BMS100_PHL1-21v1_F2022.pdf

Physiology Concepts II Flow Down Gradients – In-Class BMS 100 Week 4 Questions from prelearning? Poiseuille’s law Fick’s law Ohm’s law Combining forces There are many situations in physiology where more than one force acts on the same substance ▪ Filtration through a capillary → diffusion and hydros...

Physiology Concepts II Flow Down Gradients – In-Class BMS 100 Week 4 Questions from prelearning? Poiseuille’s law Fick’s law Ohm’s law Combining forces There are many situations in physiology where more than one force acts on the same substance ▪ Filtration through a capillary → diffusion and hydrostatic pressure ▪ Distribution of ions across a membrane → diffusion and electrostatic forces Often these forces “pull” or “push” the same substance in opposite directions ▪ Which way will the substance move? Starling forces The purpose of a capillary is to transport substances to and from tissues Water → ▪ Hydrostatic pressure ▪ Diffusion “Everything else” ▪ Diffusion ▪ Protein-mediated transport ▪ Endocytosis Starling forces - simplified [ "𝑃𝑟𝑒𝑠𝑠𝑢𝑟𝑒 𝐹𝑜𝑟𝑐𝑒𝑠" − "𝐷𝑖𝑓𝑓𝑢𝑠𝑖𝑜𝑛 𝐹𝑜𝑟𝑐𝑒𝑠" ] 𝐹𝑙𝑢𝑥 = "𝑅𝑒𝑠𝑖𝑠𝑡𝑎𝑛𝑐𝑒 𝑡𝑜 𝐻2𝑂 𝑓𝑙𝑢𝑥" Starling forces - simplified 𝐅𝐥𝐮𝐱 = 𝐋𝐩 𝐏𝐜𝐚𝐩 − 𝐏𝐈𝐒𝐅 − 𝛔 𝛑𝐜𝐚𝐩 − 𝛑𝐈𝐒𝐅 Starling forces - simplified Variables: 𝐋𝐩 = the “leakiness” of the capillary wall to water ▪ The “inverse” of resistance 𝐏 = hydrostatic pressure 𝛑 = osmotic pressure “cap” = the fluid within the capillary “ISF” = the fluid within the interstitial space 𝛔 = how much protein leaks through the capillary wall 𝐅𝐥𝐮𝐱 = 𝐋𝐩 𝐏𝐜𝐚𝐩 − 𝐏𝐈𝐒𝐅 − 𝛔 𝛑𝐜𝐚𝐩 − 𝛑𝐈𝐒𝐅 Starling forces These forces are difficult to measure experimentally ▪ The value of the variables in different situations and in different locations is the subject of much debate Flux vs. Flow? ▪ Flux = flow along a defined membrane surface area Describes tissue swelling in a wide variety of situations ▪ Inflammation/infection ▪ Changes in pressure within the circulation Starling forces and the microcirculation Nernst potential We know that: ▪ Charged particles can move across a membrane based on electrostatic forces Energy “powering” movement along the gradient? Resistance? ▪ Dissolved particles can move across a membrane based on their concentration gradient Energy “powering” movement along the gradient? Resistance? The Nernst equation tells us the balance… ▪ Does the particle move into or out of the cell, assuming it can cross the membrane? Nernst potential The equation for the Nernst potential accounts for the following: ▪ Diffusional forces and electrical fields are very small at large distances Distribution of ions very close to either side of the membrane ▪ The charge of the particle ▪ The ratio of the particles’s concentration intracellular:extracellular It does not include the flow of ions (current) or the resistance of the membrane to flow… ▪ It gives the energy gradient Nernst potential (−60𝑚𝑉) 𝑃 𝐸𝑃 = 𝑙𝑜𝑔10 𝑍𝑝 𝑃 𝑖 𝑜 𝐸𝑃 = the membrane voltage at which a particle (P) moves into and out of the cell at the same rate ▪ → Equilibrium 𝑍𝑝 = the charge and valence of P (anions are negative) 𝑃𝑖 𝑃𝑜 = ratio of intracellular:extracellular concentrations of P Describes the voltage across a membrane that is permeable to P given the ratio of [P] inside:outside Nernst potential (−60𝑚𝑉) 𝑃 𝐸𝑃 = 𝑙𝑜𝑔10 𝑍𝑝 𝑃 𝑖 𝑜 Nernst potential (−61𝑚𝑉) 𝑃 𝐸𝑃 = 𝑙𝑜𝑔10 𝑍𝑝 𝑃 𝑖 𝑜 10 Na+ 1 K+ 9 anion- Net charge +2 8 K+ 1 Na+ 11 anionNet charge -2 Nernst potential Why is there an unequal distribution of sodium and potassium across the membrane? Why is there an unequal distribution of charge? 