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Physiology

How come people from very cold climates can visit LA in the winter and walk around in shirts and shorts?

Doesn’t 55°F feel the same for everybody?!

Nope, it doesn’t! As long as their vacation is just for a week or two, they would totally feel like this LA weather, even at night, is pretty warm!

When your body temperature is dropping because it’s been consistently cold over several days or weeks, your body ramps up production of your thyroid hormone. Your thyroid hormone is what regulates your metabolism. And your metabolism is only about 40% efficient, meaning that when sugars/fats/proteins are converted to usable energy (ATP), about 40% of the original molecules are used as ATP, and 60% is given off as heat. This is why your body is 98.6°F (37°C), meaning all these metabolic processes are giving off lots of heat!  Your car engine, is about 20% efficient.  About 80% of the gasoline being burned is wasted in the form of heat, hence why that engine oil and exhaust is scalding hot!

So anyway, when the temperatures get colder… the thyroid hormone production increases, causing your metabolism to increase, CAUSING YOUR BODY TO GENERATE MORE HEAT.  This then causes you to feel HUNGRY because food is the fuel to supplement this energy production. This is why places like Minnesota are called “Meat and Potatoes Country.”  During the winter months, you may have an insatiable appetite due to this ramped up basal metabolism. It doesn’t help that we have all these holiday dinners (thanksgiving/christmas) placed at the perfect time. And of course since we wear long sleeves and big coats which helps to hide the fat, we gain weight without even realizing it.

Now, when the temperatures start warming up and your body isn’t struggling to always stay warm, thyroid production will decrease. When temperatures get downright hot and humid, thyroid production will decrease even further, to slow down metabolism. This is why in the heat, people don’t have a big appetite. Instead of having giant meals like they would’ve in the winter, they rather have light salads in the summer time.

So when a person is visiting LA from Minnesota, their base metabolic rate is very high compared to ours.  When they come here and it’s 55°F out, they can stay out here in shirts and shorts and feel fine. Eventually though, their bodies will acclimate of course. Hope that helps.  🙂

Related articles if that was interesting to you:

Examples of Neurotransmitters that are usually inhibitory

Glycine and GABA: Glycine is one of the 20 amino acids. Some neurons absorb this and it slows down electrical activity in the nervous system. Another one is gamma-aminobutyric acid (GABA). But the two we really want to focus on are serotonin and endorphins.

Serotonin is actually made from the amino acid tryptophan. While most amino acids have the ending of -ine, tryptophan doesn’t. It’s converted by some of our neurons to become 5-hydroxy tryptamine (serotonin). So serotonin is chemically known as 5-OH Tryptamine made from the amino acid tryptophan. Serotonin is very important for putting someone to sleep. It is important in natural/sleep wake patterns. This raises a whole new issue, since we know amino acids are acting like neurotransmitters.  If we eat food that contains amino acids, does that affect human behavior? The effects are subtle. The effects are not as strong like it is with drugs. There’s a lot of tryptophan in turkey which is converted by the neurons into serotonin.  But is that why they get sleepy after thanksgiving?

First off, people eat 3-4 times the normal volume of food during Thanksgiving. Secondly, they’re eating foods very high in carbs (yams, stuffing, bread). All these things make us very sleepy. Milk is also high in tryptophan (proverbial warm cup of milk). There are also cheeses high in the amino acid tyrosine that convert into the catecholamine’s.  So it’s probably not the tryptophan in turkey, but the whole combination.

Endorphins is a contraction of the word endogenous morphine meaning we have a neurotransmitter that comes from us that works like morphine.  The next time you take heroin, it mimics the action of the endorphin neurotransmitter. So when do endorphins get released? Orgasms. Orgasms are the next best thing to taking heroin. But that lasts only for some minutes or an hour. If you want to feel relaxed and sleepy for hours, then take heroin. There’s also something called a runners high that’s associated with an extended exercise session and the postulation is that is from the endorphin release. Narcotics stimulate those endorphin receptor sites for hours instead of minutes.

Why do we need these inhibitory neurotransmitters?

By having both inhibitory and excitatory, we could weigh different factors and make decisions. So it helps with decision making. When you go to sleep do your ears stop working? No. If it stopped working, your alarm wouldn’t work.  Your ears are working 24/7, so how come you’re not hearing anything when you’re asleep? Because your brain is ignoring everything and that’s due to these inhibitory neurotransmitters which allow us to ignore stimuli or input signals.  We will eventually talk about the role of neurotransmitters in terms of ADD, because that’s when somebody doesn’t have enough of the inhibitory neurotransmitters.

Summary of Neurotransmitters

The excitatory NT’s create a local depolarization (EPSP) and they activate it by opening ligand gated sodium ion channels. In the nervous system, however, there are other neurons that are inhibitory NT’s (IPSP) and when they activate a receptor site, instead of opening up a ligand gated sodium ion channel, it opens either a potassium ion channel or calcium ion channel and the inside of the cell becomes more negative (hyperpolarization).

We just went over ACh, glutamic acid and the catecholamines.

