Birth

Last post of the semester! Almost there!

Epic music for an epic topic! (Because let's face it, getting a baby out of a little hole is quite an epic feat.)

The uterus

The uterus lies in the pelvis, between the bladder and rectum. The space between the bladder and uterus is the vesicouterine pouch, whereas the space between the uterus and rectum is the rectouterine pouch, a.k.a. the pouch of Douglas. (I have a friend called Douglas, so naturally I made sure he knew about that one.) It is usually anteverted (bent forward on the long axis of the vagina) and anteflexed (bent forward on the long axis of the cervix), though in some women it is retroflexed so it lies in the pouch of Douglas.

The uterus is a very muscular organ, because it needs all those muscles to puuuuuuuuuuush the baby out of the pelvis. The myometrium, the muscular layer of the uterus, actually has 3 layers: an outer longitudinal layer, a middle layer with fibres in a figure-eight configuration, and an inner layer with circular fibres.

There are also a bunch of ligaments that hold up the uterus. One of these is the round ligament, which is like the female equivalent of the gubernaculum. It anchors the side of the uterus to the inside of the labia majora (it passes through the inguinal canal on its way down). The other main ligament is the broad ligament, which basically comes about from peritoneum on one side going over the top of the uterus and meeting up with peritoneum on the other side. (If that was a shit description, just imagine it's a big sheet-like membrane connecting the Fallopian tubes and the uterus.) The broad ligament is named different things depending on which structure it's covering. The parts of the broad ligament that cover the fallopian tubes are mesosalpinx, the parts that cover the uterus are mesometrium and the parts that cover the ovaries are mesovarium.

As for the blood supply of the uterus, uterine arteries come in and branch out into arcuate arteries and finally into spiral arteries. The spiral arteries also supply blood to the placenta.

The fetal head and female pelvis 

The fetal head lies in the false pelvis until around week 36, when the baby's head "drops" into the true pelvis. The location of the fetal head also gives rise to the idea of "stations of labour," which are essentially the vertical positions of the fetal head relative to the ischial spines. As the baby passes down into the pelvis, it competes with other organs and vessels for space, leading to issues like impaired venous return, constipation, issues with eating (feeling hungry and full at the same time), frequent urination, cramping... the list goes on. (Remind me to never get pregnant!)

I've already spoken about how the fetal head turns to get through the pelvis in the best way possible. There are other adaptations that help make this possible. For example, the fetal skull is relatively squishy as the cranial bones haven't fused yet and instead are connected by membranes. This allows the head to squish through the canal more easily, though the baby may be born with a strange shaped head, which will correct with time.

A second adaptation that helps the baby get through is the hormone relaxin. Relaxin is secreted by the placenta and corpus luteum. It increases the flexibility of the pubic symphysis and dilates the cervix.

Start of labour

It's not really certain when labour has begun. Some people say it's when some mucus is released, some say it's when the amniotic sac bursts ("waters have broken"), while others say it's when contractions begin.

First stage of labour

The first stage of labour is characterised by effacement (thinning out) and dilation of the cervix. The fetal head presses on the cervix, causing the cervix to stretch and the uterine muscle to contract, which pushes the fetal head down further, keeping the cycle going. As the cervix is stretched, it is thinned out, or effaced. The contractions that cause effacement to happen are called Braxton-Hicks contractions.

After effacement has occurred, the cervix dilates (opens up). This relies not only on the fetus' head pressing on the cervix, but also on the actions of many hormones including oxytocin, prostaglandins, oestrogen and progesterone.

Second stage 

The second stage, the actual birth, occurs once the cervix is at least around 10cm in diameter. This stage is usually less than an hour (contrast that with the first stage that can be around 10-15 hours total, if I've read the slide right). This is the puuuuuuuuuuuuuuuuuuuuuushing part, where the mother can use her own effort and voluntary muscles to puuuuuuush the baby out. After the head has done all its twisty turny stuff to get out, the rest of the body usually comes out quite rapidly.

Third stage 

The third stage of labour is the afterbirth, in which the woman essentially gives birth to the placenta. This happens because the uterus has started to contract back to its original size, and the force of its contractions rips out the placenta. The placental site bleeds a bit, which is probably why dying in childbirth used to be such a big risk, especially before we knew about proper hygiene. The uterus contracts to a tight ball, and endometrial blood vessels are cut off by smooth muscle loops that form.

Involution of the uterus

Involution of the uterus is essentially the uterus returning to its non-pregnant state. Women often have cramps while this is happening. Involution is helped along by breastfeeding, as the kid suckling the breast leads to release of oxytocin from the posterior pituitary. As well as contracting myoepithelial cells in the breast so that the kid can get milk, oxytocin also increases contractility of the uterine muscle.

And that's it for ANHB2212! Almost there!

Pelvis part 2

Second last post for ANHB2212 (and for the entire semester, unless I write some extras for funsies!)

This post is about all of the stuff that's inside the pelvis. I find the pelvis kinda tricky, because there's so many things in such a small space!

The pelvic floor
Innervation of the perineum 

The pelvic floor, to my understanding, are the muscles that make up the base of the true pelvis. These are the levator ani muscles, which are divided into the iliococcygeus and pubococcygeus, which form a massive U-shaped loop around the pelvic floor. (There's a large spot in the anterior pelvic floor where the levator ani are not present because the urethra and all that are there. This is the weakest part of the pelvic floor.) Another muscle that makes up the pelvic floor is the closely-related ischiococcygeus, or coccygeus for short, which is more posterior.

Where do the levator ani attach? Well, to answer that, I'll have to explain some of the other bits and pieces around the pelvis. The two holes at the front of the pelvis are obturator foraminae. The obturator membrane usually fills this space. On either side of the obturator membrane are the obturator internus and obturator externus muscles. The obturator fascia covers the obturator internus, and is where the levator ani attach. The point at which the levator ani attach to the obturator fascia is called the white line, or tendinous arch. There are also other points of attachment, such as the tendinous perineal body which is kinda in the middle, and the anococcygeal raphe towards the back. (A "raphe" is a place where fibres from two sides meet up.)

Why is the pelvic floor important? Well, part of the pubococcygeus muscle is the puborectalis. These are the fibres of the pubococcygeus that don't attach to the coccyx (the rest of it does, hence pubo = pubis, coccygeus = coccyx). The puborectalis forms a sling around the rectum (and by extension everything in front of it). When it contracts, it maintains a bendy anorectal angle which isn't exactly conducive to poo falling out. Hence, this muscle is important in maintaining continence.

Another important feature to take note of, even though it's not part of the pelvic floor per se, is the pudendal canal. The pudendal canal is a canal that runs through the obturator fascia. The pudendal nerve and artery, which supply all the "down below" bits with a nerve and blood supply, pass through here. The pudendal nerve branches out into the rectal nerve and the posterior labial/scrotal nerve, as does the pudendal artery (though obviously the artery branches out into arteries). If you go further back, the pudendal nerve originally arises from the ventral rami of the pelvic splanchnic nerves (S234), and the pudendal artery from the internal iliac artery.

Perineum
Urogenital region
Ischiorectal fossa

The perineum is basically the bit between your legs. It can be divided up into two roughly triangular-shaped bits (the dividing line is an imaginary line between the ischial tuberosities). The anterior part is the urogenital region, and the posterior part is the anal region.

First, I'll start with the urogenital region. The urogenital region has to be kinda tough to compensate for the fact that there's no levator ani in front. There are two main regions of the urogenital region (yup, subregions of regions).

The top region of the urogenital diaphragm is the deep perineal pouch, and has three layers (layers of subregions of regions... totally not confusing at all!). The topmost/deepest layer is a thin fascia, and then the next layer is made up of muscles, such as the sphincter urethrae surrounding the urethra (in females, it surrounds the vagina as well). Other muscles here are the transverse perineal muscles, which as you can guess run transversely across the perineum. Below the muscular layer is the thick perineal membrane.

Below the deep perineal pouch is the superficial perineal pouch. The external genitalia are here, anchored onto the perineal membrane. The genitalia are made up of two main erectile tissues: the bulb and the crus, which are paired. In the male, the two crura eventually become the corpora cavernosa of the penis, whereas the bulbs fuse and become the corpus spongiosum. In the female, the two crura become fuse at the front to become the clitoris, and the bulbs become the labia minora.

There isn't as much to say about the anal region, aside from that it doesn't have this membrane. It does have a space between the anus and the ischial tuberosities, which is usually filled with fat. This space is called the ischiorectal/ischioanal fossa.

Disposition of pelvic organs
Pelvic organs and the peritoneum 

I'm fairly sure you have an idea of what the pelvic organs are- the bladder, uterus (in females), the rectum etc. I'm not going to go into too much detail, except for note their relation to the pelvic floor. All of their tubey parts (urethra, vagina etc.) are sticking through the pelvic floor, which acts as an extra sphincter to whatever other sphincters the organs themselves may have. Hence, if the pelvic floor is weak, as can happen with age, straining, obesity or damage, you can become incontinent. If the pelvic floor is very weak, then organs may even prolapse (i.e. come out of the body) giving you inverted buttholes and so forth.

Pelvis part 1

Last topic for ANHB2212!

Introduction to the pelvis (what is the point of a pelvis?)

There are lots of reasons why pelvises are important. They provide places where muscles can attach and they contain the pelvic organs. Stuff (babies, urine, poo etc.) can also pass through the pelvis.