10 Na+ 1 K+ 9 anion- Net charge +2 8 K+ 1 Na+ 11 anionNet charge -2 Nernst potential (−61𝑚𝑉) 𝑃 𝐸𝑃 = 𝑙𝑜𝑔10 𝑍𝑝 𝑃 𝑖 𝑜 12 Na+ 1 K+ 13 anionNet charge 0 Na+ - 12 K+ 1 Na+ 13 anionNet charge 0 Nernst potential Why is it helpful to understand Nernst potentials? Living cells always have a membrane potential ▪ Established by selective transporters and channels This charge and ion balance serves important functions: ▪ Cellular signaling ▪ Transport of substances ▪ Regulation of cell volume Medications and pathologies impact the membrane potential of many different types of cells Challenge A neuron relies on an inside-negative membrane potential for the purposes of signaling ▪ Action potentials ▪ Graded potentials The membrane potential is about -75 mV in many neurons ▪ However, the Nernst potential for potassium is close to -90 mV ▪ Why is the membrane potential of a neuron close to, but not the same, as the equilibrium (Nernst) potential for K+? Challenge Hints: ▪ Goldman Field equation predicts the membrane potential when it is permeable to more than one substance V𝑚 = −61 × 𝑝𝐾 𝐾+ 𝑖+𝑝𝑁𝑎+ 𝑁𝑎+ 𝑖+𝑝𝐶𝑙 𝐶𝑙− 𝑜 𝑙𝑜𝑔10 𝑝𝐾 𝐾+ 𝑜+𝑝𝑁𝑎+ 𝑁𝑎+ 𝑜+𝑝𝐶𝑙 𝐶𝑙− 𝑖 Basically the Nernst equation, but it relates the membrane potential to the relative permeability of the membrane to sodium, potassium, and chloride 𝑝𝐾 = membrane permeability to K+, 𝑝𝑁𝑎 = membrane permeability to Na+… Physiology Concepts II Flow Down Gradients - Cases BMS 100 Week 4 Case 1 Mary is a 64-year-old woman with a 17-year history of Type 2 diabetes mellitus controlled by metformin and diet. Today she presents with slowly progressive numbness and coldness in her feet. The right foot is worse than the left On investigation, you note: ▪ Mary’s right foot is cooler and more pale than her left foot ▪ Her posterior tibial pulse is weaker on her right than on her left, and the dorsalis pedis pulse on her right is not detectable ▪ The capillary refill time on the right great toe is 15 seconds, and on the left it is 3 seconds ▪ She cannot disintguish between sharp and dull stimuli over her right foot Case 1 Below are an arteriole and an elastic artery from a patient without vascular disease and one with type II diabetes Long-term DM | No vascular disease Small vessels (arterioles) Large vessels (elastic arteries) Case 1 – Questions to answer Clearly correlate Mary’s findings on history and physical exam to the known vascular changes that accompany diabetes mellitus ▪ Use the physico-chemical laws that were discussed in the pre-learning and the lecture How many of these laws are in play? How many are less important? ▪ Try to explain every clinical feature are there some clinical features that are less likely to be due to vascular changes? What would these be? Case 2 Robert is a 75-year-old gentleman with a long history of coronary artery disease and high blood pressure. He had been diagnosed with NYHA stage II heart failure 5 years ago. Today he presents because: ▪ his foot swelling has been getting worse – at the end of the day he has a great deal of difficulty putting on his shoes ▪ He has become more short of breath in the last few days On investigation you note: ▪ His blood pressure is 156/98 mm Hg – other vitals are within normal limits ▪ His feet are notably swollen, and this swelling continues part-way up the shin ▪ He is breathing quickly at rest – his respiratory rate is 25 breaths/min Heart failure – some basics Most patients with heart failure develop two general types of problems: Impaired “forward-flow” ▪ due to decreased cardiac output and worsening blood supply to important tissues like the brain, heart, kidneys ▪ The tissues with poor blood supply suffer impaired function “fluid backup” ▪ Blood is not moved from the veins at its usual rate, since the ventricles have a worsened cardiac output ▪ Blood “backs up” in the venous system Case 2 – Questions to answer What aspect(s) of Robert’s medical history best explain his foot swelling? How about his shortness of breath? How does these relate to the physicochemical laws discussed in the pre-learning and during the lecture?