Now we're moving onto the respiratory system in PHAR3303! (And what good timing too, considering that we're learning about the respiratory system in PHYL3002 as well :P)
Demonstrate understanding of the main steps in the
manufacturing of cigarettes together with an appreciation
of the toxicological implications of some processing steps.
It can take months to prepare tobacco. In the first step, the leaves are dried through a process known as "curing." This preserves the leaf by decreasing its water content. Curing also destroys the chlorophyll, hence turning tobacco yellow. Other processes then take place, such as partial rehydration and removal of the stems. Additives can also be added to the tobacco in order to improve its flavour or aroma later on. Once the leaves are ready, they are chopped up, blended and then packaged into cigarettes.
Crop production may introduce some contaminants into the cigarette. Aside from pesticides, herbicides and so on used when growing the plant, tobacco can also become contaminated by microbes.
Now let's talk about the cigarette itself! The cigarette paper may have been treated with whitening agents, inks, adhesives and so on, which can add even more contaminants to the smoke. There are also other features of the cigarette that can affect how much stuff actually gets to the smoker's lungs. The rolling paper can affect the air flow and yield, the filter can prevent some (but not all!) of contaminants from getting to the smoker's lungs, and vents can help to dilute the smoke. Of course, this is all far from perfect, as there are still many tobacco-related deaths every year.
Show an understanding of the two common ways of
thinking about the different types of smoke released from
a burning cigarette.
There are two main ways of thinking about the different types of smoke.
In the first classification system, smoke can be classified as mainstream, sidestream or environmental. Mainstream smoke is the stuff that gets inhaled, sidestream smoke is the smoke that comes off the end of the cigarette, and environmental smoke is a mixture of sidestream smoke and the mainstream smoke exhaled when the smoker breathes out.
In the second classification system, smoke can be classified as first-hand, second-hand or third-hand. First-hand smoke is analogous to mainstream smoke, whereas second-hand smoke is analogous to environmental smoke. Third-hand smoke refers to the smoke residue that gets deposited on surfaces.
Identify 3 major carcinogen classes in tobacco smoke,
showing awareness of any role of metabolism in
converting such species to genotoxic or DNA adduct-forming
metabolites.
This lecture covered three main toxic compounds: nitrosamines, 1,3-butadiene (BD) and acetaldehyde.
Nitrosamines
Nitrosamines are bioactivation-dependent: that is, they need to be metabolised before they can start causing damage. Nicotine can undergo a process called N-nitrosation which can form NNN and NNK. NNN and NNK are potent carcinogens as they can attack DNA and form methylated bases. (These altered bases are also known as "DNA adducts.") These methylated bases can then cause incorrect base pairs to form. For example, guanine can be methylated to form O6-Me-G (the "Me" stands for "methyl"), which pairs with thymine rather than cytosine.
1,3-butadiene (BD)
1,3-butadiene is quite important, partially due to its high prevalence in tobacco smoke. BD is also present in other things such as in the synthesis of polymers or the exhaust gases from cars. In rodents, it can cause cancer in multiple different organs.
1,3-butadiene, like nicotine, is also bioactivation-dependent. CYP2E1, an isoform of CYP450, catalyses its breakdown into 1,2-epoxy-3-butene, or EB. EB can attack guanine, forming a deoxyinosine adduct which can cause incorrect base pairing and mutations.
Acetaldehyde
Acetaldehyde, which is also prevalent in tobacco smoke, does not require bioactivation to become carcinogenic. It's not 100% confirmed how it causes cancer, but it's possible that DNA adducts play a role. Deoxyguanosine, for example, can form a weakly mutagenic adduct when combined with acetaldehyde, but this adduct can also block DNA replication.
Understand the major biological outcomes of DNA adduct
formation, namely DNA repair, apoptosis and
mutagenesis.
DNA adducts have three main outcomes. Firstly, DNA repair mechanisms might kick in and fix the damage. Secondly, damage to the DNA may trigger the cell to undergo apoptosis (cell death). Thirdly, DNA adducts may cause incorrect base pairs to form, essentially causing mutations. Depending on the genes that are altered, cancer may result.
Also, it's important to note that not all of the bad stuff in cigarettes cause cancer. Some toxic chemicals are related to other negative outcomes, such as COPD. For example, acrolein is a chemical that might play a role in COPD development due to its reactivity with proteins and DNA.
Monday, April 3, 2017
Thursday, March 30, 2017
Control of Ventilation
Now we're moving onto learning about respiration! Yay...? Also, this lecture has a hell of a lot of aims, so hold onto your hat!
Describe the central generation of respiratory rhythm, including the three common hypothesis.
As mentioned here, generation of respiratory rhythm originates from centres in the medulla of the brain. There are several different hypotheses about how these centres interact:
Define apnoea, hyperpnea, hypopnea, gasping, apneusis.
See earlier post: Control of Ventilation
Explain the function of the pneumotaxic centre.
See earlier post: Control of Ventilation. Also, as mentioned earlier in this post, the pneumotaxic centre is located in the pons, so damage to the pons causes apneusis.
Identify simple respiratory patterns and how they arise
I'm not really sure what I'm meant to know for this. Apneusis maybe? But I just wrote about that...
Describe the location of the central and peripheral chemoreceptors.
The central chemoreceptors are located in the ventral medulla, whereas the peripheral chemoreceptors are located in the carotid body and aortic arch.
Describe the stimuli that these receptors respond to.
