Pre-Recorded Lecture - Friday Time Slot PDF

All right, welcome back everybody. So this is our pre-recorded lecture that is Corresponding with our Friday time slot. So hopefully you're either listening to this early or maybe over the weekend and plan to attend part of our MUW-COMM Research Day So today's topic after we finish off a couple sli...

All right, welcome back everybody. So this is our pre-recorded lecture that is Corresponding with our Friday time slot. So hopefully you're either listening to this early or maybe over the weekend and plan to attend part of our MUW-COMM Research Day So today's topic after we finish off a couple slides that we didn't get to on Wednesday is going to be an overview of a couple special circulations, but before that let's Make sure we get through these last viewpoints. So I'll update this Thank you to those that reached out about the numbering that was off So sorry to throw anybody off the the lecture on Wednesday should have said lecture 25. So this is 26 I saw that our calendar was correct when my numbering on the slides was wrong. So sorry about that So we left off here with a topic that we have touched on before as we went back to our smooth muscle Units, we talked about prostaglandins and we left off reminding Everybody that you should think of prostaglandins as not one or the other because they're a really big family that includes Type of prostaglandins that bind receptors that will cause vasodilation But there's also prostaglandin receptors that will lead to vasoconstriction. So it really just depends on the kind of receptor So, please note we are not going to be on the level of learning each of these receptors Okay, you need to understand that there are some prostaglandin receptors that will that increase cyclic AMP that's going to lead to Relaxation and of course those that are going to signal on receptors that Increase the availability of calcium and smooth muscles are going to lead to contraction This pathway includes the arachidonic acid and cyclooxygenase you've probably Or might be familiar with the aspirins target cycle oxo would affect this this pathway as well something as simple as NSAIDs, for example And then the other one the other factor is known as the endothelial derived Hyperpolarizing factor Edhf, okay, and this is a true vasodilator and how it acts as a vasodilator Is unique compared to the other The other factors that we we've covered so this Edhf and you can see this remember. This is the endothelial cell So that would be in this layer here that we've talked about before and here's our zooming in on our smooth muscle cells so edhf is going to Facilitate the opening of these calcium chant, sorry potassium channels And that are going to lead to an efflux of potassium That is going to result in a Hyperpolarization of the smooth muscle cell which means you're going to induce Relaxation and cause vasodilation this efflux of potassium is going to limit the availability of intracellular calcium And then endothelins are only vasoconstrictors We want you to think about endothelins as being released in response to different cascades some are going to be released via ang2 if you've learned about the Ras pathway that involves the renin-aldosterone angiotensin system Ang2 is one of the factors of that pathway that is going to when increased in the In the blood vessels is going to induce an increase in endothelins Endothelins are going to increase The availability of calcium in smooth muscle to cause contraction There is also along the hypoxia pathway, but also any type of trauma and this is it's silly to include a knife but trauma to the endothelial layer is going to increase endothelins this trauma could be like plaque or the tearing away as we'll talk about in states of high blood pressure that the that the endothelium here becomes very unhealthy and from the vascular smooth muscle, so Trauma very local trauma can induce endothelins which will then cause inappropriate contraction and vasoconstriction of that smooth muscle Within that vascular smooth muscle there are specific endothelin receptors and so that is going to via the IP3 pathway trigger that cause that increase in intracellular calcium So I thought I'd add this in just for review because it's a lot prettier drawing than the one we did in class and a little bit clearer so that you have a copy of this so As you go back through remember these are the two ends of the spectrum of disrupting these capillary beds where we're Comparing what is the level of? PC compared to pi C and remember pi C in the examples we're going to use in this unit are constant Okay, and it's the vast or the venule side of capillaries that often change their pressure In disease states or in some type of trauma like hemorrhage we have respectively here a drop in Venual pressure so that means that PC is much lower for a longer time over the course of the capillary bed which leads to a lot of fluid being Reabsorbed into the capillaries to try to increase blood volume where the opposite of that is as the heart fails we have essentially a backing up of this system where the veins start to accommodate too much because of this congestive heart failure which raises the pressure or PC on the venule side which leaves it higher PC is higher