These catecholamines are all derived from the same amino acid tyrosine. When the catecholamine NT’s activate the receptor site, they don’t directly cause an opening of ligand-gated ion channels. They actually trigger adenylyl cyclase which converts ATP to cyclic AMP which increases the permeability of the ligand-gated sodium ion channels which leads to increased electrical activity in the cell. Cyclic AMP acts as a second messenger (intracellular messenger) and of course there must be an enzyme that breaks down this AMP otherwise it would continue to activate whatever it is doing for the rest of your life.

MAO breaks down the catecholamine neurotransmitters, however, since it’s the c-AMP that opens up the sodium ion channels, there is an enzyme called phosphodiesterase which breaks down the cyclic-AMP.

In summarizing, there are 3 different ways of mimicking the action of catecholamines:

  • One is to give a mimetic (amphetamine and ephedrine),
  • A second way is to use a drug called a MAO inhibitor which would prevent the catecholamines from breaking down and their effects would be prolonged or exaggerated.
  • The third thing you could do is to give a drug called a phosphodiesterase inhibitor, such as caffeine, which prevents the cyclic-AMP from being broken down. These all have excitatory effects.

Nitric Oxide, a gas released from the synaptic knobs of some neurons causes blood vessels to dilate.

It’s obvious why we have excitatory NT’s, if we didn’t, nothing would happen. So why do we need inhibitory ones?

The first one is sleeping. We need inhibitory NT’s to ignore sensory input. When you go to sleep do your ears stop working and the answer is no, all your sensory neurons are continuously sending info to your brain and the only way you could go into this sleep state is to ignore all this information through the release of inhibitory neurotransmitters. It appears all vertebrate animals need sleep. The higher the level the more sleep they get. Which would make cats the most intelligence because they sleep 30 hours in 24 hours in a day.

Second role of inhibitory NT’s: it permits sensory discrimination and attention. Sensory overload leads to seizures. Epilepsy is due to over-excitation/stimulation of the brain. So if we don’t have inhibitory NT’s we go into seizures. This also comes up in the subject of ADD. So in ADD, a child or adult has trouble focusing on what’s important because they easily get distracted by other stimuli. They have no way of inhibiting the sensory input signals. They commonly could take medication and curiously they are stimulants. The stimulant drugs in your brain stimulate your brain to release inhibitory neurotransmitters.

A third reason why we have inhibitory NT’s is to give us fine motor control. In order for somebody to be a surgeon, dancer, musician, anything that involves precision, we not only activate somatic motor neurons, but simultaneously inhibit motor neurons to OTHER skeletal muscles. If somebody doesn’t have these inhibitory motor neurons their movements will be gross and exaggerated. An over stimulation of somatic motorneurons leads to convulsions. This is an over-excitation of skeletal muscles and is associated with epilepsy again.

We must clarify that there is a difference between convulsions and epilepsy.

  • A seizure is too much input signal (no way of ignoring what’s coming in).
  • A convulsion is too much motor output (too much excitation occurring going to the skeletal muscles).
  • All epilepsy is associated with seizures but not all epilepsy is associated with convulsions.

As the brain develops as you go from an infant to a child to an adolescent to an adult, the brain develops and one of the things it’s developing is the release of inhibitory NT, so concentration and attention improves as we grow older. It’s not very important for a 3 year old to stay focused. Developmentally, movements of a child exhibit gross motor movements. As we grow we develop better fine motor movements. This kind of explains why ADD is developmentally related.

Another clinical considerations: Tetanus

Tetanus is caused by a bacterial infections (c. tetani; gram negative; produces exotoxins). These exotoxins interfere with inhibitory neurotransmitters and the result is seizures and convulsions. The reason tetanus is called “lock jaw” is because the muscles of the face are the ones that constrict first and when someone dies from it, it looks like a convulsion.

Examples of Neurotransmitters that are usually excitatory

There’s literally hundreds of neurotransmitters they’ve discovered and we’re only going to mention a few of them here.  The following are usually excitatory (usually, meaning, there are exceptions!):

Acetylcholine (ACh) certainly excites the nervous system. If you inject someone with ACh, when it reaches their brain it will open up sodium ion channels and depolarize them but it wont last long because there’s acetylcholinesterase. That’s why they would use a mimetic (a synthetic drug that’s similar but slightly different than our normal neurotransmitter that would take hours for our enzyme to break down rather than minutes).

Glutamic acid: A large number of neurotransmitters are amino acids or modified amino acids. Certainly in a biology class, we have learned that amino acids are the building blocks for making proteins, but now I’m telling you another role of amino acids. Many neurons either simply release amino acids as neurotransmitters or the neurotransmitter is a modified amino acid.  Glutamic acid is a name of one of the amino acids. It excites and increase electrical activity but its effects don’t last long because there’s enzymes that break it down.

Nitric Oxide: They discovered this 30 years ago and they couldn’t believe it at the time. Nitric oxide is a gas released by some neurons from their synaptic knobs which goes into blood vessels and the main action is vasodilation.

  • First off, if you want to know about nitric oxide sooner rather than later, look up Viagra. Viagra dilates the blood vessels in the penis and it does that by triggering the release of NO in the vessels of the penis.
  • Some of you have heard that when somebody needs their coronary arteries to be dilated (like people with angina pectoris), they give a coronary vasodilator called nitroglycerine which mimics the action of nitric oxide. Nitroglycerine, in other words, is a mimetic or agonist.