Central chemoreceptors respond to the pH of the cerebrospinal fluid, which actually allows them to respond to CO2 in a very roundabout way. CO2 can diffuse through the blood-brain barrier, where it can form H+ and HCO3- by reacting with water. An increase in H+ decreases the pH, which is detected by the central chemoreceptors. It's unclear exactly how the central chemoreceptors are activated. To add even more confusion, there are many cells in the brain that can detect pH: aside from the chemoreceptors in the ventral medulla, cells in the dorsal and ventral respiratory groups, pons and hypothalamus can all respond to pH. Le sigh.
Peripheral receptors can respond to CO2, H+ and O2, though to my understanding they respond mostly to O2. Also, carotid bodies may be better at sensing H+ than aortic bodies.
Peripheral receptors can respond more rapidly than central chemoreceptors as they don't have to worry about gases diffusing through the blood-brain barrier and whatnot.
Recall the sensory input into control of ventilation, the effectors controlled and where control occurs.
Not sure what exactly I'm supposed to put here that I haven't put under another heading, so I'm just going to shove a link to my old post on ventilation control here and call it a day.
Explain how the peripheral chemoreceptors sense PO2 and PCO2
The cells of the peripheral chemoreceptors that detect O2, CO2 and pH are called glomus cells. Glomus cells are excitable and can release neurotransmitters, just like nerve cells.
CO2 can diffuse into glomus cells and cause a change in pH, just like they do in the brain. The increased H+ ions can protonate and close calcium-activated potassium channels in the membrane of these cells. As potassium can no longer leave, the cell becomes more and more depolarised, eventually leading to action potentials.
O2 is detected via a different mechanism. O2 can be converted into carbon monoxide by an enzyme called haemoxygenase. Carbon monoxide is usually known as a poisonous gas, but it can also serve as a signalling molecule in the cells. In this case, carbon monoxide causes CO-gated potassium channels to open. This keeps the membrane potential low, inhibiting action potentials. If O2 levels drop, CO levels also drop, allowing these channels to close. (This usually happens when PO2 < 60mmHg.) As mentioned before, stopping potassium from leaving causes the cell to depolarise and action potentials to be produced.
Explain the response to changes in blood oxygen, carbon dioxide and pH.
Describe the central generation of respiratory rhythm, including the three common hypothesis.
As mentioned here, generation of respiratory rhythm originates from centres in the medulla of the brain. There are several different hypotheses about how these centres interact:
- Off-switch model: In this model, inspiratory motor neurons stimulate inspiration. Inspiration then feeds back onto some integrating neurons, which then stimulate an "off-switch" to stop inspiration. Eventually, the lack of inspiration stops the "off-switch" neurons, causing the inspiratory neurons to start up again.
- Oscillator model: In this model, both inspiratory and expiratory neurons are constitutively activated. Inspiratory neurons can activate interneurons that turn the expiratory neurons off, and vice versa. If the timing is right, they can inhibit each other at the right times, generating a rhythm.
- Pacemaker kernel model: This model suggests that there are some cells that act as a pacemaker. Indeed, some cells in the pre-Bötzinger complex do show synchronised pacemaker spikes. Glutamate inhibitors can block this synchrony.
The off-switch model and oscillator models are also known as "distributed network models," as they require multiple different groups of cells to work together.
Define apnoea, hyperpnea, hypopnea, gasping, apneusis.
- Apnoea: Lack of breathing. May result from damage to the medulla.
- Hyperpnea: Increased breathing
- Hypopnea: Reduced breathing
- Hyperventilation: Increased breathing that goes beyond what your body actually needs. (Note that hyperpnea and hyperventilation both involve increased breathing, but hyperventilation is inappropriate to the situation, whereas hyperpnea is totally appropriate.)
- Apneusis: Prolonged inspirations with short expirations. May occur due to damage to the pons. (This is where the pneumotaxic centre is, as I'll explain in a bit.)
- Gasping: The opposite of apneusis: prolonged expirations with short inspirations.
See earlier post: Control of Ventilation
Explain the function of the pneumotaxic centre.
See earlier post: Control of Ventilation. Also, as mentioned earlier in this post, the pneumotaxic centre is located in the pons, so damage to the pons causes apneusis.
Identify simple respiratory patterns and how they arise
I'm not really sure what I'm meant to know for this. Apneusis maybe? But I just wrote about that...
Describe the location of the central and peripheral chemoreceptors.
The central chemoreceptors are located in the ventral medulla, whereas the peripheral chemoreceptors are located in the carotid body and aortic arch.
Describe the stimuli that these receptors respond to.
Central chemoreceptors respond to the pH of the cerebrospinal fluid, which actually allows them to respond to CO2 in a very roundabout way. CO2 can diffuse through the blood-brain barrier, where it can form H+ and HCO3- by reacting with water. An increase in H+ decreases the pH, which is detected by the central chemoreceptors. It's unclear exactly how the central chemoreceptors are activated. To add even more confusion, there are many cells in the brain that can detect pH: aside from the chemoreceptors in the ventral medulla, cells in the dorsal and ventral respiratory groups, pons and hypothalamus can all respond to pH. Le sigh.
Peripheral receptors can respond to CO2, H+ and O2, though to my understanding they respond mostly to O2. Also, carotid bodies may be better at sensing H+ than aortic bodies.
Peripheral receptors can respond more rapidly than central chemoreceptors as they don't have to worry about gases diffusing through the blood-brain barrier and whatnot.
Recall the sensory input into control of ventilation, the effectors controlled and where control occurs.
Not sure what exactly I'm supposed to put here that I haven't put under another heading, so I'm just going to shove a link to my old post on ventilation control here and call it a day.
Explain how the peripheral chemoreceptors sense PO2 and PCO2
The cells of the peripheral chemoreceptors that detect O2, CO2 and pH are called glomus cells. Glomus cells are excitable and can release neurotransmitters, just like nerve cells.