The parts of the pelvis 

The main parts of the pelvis are the sacrum and the os coxa (hipbones). The hipbones are actually made up of 3 main bones fused together. (There are many others when we are babies, but they fuse up pretty quickly). The three bones that make up the pelvis are the ilium (the wide flarey bits), pubis (the bit in front) and ischium. The ischium and pubis both have a body and a superior and inferior ramus. The three bones are initially joined by triradiate cartilage, which fuses during childhood.

The pelvis can also be divided into the "true pelvis" and the "false pelvis." These parts are separated by the pelvic brim, which is basically the bits of bone around the edge of the main "hole" in the pelvis. More specifically, the pelvic brim is the promontory and alae of the sacrum (the front part of the body and the wingy bits), the pubic symphysis and the iliopectineal lines joining the two (made up of arcuate line, iliopubic eminence and pecten pubis, in that order from back to front). Everything above the pelvic brim is the false (or greater) pelvis, and everything below the pelvic brim is the true (or lesser) pelvis.

The pelvic brim is also known as the pelvic inlet. As you might guess, there is also a pelvic outlet. This is the inferior opening of the pelvic cavity, surrounded by the ischial tuberosities, ischiopubic rami and sacrotuberous ligaments.

Joints of the pelvis
Ligaments of the pelvis

The most important joints of the pelvis are the lumbosacral joints (between L5 and S1), the sacroiliac joints (between sacrum and ilium) and the pubic symphysis. All of these are heavily reinforced by ligaments.

We'll start with the pubic symphysis, because it's the joint that you're probably the most familiar with. As you can guess from its name, it is a symphysis. (If you've forgotten what a symphysis is, see here.) It is reinforced by the arcuate ligament and the superior pubic ligament. It is rare for the pubic symphysis to become fused. In fact, in women who have had children, joint cavities can develop here.

The sacroiliac joint is the joint between the sacrum and ilium. It is a synovial joint that is reinforced by a bunch of ligaments, most notably the dorsal interosseous sacroiliac ligament, which is very strong. (There is also a ventral sacroiliac ligament, don't you worry.) The articular surfaces are not flat, they're rough, and the degree of roughness is one of the things that forensic anthropologists look at when trying to work out how old a person was when they died. The roughening up of the articular surface may also change according to activity (horse-riding etc.).

Biomechanics of the pelvis

The centre of gravity is actually a bit in front of the sacroiliac joint, so there is a tendency for the lumbar vertebrae to slide forwards. Usually, this is adequately resisted by ligaments such as the iliolumbar ligament, which attaches between lumbar transverse processes and the iliac crest. The articular processes also interlock to prevent slippage. However, some people have a weakness in the pars articularis. The pars articularis of the lumbar vertebra is the bony bit that connects the inferior articular processes and spinous processes to the vertebral body and superior articular processes. If this is weak, the articular processes do not provide enough support, leaving the person prone to spondylolisthesis (slipping forward of the lumbar vertebrae).

There is also a tendency for the sacrum to slide down between the ilia, a phenomenon known as sacroiliac subluxation. This is usually resisted by the iliolumbar ligament as well as all of the ligaments reinforcing the sacroiliac joint. These ligaments also prevent any possible rotation of the sacrum from the lumbar vertebrae pressing down more on the anterior than posterior side. All of these issues are even more pertinent if you're pregnant. (Remind me to never become pregnant.)

Male and female pelvis

As you're probably well aware, female pelvises are usually wider to allow babies to pass through. However, it's a bit more complicated than that: male pelvises are actually normally larger externally to provide more points of attachment for big, manly muscles. Female pelvises are wider internally (i.e. wider pelvic inlet/outlet) to allow babies to pass through.

There is still a wide variation though. While having a nice, feminine gynecoid pelvis would be optimal for a baby's head, not every female has the luxury of having a gynecoid pelvis. In fact some have anthropoid pelvises, which are like typical male pelvises in that the inlet and outlet are smaller. Some people have android pelvises, which have a wider inlet than outlet which makes it hard for a baby's head to get out, while some really unfortunate people have platypelloid pelvises which have a wider outlet than inlet and make it hard for the baby's head to even get into the true pelvis in the first place.

Usually, a baby's head will turn as it passes through the pelvis. At the pelvic inlet, the baby will face sideways as the pelvic inlet is wider transversely there. As it moves further down, it will turn its head so that it is facing posteriorly at the pelvic outlet, again for optimal movement.

And I think that's it for part 1!

Development of the Kidneys

Back to ANHB2212 stuff!

Recognise the pattern of kidney development as a reflection of vertebrate development

This is basically the whole "ontogeny recapitulates phylogeny" thing that I mentioned a long time ago (and is a very useful idea for understanding how organs develop).

The intermediate mesoderm, which develops into kidneys, is segmented into divisions called "nephrotomes." These nephrotomes become three different types of kidneys. In the neck, they become the pronephros, in the thorax and abdomen they become the mesonephros and in the pelvis they become the metanephros. Ultimately only the metanephros becomes the kidneys in the human, but the other two can be found fully functioning in some other species.

Pronephros

The first "kidney," the pronephros, is never functional in humans and degenerates by day 26. However, it's important in freshwater fish. Fresh water is more dilute than the body fluids, so there is a risk of too much fluid moving into the body via osmosis. Hence, the pronephros has to keep removing all of that excess water, while conserving salts.

The pronephros forms when a cavity develops in the intermediate mesoderm, and balls of blood vessels from the aorta (or aortas, as the embryo starts with two aortas that eventually fuse) start bulging into this space. These balls of blood vessels are the glomeruli of the pronephros. Initially water filters through directly into the coelom, but afterwards the intermediate mesoderm cavity joins up with other segments to form a pronephric duct through which water can drain.

Mesonephros

The mesonephros is pretty much the opposite of the pronephros. Instead of getting rid of as much water as possible and conserving the salts, the mesonephros' job is to conserve the water and get rid of the salt. Many saltwater fish have a mesonephros.

The mesonephros has a smaller glomerulus than the pronephros, in order to produce less filtrate. It also has a larger system of tubules to ensure that more of the fluid gets reabsorbed. The tubules connect to a mesonephric duct, which drains into the cloaca (a cavity at the end of the digestive tract for excretory and genital products).

In humans, the mesonephros appears in week 4 and produces urine (which at this stage isn't so much to get rid of waste but to increase the amniotic fluid). The thoracic segments begin to regress at week 5, but the remaining segments retain their function until around week 12. The mesonephric duct and paramesonephric (para = next to) ducts eventually go on to form parts of the reproductive system- I'll go into detail later. (They did also get a brief mention in one of my PHYL2001 posts, if you're impatient.)

Metanephros

The metanephros is what actually becomes our kidneys.

Development of the metanephros actually starts with the mesonephros. The mesonephros forms ureteric buds which spout from the mesonephric ducts. These ureteric buds induce the formation of the metanephros from surrounding intermediate mesoderm. The ureteric buds also bifurcate repeatedly, forming the calyces and connecting ducts of the kidneys.

The kidneys begin to function around week 12, around the time when the mesonephros stops functioning. Once again, the urine produced here doesn't get rid of waste- it increases the volume of amniotic fluid, which the fetus drinks. (Yeah, hate to break it to you but you used to drink your own piss.)

Understand the fate of the mesonephric duct in males and paramesonephric duct in females

Primitive vertebrates would release their eggs and sperm straight into the coelom before entering the cloaca through small pores. In humans and other higher vertebrates, eggs are still released into the coelom, but are picked up by the paramesonephric ducts. Sperm are a bit different though, as the testes develop direct connections with the mesonephric ducts.

Initially, both males and females have both ducts. In the female, however, the mesonephric duct degenerates, and the two paramesonephric ducts become the fallopian tubes, fusing distally to become the uterus and vagina. (Failure to fuse results in a bicornuate uterus, which is basically like two mini uteruses stuck together.) In the male, the opposite happens: the paramesonephric duct degenerates, and the mesonephric duct forms the epididymis, vas deferens and seminal vesicles. For more information on how hormones cause all of these changes, take a look at my PHYL2001 post.

The gonads originally start in the upper abdomen, but they don't stay there. They are connected to the labioscrotal fold by the gubernaculum, which grows much more slowly than the rest of the fetus, causing the gonads to be dragged down. In males, this pulls the testes into the scrotum, and in females, this pulls the ovaries down next to the uterus.

While we're talking about things moving around, let's talk about the kidneys moving around! The kidneys begin to ascend around week 6, though sometimes one or both kidneys may fail to ascend, resulting in a pelvic kidney. As the kidneys ascend, the metanephric ducts elongate to become ureters. As the kidney ascends, new segmental arteries are gained from the aorta and arteries lower down are lost, so the kidney appears to "climb a ladder." Hence, sometimes vestigial arteries are found on the kidneys.

Another thing that can happen is that the kidneys can fuse together, forming a "horseshoe kidney." Horseshoe kidneys can't ascend past the inferior mesenteric artery- they get stuck.

Normal kidneys eventually reach their final position with the tops of the kidneys around T11/12 (right kidney is lower because of the liver) and rest on the psoas muscle. The diaphragm is behind the upper half of the kidneys, and so the kidneys move with breathing. As for the arteries and all that, the renal vein is most anterior, followed by the renal artery and then the ureters. The left renal vein is longer as it has to cross the aorta.

And that's pretty much it for that topic! Next we'll be talking about the pelvis, which is probably my weakest topic in this unit >_>

Gastrointestinal Function part 3

Last post for PHYL2001!