Catecholamines

  1. norepinephrine (noradrenalin)
  2. epinephrine (adrenalin)
  3. dopamine

The three neurotransmitters above are made from the amino acid tyrosine and are collectively called catecholamines.  Tyrosine is one of the essential amino acids and it absorbs something called L-DOPA (dihydroxy-phenylalanine) and some of the enzymes convert it into dopamine.

  • Other neurons turn the dopamine enzymatically into norepinephrine (which has a OH group).
  • Other neurons, after they form norepinephrine, convert it one more step into epinephrine (which has a CH3 group).

If you inject someone with epinephrine, it’s going to increase their electrical activity in their body and last for 5 minutes because the enzymes break it down really quickly. The enzyme that breaks down all three catecholamine’s is called Monoamine Oxidase (MAO). Just like how acetylcholinesterase breaks down acetylcholine, MAO’s break down catecholamine’s.

Why do MAO and MAO inhibitors work with catecholamines?

At the end of dopamine is NH2.   That’s an amine.  The end of norepinephrine and epinephrine have NH2 as well. So they all have one amine group (monoamine) and monoamine oxidase can break that off.

If you want the effects of epinephrine going on, you have to give an IV drip, but one of the things you could do to make the epinephrine last longer is stop the enzyme from working. This is how monoamine oxidase inhibitors (MAOI) work, which are commonly anti-depressants, although they are not prescribed as often now.

The chemical structures of amphetamine and epinephrine look very alike. Structurally they are very similar. The main difference between epinephrine and amphetamine are the missing OH’s.  Due to this, amphetamine will activate the same receptor sites as norepinephrine but not break down as quickly.

There’s a little more to the story for catecholamine’s.

When we went over proteins in the cell membrane, we went over a diagram.  When a ligand attaches to a receptor site, it activates a g-protein and normally most neurotransmitters (ligands) cause an ion channel to open. We gave the example of acetylcholine activating the receptor site causing the sodium channels to open (exactly what happens at the neuromuscular junction). Epinephrine does not directly open up an ion channel. It activates an enzyme. So it works a little bit different than most NT’s.  All catecholamine’s activate an enzyme called adenyl cyclase. (They’ve changed the spelling of the name to adenylyl cyclase).

Adenylyl cyclase converts a small number of ATP’s (adenosine TRIphosphate) into cyclic-AMP and PPi.

  • PPi = two phosphate groups
  • AMP = one phosphate group

Adenylyl cyclase converts A-P-P-P(ATP) into A-P (AMP) because cyclase enzyme breaks it off before the second phosphate. Now what the hell is AMP? AMP is commonly called the intracellular messenger (the second messenger) and it causes the opening up of sodium ion channels.  In other words, cyclic AMP is what increases the permeability of the sodium ion channels.

Aren’t I still saying that the catecholamine’s open up the sodium ion channels? Yes, but we’ve added an intermediate step for catecholamine’s that c-AMP has to be formed that is actually what is opening up the sodium ion channels.

Just like how there is an enzyme for everything, you have to break down c-AMP because it’s what’s actually making the sodium channel open.  The enzyme that breaks down c-AMP is phosphodiesterase is what breaks down c-AMP into the “metabolite” 5’AMP.   The metabolite is the inactivated form.

So, the catecholamines activate adenylyl cyclase enzyme that creates c-AMP.  And phosphodiestease is what breaks down c-AMP to be inactive.

What if we had a drug that inhibited phosphodiesterase?

That means c-AMP won’t be broken down and it will accumulate.  Cyclic AMP excites our neurons because of the indirectly-adrenalin-made c-AMP.  The phosphodiesterase inhibitor that all of us have tried is caffeine.

So you could take a mimetic like methamphetamine or take a MAOI or a phosphodiesterase inhibitor and they would all do the same thing.

People talk about herbal and regular tea. Herbal teas are like chamomile, mint, etc and they don’t have caffeine in them. Real tea has “caffeine” in it but it’s actually not caffeine but it’s similar to it. Theophylline is the caffeine-like chemical that’s in tea that’s also a phosphodiesteraste inhibitor and is used in medicine under the brand name Theodur or Monodur.

The context that they use these are for people with really bad asthma. So they won’t usually give them adrenalin but something that mimics adrenalin called albuterol (proventil) that actives these receptor sites but specifically on the airways and helps dilates airways. When it’s really bad asthma, they add theophylline (side effect is that it speeds up the heart rate) to the albuterol to really help jack up the c-AMP levels.

Now let’s go over examples of neurotransmitters that are USUALLY inhibitory…

Actions of Excitatory and Inhibitory Neurotransmitters

Some neurons in the CNS release neurotransmitters that excite other neurons (meaning to fire off APs) and some inhibit (prevent) the generation of action potentials.

Action of Excitatory Neurotransmitters

Presynaptic neurons are the neurons that conduct the AP to release a neurotransmitter and they affect the postsynaptic neurons. What ALWAYS causes a neuron to release any neurotransmitter (whether it is excitatory or inhibitory) is an action potential.

Question and reminder: Where are most of the potassium ions normally found in the body?