CO2 can diffuse into glomus cells and cause a change in pH, just like they do in the brain. The increased H+ ions can protonate and close calcium-activated potassium channels in the membrane of these cells. As potassium can no longer leave, the cell becomes more and more depolarised, eventually leading to action potentials.
O2 is detected via a different mechanism. O2 can be converted into carbon monoxide by an enzyme called haemoxygenase. Carbon monoxide is usually known as a poisonous gas, but it can also serve as a signalling molecule in the cells. In this case, carbon monoxide causes CO-gated potassium channels to open. This keeps the membrane potential low, inhibiting action potentials. If O2 levels drop, CO levels also drop, allowing these channels to close. (This usually happens when PO2 < 60mmHg.) As mentioned before, stopping potassium from leaving causes the cell to depolarise and action potentials to be produced.
Explain the response to changes in blood oxygen, carbon dioxide and pH.
As alluded to before, low levels of oxygen (<60mmHg) cause a large increase in ventilation. Aaaaand I don't really have much else to say here.
Most of the response to carbon dioxide (60-80%) occurs via central chemoreceptors, though peripheral receptors play a part too, as discussed above.
Another interesting phenomenon to take note of is that of "synergistic drives." Essentially, this means that when oxygen levels are low, your cells become more responsive to high CO2, and vice versa. This is because the detection of oxygen and carbon dioxide occur through similar mechanisms: the opening or closing of potassium channels of glomus cells.
Smooth Muscle Mechanics and Adhesion
So far, I've talked a lot about things that can trigger contraction in smooth muscle, but I haven't spoken about how that contraction is actually caused. Well, now's the time!
Define dense bodies, dense bands and adherens.
Dense bodies are so-called because they look like dense, dark splotches under an electron microscope (I think). These are locations where actin filaments in the cell are cross linked with α-actinin.
Dense bands are very much like dense bodies, in that they also contain actin filaments cross-linked with α-actinin. Dense bands, however, also help form junctions between the cell and the extracellular matrix, or between the cell and other cells. These junctions are also known as adherens.
Explain the how smooth muscle cells attach to other cells and extra-cellular matrix.
As I just mentioned, junctions form at dense bands, which consist of actin filaments cross-linked with α-actinin. There are a few more proteins involved, however.
In a cell-matrix junction, actin and actinin associate with other proteins such as vinculin and talin. Talin is probably the more important one for our purposes, as it also binds to integrin. Integrin is a transmembrane protein that can connect to proteins in the extracellular matrix, such as fibronectin. Hence, integrin is sometimes known as the fibronectin receptor. In this way, actin filaments are anchored to the extracellular matrix.
In a cell-cell junction, actin and actinin still associate with vinculin, but they associate with catenin instead of talin. Catenin binds to cadherin, which, like integrin, is a transmembrane protein. Cadherin's binding site, however, is the cadherin on a neighbouring cell. Hence, cadherin serves as a "bridge" that links multiple cells together.
Recall and explain the crossbridge cycle and how it is regulated in smooth muscle.
As you may or may not know, contraction in cells relies on the movement of different filaments. Firstly, I'm going to take a step back and describe the structure of the filaments.
Thick filaments are polymers of myosin II, which has two heads. (There's also a myosin I, but that's not important for contraction. Myosin I has only one head, and it can bind and transport vesicles down actin.)
Thin filaments are polymers of actin and tropomyosin. Another fun fact to store for later (by later I mean probably a future lecture so you don't have to hold this in your head for now): monomers of actin are also known as G-actin, whereas polymers of actin are known as F-actin, or filamentous actin.
Now it's time to explain the crossbridge cycle!
Before binding can occur, the myosin head has to be in the "cocked" position. This occurs when ATPases break down ATP into ADP and Pi (phosphate). From this position, it can bind to actin, releasing a phosphate at the same time. The release of this phosphate causes a conformational change in the myosin from the cocked to the uncocked position, and it's this that causes the movement (also known as the "power stroke"). This movement triggers the release of ADP from the myosin head, which causes unbinding of myosin and actin. (Fun fact: in rigor mortis, the ADP is unable to unbind, causing stiffness.) Release of ADP also allows ATP to bind, which can then be broken down by ATPases, cocking the myosin head for the next cycle.
In smooth muscle, the rate-limiting step is the ATPase part. ATPases in smooth muscle require the regulatory light chain of myosin to be phosphorylated by myosin light chain kinase (MLCK), as mentioned here.
Explain relationship between length and tension in smooth muscle.
The optimum length for contraction occurs when myosin and actin overlap each other, allowing the maximum number of cross-bridges between the two to occur. When the muscle is made longer, less overlap occurs and less force is produced. When the muscle is made shorter, force can still be generated, but if you make the muscle too short, dense bodies might get in the way of contraction.
It's also important to note that, in smooth muscle, all of the actin/myosin combinations within the muscle are in different stages of contraction (i.e. it's not coordinated as nicely as skeletal muscle).
Define pre-load and after-load, isometric and isotonic contractions.
Pre-load and after-load have pretty much the same definitions in smooth muscle as they did in cardiac muscle. Pre-loads are loads that stretch the muscle to its starting point, and after-loads are loads that the muscle contracts against.
Isometric contractions are contractions in which the length stays the same. Just like in cardiac muscle, this is due to after-loads being too great. Muscles undergoing isometric contraction generate force without shortening.
Isotonic contractions are contractions in which the force stays the same. These may occur when there is little to no afterload, allowing the muscle to shorten without generating force.