Understand how bile is stored, released and recycled during digestion.
Know how bile salts and lipase work together to aid fat digestion.

In my last post, I wrote about how bile from the liver gets stored in the gallbladder, and is released when CCK causes the gallbladder to contract. I didn't get around to explaining what bile does and what happens to it later. Well, time to make up for it!

Bile salts are amphipathic, meaning that they have a hydrophilic (water-loving) and a hydrophobic (water-fearing) part. The hydrophobic part dissolves fats, while the hydrophilic part dissolves water. Hence the bile salts help fat molecules to break up and dissolve in water. Breaking up of larger droplets into smaller droplets is called "emulsification," and it increases the total surface area available for lipases to come in and attack. (Lipases are enzymes that break fats up into free fatty acids and monoglycerides.)

Bile salts are precious, so the body wants to conserve them as much as possible. This occurs by reabsorption, a phenomenon also known as "enterohepatic circulation." (Enterohepatic circulation also occurs in some drugs, as I mentioned in an early post on PHAR2210.) Essentially the bile salts that are secreted in the duodenum are reabsorbed later down the digestive tract, usually in the ileum (second half of the small intestine).

Be familiar with the structures within the small intestine that increase absorptive surface area.
Be familiar with the basic roles of the jejunum and the ileum.

I feel like I've covered this in my ANHB2212 post on tubes. Perhaps the main thing that I didn't cover so well was the differences between jejunum and ileum. The jejunum is wider and thicker than the ileum, and the patterns of arteries that supply the two regions are different (though I don't really think it's necessary to go into detail here). The ileum also has "Peyer's patches," made up of lymphoid tissue, that protect from bacteria of the colon.

Most absorption takes place in the jejunum- the ileum is just a "reserve absorptive area" in case your body needs a bit more than what's absorbed in the jejunum. However, bile salts and B12 are only absorbed in the ileum.

It's important to note, though, that the boundary between jejunum and ileum isn't clearly defined.

Understand how fats, carbohydrates, and proteins, are digested and absorbed in the small intestine

The basic idea to understand here is that stuff gets broken down and then transported through the enterocytes of the epithelial layer lining the intestines (except in the case of fats, where the fats can simply diffuse straight through the membrane). Nevertheless, let's have a closer look:

Fats

Fats, as I mentioned above, are broken down into monoglycerides and free fatty acids with the help of bile salts. These smaller molecules can diffuse into the enterocytes much more easily than large fat molecules. Once inside the enterocytes, they reform into triglycerides and are coated with protein. This fat and protein structure is called a "chylomicron," and it is soluble in water. The chylomicron is then exocytosed into the lymph system, which eventually drains into the subclavian veins.

Carbohydrates

Breakdown of carbohydrates happens all throughout the digestive system, thanks to α-amylase from the saliva and pancreas. α-amylase breaks α-1,4-linkages (i.e. straight chain linkages, NOT branch points- for more information on terminology, see here) in carbohydrate chains, such as starch. This produces maltose (two glucose molecules joined together), maltotriose (three glucose molecules joined together) and α-limit dextrans which are short chains of glucose that include a branch point.

In the intestines, even more enzymes come into play to digest carbohydrates. You don't have to know their names, but here they are just for completeness:

• Lactase- splits lactose into glucose and galactose.
• Glucoamylase- breaks maltose and maltotriose down into individual glucose monomers
• Sucrase-isomaltase- has two parts. The sucrase part breaks down sucrose, maltose and maltotriose. The isomaltase part breaks the branches of the α-limit dextrans.

After being broken down into single units, they can be taken up by transporters on the cell membranes of the enterocytes. The main transporters here are SGLT1 (sodium glucose-like transporter) which transports glucose and galactose (with some help from Na+ moving down its concentration gradient), and GLUT5, which transports fructose. All three monosaccharides are transported out the other side of the enterocyte via the transporter GLUT2. As far as I can tell, this all happens via diffusion down a gradient.

Proteins

Proteins are a bit simpler. Some protein digestion occurs earlier in the digestive tract through enzymes such as pepsin and trypsin. In the intestines, peptidases on the surface of enterocytes can break peptides down even further. Any peptide chain less than four amino acids long (i.e. 1-3 amino acids) can go through one of many amino acid or peptide transporters into the cell. (Some of these amino acid transporters also rely on Na+ moving down its concentration gradient.) Within the cell, di- and tripeptides are broken down further by dipeptidases and tripeptidases, respectively. Amino acids are transported out the other end by more amino acid transporters.

Know how salts and water are absorbed in the small intestine.

This is pretty simple, as it's quite similar to how salts and water are reabsorbed in the kidney. (If you need a refresher, see here.) Essentially the basolateral membrane has Na⁺/K⁺ pumps that create a diffusion gradient for Na⁺, allowing Na⁺ to diffuse through Na⁺ channels on the luminal membrane. Cl^- then follows because of the electrochemical gradient created by movement of Na⁺, and water follows because of the osmotic gradient that has been produced by the movement of all of those salt particles.

Be familiar with the basic role of the colon. 

The colon (large intestine) has three main purposes: absorbing even more salt and water, digesting dietary fibre (gut bacteria help out here) and storing fecal matter before it gets excreted. By the looks of things, we don't need to know about any of these functions in great detail.

And that's it for PHYL2001! Good luck with exams everyone :)

Gastrointestinal Function part 2

Second last post for PHYL2001!

Understand the structure and function of the gastric mucosal layer.

I've talked about the function before- the mucous protects the stomach against HCl. It does this because it has bicarbonate ions in it, which neutralise HCl. Additionally, the gel-like consistency of the mucous prevents rapid diffusion of H⁺ down its concentration gradient from the lumen to the stomach wall (and prevents bicarbonate from rapidly moving in the opposite direction).

Be familiar with the basic anatomy of the exocrine pancreas.
Know the substances secreted by the pancreas and how they play a role in acid neutralisation and the digestion process.

The exocrine pancreas is the part of the pancreas that secretes digestive hormones. (It doesn't secrete insulin or glucagon- that's the endocrine pancreas' job). It is made up of duct cells, which secrete bicarbonate ions to neutralise acidic chyme coming out of the stomach, and acinar cells, which secrete the digestive enzymes. These enzymes include proteases, lipases, amylases and nucleic acid enzymes, so that pretty much everything gets broken up.

Understand the basic anatomy of the bilary system.

Bile is produced in the liver, and then travels down the hepatic ducts (left and right hepatic ducts which join to form a common hepatic duct) and then down the cystic duct to the gallbladder. The gallbladder stores the bile until it needs to be used. When stimulated by cholecystokinin (CCK), a hormone you're going to hear a lot about, the gallbladder contracts, squeezing bile back out of the cystic duct and down the common bile duct. The common bile duct meets up with the pancreatic duct, and together they leave through the major duodenal papilla into the duodenum. Guarding this opening is the Sphincter of Oddi, which helps to control the release of biliary secretions.

Know the control pathways responsible for pancreatic enzyme secretion (cholecystokinin/CCK via the vagus afferents).
Understand the role of CCK RF and trypsin in the control of CCK release and the role of CCK on the gall bladder and the sphincter of Oddi.

As I just mentioned, CCK is important in gallbladder contraction. CCK also causes the sphincter of Oddi to relax, and inhibits gastric secretion and emptying. Its major role, however, is to stimulate the acinar cells to secrete pancreatic enzymes.

CCK release is a bit unusual. CCK RF (CCK releasing factor) and trypsin are released continuously. Between meals, trypsin eats up the CCK RF and so it doesn't reach its target. During the digestion of food, however, trypsin is busy eating up food rather than the CCK RF. This allows CCK RF to bind to target cells in the duodenum, triggering release of CCK.

CCK does not actually stimulate the pancreas directly- instead, it stimulates vagal afferent nerves, which go up to the brain and stimulate vagal efferent nerves. It is these nerves that go down to the pancreas and stimulate secretion of enzymes.

Know the control pathways responsible for pancreatic bicarbonate secretion (secretin directly & via vagus nerve) 

Secretin is a bit more simple than CCK in terms of its secretion. It is released from duodenal cells called enterocytes in response to acid (remember, the food coming out of the stomach is acidic as it is mixed with stomach acid). Secretin acts in two ways: most of it travels through the blood to affect the pancreas, while the rest of it stimulates vagal nerves like CCK does. The end result is that the duct cells of the pancreas produce bicarbonate in order to neutralise the stomach acid.

One more to go!

Gastrointestinal Function part 1

Understand the basic structure of the GIT

The mouth bone is connected to the oesophagus bone, the oesophagus bone is connected to the- wait, these aren't bones. But you should know the general idea: mouth, oesophagus, stomach, duodenum, jejunum, ileum, large intestine, rectum, anus, outside world. For more information you can look at my ANHB2212 posts:

• Gastrointestinal Tract: Mesenteries, Blood and Nerve Supply
• Tubes 

Be familiar with the overall nervous innervation of the GIT

There are two main nervous systems innervating the gut. Extrinsic control of the GIT is achieved via the parasympathetic and sympathetic nervous systems, whereas intrinsic control is achieved via the enteric nervous system which is basically like the gut's own personal nervous system. The enteric nervous system is made up of pacemaker regions, as well as a few plexuses of nerves. These communicate with the effector systems (muscles, exocine/endocrine cells etc.) and the sensory systems (chemoreceptors etc.).