Most are found inside the cells and of course there are negatively charged proteins inside the cell.

Where are most of the sodium ions found?

Outside the cell. There is an excess of negative charges inside and excess of positive outside  and this is known as the resting state).

ALL excitatory neurotransmitters cause an opening of ligand-gated sodium ion channels.  As a result, sodium ions flow in and the cell becomes less negative on the inside.  When we talk about acetylcholine, it activates ACh receptor sites and ligand gated sodium ion channels open.  These excitatory neurotransmitters create a local increase of permeability of sodium ion channels (ligand gated sodium channels open) which leads to a local depolarization that’s known as an Excitatory Postsynaptic Potential (EPSP) because we are exciting the post-synaptic cell.  So whether the excitatory neurotransmitter is dopamine or norepinephrine or anything else, it’s going to always open up ligand-gated sodium ion channels, causing the inside to be less negative.

Action of Inhibitory Neurotransmitters

If an action potential goes down the synaptic knob of another neuron and releases an inhibitory neurotransmitter, it’s going to be activating specifically different receptor sites on the cell membrane of the postsynaptic cell.

When an inhibitory NT activates the receptor site, it causes additional potassium channels to open which may cause potassium ions to flow out of the cell and if additional positively charged potassium ions flow out of the cell, the inside of the cell will become more negative.

In other words, inhibitory neurotransmitters cause an opening of ligand-gated potassium ion channels which leads to a local hyperpolarization (more negative than normal).  This is known as a Inhibitory Postsynaptic Potential (IPSP) because it’s going to be LESS likely to throw off an action potential.

Contrast that with exitatory NTs: All excitatory neurotransmitters cause an opening of ligand-gated sodium ion channels.

The inhibitory NT could also cause an opening up of ligand-gated Chloride Ion channels. Chloride is mostly outside the cell and it’s negatively charged. When these channels open, negatively charged ions will flow inside the cell, making it more negative (local hyperpolarization).

Whether potassium ions go out the cell or chloride ions go in the cell, the cell becomes hyperpolarized.

Summation of Post-Synaptic Potentials

So what’s this postsynaptic neuron going to do if both these EPSP and IPSP’s are firing off together? It depends on the sum of all these influences. Whether a neuron generates an Action Potential, or not, this depends on the overall sum of EPSP’s and IPSP’s occurring in the neuron at any moment in time.

Remember how generating an AP is like pushing a boulder over a cliff to get it over the threshold? With EPSP’s and IPSP’s we have people (excitatory NT’s) pushing the boulder uphill, trying to push it over trying to generate a AP and we also have others (the inhibititory NT’s) pushing it the other way.

Oversimplified stupid example

Let’s say there’s a neuron in my brain that determines whether I buy pizza or not…

Let’s pretend it’s an interneuron (since those are involved with memory, learning, and decision making). Imagine someone walks in with fresh pizza and I go “Wow I want pizza!” It’s going to be pushing the action potential of that neuron to the edge. Then you think maybe I shouldn’t cause I just ate and I’m not even hungry! But then I smell the pizza and I really want it again. Now I’m thinking I have only $2 on me so I really shouldn’t buy the pizza. So should I? There’s factors telling me I should and shouldn’t buy the pizza.

The point is, the way our nervous system allows us to make decisions are with the summation of Excitatory Postsynaptic Potentials (EPSP) and Inhibitory Postsynaptic Potentials (IPSP). It’s like the devil and angel on the shoulders-act.

Temporal summation

  • Temporal summation is the summation of EPSP’s or IPSP’s due to repeated stimulation by one neuron.
  • Stimuli applied to the same axon sufficiently close together in time add together to depolarize the membrane.

Look at the picture on the right.  The Y-axis of the graphs are Membrane Potential (mV) and it shows that the cell starts out with -70.

At the bottom graph, when one neuron repeatedly fires, affecting a pos synaptic neurons, this is summing in time (temporal summation) that causes an action potential.

What would’ve happened if neuron B released its inhibitory NT repeatedly? It would hyperpolarize more and more, making it more and more negative, making it less and less likely to fire off an AP.

Spatial Summation

There’s also something called spatial summation which is the summation of EPSP’s or IPSP’s due to stimulation by more than one neuron simultaneously.

Top graph: Let’s see what causes a local depolarization (an action potential).

Neuron #1 releases, Neurons #2 releases, Neuron #3 releases.  Then Neurons 1 and 2 release.  When Neurons 1+2+3 release at the same time, the sodium channels open, we go beyond the threshold potential and have an action potential.

Question: What if neuron A released its excitatory NT at the same time neuron B released its inhibitory NT?

Answer: They would cancel out and there wouldn’t be much difference.

The Renin Angiotensin Aldosterone Reflex

We are going to talk about the homeostatic reflex mentioned as the following things in a textbook:

  • renin-angiotensin system (RAS)
  • renin-angiotensin-aldosterone system (RAAS)
  • renin-angiotensin-aldosterone pathway (RAA pathway)

Don’t let these words scare you!  We’re going to follow a pattern here.  Renin leads to Angiotensin being released which eventually leads to Aldosterone being released.  We’re going to explain all that in detail.