Why does this happen? Well, force is generated when actin and myosin are bound. Muscle can't shorten when actin and myosin are bound- you need the full crossbridge cycle to occur multiple times for muscle shortening to occur. So, in short: when actin and myosin are attached, force is generated; when actin and myosin are moving, movement is generated.
Explain the relationship between force and velocity for smooth muscle in terms of crossbridge function
This is pretty much related to the point that I just made. If crossbridges are all attached and are therefore not moving, maximal force is generated, but velocity is essentially 0. As crossbridges begin to move, force decreases but velocity increases.
Define dense bodies, dense bands and adherens.
Dense bodies are so-called because they look like dense, dark splotches under an electron microscope (I think). These are locations where actin filaments in the cell are cross linked with α-actinin.
Dense bands are very much like dense bodies, in that they also contain actin filaments cross-linked with α-actinin. Dense bands, however, also help form junctions between the cell and the extracellular matrix, or between the cell and other cells. These junctions are also known as adherens.
Explain the how smooth muscle cells attach to other cells and extra-cellular matrix.
As I just mentioned, junctions form at dense bands, which consist of actin filaments cross-linked with α-actinin. There are a few more proteins involved, however.
In a cell-matrix junction, actin and actinin associate with other proteins such as vinculin and talin. Talin is probably the more important one for our purposes, as it also binds to integrin. Integrin is a transmembrane protein that can connect to proteins in the extracellular matrix, such as fibronectin. Hence, integrin is sometimes known as the fibronectin receptor. In this way, actin filaments are anchored to the extracellular matrix.
In a cell-cell junction, actin and actinin still associate with vinculin, but they associate with catenin instead of talin. Catenin binds to cadherin, which, like integrin, is a transmembrane protein. Cadherin's binding site, however, is the cadherin on a neighbouring cell. Hence, cadherin serves as a "bridge" that links multiple cells together.
Recall and explain the crossbridge cycle and how it is regulated in smooth muscle.
As you may or may not know, contraction in cells relies on the movement of different filaments. Firstly, I'm going to take a step back and describe the structure of the filaments.
Thick filaments are polymers of myosin II, which has two heads. (There's also a myosin I, but that's not important for contraction. Myosin I has only one head, and it can bind and transport vesicles down actin.)
Thin filaments are polymers of actin and tropomyosin. Another fun fact to store for later (by later I mean probably a future lecture so you don't have to hold this in your head for now): monomers of actin are also known as G-actin, whereas polymers of actin are known as F-actin, or filamentous actin.
Now it's time to explain the crossbridge cycle!
Before binding can occur, the myosin head has to be in the "cocked" position. This occurs when ATPases break down ATP into ADP and Pi (phosphate). From this position, it can bind to actin, releasing a phosphate at the same time. The release of this phosphate causes a conformational change in the myosin from the cocked to the uncocked position, and it's this that causes the movement (also known as the "power stroke"). This movement triggers the release of ADP from the myosin head, which causes unbinding of myosin and actin. (Fun fact: in rigor mortis, the ADP is unable to unbind, causing stiffness.) Release of ADP also allows ATP to bind, which can then be broken down by ATPases, cocking the myosin head for the next cycle.
In smooth muscle, the rate-limiting step is the ATPase part. ATPases in smooth muscle require the regulatory light chain of myosin to be phosphorylated by myosin light chain kinase (MLCK), as mentioned here.
Explain relationship between length and tension in smooth muscle.
The optimum length for contraction occurs when myosin and actin overlap each other, allowing the maximum number of cross-bridges between the two to occur. When the muscle is made longer, less overlap occurs and less force is produced. When the muscle is made shorter, force can still be generated, but if you make the muscle too short, dense bodies might get in the way of contraction.
It's also important to note that, in smooth muscle, all of the actin/myosin combinations within the muscle are in different stages of contraction (i.e. it's not coordinated as nicely as skeletal muscle).
Define pre-load and after-load, isometric and isotonic contractions.
Pre-load and after-load have pretty much the same definitions in smooth muscle as they did in cardiac muscle. Pre-loads are loads that stretch the muscle to its starting point, and after-loads are loads that the muscle contracts against.
Isometric contractions are contractions in which the length stays the same. Just like in cardiac muscle, this is due to after-loads being too great. Muscles undergoing isometric contraction generate force without shortening.
Isotonic contractions are contractions in which the force stays the same. These may occur when there is little to no afterload, allowing the muscle to shorten without generating force.
Why does this happen? Well, force is generated when actin and myosin are bound. Muscle can't shorten when actin and myosin are bound- you need the full crossbridge cycle to occur multiple times for muscle shortening to occur. So, in short: when actin and myosin are attached, force is generated; when actin and myosin are moving, movement is generated.
Explain the relationship between force and velocity for smooth muscle in terms of crossbridge function
This is pretty much related to the point that I just made. If crossbridges are all attached and are therefore not moving, maximal force is generated, but velocity is essentially 0. As crossbridges begin to move, force decreases but velocity increases.
Overview of Metabolism
This lecture was a nice little refresher on concepts from 1st and 2nd year. Enjoy :)
Explain the processes of cellular energy generation - the three phases of metabolism and the cell compartments involved.
The phases mentioned in the lecture are glycolysis (in the cytosol), the citric acid cycle (in the mitochondria) and oxidative phosphorylation (in the inner membrane of the mitochondria). I've blogged about all of these before, so here are some posts that explain each of these processes:
Explain the relationship between anabolic and catabolic reactions and the energy requirements of the cell.
See earlier post: Cellular Respiration and Protein Synthesis
Explain redox potentials.
See earlier posts: Basics of Redox and Redox again- Electrolytic cells and some other stuff
Understand the role of activated carrier molecules.