across the entire capillary bed, which means that a lot of fluid from Blood is going to be moved into the interstitium leading to edema So what's next today? We're gonna talk about a bit more detail about the principle of auto regulation of blood and This is going to occur in a number of regions of our body We're going to pick the brain and skeletal muscle to talk about in more detail as to Organ systems that we have already covered in in this course So let's move on to lecture 26 here and Talk about the unique Circulation needs here. So please note we don't have a learning objective here because we do not want you to memorize these Percentages this is just to give you an idea Where blood is going? Proportionately, and this is mostly at rest. So When blood comes from from the heart goes to the lungs Gets oxygenated and then that oxygenated blood needs to be delivered right to all Of the rest of the body so you can see a lot goes to the GI tract Proportionately a fair number goes percentage goes to the brain and the skeletal muscle But these can change I should also point out that the kidneys is another big contributor But particularly in in the brain We want to make sure that this flow rate stays consistent and that is principle called called auto-regulation These what's considered special circulations would be cerebral hepatic Skeletal coronary splint neck and renal so that's why we picked cerebral and skeletal muscle today to kind of highlight some of the unique natures of the circulation to to these organs So the cerebral circulation Even though the brain makes up a very very small amount of the respective body weight of an individual it requires a high need of cardiac output So cardiac output is basically how many liters per minute to the heart is pumping? Oftentimes abbreviated co will talk a lot more about that in January But this this relatively light organ requires a lot of blood supply And this just reflects the high metabolic rate and need of our brains this Feature unique feature to this is that the brain really doesn't have any stores or release valves for all this high metabolic activity other than the cerebral circulation Which is going to need to bring highly oxygenated blood to the brain and quickly take away the result of the high metabolic processes So this gives us the opportunity to touch on the blood- brain barrier in our class so and it relates to Aspects, we've seen before right we recognize here on this sorry on This neurotransmitter here. We recognize one of our favorite excitatory Neurotransmitters glutamate, right? So we talked about how astro sites are helpful in this Microenvironment to ensure proper glutamate signaling we talked about how Astro sites are responsible for moving in particular potassium But also calcium away from sites of high neuronal activity and these astro sites also Play a role in ensuring this barrier is maintained. So we have Arteries and particularly penetrating arteries that are going to come into the brain and then these astro sites basically wrap These vessels to ensure that there's an additional layer here We see the presence of gap junctions like we saw in our last unit when we have in particular potassium shuffling going along And so this is considered a characteristic feature to this special circulation of of the brain is that it is a protective measure to make sure that not only is is flow consistent, but that It's very selective as to what can pass through The blood- brain barrier we've mentioned this as it relates to lipophilic drugs that we've covered in the past and so Most drugs are not Biochemically suited to cross the blood-brain barrier. There are some that are but generally most drugs do not and So this also helps protect the composition Sorry, it protects the the brain from any type of changes in blood composition so That that way that there's not going to be Usually a toxic buildup of substances Leading up to circulation in in the brain if these regions become injured or damaged or infected A lot of neuroglia cancer happens in beginning in astrocytes, which is why it is unfortunately such a lethal form of cancer That it's going to vastly disrupt brain function when the blood-brain barrier is compromised So let's take a little bit closer. Look at the structure here. So this Figure in B looks very similar to what we what we just saw here If we zoom in on kind of a cross section here You can kind of visualize some of the mechanisms that are and are not Capable of passing through the blood-brain barrier. There are some gases and and small lipid soluble materials that can diffuse across this extra layer, but for the most part the blood-brain barrier because of the lack of fenestrations and the tight junctions that essentially seal These layers together are going to limit The availability of traversing this blood-brain barrier Pinocytosis as we discussed in in our last lecture for larger Cargo can can happen, but that is very limited in the blood-brain barrier structure really it's just oxygen CO2 that we want to readily diffuse across this capillary But structurally it's it's very different than most capillary beds in our in the rest of our body And so there are transporters here This is almost exclusively for glucose Fatty acids amino acids