We begin with the kidney. The kidney is an endocrine gland (since it secretes several hormones) and it excretes two hormones we are going to learn about: renin (renal means kidney) and erythropoietin (brand name Procrit). The cells that secrete renin are called Juxtaglomerular (J-G) cells.

Three triggers that cause JG cells to secrete Renin into the blood stream:

  1. A drop in blood pressure,
  2. A decrease in blood sodium levels,
  3. An increase in blood potassium levels.

That triggers this hormonal homeostatic reflex. A homeostatic reflex is there to compensate or correct for a stress.

Examples of homeostatic reflexes:

The RAA pathway ensures that it will correct for all three of these triggers.  It makes this a very important reflex because it controls your blood pressure and your two most important minerals in your body: sodium and potassium.

When Renin is secreted, it stimulates a protein in your blood stream called angiotensinogen.  The liver makes most of these plasma proteins (such as albumin).  This angiotensinogen is always circulating in the blood stream.  Renin activates it and turns it into angiotensin-1.

(There are many proteins that have to be “activated.”  The inactivated form usually it ends with -gen.  Then when it’s activated, you drop that ending so it becomes angiotensinogen to angiotensin 1.  For example: Your stomach cells secrete something called pepsinogen and the hydrochloric acid activates it into pepsin.  During blood clotting, Fibrinogen is turned into fibrin.)

How does Renin activate Angiotensin?

Angiotensinogen is a polypeptide.  Renin cleaves four of the last amino acids in the molecule, and changes it to Angiotensin I, so to say it got activated, was to mean it got shorter.

There’s an enzyme in your lungs called ACE which stands for Angiotensin Converting Enzyme and as Angiotensin-1 is carried to your blood stream to your lungs, it becomes Angiotensin-2.    ACE basically cleaves off the last 2 amino acids of Angiotensin-I, making it an even shorter polypeptide chain and that is Angiotensin-2 now.  So it’s been cleaved/spliced twice so far.

Angiotensin-2 is now in the blood stream and it specifically activates the adrenal cortex to secrete aldosterone and other mineralcorticosteroids.  Remember the adrenal cortex secretes: adrenoandrogen, glucocorticosteroids and mineralcorticosteroids.

This aldosterone that is released from the adrenal cortex (due to the angiotensin-2) will affect the kidneys.

Aldosterone will make the kidneys do three things:

  1. Increases Potassium excretion; Potassium in the blood stream is excreted into the urine (to be eliminated).  That compensates for when your blood potassium level is too high (one of the 3 original triggers!).  When the K+ is too high, the RAA system causes the potassium to be excreted out.  Remember when we talked about Hyperkalemia we said the reason there’s no warning label on every Chiquita banana for its potassium content because your kidneys will excrete it out.
  2. Increase salt retention: It causes your kidneys to retain salt and compensate for low sodium levels.  Instead of kidneys peeing out that salt, you retain it.
  3. Increase water retention which together with the increased salt retention, that causes your blood pressure to increase in your vessels.  This is not like ADH.  ADH causes you to retain ONLY water to dilute the salt.  Here you retain both salt and water, so you are retaining isotonic fluid.  The purpose of this is to expand your blood volume and by doing that, that raises your blood pressure, and that compensates for what initiated this reflex (a drop in blood pressure).  If you have a cut and you’re losing blood, your blood pressure will drop.  If you increase the amount of water and salt retention, you will increase the blood pressure.  How cool is that?

The Aldosterone will raise the BP, raise Na+, decrease K+ because it causes the kidney to retain salt and water. People always confuse this with Anti-Diuretic Hormone (ADH), so make sure you don’t. 🙂

What’s the difference between ADH and Aldosterone?

If you eat food that’s high in salts, you increase the tonicity of your bloodstream when it’s absorbed and become hypertonic. That triggers ADH which causes your kidneys to retain water and only water.  A drop in blood pressure will also cause ADH release because there’s a multiplicity to the body all the time.

There’s never been a clinical case of somebody overproducing ADH.  But there are clinical cases of lower than normal ADH levels (deficiency) which goes by the name of diabetes insipidus.  What’s diabetes insipidus?  If you can’t make ADH, you pee a lot because you have no way of not-peeing a lot.  The word diabetes means to pee a lot.  There’s diabetes mellitus.  Mellitus means sweet.  So this is sweet pee.  Insipidus is pee that doesn’t taste sweet.  These two diabetes were recognized by ancient greeks.  When people would pee a lot, they would taste their urine.  If it tastes sweet, it was called diabetes mellitus, and if it wasn’t sweet it was called diabetes insipidus.

With diabetes mellitus, you don’t have enough insulin so it leads to hyperglycemia which spills into the urine (glycosuria, tested by dipstick), and it osmotically draws water (osmotic diuresis) with it, so people with diabetes pee a lot. Review ketoacidosis in unmanaged diabetes section.

Here’s a chart below to help you note the differences.

On the right is aldosterone which increases both salt and water retention and increases potassium secretion… it regulates your Na+K+ and blood volume.