The carrier molecules covered in this lecture were NADH, NADPH, FADH2 and acetyl CoA. I've covered the first three in an earlier post: Overview of How the Cell Works. Acetyl CoA (acetyl coenzyme A) has a high-energy bond which facilitates the transfer of two carbon atoms to another molecule. This is important in processes such as fat anabolism, as mentioned here.
Explain the processes of cellular energy generation - the three phases of metabolism and the cell compartments involved.
The phases mentioned in the lecture are glycolysis (in the cytosol), the citric acid cycle (in the mitochondria) and oxidative phosphorylation (in the inner membrane of the mitochondria). I've blogged about all of these before, so here are some posts that explain each of these processes:
- Glycolysis and the citric acid cycle- Cellular Respiration and Protein Synthesis
- Oxidative phosphorylation- Cell Biology- Introduction and Energy Production
Explain the relationship between anabolic and catabolic reactions and the energy requirements of the cell.
See earlier post: Cellular Respiration and Protein Synthesis
Explain redox potentials.
See earlier posts: Basics of Redox and Redox again- Electrolytic cells and some other stuff
Understand the role of activated carrier molecules.
The carrier molecules covered in this lecture were NADH, NADPH, FADH2 and acetyl CoA. I've covered the first three in an earlier post: Overview of How the Cell Works. Acetyl CoA (acetyl coenzyme A) has a high-energy bond which facilitates the transfer of two carbon atoms to another molecule. This is important in processes such as fat anabolism, as mentioned here.
Exercise Metabolism
Now I've finally gotten through that post with all the graphs, I can move on with my life! I'm going to write a bit about biochemistry, because surprisingly enough, that's been the easiest subject to write about so far.
This is the last lecture about nutrition, and it probably has more new content in it than all of the other nutrition lectures combined (not like that's an amazing achievement). Enjoy :)
Be familiar with the different fiber types and their metabolic characteristics
There are two main types of muscle fibres: type I and type II. Type II can be further subdivided into type IIa and IIb. Most muscles have a mixture of different types of fibres- it's the proportions that matter.
Type I fibres have a low power output, but they are very fatigue resistant. Muscles that have a high proportion of these fibres include postural muscles and other muscles that work pretty much all the time without you even noticing. They use mostly oxidative metabolism due to their abundant mitochondria, which contributes to their fatigue resistance.
Type IIa fibres have a higher power output. They are not as fatigue resistant as type I fibres, but they still do reasonably well. They generally use a mixture of oxidative and glycolytic metabolism.
Type IIb fibres also have a high power output. They are readily fatigued as they mostly use glycolysis to generate energy. I've mentioned here that glycolysis on its own can result in lactic acid production, resulting in pain and fatigue.
Be able to explain the different types of fuels which can be used during exercise.
Know the advantages and limitations of the different types of metabolic pathways.
As you should know by now, ATP is basically the energy currency of the cell. The main fuels used to produce ATP are glycogen, fatty acids and phosphocreatine (PCr). The first two are probably already pretty familiar to you, so let's talk about phosphocreatine first.
Phosphocreatine (PCr) can be broken down rapidly into creatine and ATP during bursts of heavy activity. It can produce ATP pretty quickly, which is nice, but unfortunately we only have small reserves of PCr to draw on. Fortunately, however, it is fairly easy to restore phosphocreatine levels once you're resting: creatine and ATP can combine back together to form PCr, ADP and H+.
Now let's go back into the familiar stuff!
Glycogen stores can be broken down to form glucose and, as mentioned here, glucose can be broken down further via glycolysis. If limited oxygen reserves are available, the process pretty much stops once the glucose becomes pyruvate, at which stage it gets converted into lactic acid. This still produces some energy, and it produces it fairly quickly (in seconds), but this pathway can cause fatigue. If oxygen is available, pyruvate can enter the citric acid cycle to produce more ATP. This process doesn't cause fatigue, but is slower and has a limited capacity to supply ATP (possibly due to limitations on oxygen supply or mitochondria ability).
Fatty acids can also become oxidised to release ATP. Some of the pathways involved, like the citric acid cycle, are similar to those involved in the breakdown of glucose. The limitations are also similar: the process is slow, especially because releasing fatty acids and delivering them to the muscle takes time. It might take around 30min for fatty acid oxidation to become optimal. Also, we only have a limited ability to oxidise fatty acids, so more carbohydrates get used as exercise intensity increases.
Know which metabolic pathways (eg aerobic and anaerobic) are used during different types of exercise
Be able to explain which metabolic pathways are used as exercise intensity increases
All of the pathways pretty much get started as soon as the muscles move, but obviously the faster pathways (the anaerobic ones) will kick in sooner. Hence, short, intense exercise (~5sec) will use mainly PCr at first, which gradually gets replaced by mostly glycolysis at around 30sec (i.e. just the glycolysis to lactate part, not the citric acid cycle part) to eventually mostly oxidative pathways at around 2-3min.
Be able to explain VO2 max.
This wasn't actually in the lecture outline, but it looks important, so I'm going to include it. VO2 max is a measure of the maximum capacity to transport and utilise oxygen, as well as an indirect measure of aerobic ATP consumption. It can be measured by exercise tests. Well-trained subjects will usually have a higher VO2 max as they have a higher density of mitochondria, more enzymes for the citric acid cycle, a higher maximum cardiac output and more muscle and cardiac capillaries.
Be able to explain how the different types of exercise affect protein synthesis in muscles.