Know the different phases of the digestion process

There are four main phases of the digestive process:

1. Interdigestive- between meals
2. Cephalic- seeing, smelling and tasting food- gets your stomach rumbling before the food is even in your belly!
3. Gastric phase- digesting of food in the stomach
4. Intestinal phase- digesting of food in the intestines

Understand the role of the mouth in digestion

The mouth carries out both mechanical and chemical digestion. The teeth grind up food, breaking it down into smaller bits (mechanical digestion). At the same time, salivary glands secrete enzymes such as amylase, which plays some roles in chemical digestion. They also secrete mucus and lysozymes. Secretion of saliva is mainly dictated by the parasympathetic nerves. Sympathetic nerves play a small role- they can modify the saliva composition. (When we're running away from tigers, we probably don't need enzymes that can help digest our food, but we do need to stop our mouths from drying out.)

Have a knowledge of stomach structure and the substances secreted by this organ

The stomach has three main regions: the fundus, body and antrum. Each end of the stomach also has a sphincter- the top one, the cardiac sphincter (named for being close to the heart, not because it is part of the heart or anything), stops food from coming back up, and the pyloric sphincter at the bottom stops the duodenum from becoming overwhelmed with lots of food at once. The fundus is at the top of the stomach and normally contains gas. The body is the main bit of the stomach, and contains cells that secrete a bunch of useful substances. Finally, the antrum is at the bottom which is quite muscular to allow mixing to take place.

As I just mentioned, the body cells secrete lots of useful stuff. These include mucus, HCl, intrinsic factor (which binds B12, aiding in its absorption) and pepsinogen (the precursor for the enzyme pepsin, which breaks proteins down- see my post on proteolytic enzymes for more detail). Essentially, HCl helps to denature and break down proteins, pepsinogen breaks down stuff once activated to pepsin by HCl, intrinsic factor helps absorb vitamin B12 and mucus protects the stomach lining from the harmful effects of the HCl.

Understand the control of acid and pepsinogen secretion during the cephalic, gastric and intestinal phases of digestion. 

I'm just going to start out with the diagram that I wish our lecturer started with, because I think it would have made it much easier to follow along in the lecture.

That probably seems quite complicated, but you'll get familiar with all the names of things in the diagram soon.

Firstly, I'll talk about the cells themselves and how they work.  The body of the stomach has glands containing mucous cells, parietal cells and chief cells. Other important cells are G-cells and ECL (enterochromaffin-like) cells.

Mucous cells aren't on the diagram above, but basically they come in two flavours: mucous surface cells (MSC) and mucous neck cells (MNC), depending on their location. They secrete mucus, hence the name.

Parietal cells secrete HCl and intrinsic factor. They have internal folds called intracellular cannaliculi, which increase the surface area. They also have shitloads of mitochondria because they need lots of energy to pump out those hydrogen ions. And yes, hydrogen ions are simply directly pumped out by a H⁺/K⁺ transporter (a.k.a. "proton pump") in the cannalicular membrane. From the diagram above, you can see that they are stimulated by histamine, gastrin and ACh. Of these, histamine has the biggest effect.

There's not much to say about chief cells, other than that they secrete pepsinogen, which gets converted to pepsin when it meets up with HCl. Synergy ftw!

G-cells are gastrin-secreting cells located in the antrum. From the diagram you can see that they are activated by the parasympathetic nervous system. They also have microvilli covered in chemoreceptors that sense peptides and amino acids. This also increases gastrin secretion. Also, from the diagram I'm looking at right now, the cells are triangle-shaped and look kinda like Illuminati logos. Hate to break it to y'all, but this must totally mean that we're all owned by the Illuminati and our digestion is under their control.

I won't talk much about ECL cells either, except that they produce histamine, which as I mentioned above, is pretty much the main activator of parietal cells.

Now let's see how this works during two of the phases of digestion!

The cephalic phase mainly involves nerves, as it's basically the phase that makes you get hungry from simply seeing food. This activates the vagus nerve of the parasympathetic nervous system, which from the diagram above, causes parietal cells to secrete hydrochloric acid (HCl) and intrinsic factor, and chief cells to secrete pepsinogen. The parasympathetic nervous system also acts on histamine-secreting ECL (enterochromaffin-like) cells and gastrin-secreting G-cells to intensify these effects. Overall, the cephalic phase is responsible for 30% of gastric secretions.

The gastric phase is the filling of the stomach. This distends the stomach, activating stretch receptors, which activate afferent vagal nerves travelling to the brain. This causes efferent nerves to intensify the effect of the parasympathetic nervous system, causing more acid and so forth to be released.

The intestinal phase is basically what happens when the food is in the intestines. When food begins to enter the duodenum (the C-shaped curve at the very top of the intestine), the food causes the last 10% of gastric acid to be released. However, any more food begins to inhibit gastric acid secretion in order to protect the duodenum from becoming overloaded. This is due to a whole bunch of nervous reflexes between the duodenum and antrum, thanks to plexuses in the duodenal and antral walls and receptors in the duodenal mucosa that are triggered by distension of the duodenum.

The rest of the intestinal phase of digestion deals with hormones that cause the pancreas to secrete enzymes (to digest the food) and bicarbonate (to neutralise the acidic chyme from the stomach), as well as carry out other functions related to digestion. That'll be covered in my next post!

Part one done! Only two more lectures to cover! I see the light!

Endocrinology of Reproduction part 3

As promised, I'm finally going to talk about the female!

The female seems complicated because there's the menstrual cycle (the cycle of the functional layer of the uterus being built up and shed) and the ovarian cycle (the cycle of the follicles developing and so forth). These cycles are actually very closely intertwined, however.

The Ovarian Cycle

First, we're going to look at the changes in the ovaries. There are two main phases: the follicular phase, in which a follicle is being developed. At the end of this stage, the follicle ruptures, releasing an ovum into the fallopian tubes. Following this is the luteal phase, in which the ruptured follicle becomes the corpus luteum ("yellow body") which secretes progesterone to prepare the uterus for pregnancy.

A follicle starts out as a single ovum surrounded by some granulosa cells, which are surrounded by thecal cells (which are essentially just differentiated ovarian connective tissue cells). As the follicle grows, a fluid-filled space called the antrum forms within the granulosa cells. While several follicles begin developing each cycle, only one is "chosen" to develop fully: the Graafian follicle. (If multiple follicles fully develop, you can get twins.) This continues to grow until eventually the follicle ruptures and the ovum inside is released, still surrounded by a few granulosa cells.

The ruptured follicle then degenerates to become the corpus luteum, which as I said secretes hormones to build up and maintain the functional layer of the uterus.

Hormones in the Follicular Phase

At the beginning of the follicular phase, FSH is slightly elevated to help the follicle to grow. As the follicle grows, it secretes ever-growing amounts of oestrogen, which exerts negative feedback on the hypothalamus and anterior pituitary, and so levels of FSH decline around midway through the follicular phase. Oestrogen, however, continues to grow, as oestrogens stimulate proliferation of granulosa cells, which then go on to produce more oestrogen.

As an aside, remember how I mentioned the ability of androgens and oestrogens to interconvert in my last post? Well, this is important here. You see, LH stimulates the thecal cells to turn cholesterol into androgens. These androgens then diffuse into the granulosa cells. FSH then stimulates the granulosa cells to convert androgens to oestrogens with the help of an enzyme called aromatase (which for some reason reminds me of Roserade). And that's how the follicle produces oestrogen!

Anyway, back to the story. Eventually oestrogens climb so high that they actually start producing positive feedback instead of negative feedback. This produces the LH (and FSH) surge, where these levels spike. (Normally this is simply referred to as the LH surge as LH spikes much more than FSH.) Following this surge, the hypothalamus and anterior pituitary become desensitised, allowing LH and FSH levels to rapidly fall again. The most important part about the LH surge is that it's what causes the follicle to rupture and ovulation to occur.

Hormones in the Luteal Phase

As I've mentioned several times now, following ovulation, the follicle degrades to become the hormone-secreting corpus luteum. Progesterone (and oestrogen) from the corpus luteum prepares the uterus for pregnancy. Eventually degradation of the corpus luteum causes progesterone levels to fall, which causes the functional layer of the uterus to degrade, which causes menstruation. This also reduces negative feedback to the hypothalamus and anterior pituitary, however, so FSH/LH levels can rise again.

If a pregnancy does occur, this doesn't happen, as the embryo secretes hCG (human chorionic gonadotropin), which maintains the corpus luteum. The corpus luteum is then maintained until the placenta can secrete progesterone by itself.

And I think that's pretty much it for the reproductive system! Just one more body system (gastrointestinal) to go for this unit!

Endocrinology of Reproduction part 2

Now we're going to talk more about LH and FSH and what they do! We'll start off by talking a lot about the male, though there is some overlap with the female.

The Male

In a nutshell, endocrine control of the male reproductive system starts with release of GnRH by the hypothalamus, which triggers release of LH and FSH from the anterior pituitary. LH then stimulates Leydig cells in the testes to produce androgens (which then go on to stimulate sperm development), whereas FSH stimulates the Sertoli cells to aid in the survival of sperm. Of these two, LH is more important: without FSH, there may be sperm malformations, but without LH there is complete infertility.

To prevent LH and FSH levels from climbing up too high, there are negative feedback loops in place. As a reminder, negative feedback is where production of a product inhibits production of more products. In the case of the male reproductive system, there are two main inhibitory hormones. The first, inhibin, is secreted by Sertoli cells. It inhibits release of FSH from the anterior pituitary. The second, testosterone, is from the Leydig cells, as mentioned above. Some testosterone goes back to the hypothalamus and anterior pituitary, where it is converted into oestradiol, which inhibits GnRH and LH release.