Anti-Diuretic Hormone (ADH; Vasopressin) Aldosterone
Source of Hormone produced by hypothalamic neurons; stored and secreted from the Pituitary Gland (neurohypophysis) secreted by the Adrenal Cortex
Factors that lead to the release of the Hormone ↑ Osmolarity (tonicity) of CSF.
↓ Systemic arterial BP		 ↓ Renal Blood Pressure (1)
↓ Plasma [Na+] (2)
↑ Plasma [K+] (3)
[-> Renin -> Angiotensin]
Action of Hormone ↑ permeability of urine collecting ducts to H2O
Small volume of concentrated urine.		 stimulates Na+/K+-ATP pumps in the distal convoluted tubule portions of the nephrons -> Small Volume of Isotonic Urine
Function of Hormone ↑ H2O retention
Maintenance of Plasma Osmolarity (Tonicity)		 ↑ NaCl and H2O reabsorption
↑ K+ excretion
Maintenance of Plasma Na+ and K+ electrolyte levels
Syndrome Associate with Hormone Excess (not clinically reported) Hyperaldosteronism
↑ NaCl retention (hypernatremia)
↑ H2O retention (hypervolemia; + blood volume; renal hypertension)
↑ K+ excretion (hypokalemia and hyperpolarization; slowing down)
Syndrome Associated with Hormone Deficiency Diabetes insipidus.
Production of large volumes of isotonic (or even hypotonic) urine.		 Hypoaldosteronism
↓ NaCl retention (hyponatremia)
↓ H2O retention (hypovolemia; – decreased blood volume; circulatory shock)
↑ K+ retention (hyperkalemia and depolarization;speeding up)

Hyperaldosteronism:  At the lower right, we talk about too much aldosterone. It causes a rise in the blood pressure, called renal hypertension because you’re retaining salt and water which leads to hypervolemia, hypernaremia and hypokalemia.  This is a problem but not fatal.

Hypoaldosteronism: A deficiency in aldosterone is fatal because you don’t retain salt or water and don’t excrete potassium which leads to hyponatremia, hypovalemia and hyperkalemia which leads to depolarization of all the cells in the body, which causes increased activity of your muscle cells and what kills you is eventually the fibrillation of the heart.  By retaining less volume and salt, your blood volume drops and your blood pressure drops and this is circulatory shock.

Since we mentioned renal hypertension as a cause of hyperaldosteronism, let’s go over hypertension.

Types of Hypertension

Since we mentioned renal hypertension as a cause of hyperaldosteronism, let’s go over hypertension.

What is the normal blood pressure?

A typical normal blood pressure is like 120/75 or 120/80 and the units are mm of Mercury, known as TORR. We’ll learn about the two numbers further later. What’s the definition of high blood pressure? As a definition, it’s 140/90… some say 135/85 is borderline high blood pressure. What is the cause of high blood pressure? Well, there’s two MAJOR types of different types of hypertension, just like how there’s two types of diabetes (mellitus and insipidus)

1. Essential / Primary / Idiopathic hypertension. Idiopathic means “We don’t know what’s causing it” however the general consensus is that it’s probably due to atherosclerosis (atherosclerotic plaque on the coronary arteries). This is the most common type of hypertension.

2. Renal hypertension is due to hyperaldosteronism, excessive levels of aldosterone hormone, which cause your kidneys to retain higher amounts than normal of salt and water, which raises your blood volume and raises your blood pressure.

Drugs used to treat Hypertension

There’s many drugs to control high blood pressure and it’s a massive subject you’ll go over in your clinical classes. The first two we’ll go over are the Beta Blockers.

1. They work as sympatholytics (adrenergic blockers). What does stress do to your blood pressure? It raises it. They will use drugs that block this sympathetic response, especially on your heart, to not allow the blood pressure to increase.

2. RAA Blockers (diuretics). This would make sense during hyperaldosteronism. Diuretics. Many are renin-angiotenson-aldosterone blockers, in other words, they block the RAA reflex and by blocking the RAA reflex that reduces the amount of salt and water retention and therefore lowers your blood volume and lowers your blood pressure.

They use both diuretics and beta blockers for both essential hypertension as well as renal hypertension but it certainly makes sense to use the RAA Blockers when you have renal hypertension, because that’s the fundamental problem.

Among the earliest drugs they used to reduce aldosterone action were aldosterone blockers that blocked on the aldosterone receptors on the kidneys. When they discovered that Angiotensin 2 is what causes aldosterone to be made, they made angiotensin 2 blockers such as Cozaar. When they discovered that Angiotensin Converting Eznyme is what made Angiotensin 2, they made ACE blockers such as Accuprill. ACE Inhibitors, which are very popular, end with –IL so you have drugs such as zestril, accupril, quinapril and so forth. 

The trend is to develop drugs that block earlier in the sequence because each time you form a new chemical, they have multiplicities of effects and eventually they’ll have something that stops the release of renin.

Example: Check out the wikipedia article for Quinapril. The pharmacological category for Quinapril is a angiotensin-converting enzyme (ACE) inhibitor. It’s use is management of hypertension and treatment of congestive heart failure.

Some new info not found in your textbooks, at least not at this level:

Research Shows Skeleton to be Endocrine Organ: Crucial to controlling weight and metabolism; discovery opens door to therapy for type 2 diabetes

The above link gives you an idea of what you’ll be reading through your professional career. It’s a summary published in 2007 and it’s printed with a title “Skeleton is an endocrine organ.” It talks about a new hormone they’ve discovered that controls our sugar metabolism and weight. This is cutting edge stuff not found in your textbook.