The main types of exercise are aerobic ("cardio") and resistance (weight-lifting etc.). Aerobic exercise increases the synthesis of mitochondrial proteins and of type I and IIa fibres. Resistance exercise increases muscle mass and type IIb fibres.
This is the last lecture about nutrition, and it probably has more new content in it than all of the other nutrition lectures combined (not like that's an amazing achievement). Enjoy :)
Be familiar with the different fiber types and their metabolic characteristics
There are two main types of muscle fibres: type I and type II. Type II can be further subdivided into type IIa and IIb. Most muscles have a mixture of different types of fibres- it's the proportions that matter.
Type I fibres have a low power output, but they are very fatigue resistant. Muscles that have a high proportion of these fibres include postural muscles and other muscles that work pretty much all the time without you even noticing. They use mostly oxidative metabolism due to their abundant mitochondria, which contributes to their fatigue resistance.
Type IIa fibres have a higher power output. They are not as fatigue resistant as type I fibres, but they still do reasonably well. They generally use a mixture of oxidative and glycolytic metabolism.
Type IIb fibres also have a high power output. They are readily fatigued as they mostly use glycolysis to generate energy. I've mentioned here that glycolysis on its own can result in lactic acid production, resulting in pain and fatigue.
Be able to explain the different types of fuels which can be used during exercise.
Know the advantages and limitations of the different types of metabolic pathways.
As you should know by now, ATP is basically the energy currency of the cell. The main fuels used to produce ATP are glycogen, fatty acids and phosphocreatine (PCr). The first two are probably already pretty familiar to you, so let's talk about phosphocreatine first.
Phosphocreatine (PCr) can be broken down rapidly into creatine and ATP during bursts of heavy activity. It can produce ATP pretty quickly, which is nice, but unfortunately we only have small reserves of PCr to draw on. Fortunately, however, it is fairly easy to restore phosphocreatine levels once you're resting: creatine and ATP can combine back together to form PCr, ADP and H+.
Now let's go back into the familiar stuff!
Glycogen stores can be broken down to form glucose and, as mentioned here, glucose can be broken down further via glycolysis. If limited oxygen reserves are available, the process pretty much stops once the glucose becomes pyruvate, at which stage it gets converted into lactic acid. This still produces some energy, and it produces it fairly quickly (in seconds), but this pathway can cause fatigue. If oxygen is available, pyruvate can enter the citric acid cycle to produce more ATP. This process doesn't cause fatigue, but is slower and has a limited capacity to supply ATP (possibly due to limitations on oxygen supply or mitochondria ability).
Fatty acids can also become oxidised to release ATP. Some of the pathways involved, like the citric acid cycle, are similar to those involved in the breakdown of glucose. The limitations are also similar: the process is slow, especially because releasing fatty acids and delivering them to the muscle takes time. It might take around 30min for fatty acid oxidation to become optimal. Also, we only have a limited ability to oxidise fatty acids, so more carbohydrates get used as exercise intensity increases.
Know which metabolic pathways (eg aerobic and anaerobic) are used during different types of exercise
Be able to explain which metabolic pathways are used as exercise intensity increases
All of the pathways pretty much get started as soon as the muscles move, but obviously the faster pathways (the anaerobic ones) will kick in sooner. Hence, short, intense exercise (~5sec) will use mainly PCr at first, which gradually gets replaced by mostly glycolysis at around 30sec (i.e. just the glycolysis to lactate part, not the citric acid cycle part) to eventually mostly oxidative pathways at around 2-3min.
Be able to explain VO2 max.
This wasn't actually in the lecture outline, but it looks important, so I'm going to include it. VO2 max is a measure of the maximum capacity to transport and utilise oxygen, as well as an indirect measure of aerobic ATP consumption. It can be measured by exercise tests. Well-trained subjects will usually have a higher VO2 max as they have a higher density of mitochondria, more enzymes for the citric acid cycle, a higher maximum cardiac output and more muscle and cardiac capillaries.
Be able to explain how the different types of exercise affect protein synthesis in muscles.
The main types of exercise are aerobic ("cardio") and resistance (weight-lifting etc.). Aerobic exercise increases the synthesis of mitochondrial proteins and of type I and IIa fibres. Resistance exercise increases muscle mass and type IIb fibres.
Venous Pressure and Vascular Function Curves
This lecture was more complicated than it looked at first, which isn't all too helpful given that I can feel a headache coming on :P Oh well. This will be our last lecture on cardiovascular physiology for this unit for a little while.
Explain how central venous pressure determines cardiac pre-load and output.
As you should hopefully know by now, blood flows from a place of higher pressure to a place of lower pressure until the pressures are equal. Hence, blood will flow from the veins into the ventricles of the heart during diastole until the pressures are equal. The central venous pressure thus determines the amount of filling, which determines cardiac pre-load. As covered here and here, increased end-diastolic volume/increased pre-load increases stroke volume and, by extension, cardiac output.
Understand how central venous pressure is regulated through the vascular function curve, including the actions of blood volume, vasotone and veno-tone.
Blood volume alters venous pressure pretty much the same way it alters arterial pressure: increasing blood volume increases pressure and decreasing blood volume decreases pressure. So far, so good.
The effects of vasotone (arterial contraction) on central venous pressure are less intuitive. If vasotone increases, less blood can get through to the venous side. (Remember, flow is inversely proportional to resistance, and resistance increases as you constrict the blood vessels). Hence, increased vasotone will actually decrease venous pressure.
The effects of venotone (venous contraction) are a bit easier to grasp. Increased venous constriction will increase the pressure, and vice versa.
