver Inhibits/stimulates stomach, intestines and pancreas Inhibits/stimulates urination Promotes ejaculation and vaginal contractions Promotes an erection Cornell Grad Discovers Adrenaline William H. Bates (1886), a Cornell graduate (1881) discovered a new chemical in the extracts of adrenal glands that would later be called adrenaline. George Oliver (1893) began to study the effects of adrenaline. He built an instrument that could measure the diameter of blood vessels that were close to the surface of the skin. He gave his son a small dose of adrenaline and noticed that the diameter of his son's arteries decreased and his blood pressure rose. Adrenaline Mimics the Sympathetic Nervous System Oliver (1880s) injected adrenaline into the vein of a dog and immediately after the injection, the blood pressure rose past the limit of the blood pressure gauge. After seeing that Oliver began a series of studies on the effect of adrenaline on the other organs of the body. Noting that adrenaline caused an increase in the heart rate, certain blood vessels to contract and certain skeletal muscles to tone up, they concluded that the adrenaline mimicked the sympathetic nervous system. Adrenaline Causes Pupils to Dilate Max Lewandowsky (1898) noticed that adrenaline also caused pupils to dilate and eyeballs to bulge, two more effects usually caused by stimulation of the sympathetic nervous system. Adrenaline Mimics Sympathetic Nervous System
John Langley (1901) showed that adrenaline mimicked stimulation of the sympathetic nervous system in more ways, including inhibition of sphincter action in the stomach, bladder contraction and uterus contraction. Thomas Elliot continued work in Langley's lab and suggested that: Adrenaline as the Neurotransmitter? "Adrenaline might then be the chemical stimulant liberated on each occasion when the [sympathetic nerve] impulse arrives at the periphery." An adrenalinelike substance known as noradrenaline is the effective agent (i.e. neurotransmitter) that is released by the sympathetic nervous system at the target tissue. The Power of Chemicals Walter Dixon took a number of hallucinogens and realized the power of certain chemicals on the body. After taking mescaline, he wrote: "When sitting with closed eyes, balls of red fire pass slowly across the field of vision, Later these change to kaleidoscopic displays...." Walter Dixon Found and Agent that Slowed The Heart Beat Down
In order to look for the effect of chemicals on important bodily functions, Dixon (1907) electrically stimulated a heart for 30 minutes. Then he placed the heart in boiling water for 10 seconds and extracted it with alcohol. He put the extract on a fresh beating heart and found that, in contrast to adrenaline, it slowed the heart beat down. The action of the extract mimicked the parasympathetic nervous system. Ergot of Rye Henry Wellcome, head of the Burroughs Wellcome and Co. was interested in the history of medicine and knew that ergot of rye was used by midwives for centuries to produce contractions of the uterus. Henry Dale that he study the properties of ergot of rye in his spare time. Wellcome suggested to Ergot of Rye Henry Dale Dale purified the compound from ergot of rye that caused the contraction of the uterus. The extract mimicked other parasympathetic effects, including stimulating salivation, stimulating contraction of the stomach, intestine and bladder and slowed down the heart beat. mimicked the parasympathetic nervous system and saw that it was acetylcholine. Dale isolated the chemical from ergot of rye that Acetylcholine Mimics the Parasympathetic Nervous System
By 1914, Dale had concluded that acetylcholine was the most potent mimic of the parasympathetic nervous system, but he had not yet realized that acetylcholine was more than just an interesting product of a plant pathogen, but was naturally Otto Loewi was a Good Guesser Otto Loewi knew that the parasympathetic nervous system slows down the heart beat. He knew that Dale had shown that acetylcholine mimicked the parasympathetic nervous system. He guessed that acetylcholine may be the chemical signal produced by the parasympathetic nervous system that slows down the heart. Then Loewi Had a Dream
In 1921, Loewi woke from a dream and jotted down an experiment that could show that the stimulated nerve produced a chemical, that slowed down the heart beat. Isolation of Acetylcholine from the Body After seeing Otto Loewi's results, Henry Dale believed that acetylcholine was probably produced in the body and he was determined to find it. Dale collected 71 pounds of spleens from horses and oxen at a local slaughterhouse. He ground up the spleens and extracted them with alcohol. He purified 0.3 grams of acetylcholine and was THRILLED! At that moment, acetylcholine changed from a curious plant extract to a natural regulatory constituent of the body. Is Acetylcholine a Natural Regulator of the Heart Beat? Stimulation of the parasympathetic nervous system slows down the heart beat. Acetylcholine mimics the effect of the parasympathetic nervous system. Acetylcholine is found in the spleen. But, does the parasympathetic nervous system produce and release acetylcholine as a natural regulator of the heart beat? The Leech Muscle Bioassay Attach a Hungarian leech muscle to a strain gauge that can measure when a muscle contracts. Bathe the muscle in an aerated salt solution. Perfuse the solution