Hundreds of hormones have been identified and we’ve only talked about a few of them so we’re not even close to touching them. What this link above is saying is that people with type 2 diabetes have been shown to have low osteocalcin levels. There are people who inject insulin everyday and are still not without problems, which means that insulin is not the only thing they are lacking or have too much of. They are now seeing that these people are also deficient in osteocalcin and if it proves to be the case, people may also be taking synthetic osteocalcin for their diabetes one day.

Nowadays diabetics may inject insulin but the newest approach is to wear an insulin pump. This is connected by a catheter to their blood stream. They can’t take it off when they take a shower. The benefit is that not only do you not deal with needles, but it only secretes as much blood sugar as you need. This is the next best thing to having a pancreas. This will continue to be the case unless osteocalcin proves to be the case.

Now we made our segway into the cardiovascular system…

The Four Hormones Essential for Living

While there are hundreds, there are only 4 that are essential to life and if you don’t have them, you die. We’ve only talked about two of them in detail, which is insulin and the glucocorticosteroids, such as cortisol.  We can’t explain cortisol really well, and it’s weird because it breaks down protein, reduces immune system and reduces inflammatory response. Don’t think for a moment we understand how everything works but we do know that someone will die within a week without this hormone.

Four Hormones Essential to Life

  1. Insulin
  2. Parathyroid Hormone (PTH)
  3. Glucocorticosteroids (Cortisol)
  4. Mineralcorticosteroids (Aldosterone)

1. Insulin is the only hormone that in its totality, is anabolic in its actions.  That is to say, purely growth, healing and repair occur by way of glycogenesis, lipogenesis, and protein synthesis. While there are some hormones that provide catabolic and some that do a mixture, this is exclusively anabolic and we can’t live without it. The hormone that has the exact reverse action and is totally catabolic in nature is glucagon.  It exclusively promotes glycogenolysis, lipolysis, protein catabolism, and gluconeogenesis.

Very Relevant to this: How Glucose Levels are Regulated in the Blood Stream. Insulin and glucagon are important in shifting metabolic pathways between absorptive and postabsorptive states, which maintains the appropriate plasma levels of nutrient molecules.

2. Parathyroid Hormone (PTH) from the parathyroid glands regulates calcium level and it’s needed for muscle contraction and blood clotting.  It’s critical to maintaining plasma concentration of Ca+2.  PTH is essential for life because of calciums effect on neuromuscular capability.  In the absence of PTH, death rapidly occurs from asphyxiation caused by pronounced spasms of the respiratory muscles.

Parathyroid Hormone activates osteoclasts which break down bone tissue and release the minerals, resulting in a transfer of calcium from bone to the blood. This is known as bone resorption.

Calcitonin (aka thyrocalcitonin) is the reverse of PTH.  Calcitonin activates osteoblasts to form bone tissue by transferring calcium from the bloodstream to the bone tissue.  This is known as ossification (or osteogenesis, synonymous with bone tissue formation).

3. Cortisol, the primary glucocorticosteroid secreted by your adrenal cortex, increases catabolism of proteins and thus, the plasma concentrations of glucose, fatty acids, and amino acids above normal.  We talked about cortisol in great detail already when we talked about how ACTH releases glucocorticosteroids such as Cortisol.  Although these actions destabilize the concentrations of these molecules, they indirectly contribute to homeostasis by making the molecules available as energy sources or building blocks for tissue repair to help the body adapt to stressful situations.  Review the topic specifically on stress and cortisol!

4. Aldosterone, the primary mineralcorticosteroid secreted by your adrenal cortex, is absolutely essential to your life.  Without it, you will die within a week.  It’s essential for Na+ and K+ balance.  Because of sodiums osmotic effect, sodium balance is critical to maintaining the proper ECF volume and arterial blood pressure.  This action is essential for life.  Without aldosterone’s sodium and water-conserving effect, so much plasma volume would be lost in the urine that death would quickly occur.  Maintaining potassium ion balance is also essential for homeostasis because changes in ECF K+ profoundly impact neuromuscular excitability, most importantly of the heart.

The absolutely unbelievable, fantastic, incredible, homeostatic reflex involved with this is called the renin angiotensin system or renin-angiotensin-aldosterone reflex (or RAA pathway) which we’ll dive into next.

Birth Control

Primers to help you better help understand how birth control works: The Menstrual Cycle and FSH and LH (Gonadotropic Hormones)

If a woman took a pill containing estrogen everyday and raised the estrogen level in the blood, that would inhibit her pituitary from releasing Follicle Stimulating Hormone (FSH), which means the ovarian follicles will NOT develop in her ovaries. FSH is what causes ovarian follicles to grow, so you can’t get pregnant if there’s no egg growing in the ovary.

What if she takes a pill everyday that has progesterone in it? It will raise progesterone in her blood which will inhibit the pituitary from releasing Luteinizing Hormone (LH). You need LH to make an egg ovulate, so if progesterone causes LH to be inhibited, there egg will never ovulate even if an ovarian follicle had developed.