The relationship between cardiac output and central venous pressure can be plotted on the vascular function curve:
This graph can be a bit tricky to interpret. For starters, you actually have to read it the "wrong way around": you have to find a venous pressure from a given cardiac output, not the other way around. It's done this way so that both the vascular function curve and the cardiac function curve can be plotted on the same axes, as you shall soon see.
Another thing you'll notice about this graph is that the graph levels out below a certain venous pressure. This is because ventricular filling depends on a pressure gradient between the veins and the ventricles, and if venous pressure drops to the same pressure or lower than ventricular pressure, then the ventricles cannot fill any more and cardiac output cannot be increased. One more thing to point out is the x-intercept at the graph: this point represents the venous pressure if there was no cardiac output (i.e. if the heart had stopped and the blood pressure was allowed to simply equilibrate throughout the entire system of blood vessels). This pressure is also known as the mean circulatory (MC) pressure, and is usually around 7mmHg.
When blood volume is increased, such as during a blood transfusion, the entire graph shifts up and right. A greater cardiac output can be produced, and the MC pressure is higher. (Remember, if you have more "stuff" in what is essentially the same amount of space, you're going to have a higher pressure.) The reverse is true for when blood volume is decreased.
Now, blood vessels are not just passive: they can constrict and relax. How does that affect the vascular function curve?
Venoconstriction has a similar effect to increasing the blood volume: it raises the curve up and right. It also changes the slope of the curve slightly (the above picture is possibly exaggerated), leading to a higher possible venous pressure at zero cardiac output. This makes sense: pressure is inversely proportional to volume, so if you constrict the veins, thereby reducing the space inside, you'll increase the pressure. Vasoconstriction, on the other hand, does not change venous pressure when cardiac output is zero. (I'm not sure why- I'm thinking it's because arteries are smaller than veins and thus vasoconstriction has less of an overall effect on volume than venoconstriction? That's something I'll have to check.) Maximum cardiac output is greatly reduced- as mentioned here, MAP = CO*TPR. Rearranging this equation gives CO = MAP/TPR, so it follows that an increased peripheral resistance, as occurs during vasoconstriction, will decrease cardiac output.
Understand how cardiac output is set by the interaction between the vascular and cardiac function curves.
Some of the stuff in this post might seem a bit unintuitive, especially given the relationship between diastolic volume (and venous pressure) and cardiac output. In previous posts, I've said that stroke volume, and therefore cardiac output, is dependent on ventricular filling, which in turn is dependent on venous pressure. However, venous pressure is also dependent on cardiac output! Increasing cardiac output increases the amount of blood taken out of the veins and put into the arteries, and thus decreases venous pressure. So how can we put all of this together into a coherent picture?
The answer is simply to use two graphs: the vascular function curve, which I mentioned above, as well as the cardiac function curve (the one I showed you when talking about the Frank-Starling Law). These two graphs can be plotted on the same axes. The place at which they overlap gives the cardiac output and central venous pressure at steady state.
When there is a deviation from steady state, the cardiac output and venous pressure will gradually adjust until steady state is reached. As an example, let's say that we have some venoconstriction, raising the venous pressure:
Venoconstriction raises the venous pressure to point A. From the cardiac function curve, that venous pressure will cause the cardiac output to increase to point B. However, from the vascular function curve, that cardiac output should cause the venous pressure to decrease to C'. Because of the conflicting results from these curves, the venous pressure decreases a bit, causing cardiac output to decrease, and then venous pressure decreases a bit more, and so on until steady state is reached again.
Any stimulus that causes one or both of these curves to change can change the steady state. For example, as mentioned here, increased inotropy will raise the cardiac function curve:
As can be seen in the graph above, changing the cardiac function curve will also change the intercept between the vascular and cardiac function curves.
Of course, there are many different stimuli that can affect the curves, but I feel like I've already drawn more than my fair share of crappy Paint diagrams for this post. If you want to see how a particular stimulus will affect steady state, why not draw a diagram for yourself and find out?
Explain how central venous pressure determines cardiac pre-load and output.
As you should hopefully know by now, blood flows from a place of higher pressure to a place of lower pressure until the pressures are equal. Hence, blood will flow from the veins into the ventricles of the heart during diastole until the pressures are equal. The central venous pressure thus determines the amount of filling, which determines cardiac pre-load. As covered here and here, increased end-diastolic volume/increased pre-load increases stroke volume and, by extension, cardiac output.
Understand how central venous pressure is regulated through the vascular function curve, including the actions of blood volume, vasotone and veno-tone.
Blood volume alters venous pressure pretty much the same way it alters arterial pressure: increasing blood volume increases pressure and decreasing blood volume decreases pressure. So far, so good.
The effects of vasotone (arterial contraction) on central venous pressure are less intuitive. If vasotone increases, less blood can get through to the venous side. (Remember, flow is inversely proportional to resistance, and resistance increases as you constrict the blood vessels). Hence, increased vasotone will actually decrease venous pressure.
The effects of venotone (venous contraction) are a bit easier to grasp. Increased venous constriction will increase the pressure, and vice versa.
The relationship between cardiac output and central venous pressure can be plotted on the vascular function curve:
Another thing you'll notice about this graph is that the graph levels out below a certain venous pressure. This is because ventricular filling depends on a pressure gradient between the veins and the ventricles, and if venous pressure drops to the same pressure or lower than ventricular pressure, then the ventricles cannot fill any more and cardiac output cannot be increased. One more thing to point out is the x-intercept at the graph: this point represents the venous pressure if there was no cardiac output (i.e. if the heart had stopped and the blood pressure was allowed to simply equilibrate throughout the entire system of blood vessels). This pressure is also known as the mean circulatory (MC) pressure, and is usually around 7mmHg.