with tiny amounts of acetylcholine (e.g. 1/500,000,000 dilution) and the muscle contracts. Add tiny amounts of an unknown. If the muscle contracts, the unknown contains acetylcholine. Bioassays Only a canary was sensitive enough to sense the presence of traces of odorless poison gas in a Victorian coal mine. Miners used canaries to warn them of the presence of a poison gas. Hungarian leech was sensitive enough to detect the presence of acetylcholine. Similarly, only a living system, like the Acetylcholine is a Natural Regulator of the Heart Beat Otto Krayer developed a technique for drawing blood from veins and Wilhelm Feldberg developed the Leech muscle technique. When they stimulated the parasympathetic nervous system and then added the venous blood to the bioassay, the leech muscle contracted, indicating that the parasympathetic nervous system produces acetylcholine, which enters the blood stream. Walter Cannon found the underlying simplicity in this myriad of results concerning adrenaline and acetylcholine. Walter Cannon "As a matter of routine I have long trusted unconscious processes to serve me.... [One] example I may cite was the interpretation of the significance of bodily changes which occur in great emotional excitement, such as fear and rage. These changes--the more rapid pulse, the deeper breathing, the increase of sugar in the blood, the secretion from the adrenal glands--were very diverse and seemed unrelated." Walter Cannon
"Then one wakeful night, after a considerable collection of these changes had been disclosed, the idea flashed though my mind that they could be nicely integrated if conceived as bodily preparations for supreme effort in flight or in fighting." Adrenaline Moves Through the Blood Stream Cannon measured the amount of adrenaline in the blood of calm cats. Then he measured the amount of adrenaline in the blood of cats that had been stressed out by a barking dog. Adrenaline is released into the blood whenever a cat is stressed. The Effect of Stress on the Body Cannon wrote in his diary: January 20, 1911. "Got idea that adrenals in excitement serve to affect muscular power and mobilize sugar for muscular use--thus in a wild state readiness for flight or fight." Homeostasis and Allostasis The nervous system In serene times, the parasympathetic nervous system acts by using acetylcholine as a neurotransmitter (which also travels through the blood). In stressful times, the sympathetic nervous system acts by using adrenalinelike noradrenaline as a neurotransmitter. The sympathetic nervous system activates the adrenal glands to produce adrenaline. Blood stream carries adrenaline to amplify and prolong the action of the sympathetic nervous system. The endocrine system Adrenaline Prepares one for Emergencies In time of injury, adrenaline shortens blood clotting time. When it is stressfully cold, adrenaline causes the constriction of peripheral blood vessels to prevent heat loss and causes the elevation of hair (goose bumps). In high altitudes, where the air is thin, adrenaline causes an increase in the heart rate which brings more oxygen to the cells. When your muscles work too hard and your blood sugar becomes low, adrenaline causes a release of sugar from the liver into the blood and gives you a "second wind." During times of "fight or flight", adrenaline Adrenaline and the Blood Supply causes a dilation of the blood vessels that bring blood to the heart, brain and skeletal muscles and diverts it from the skin, digestive system and kidneys. This diversion of blood keeps us on our toes. results in the stoppage of the mechanical movement of the digestive organs first observed by Cannon in the late 1800s. The diversion of blood from the digestive system How long and how often can this emergency system be used? In emotionally stressful situations, including both positive and negative stresses, as well as real or imagined, we use the same adrenalinebased allostatic mechanisms. Since adrenaline causes an increase in blood sugar, prolonged stress is likely to lead to a "psychosomatic" diabetes. Stress and Corticosteroids The cortex of the adrenal glands produce steroids in response to stress and these steroids are known as corticosteroids. They are synthesized from cholesterol. Aldosterone is a corticosteroid that stimulates the kidney to reabsorb NaCl and consequently more water to increase the blood pressure. The higher the blood pressure, the faster the blood flows and it is more likely that the brain, heart and necessary skeletal muscles will get sufficient oxygen. Prolonged hypertension will result in artery, heart and kidney damage as well as greater risks of heart attack and stroke. Stress and Corticosteroids Other corticosteroids, including cortisol, induce the breakdown of skeletal muscle proteins into glucose and ammonia so that the glucose can be used for energy. While this provides readilyusable energy in times of emergency, prolonged exposure to stress leads to the breakdown of the body itself. Again, it is the golden age of biology! If you understand biology, you can get rich! Walter Cannon (1939): Homeostasis and Society
"It seems...that the means employed by the more highly evolved animals for preserving uniform and stable their internal economy...may present some general principles for the establishment, regulation and control...
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- Spring '07