that are going to be important most important to the brain We also will find aquaporins to mitigate water And then we do have some channels generalized We're not going to go into specific channels, but channels and exchangers and pumps that are going to be moving ions and protons as needed So the The specific capillary endothelial cells are going to contain the workhorses to support the necessary formation of neurotransmitters There's going to be enzymes that are capable of degrading hormones because remember while we've not covered the hypothalamus This is going to be the gateway to the to the hypothalamus and the The workhorses that I would consider are Monamine oxidase peptidase Peptidases and some acid hydrolases. So there are enzymes in these endothelial layer that are more unique to the blood blood supply of the brain and Collectively, they're going to act very much as a chemical barrier To protect the brain Another unique feature to the blood-brain barrier is known as these circumventricular organs or CVOs So we want you to be aware of these windows if you will where? over the course of the entire brain we mentioned In the entire blood-brain barrier, I should say we mentioned that there is Generally no fenestrations the exception to that comes with these CVOs Which are very much as I said kind of thought of as windows, right? the brain needs to be suited to both sense and secrete as Needed and so specifically there are sensory CVOs To help the hypothalamus and the brain stem in particular sense What is happening in the rest of the body so these sensory CVOs are color-coded here in in green We are just going to talk about them as sensory CVOs versus secretory. We're not going to list them by name And the role of secretory CVOs is also connected in particular to the hypothalamus in trying to sense and maintain homeostasis and of course hypothalamus is responsible for Secreting the appropriate hormones and so the blood-brain barrier Does have these windows of very? Small fenestration that are highly vascularized, but they are very limited and they have very specific roles so this would be the exception to the rule of no fenestrations throughout the rest of the blood-brain barrier except in these unique sensory CVOs and secretory CVOs which brings us to the principle of auto regulation and this is important to maintain over a varied amount of pressures in in the body a Consistent perfusion rate of blood to the brain So what we're seeing here on the left is a typical diagram in blue is going to be someone A patient for example that has more of a a normal Normal mean or total pressure normal blood pressure And the respective response of cerebral blood flow so over a certain amount of this range Where you see where it gets flat here? Okay, this is the what we call the normal auto- regulatory range that Across this wide variety of pressures the brain has the ability to maintain A Persistent perfusion and with even in a patient where you see this this Is shifted to the right here and chronic hypertension. So someone that has high blood pressure even despite that change in mean or to pressure the brain Unlike other organs is capable of maintaining the same Cerebral blood flow rate despite an increase in pressure now There does come a point where whether it's a person that isn't experiencing Hypertension or someone that is where it gets too high of a pressure and the cranial blood flow rate will be affected But what we wanted to highlight here is that even in normal and what's considered disease state of hypertension The brain is capable of maintaining a consistent flow rate We see that cerebral blood is also sensitive to Carbon dioxide so the it specifically cerebral vessels are going to dilate To the same metabolic factors that we mentioned on Wednesday But in particular they are more sensitive Cerebral vessels are blood vessels are to changes in carbon dioxide This is not as much found in Blood vessels in other areas of the brain now we think of the brains function This makes a lot of sense, right? We want the brain to if if carbon dioxide levels are increasing We want that to be washed away as quickly as possible But and that can be accomplished by vasodilation of the cerebral vessels So what we see here is it's a linear relationship if this point identified as normal of cerebral blood flow and normal arterial Essentially its concentration the P stands for pressure, but it's essentially the concentration of Carbon dioxide in blood. It's a linear relationship that just a modest increase in the amount of carbon dioxide in arterial blood will cause a Immediate rise in the cerebral blood flow such so that it's a linear relationship And we also see the brain Adaptate and shift The cranial blood flow by regions of the brain depending on what someone is experiencing. So we just you don't need to recognize these patterns just the takeaway here is understanding that the brain will Shift where blood is at any given time depending on what is being experienced So at a state of rest, you can see there's a lot more blood flow To the front of the brain in terms of high flow And this will shift during experiences like pain and for example example more higher order like reading reading writing Any activity that's going to require