As an aside, the reason why some guys get "man boobs" on steroids is because the testosterone is being converted to oestradiol and inhibiting FSH and LH. Be careful with yo' steroids, kids! Additionally, high exposure to other chemicals that look like oestrogens, such as xeno-oestrogens and phyto-oestrogens, are hypothesised to be responsible for dropping sperm counts etc.

But oestrogen isn't all bad for guys. Oestrogens, including oestradiol, plays roles in the growth spurt, as well as the closing of epiphyseal growth plates near the ends of long bones. The reason why girls stop growing before guys is because girls have more oestrogens, so the epiphyseal growth plates close up sooner.

High alcohol consumption is also bad for fertility, in both men and women. Alcohol increases levels of β-endorphins, which make you feel good after drinking alcohol. At high levels, this can injure virtually all cells of the reproductive system, from GnRH-producing cells in the hypothalamus, to the LH- and FSH-secreting cells of the anterior pituitary, to the Sertoli and Leydig cells of the testes themselves.

The Female

Women are a bit more complicated, because monthly cycles and all that. Still, the general principle is the same: GnRH stimulates release of LH/FSH, which stimulate the gonads (except now we're talking about ovaries). Also, instead of androgens, we're now dealing mainly with oestrogens and progesterone.

Just as an aside, the female hormones and male hormones can interconvert. In fact the oestrogens pretty much all come from androstenedione (a weak androgen), which in turn comes from DHEA (dehydroepiandrosterone), which comes from the zona reticularis adrenal cortex. All of these eventually trace back to cholesterol, the mother of all steroid hormones. There's not much more to say on the female from this lecture, but not to worry- the next post will focus almost entirely on the female.

Puberty

So what causes us to hit puberty in the first place? An increase in GnRH causes us to go through puberty, but what causes the change in GnRH to start with? In some cases, people may have GnRH-secreting tumours which cause them to go through puberty very young (i.e. younger than age 8-9), but that's not the case for everyone.

One hypothesis is that leptins, hormones secreted by adipose (fat) cells, cause us to go through puberty. The idea is that when we have enough fat, the leptin levels become high enough to stimulate the hypothalamus and anterior pituitary. If someone isn't nourished enough, or is still small, they may not go through puberty.

Stress and strenuous exercise can delay puberty. It's hypothesised that stress and strenuous exercise increase β-endorphins (just like alcohol), so these factors can have similarly destructive effects on our reproductive systems. Strenuous exercise may also decrease our fat reserves, decreasing leptins and thus delaying puberty.

Endocrinology of Reproduction part 1

(This lecture has so much Comic Sans in it. Sooooo much...)

Sexual Differentiation

Firstly, some definitions. There are three levels of sexual differentiation:

1. Genetic sex: XX vs. XY
2. Gonadal sex: ovaries vs. testes
3. Anatomical sex: female genitalia vs. male genitalia

Genetic sex is determined by which sperm meets the egg. Nothing more here, so moving on...

Gonadal sex is determined by the presence (or absence) of the Y chromosome. Being a girl is the default state, but a person can become a guy if they have a Y chromosome. More specifically, the H-Y antigen in the SRY (sex-determining region of Y chromosome) is responsible for the formation of testes. Formation of testes then leads to the secretion of androgens, which then leads to male genitalia.

Anatomical sex is determined by what hormones are present, so in a way gonadal sex determines anatomical sex (as gonads determine the presence or absence of testosterone).

First, I'll talk about the internal genitalia (the tubes and all that). Originally, we have two pairs of ducts: the mesonephric (Wolffian) ducts, and the paramesonephric (Müllerian) ducts. (I'll talk about these a bit more when I get onto studying for ANHB2212.) In the male, Sertoli cells in the testes secrete AMH (Anti-Müllerian Hormone) which causes the Müllerian ducts to degrade, while Leydig cells (also in the testes) maintains the Wolffian ducts. In the female, absence of testosterone causes the Wolffian ducts to degrade, and absence of AMH prevents the degradation of Müllerian ducts.

As for the external genitalia, we all start with a genital tubercle, urethral folds and a urogenital slit. The genital tubercle develops into the penis or clitoris, the urethral folds develop into the labia or scrotum and the urogenital slit develops into the vaginal opening and urethra (in the female, not sure about the male). Testosterone is pretty important here too: testosterone, as well as dihydrotestosterone (which is basically just testosterone after undergoing a reaction catalysed by 5α-reductase) both lead to the development of male external genitalia. Some people have a 5α-reductase deficiency, causing them to have a micropenis or suffer the "penis at 12" syndrome (where they only get a penis when they hit puberty and their testosterone levels peak. Not nice when you'd thought you were a girl for all of your childhood). Some people also have androgen insensitivity syndrome, so even if they are producing these enzymes, they won't get the effects.

Neuroendocrine Control of Reproductive Function

The main thing you need to remember here is that the hypothalamus secretes GnRH (gonadotropin-releasing hormone), which then goes to the anterior pituitary and stimulates secretion of LH (luteinising hormone) and FSH (follicle-stimulating hormone). LH and FSH then go to the gonads to stimulate all the processes that help us become fertile. For the most part, LH stimulates hormone secretion whereas FSH stimulates germ cell development.

First, we'll start off by looking at GnRH, as that has the same effects in both sexes. GnRH has a pulsatile release- that is, it is released in pulses every 2 hours or so, rather than a continuous stream. This pattern does change a bit throughout life- GnRH is high in the fetal and neonatal stages as that's when we get our genitalia, goes down when during childhood, and rises again when we hit puberty. It later drops off past our main reproductive years. Additionally, GnRH release may vary throughout the month with a woman's reproductive cycle.

Reproduction in the Male

Now we'll look at the male, and how sperm are developed. Spermatogenesis takes place in the seminiferous tubules of the testes, which contain spermatogenic cells (will become sperm) and Sertoli cells ("nurse cells" that nourish the spermatogenic cells). Sertoli cells are joined by tight junctions, which are the basis of the "blood-testis barrier" which keeps nasty stuff away from the sperm. It also secretes seminiferous tubular fluid which contains androgen-binding protein as well as some hormones. Sertoli cells are also able to phagocytise damaged sperm.

Back to the growing sperm! Spermatogenic cells originally start on the basement membrane of the seminiferous tubules, and gradually make their way towards the lumen as they mature. As they move, they can cross the tight junctions of the Sertoli cells by breaking those junctions, which then re-seal behind them. As spermatogonia (original sperm cells) mature and divide, they become primary spermatocytes, secondary spermatocytes and finally spermatids. Spermatids are temporarily connected by cytoplasmic "bridges." You see, half the sperm cells will have a Y chromosome, which contains less information than the X chromosome. These "bridges" therefore help proteins and so forth encoded on the X chromosome to make their way into the sperm that only have a Y chromosome.

A developed sperm has a head, body and tail. The tip of the head contains an acrosome, which contains enzymes for digesting the barriers around the ovum. The head also contains the nucleus, which takes up most of the room in the head. The body contains mitochondria, and the tail allows the sperm to swim to its destination.

This is a somewhat abrupt place to end a post, but that's where the lecture ended. The next post will talk more about the hormones, like LH and FSH.

Renal Physiology: Secretion

After two fairly lengthy posts on reabsorption, this post on secretion should be relatively short!

Most of the secretion that I'm going to talk about occurs in the distal tubule, but that's not to say that secretion doesn't take place anywhere else- as mentioned in one of my pharmacology posts, active secretion of many drugs and other organic compounds occurs in the proximal tubule via specific carriers.

Potassium Secretion

Just like in the proximal tubule, there are Na⁺/K⁺ pumps in the distal tubule. However, while the proximal tubule has K⁺ channels in the basolateral membrane, the distal tubule has K⁺ channels in the luminal membrane. That means that the K⁺ that is pumped in by the Na⁺/K⁺ pumps is secreted into the tubule, rather than being released back into the blood.

Why is it important to control the secretion of K⁺? Well, K⁺ is important in the action potentials of nerves and muscles. If there is too much K⁺, the muscles and nerves can become over-excitable, and if there is too little K⁺, the muscles and nerves have a reduced excitability, leading to muscle weakness and so forth.

K+ secretion can be controlled by aldosterone. As mentioned in my previous post, aldosterone increases the number of Na⁺/K⁺ pumps as well as Na⁺ channels. It also increases K⁺ channels. An increased K⁺ in the blood can directly increase aldosterone secretion from the adrenal cortex, which in turn increases K⁺ secretion via the pumps and channels in the distal tubule.

Kidneys and Acid-Base Balance

As you should know by now, the main pH buffer system of the blood goes something like this:

CO₂ + H₂O <--> H₂CO₃ <--> H⁺ + HCO₃^-

This buffer system is regulated by the lungs, which regulate CO₂ levels as explained here, and the kidneys, which regulate HCO₃^- levels. Since this is a post on renal physiology, let's have a look at how the kidneys regulate HCO₃^-!