When blood volume is increased, such as during a blood transfusion, the entire graph shifts up and right. A greater cardiac output can be produced, and the MC pressure is higher. (Remember, if you have more "stuff" in what is essentially the same amount of space, you're going to have a higher pressure.) The reverse is true for when blood volume is decreased.
Now, blood vessels are not just passive: they can constrict and relax. How does that affect the vascular function curve?
Venoconstriction has a similar effect to increasing the blood volume: it raises the curve up and right. It also changes the slope of the curve slightly (the above picture is possibly exaggerated), leading to a higher possible venous pressure at zero cardiac output. This makes sense: pressure is inversely proportional to volume, so if you constrict the veins, thereby reducing the space inside, you'll increase the pressure. Vasoconstriction, on the other hand, does not change venous pressure when cardiac output is zero. (I'm not sure why- I'm thinking it's because arteries are smaller than veins and thus vasoconstriction has less of an overall effect on volume than venoconstriction? That's something I'll have to check.) Maximum cardiac output is greatly reduced- as mentioned here, MAP = CO*TPR. Rearranging this equation gives CO = MAP/TPR, so it follows that an increased peripheral resistance, as occurs during vasoconstriction, will decrease cardiac output.
Understand how cardiac output is set by the interaction between the vascular and cardiac function curves.
Some of the stuff in this post might seem a bit unintuitive, especially given the relationship between diastolic volume (and venous pressure) and cardiac output. In previous posts, I've said that stroke volume, and therefore cardiac output, is dependent on ventricular filling, which in turn is dependent on venous pressure. However, venous pressure is also dependent on cardiac output! Increasing cardiac output increases the amount of blood taken out of the veins and put into the arteries, and thus decreases venous pressure. So how can we put all of this together into a coherent picture?
The answer is simply to use two graphs: the vascular function curve, which I mentioned above, as well as the cardiac function curve (the one I showed you when talking about the Frank-Starling Law). These two graphs can be plotted on the same axes. The place at which they overlap gives the cardiac output and central venous pressure at steady state.
Any stimulus that causes one or both of these curves to change can change the steady state. For example, as mentioned here, increased inotropy will raise the cardiac function curve:
Of course, there are many different stimuli that can affect the curves, but I feel like I've already drawn more than my fair share of crappy Paint diagrams for this post. If you want to see how a particular stimulus will affect steady state, why not draw a diagram for yourself and find out?
Monday, March 27, 2017
Pharmacological Targets for Controlling Hypertension
We finally get the lecture on the stuff we were quizzed on last week! I love it when that happens... not...
Ca2+-channel blocking drugs
I've explained quite a bit about the role of calcium in the cardiovascular system (see here for cardiac muscle and here, here and here for smooth muscle). In a couple of those posts, I also mentioned that there are drugs available that block this system. Here's a brief list:
RAAS blockers
An explanation on the RAAS system is given here.
Activation of β1 receptors, present on the heart, increase heart rate and contractility in order to increase cardiac output and therefore blood pressure . Hence, drugs that inhibit these receptors decrease heart rate and contractility. Drugs that inhibit these receptors include metoprolol, atenolol and many other drugs ending in -olol.
Activation of α1 receptors, present in many blood vessels, cause vasoconstriction. This increases total peripheral resistance and, by extension, blood pressure. Prazosin, which inhibits these receptors, decreases peripheral resistance and blood pressure.
Diuretics
Diuretics work by reducing your blood volume, generally by making you pee more. A certain class of diuretics, known as thiazides, work by blocking reabsorption of Na+ in the distal tubule. If this makes no sense to you, I've written quite a bit on reabsorption in the kidneys here and here.
Choice of Drugs
Given all of this, which drugs do we use? Here's the approach that seems to give the most benefit for the least risk:
Ca2+-channel blocking drugs
I've explained quite a bit about the role of calcium in the cardiovascular system (see here for cardiac muscle and here, here and here for smooth muscle). In a couple of those posts, I also mentioned that there are drugs available that block this system. Here's a brief list:
- Cardioselective (i.e. selective on the heart): Verapamil
- Vascular selective (i.e. selective on the blood vessels): Dihydropyridines such as nifedipine, felodipine and amlodipine (all end with -dipine)
- Non-selective (i.e. act on heart and blood vessels): Diltiazem
RAAS blockers
An explanation on the RAAS system is given here.
- ACE (angiotensin-converting enzyme) inhibitors: Ramipril, perindopril, many other drugs ending in -pril
- AT1 blockers/ARBs (angiotensin-receptor blockers): Candesartan, irbesartan, many other drugs ending in -sartan
Activation of β1 receptors, present on the heart, increase heart rate and contractility in order to increase cardiac output and therefore blood pressure . Hence, drugs that inhibit these receptors decrease heart rate and contractility. Drugs that inhibit these receptors include metoprolol, atenolol and many other drugs ending in -olol.
Activation of α1 receptors, present in many blood vessels, cause vasoconstriction. This increases total peripheral resistance and, by extension, blood pressure. Prazosin, which inhibits these receptors, decreases peripheral resistance and blood pressure.
Diuretics
Diuretics work by reducing your blood volume, generally by making you pee more. A certain class of diuretics, known as thiazides, work by blocking reabsorption of Na+ in the distal tubule. If this makes no sense to you, I've written quite a bit on reabsorption in the kidneys here and here.
Choice of Drugs
Given all of this, which drugs do we use? Here's the approach that seems to give the most benefit for the least risk:
- Start off with a thiazide, ACE inhibitor, ARB OR Ca2+ channel blocker
- If control is still inadequate, add a second or third drug
- If control is still inadequate, try an α- or β-blocker
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