different centers of the brain the flow rates will change And this is one way that assessing a patient that might be experiencing a coma they're going to look at where are the flow rates to The brain and the different centers of the brain because there are recognizable patterns for example of high and flow rates high and low flow rates in in someone who Is in a permanent coma and you will see that even with stimulation these the brain becomes Unresponsive to what we would see here on the top, which would be normal shifts of blood flow rates that someone that's experiencing a coma There's not going to be a redistribution of blood Where this relates to Some clinical implications and where we're going to go with some of the therapies we're going to talk about Is stroke so stroke and these these Acknowledgies are a bit outdated. We need to pull more More data from the CDC because I wager to say it has not gotten better sadly but as far back as as 2018 one in six deaths is going to be from cardiovascular disease from stroke and so stroke is sadly common as many as Every 40 seconds in the United States someone is experiencing a stroke and Almost all of these are going to be considered ischemic stroke And what that means is just that that blood flow is being blocked to an area of the brain And it's the leading cause of long-term disability. So this obviously has a Wide-ranging effect from very personal Personal level but also to national policies and procedures And allocated funds to support those on long-term disability So just a little bit about the pathophysiology of stroke And some of the leading causes because we're going to get into some of the treatment of the causes in this unit Leading up to what could cause a stroke So the this poor blood flow that's going to cause damage to a brain is going to Usually be through thrombrosis or an emboli. So that's going to be you know a building up of plaque in arteries or Somewhere in circulation that then breaks off and basically blocks an area of the brain to blood flow Leading up to this this is correlates with high blood pressure Obesity. Oh, we have high blood pressure on there twice. That should probably be high cholesterol. Sorry about that so high blood pressure and high cholesterol are two of The clinical connections that we will be addressing through our pharmacology lectures in this unit over here our Relatively new Acronym for knowing the stroke warning signs because Time is is of the essence in in catching a stroke. So be fast Balance can be affected blurred vision a drooping of face the facial feature usually on one side in particular Weakness usually on one side depending on what side of the brain is affected Difficulty in speech oftentimes slurring words and a really sudden headache would be definitive warning signs to report to the hospital for the warning signs of a stroke And so some of the preventative measures that we're going to talk about in the coming weeks are going to be minimizing the occurrence of clots And these three preventative measures are great ways to reduce The chances of an ischemic event that would lead to stroke So let's finish off by touching on the other organ That's considered a special circulation that we've covered in our course so far So we're going to throw it back to skeletal muscles And talk about the unique vasculature that helps support their function so if you remember the orientation of our Muscle fibers here in these bundles that are made up of myofibrils That then are all bundled together to make up a muscle Fascicle here you can see that there is a unique pattern of capillaries that are going to be surrounding these Muscle fibers here and because muscles are going to have high metabolic needs similar But different to the brain there is a very Organized pattern to ensure that capillaries are well suited to be able to wash away the wastes of Metabolic exercise while bringing efficiently lots of oxygen to skeletal muscles And so the stars we're looking all the way already at capillary beds here, but the vasculature Is going to start with arteries that are going to branch multiple times to then become arterioles which will then Be the capillaries that we are seeing here So remember we're already well zoomed into a capillary bed here, but these would go back to Arter so it should be arterioles then arteries and each of these Fibers here okay are going to be usually having three to four capillaries that are Surrounding that that muscle fiber and so similar to we talked about the capillary bed control unique to skeletal muscle There are local versus central controls of blood flow So the local controls are going to vary whether a muscle is at rest or considered active so at rest when Muscles are not being continue skeletal muscles are not being continually contracted Very small percentage of those capillaries are going to be completely perfused and so that means those resistant vessels that we mentioned on Wednesday are going to be more constricted because the the needs of skeletal muscle for Perfused capillaries are not high during rest this changes during more active periods where you start to see a metabolic rise in the concentration And so those arterioles are going to dilate and then those Resistant vesicles that were