HCO₃^- is filtered and must be reabsorbed. (Yes, I know I said this post was going to be about secretion. I lied.) The reabsorption of HCO₃^- is kinda unique. There are no carriers for HCO₃^-, so HCO₃^- must react with H⁺ to form CO₂ and H₂O. CO₂ can then diffuse into the cell. Within the cell, it undergoes the reverse reaction (i.e. CO₂ and H₂O become H⁺ and HCO₃^-), facilitated by the enzyme carbonic anhydrase. (Carbonic anhydrase was also mentioned when I wrote about the respiratory system.) The HCO₃^- can then pass through the basolateral membrane via HCO₃^-/Cl^- antiports. (Antiports transport two substances in opposite directions. Also, you probably won't have to know that last little detail about which antiports transport HCO₃^- - it wasn't in the lecture, but it was in the textbook.)

What about the extra H⁺ in the cell? Well, that is pumped out into the lumen, where it can react with more HCO₃^- and make the cycle start over again. Since too much H⁺ can damage the epithelial layer of the lumen, H⁺ is usually co-secreted with weak bases like NH₃ and NaPO₄^-.

These mechanisms allow the kidneys to help prevent the body from being too damaged by respiratory acidosis (build-up of CO₂) or respiratory alkalosis (not enough CO₂). You see, CO₂ from the blood can also diffuse into the cells of the tubule and carry out the carbonic anhydrase-catalysed reaction, resulting in H⁺ and HCO₃^-. The H⁺ is then pumped into the tubule, where it reacts with all of the HCO₃^- and causes all of it to become reabsorbed. When CO₂ levels drop, this process doesn't happen so more HCO₃^- is lost in the urine.

And that's it for renal physiology! Only two small topics to go!

Renal Physiology: Reabsorption part 2

Second post on reabsorption! I've broken it up because the Loop of Henle stuff is kind of complicated (to me, anyway).

Loops of Henle

The Loops of Henle in the juxtamedullary nephrons (remember, they are close to the medulla and have long loops of Henle) create a vertical osmotic gradient. This vertical osmotic gradient is essentially an increase in osmolarity as you go deeper into the kidney. It can be used to create urine of varying concentrations- otherwise you'd be stuck with only being able to create urine of 300mOsm/L (the standard osmolarity of the extracellular fluid). The vertical osmotic gradient can produce urine as dilute as 100mOsm/L or as concentrated as 1200mOsm/L.

The most important thing with regards to the production of the vertical osmotic gradient is that the descending and ascending limbs of the Loop of Henle are permeable to different things. The descending limb is permeable to water but not salt, and the ascending limb is permeable to salt and not water.

Salt is actively transported out of the ascending loop of Henle. This increases the osmolarity of the surrounding interstitial fluid. This increase of osmolarity also causes passive diffusion of water out of the descending loop of Henle, which also increases the osmolarity of the fluid in the descending loop. Since less salt is pumped out as you go up the ascending loop of Henle (due to most of the salt already having been pumped out by the pumps near the bottom), what you get is a higher salt concentration and higher osmolarity in the tubules and interstitial fluid near the bottom of the loop, and a lower salt concentration and lower osmolarity near the top of the loop.

Hopefully that made sense- I'm not 100% sure if I've grasped this all too well, let alone explained it well.

The Loop of Henle is also home to a special co-transporter: the Na⁺/Cl^-/K⁺ cotransporter in the luminal membrane (presumably of the ascending loop, as the descending loop is impermeable to salt). Two Cl^- ions are transported out for every Na⁺ and K⁺ ion. Just like in the proximal tubule, this is secondary active transport as while it doesn't require energy on its own, it requires a concentration gradient that is produced by the energy-consuming Na⁺/K⁺ pump.

Another interesting point to mention is that different animals with different urine-concentrating needs have differences in their Loops of Henle. Beavers, who are surrounded by water, don't have as much of a need to conserve as much water as possible. They only have very short loops of Henle which can produce concentrations of up to 500mOsm/L. On the other hand, desert hopping mice have very long loops of Henle which can produce concentrations of up to 9400mOsm/L.

Now, in case you ever wanted to know why you can't drink seawater, here's an explanation! As mentioned earlier, we can produce urine of a concentration of up to 1200mOsm/L. Sea water has a concentration of 2400mOsm/L. Hence, if we drank one litre of seawater, we'd need to pee out two litres just to get rid of all of the salt. That means that we'd become even more dehydrated than we were before we drank the seawater! (Those desert mice would have no issue though. Lucky them.)

Urea

Urea, produced from the breakdown of proteins, also contributes to the ability of the nephrons to concentrate urine. Reabsorption of water in the proximal tubule causes concentration of urea to be higher inside the tubules than outside. This causes urea to diffuse down its concentration gradient and become reabsorbed. The proximal tubules are only somewhat permeable to urea, however, so normally only around 50% of urea is reabsorbed.

As you go down the tubule, however, the concentration of urea in the interstitial fluid is higher than that in the descending Loop of Henle. This allows urea to be secreted into the Loop of Henle.

The ascending Loop of Henle and distal tubule are impermeable to urea. Whatever urea they have, they keep. Water is still being moved out, however, resulting in increasing concentrations of urea.

Finally, the collecting ducts receive urine with a high concentration of urea from the distal tubule. As the collecting duct is reasonably permeable to urea, urea can diffuse out into the interstitial fluid. As the permeability increases as you go down, more urea can diffuse out as you go down, contributing to the vertical osmolarity gradient.

All in all, the reabsorption of urea in the proximal tubule and collecting duct allows urea to contribute to the osmolarity of the surrounding fluid, as well as to the vertical osmolarity gradient.

As urea is a product from the breakdown of protein, people on high-protein diets are better able to concentrate urine, and malnourished people are less able to concentrate urine.

The Distal Tubule and Collecting Duct

I've already written about the reabsorption of water and salts in the proximal tubule and Loop of Henle, but I haven't written about the collecting duct yet. The collecting duct is more interesting because its ability to reabsorb water and salts depends on the action of hormones such as vasopressin (a.k.a. ADH- antidiuretic hormone) and aldosterone.

Water Reabsorption

First, we'll have a look at water. Osmoreceptors in the hypothalamus are sensitive to changes in osmolarity. When osmolarity increases, this is a sign that the body needs to conserve more water to return osmolarity back to normal. Hence an increased osmolarity causes osmoreceptors to send messages to the posterior pituitary, which releases vasopressin. Vasopressin binds to V₂ receptors on the basolateral membrane of distal tubule or collecting duct cells. V₂ receptors are G-protein coupled receptors that insert AQP-2 (aquaporin 2) water channels on the luminal membrane. Water can thus diffuse through AQP-2 into the cell, and then through AQP-3 or AQP-4 channels (which are permanently positioned on the basolateral border) in order to be reabsorbed into the body. Water diffuses down the vertical osmotic gradient created by the Loop of Henle.

When osmolarity is decreased, no vasopressin is secreted and thus no AQP-2 is inserted into the luminal membrane. Any AQP-2s on the membrane are sequestered if the cells don't get any stimulation by vasopressin. This causes the luminal membrane to become impermeable to water. As the osmolarity of the fluid at the top of the ascending loop of Henle is 100mOsm/L, the minimum urine concentration of 100mOsm/L is produced.

Vasopressin is also released in response to decreased blood pressure. However, blood pressure must decrease significantly (larger than 10% decrease) for this to kick in.

Other factors that affect vasopressin/ADH release include:

• Nicotine- increases ADH
• Emotional stress- increases ADH
• Swallowing- decreases ADH. Swallowing is picked up by oropharyngeal mechanoreceptors, and it's why you still need to pee when you drink isotonic saline.
• Alcohol- decreases ADH. This is why people need to pee more when they drink.

Random fact of the day: even small changes in the rate of fluid absorbed can make a big difference. Usually 125mL/min is filtered, and 124mL/min is reabsorbed, giving a net urine production of 1mL/min. If only 123mL/min was to be reabsorbed (a change of less than 1%), net urine production would rise to 2mL/min, which is a 100% increase in urine production.

Salt Reabsorption

Salt is also important for regulation of blood pressure, as wherever salt goes, water will follow. In fact, blood pressure is a large factor governing the regulation of salt reabsorption.

Granular cells (mentioned in my post about filtration) secrete renin in response to low blood pressure (which they can detect directly, as they act as baroreceptors). They can also sense a decrease in renal sodium directly, and are also stimulated by the sympathetic nervous system (which kicks in when blood pressure is low).

Renin converts angiotensinogen, released from the liver into the circulation, to angiotensin I. (Protip: a name that ends with -gen is generally an enzyme precursor. For example, pepsinogen becomes pepsin, as I'll talk about when I talk about gastrointestinal physiology.) As angiotensin I passes through the lungs, it is converted by angiotensin-converting enzyme into angiotensin II. Angiotensin II stimulates release of aldosterone from the adrenal cortex. Aldosterone increases the number of Na⁺ channels in the luminal membrane of the collecting duct and Na⁺/K⁺ pumps in the basolateral membrane, which in turn causes reabsorption of salt. This pathway is collectively known as the RAAS (Renin-Angiotensin-Aldosterone System) pathway.

Aside from increasing aldosterone, angiotensin II also has more direct effects. It can directly cause vasoconstriction of the afferent and efferent arterioles, reducing GFR and thus reducing salt and water loss. Angiotensin II can also stimulate the brain to produce more vasopressin/ADH, again causing reduced water loss. Stimulation of the brain by angiotensin II also increases thirst, driving the person to up their water intake.

While ADH/vasopressin is mostly sensitive to changes in osmolarity, the RAAS pathway is mainly sensitive to changes in blood pressure through the mechanisms outlined above. The RAAS pathway is useful for keeping blood pressure up.

Opposing the RAAS system is the ANP (atrial natriuretic peptide), which reduces blood pressure. It is activated when blood pressure is relatively high (8-10% higher than normal). It is secreted from the atria when the atria are stretched, as when blood pressure is high. ANP has quite widespread effects- it inhibits the sympathetic nervous system, directly inhibits Na⁺ reabsorption, and decreases ADH, renin and aldosterone.

In Practice...

How does all of this work in real life? Well, let's take a look at three scenarios.

1. A person drinks a large volume of water. This decreases osmolarity, which is picked up by osmoreceptors. This inhibits ADH, causing aquaporins in the distal tubule and collecting duct to be sequestered. Thus, more water is lost as urine.
2. A person drinks a large volume of water and exercises. This has similar effects on osmolarity. However, water loss doesn't happen right away- the activation of the sympathetic nervous system causes vasoconstriction and a reduction in glomerular filtration rate. This delays the loss of water as urine.
3. A person drinks isotonic saline. This is an interesting case. Osmolarity does not change, and thus there should be no change in ADH. However, you still do lose this water. This is probably due to other mechanisms, such as the activation of the oropharyngeal (swallowing) reflex, which decreases ADH.

Note that the ANP pathway is not active in any of these cases. This is because ANP is only released following a large increase in blood pressure, which is unlikely to happen unless you are drinking ridiculous amounts of fluid.

Renal Physiology: Reabsorption part 1

As I mentioned in my last post, if filtration was all there was to it, we'd pee every four minutes. Thankfully reabsorption is a thing! Roughly all sugars, 99.5% of salts and 99% of water is reabsorbed so that we don't pee ourselves to death.

General Stuff to do with Reabsorption

When substances are reabsorbed, they need to pass either through or between the cells of the tubules, pass through the interstitial space and go into the blood. Substances that pass through the cells obviously need to pass through two sides of the cell: the luminal membrane (that faces the inside of the tubule) and the basolateral membrane (which faces the outside of the tubule). Substances can move across or between cells down concentration gradients if there are pores or channels permeable to that particular substance. There are also pumps that can move substances up concentration gradients if need be.

Proximal Tubule Reabsorption

I'm going to talk about sodium reabsorption first, as it actually drives the reabsorption of a lot of other stuff.

Around 67% of sodium is reabsorbed in the proximal tubule. A Na⁺/K⁺ pump on the basolateral membrane pumps sodium out of the cell and potassium into the cell, so that the Na⁺ concentration inside the cell is low. This allows Na⁺ to passively diffuse into the cell via Na⁺ channels located on the luminal membrane. (As for the potassium- that goes back out via K⁺ channels in the basolateral membrane.)

Aside from passive Na⁺ channels, there are also cotransporters that transport Na⁺ along with other stuff. Glucose and amino acids are reabsorbed via Na⁺/glucose cotransporters and Na⁺/amino acid transporters, respectively. There are also transporters that transport Na⁺ and H⁺, but in opposite directions, allowing H⁺ to be secreted while Na⁺ is reabsorbed. As there are only a finite amount of these transporters, however, only a finite amount of glucose and amino acids can be reabsorbed. The highest amount that can be reabsorbed is called the Tm. For example, the Tm of glucose is 375mg/min- any excess that comes through will be excreted in the urine.

Cl^- is reabsorbed as a consequence of Na⁺ reabsorption. (See, I told you that sodium reabsorption drives the reabsorption of a lot of other stuff!) You see, reabsorption of Na⁺ creates an electrochemical gradient, with more positive stuff in the blood. This causes Cl^- to diffuse down the electrochemical gradient. Cl^- actually passes through the gap junctions between cells lining the tubule.

H₂O is yet another substance reabsorbed as a consequence of Na⁺ reabsorption. The reabsorption of Na⁺ creates an osmotic gradient for water to become reabsorbed.

In my next post, I will talk about reabsorption in the Loop of Henle and how it allows us to produce urine of varying concentrations.

Renal Physiology: Filtration

Well, this is interesting. We had four lectures on renal physiology, but the lecture slides are just in one long powerpoint, so I've got to work out where I should divide it up.

In this first post, I will be touching on the anatomy of the kidney as well as the first step in the processing of urine: glomerular filtration.

Anatomy

The urinary system is made up of four main components: kidneys, ureters (which take urine from the kidneys to the bladder), the bladder and the urethra (which takes urine from the bladder out of the body).

The functional unit of the kidney is the nephron. It is made up of a tubular component (where urine is formed) and a vascular component (i.e. the blood vessels surrounding the tubular component). The arrangement of nephrons gives two distinct regions: the renal cortex, which is the outside bit, and the medulla, which form small structures called "pyramids." Nephrons that only dip slightly into the medulla are called cortical nephrons, whereas those that dip fully into the medulla are called juxtamedullary nephrons.

Let's look at the nephron more closely, shall we? Afferent arterioles (from the renal artery) take blood to the glomerulus, from which blood is filtered into the tubular part (more on this in a bit). The arteries then branch out, forming peritubular capillaries (peri = next to), before rejoining to form venules and the renal vein. As for the tubular part, it starts with a cup-shaped bit surrounding the glomerulus known as the Bowman's capsule. This narrows into a proximal tubule, loops around in a Loop of Henle, comes back up as a distal tubule and joins a collecting duct, which then drains into the minor calyces, major calyces, renal pelvis and ureters. From there, urine goes to the bladder to be held before being peed out.

Filtration

The overall process of how stuff works in the kidneys is that lots of blood gets filtered, and then some of the substances in the blood gets reabsorbed. At the same time, some other stuff is being actively secreted into the urine. For now, we're only going to look at the filtration part.

Filtration requires that fluid pass through three main barriers: the glomerular capillary wall, the basement membrane and podocytes. The glomerular capillary wall is a single cell layer, just like every other capillary in the body. The basement membrane is made up of collagen, which maintains structure, and glycoproteins, which are negatively charged and thus repel plasma proteins which are also negatively charged. Podocytes are cells surrounding the glomerulus. They have little "feet," hence their name (podo = foot). The spaces between the "feet" serve as filtration slits that things can pass through. These slits can be opened or closed to allow more or less fluid through.

Now let's look at the main forces affecting filtration! These are very much like the forces affecting capillary filtration (see here). Essentially, the blood pressure inside the glomerular capillaries pushes fluid into the tubules. There is also some hydrostatic pressure from Bowman's capsule, as well as the plasma colloid pressure of the proteins inside the blood (proteins don't get filtered here either). Overall, the net filtration pressure pushes blood out of the capillaries and into the tubules. (This may change in pathologic conditions- for example, a kidney stone could cause the hydrostatic pressure in Bowman's capsule to build up.) 

Of these three forces, the first one (glomerular blood pressure) is probably the most readily manipulated. Glomerular blood pressure can be manipulated by changing the radii of the afferent and efferent arterioles. When the afferent arteriole increases in size, more blood goes into the glomerulus, thereby increasing glomerular hydrostatic pressure. (Same thing happens when our overall blood pressure increases.) When the efferent arteriole decreases in size, blood dams up in the glomerulus, also increasing glomerular hydrostatic pressure. And if you're wondering why we don't pee ourselves to death during exercise (due to vasoconstriction of the efferent arteriole and an increase in blood pressure), don't worry, I'll cover that eventually.

Glomerular Filtration Rate

An important parameter to know is glomerular filtration rate, or how much fluid is being filtered at the glomerulus every minute. This depends on net filtration pressure as well as a filtration coefficient K_f, which is determined by factors such as permeability and surface area of the glomerulus. Usually, K_f is around 12.5mL/min. As for net filtration pressure, it's based off three forces as described above: glomerular blood pressure (~55mmHg), plasma-colloid osmotic pressure (~30mmHg) and Bowman's capsule hydrostatic pressure (~15mmHg). As the first force is into the tubules and the latter two are into the glomerulus, the net filtration pressure of fluid into the tubules can be given by 55 - 30 - 15, which is equal to 10mmHg.

Now, glomerular filtration rate can be given by the equation GFR = NFP*K_f. (GFR = Glomerular Filtration Rate, NFP = Net Filtration Pressure). From the numbers above, this gives GFR = 10*12.5 = 125mL/min.

Of course, you don't produce urine at 125mL/min. Our bladders can only hold around 500mL of urine, so if filtration was all there was to it, we'd pee ourselves every four minutes, and rapidly lose a lot of water. Eventually, I'll talk about how reabsorption works to prevent this from happening.

Control of GFR

As I've mentioned, factors such as blood pressure and afferent/efferent arteriole radii can affect glomerular blood pressure, which affect net filtration pressure, which affect GFR. If that was all there was to it, though, we'd produce a lot more urine every time we stood up or exercised, due to the actions of the sympathetic nervous system.

Autoregulation maintains our GFR when our blood pressure is between 80 and 180 mmHg. There are two main mechanisms for this: the myogenic mechanism and juxtaglomerular feedback. The myogenic mechanism works pretty much the same as it does in other areas of the body: increased pressure stretches the arterioles, which respond by constricting. This keeps blood flow to the glomerulus constant despite fluctuations in pressure.

The juxtaglomerular feedback mechanism relies on the macula densa cells of the distal tubule, which, due to the looping around of the nephron, are located very close to the glomerulus (hence juxtaglomerular- juxta = "next to"). An increase in glomerular blood pressure sends more fluid and salts through the tubule. The increased salts are picked up by the macula densa cells, which respond by releasing ATP and adenosine. ATP and adenosine is then picked up by the granular cells of the afferent arteriole, which are basically modified smooth muscle cells that can respond to juxtaglomerular feedback. Hence, ATP and adenosine released by the macula densa results in constriction of the afferent arterioles. When less salt is delivered to the tubules, the macula densa may secrete nitric oxide, which vasodilates the afferent arterioles instead.