cinched off if you will constricted limiting blood flow the capillaries are now Going to relax and the capillaries are going to fill with blood So that's what's happening locally, but there are also what we call central controls, which is going to be through the sympathetic nervous system the sympathetic nervous system will have What we consider like a resting tone, which is going to be at a very minimal signaling level at rest and when arterial pressure falls That there's going to be a sympathetic nervous system Increase in activity and this is a normal reflex. So when Arterial pressure is low that is going to essentially be interpreted by the sympathetic nervous system That there doesn't need to be a change in blood flow to the skeletal muscles during exercise This is where it's going to the change is going to be predominate predominated by the local metabolites okay, so Since the sympathetic nervous system is kind of keeping Feedback at rest, but really during exercise It's going to be those local metabolites that are going to take over the vasodilation So it's not that the sympathetic nervous system isn't involved but it essentially is going to Keep flow rates help promote low flow rates at rest So to round us out. Let's talk about the difference between isotonic and active hyperemia and reactive hyperemia, so Let's start with isotonic exercises this can be like jogging or swimming where the exercise is very rhythmic and It's over a more prolonged period of time And so isotonic exercises induce what we call active hyperemia and so this is going to lead to a longer increase in the Blood flow to muscles versus reactive hyperemia like weightlifting that we'll talk about next So as we see here in our diagram Over a period of 20 minutes for instance or longer if you're taking a longer jog or a swim you're going to see Increase decrease increase decrease in muscle blood flow rate. This is because the blood the skeletal muscles are contracting and that's going to cause Variants up and down up and down of the amount of blood flow to the muscle when that exercise stops though This is where you see an additional increase a prolonged tapering of blood flow well after Oh, actually, I thought this was minutes. This is seconds. Okay, so but it could be minutes So depending on what kind of exercise you're doing Prolonged period of Increase in blood flow well after this compression of skeletal muscle has ended Okay, and so you see that that's that kind of tapers off This can be described after a long run along Road cycling session as kind of that that runners high after the completion of Isotonic exercise so this can also be visualized from this text here. So this is still showing active Hyperemia, but it's kind of putting it all together where you know the There's a period of Increased metabolic rates and then you have a vast increase in and for a much longer period of Active hyperemia. So maybe the exercise it doesn't exactly say here, you know, it takes place here, right? And then it's there's going to be a prolonged period of where there's increased Perfusion of blood to to skeletal muscles now, let's compare that to more what we consider Isometric like lifting weights. This is where there's a complete inhibition of blood flow for just a couple seconds and so The lifting weights is a perfect example of this where it's it's not usually it's a very that is very different than the prolonged nature and requirement of skeletal muscle Support and contraction for instance on a run, right? So these isometric contractions induce a stoppage of blood flow Which we can see here on this on this diagram and this induces what we call reactive hyperemia because it induces a once that period of isometric contraction stops and and blood flow is is Is restarted You're going to see a large but very temporary Increase in blood volume to that area that was occluded by the isometric Exercise if you've seen videos of weight lifters passing out you are seeing the consequences of isometric arrest and then a Consequential reactive Hyperimia, but if this if this is too long this period of arrest That is where a weight lifter could be set susceptible to passing out so the take homes here are comparing and contrasting and associating isometric contractions with a reactive hyperimia versus isotonic contractions inducing what's known as an Active hyperimia, which is often longer so the magnitude can be similar but the duration is much different based on the type of contractions of skeletal muscle So with that, let's look at what's ahead. So I hope everyone enjoys a nice weekend. We'll welcome Dr. Skinner back into our classroom for both Monday and Wednesday's lecture where he will Tell us all about blood thinners both anticoagulants and anti-platelets both of which in their own regard can help minimize or prevent subsequent strokes and ischemic events So if by chance you haven't gotten a chance to listen to dr. Skinner's clinical case From Monday, this would be a great opportunity over the weekend to listen to it because he gives you a preview of some of the material that he will cover next Week and a very personal story to go along with it. I hope everyone has a great weekend of office hours on Monday Please reach out with any questions. Thank you