Aside from autoregulation mechanisms, the sympathetic nervous system can also regulate GFR. The sympathetic nervous system overrides autoregulation. When blood pressure drops quite low (below around 80mmHg), the sympathetic nervous system kicks in and causes vasoconstriction of the arteries supplying the kidneys. This decreases glomerular blood pressure, which decreases GFR. This is to maintain as much fluid as possible in order to stop blood pressure from falling any more.

Conversely, if you drink so much that your blood pressure increases (you'd actually need to drink a lot), the baroreceptor reflex will kick in, decreasing sympathetic output. This causes vasodilation, increasing GFR.

Special Circulations and Temperature Regulation

Last post on the circulatory system!

Give the relative importance of pressure, metabolic activity and neural control for blood flow through skeletal muscle, heart and brain.
Explain how blood is directed to active muscle during exercise.

During rest, only around 15-20% of blood goes to skeletal muscles (this goes up to 80-85% during exercise). At rest, this blood flow is controlled by the actions of sympathetic nerves. During exercise, this is mainly controlled by local metabolites. This also explains why active muscles get more blood: they produce more metabolites than inactive muscles. (For more information, please see my previous post.)

The heart always has around 5% of the blood flowing towards it, as the heart is pretty damn important. Blood flow to the heart is not affected by sympathetic nerves or by hormones: blood flow is almost entirely controlled by active hyperaemia.

Blood flow to the brain is controlled mainly by autoregulation, though these vessels also respond well to local metabolites. (Like the vessels supplying the heart, they do not respond well to sympathetic stimulation.) Although the percentage of cardiac output that the brain receives actually drops during exercise, since the total cardiac output has risen, the brain does receive more blood during exercise. The processes just described (autoregulation and regulation via metabolites) work pretty well when the blood pressure is between 60-160mmHg. When the blood pressure drops below 60mmHg, the Cerebral Ischaemic Response kicks in, as described here. Above 160mmHg, the pressure pushes fluid out of the capillaries into the brain, causing cerebral oedema.

Describe how contraction alters blood flow in skeletal muscle and coronary circulation.

I'm not really sure what is meant here, but my interpretation is that it's to do with how blood is shunted around the body. As alluded to in previous posts, contraction of various blood vessels shunts blood away from those vessels and towards other blood vessels that need it, like skeletal muscles, heart and brain.

Define Atherosclerosis.

Atherosclerosis is the stiffening and narrowing of blood vessels due to the deposition of fatty plaques. This increases the resistance as the lumen is effectually narrowed due to the presence of the plaques.

Define autoregulation for blood flow and its role in control of cerebral blood flow.

I mentioned autoregulation earlier on, but what exactly is it and how does it work? Autoregulation is a way of keeping blood flow constant despite small fluctuations in pressure. As mentioned above, it is a major player in control of cerebral blood flow.

So how does autoregulation work, exactly? Well, there are several mechanisms. Aside from the use of local metabolites, as described earlier, there is another main mechanism called the myogenic mechanism. Essentially, when pressure stretches the smooth muscle, the smooth muscle will contract in response. This increases resistance and decreases flow back to normal.

Describe the role of skin blood flow in temperature control.
Know the normal value for core body temperature.
Explain how changes in skin and core temperature alter skin blood flow including the role of the hypothalamus, neural reflexes and direct actions.

The skin actually receives a lot more blood flow than it really needs during rest, which sounds like a waste of blood flow until you realise that that's how the body gets rid of heat. Blood is cooled down after being transported to the skin. The normal value for core body temperature is around 37°C. This temperature is maintained through increasing or reducing the flow of blood to the skin.

There are several mechanisms through which skin blood flow is increased or reduced:

1. Skin blood vessels dilate when warm and contract when cold.
2. Sensory nerves detect skin temperature. This information is sent to the hypothalamus, which then activates sensory nerve fibres.

Define frostbite, hypothermia, heat exhaustion, heat stroke.
Explain how exercise in hot conditions can produce heat exhaustion.

As I've just mentioned, less blood flows to the skin when it's cold. In extreme cold, reduced blood flow to the skin damages the tissue, resulting in a condition called frostbite. However, even larger drops in temperature increase blood flow to the skin. This is probably the reason why people with hypothermia (an extremely low core body temperature) feel warm.

When skin or core temperature rises above 37°C, people start to sweat. This is due to the activation of sweat glands by the sympathetic nervous system (random reminder here that acetylcholine, not adrenaline/noradrenaline, stimulates sweat glands). The sweat glands also release bradykinin, which is a vasodilator and thus increases blood flow to the skin and sweat glands even more.

The good thing about this is that it gets rid of heat. The bad thing is that sweating reduces blood volume, which decreases mean arterial pressure. The baroreceptor reflex can make up for this, but this puts a lot of stress on the cardiovascular system.

Heat exhaustion is a condition in which the cardiovascular system is no longer able to supply blood to both the muscles and the skin. It often happens during exercise in hot conditions, because as I just said sweating puts stress on the cardiovascular system, which is already stressed because of exercise. Heat stroke is a far more serious condition in which the body is unable to cool itself down. This causes core body temperature to continue to rise until death.

That's a pretty bad note to end a series of posts on, so here's a nicer note: We're done with the cardiovascular system! Yay! Next we'll be moving on to renal physiology!

Control of Blood Pressure

Second last post on the heart. Almost there!

List the actions of local metabolites, autonomic nerves, adrenaline and vasopressin on blood vessels.
Describe the role of vasopressin in control of blood pressure.
Explain how long term regulation of blood pressure depends on regulation of ECF volume.

I've already described the action of local metabolites in my previous post, so let's get on to the other stuff!

As I've also already touched on several times before, adrenaline and noradrenaline released by the sympathetic nervous system cause vasoconstriction. But there's another interesting point that I want to tell you. The sympathetic nervous system also stimulates chromaffin cells to reduce adrenaline and noradrenaline, as mentioned here. More adrenaline than noradrenaline is released, however. Adrenaline actually has a higher affinity for β₂ receptors than for alpha receptors, which is helpful: activation of β₂ receptors causes vasodilation, so adrenaline is helping out with the vasodilation of vessels supplying skeletal muscles and the heart! And it helps these places preferentially: the skeletal muscles and heart have more β₂ receptors than anywhere else in the body. Cool, right?

Oh, and another important point is that the parasympathetic nervous system has very little to no effect on blood vessels, as they don't have receptors for acetylcholine.

Vasopressin is a hormone that can have a longer-term effect on blood pressure. As I will discuss when I get onto the renal stuff, vasopressin causes retention of water. Retention of water means more fluid, which means more blood, which means an increase in blood pressure. Angiotensin II, which is part of the RAAS pathway for conservation of salts (yes, I'll get onto this during the renal stuff, don't you worry), also causes retention of water, which increases blood pressure. (This is because taking in salt increases osmolarity, which drags water back into the body too. Once again, this will all make more sense when I cover renal physiology.) Aside from these effects, vasopressin and angiotensin II can both directly cause vasoconstriction.

Define inotropy/inotropic.
Draw and describe the effect of inotropic agents on the cardiac function curve.
Describe the actions of autonomic stimulation on the heart.

As mentioned briefly before, inotropic agents are agents that affect the strength of contraction. (Chronotropic agents affect the heart rate.)

Now for a refresher on the cardiac function curve! (Yup, it's this incredibly boring graph again...)

An increase in inotropy will increase the stroke volume (and hence cardiac output) at a given left ventricle end-diastolic volume, and vice versa.

The sympathetic nervous system, which innervates the whole heart, is both inotropic and chronotropic: it increases heart rate and force of contraction.

The parasympathetic nervous system is much more limited in its effects. It only stimulates the atria (as well as the sinoatrial and atrioventricular nodes), and the Purkinje system. (That means that most of the ventricles do not receive parasympathetic stimulation.) It has chronotropic effects (slows the heart), but very little inotropic effect.

Define baroreceptor and describe the baroreceptor reflex.
Describe the function of the baroreceptor reflex at rest, on standing and in haemorrhage.
Define and describe the Central Ischaemic Response.

Baroreceptors are pressure receptors (baro = pressure). They are located in the aortic arch and carotid sinus. (As mentioned before, these are also locations of the peripheral chemoreceptors.) The receptors in the carotid sinus are more receptive than those in the aortic arch.

When baroreceptors detect a change in blood pressure, their rate of firing changes. This is picked up by the cardiovascular control centre in the medulla of the brain, which alters the ratio between sympathetic and parasympathetic activity to the heart and blood vessels, restoring original blood pressure.

One example of where this happens is during standing up. When we stand up, blood volume shifts towards the feet and away from our heads, which isn't good for our heads. The fall in blood pressure is detected by baroreceptors, which send out fewer action potentials in response to the drop in blood pressure. The decrease in action potentials is picked up by the medulla and the ratio of sympathetic to parasympathetic activity changes accordingly, so that we don't faint every time we stand up.

The Central Ischaemic Response is pretty much an emergency response to very low blood pressure (<60mmHg). It is like the baroreceptor reflex, but much more potent: it can drive blood pressure up to 200mmHg and cut off blood from everywhere except the heart, lungs and brain. For emergencies only!