In fact, most birth control pills contain both estrogen and progesterone and there’s hundreds of variations of them. Estrogen inhibits FSH so ovaries wont develop. Progesterone inhibits LH so the egg can’t ovulate.  Got it? Okay, let’s move on.

How come women who take birth control pills have a period?

Hypothalamus GnRH -> Pituitary releases FSH -> Ovaries to secrete Estrogen

Hypothalamus GnRH -> Pituitary releases LH -> Ovaries to secrete Progesterone

Birth control pills for women come in many different cute cases. Heart shaped, tear shaped, etc. If they did it for a guy, it would come in a cardboard box because they could care less. They always have 28 pills because the cycle lasts 28 days. As I use the word “birth control pills” obviously women do take these to NOT get pregnant, but that’s not the only reason why they are doing it.  It’s useful for those that have very irregular menstrual cycles or have amenorrhea (the absence of menstruation flow). Birth control causes them to have perfect menstrual cycles, so it doesn’t always mean they are taking BC for not getting pregnant.

A woman is supposed to take 1 of these each day from the pill case. Commonly, many of the pills are different colors. Let’s assume the first 7 are white, then the next 7 are red, then the remaining pills are going to be green. The purpose for the color, other than being decorative, are to indicate what’s in them. The white ones don’t have anything in them, you don’t even have to take them, they are placebo pills, the point of them is so the woman stays in the habit of taking the pill everyday. The red ones have increasing levels of estrogen. The green ones have increasing levels of progesterone.

The estrogen and progesterone inhibit the pituitary gland but they also affect their own uterus, just like these chemicals normally would.  With increasing levels of estrogen, they also cause a slight thickening of the endometrial lining, just like estrogen naturally would. Then around day 15, 16, 17, we take pills with increasing amounts of progesterone, which not only inhibits LH, but causes significant thickening of the endometrial lining, mimicking her own menstrual cycle.  Instead of the progesterone coming from her ovaries, it’s coming from the pill.

When she finishes pill #28 which has progesterone in it, and her next pill is the white one, with nothing in it, all of a sudden the progesterone level drops. What happens when progesterone level drops? Shedding of the endometrial lining (Menstruation!). Normally her own ovaries stop the progesterone which causes the shedding. She will have this perfect menstrual cycle and the whole thing repeats over again. So the uterus is functioning normally, if not better.

If you forget to take the pill, what do you do?

It depends on WHICH pill you forgot to take and what formulation you are taking.  Every single one has different instructions. Some say take 2 the next day. Some say continue like normal. Some say ALL BETS ARE OFF, don’t have sex for 2 weeks.

Summary

Hormone Source Functions Factors that stimulate its release Factors that inhibit (or decrease) its release
Follicle Stimulating Hormone (FSH) Adenohypophysis (Anterior Pituitary Gland) In Males: Stimulates sperm production.In Females: Stimulates growth of ovarian follicles and estrogen secretion. GnRH In males: increased InhibinIn females: Increased Estrogen
Luteinizing Hormone (LH) Adenohypophysis (Anterior Pituitary Gland) In males: Stimulates Testosterone secretion.In females: Stimulates ovulation & progesterone secretion GnRH In males: Increasing testosteroneIn females: Increasing progesterone
Human Chorionic Gonadotropin (HCG) Chorionic Villi (of the placenta/outer sac) Stimulates the follicle cells of the Corpus Luteum to secrete Progesterone (which maintains vascularity of endometrium of uterus during pregnancy. Pregnancy (**the test for pregnancy is the detection of HCG) Termination of pregnancy.

Next up… the four essential hormones that are essential for life.

FSH and LH (Gonadotropic Hormones)

The hypo­thal­a­mus releases the fol­low­ing Releas­ing Hor­mones that stim­u­late the release of dif­fer­ent hor­mones from the adenohypophysis:

  1. Cor­ti­cotropin Releas­ing Hor­mone (C.R.H. causes the release of ACTH)
  2. Thy­rotropin Releas­ing Hor­mone (T.R.H. causes the release of Thy­roid Stim­u­lat­ing Hor­mone aka Thyrotropin)
  3. Gonadotropin Releas­ing Hor­mone (GnRH releases LH and FSH.)
  4. Growth Hor­mone R.H. & Growth Hor­mone I.H.
  5. Pro­lactin R.H. & Pro­lactin I.H.

In this post, we’re concerned with #3.

Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH).  Both these hormones affect the reproductive organs of both the female and the male. They are named for what they do for the ovaries of a female, although they do affect the testes of the male as well. We’ll deal with guys first, then the more complicated women.

FSH and LH in men

  • FSH stimulates sperm production in testes.
  • LH stimulates testosterone secretion by the testes.

Study Tip: I remember FSH produces sperm because the “follicle” reminds me of a hair follicle with hair, that reminds me of a flagellum [of a sperm].

By age 13, the pituitary gland starts producing FSH and LH in guys, to promote sperm and testosterone and this process continues until the day you die. Sperm levels and testosterone levels go down with time but a 95 year old can still father a child and will try if given the chance.

Negative Feedback Loop Regulation: The more LH there is, the more testosterone is secreted and as testosterone rises in the blood stream, this will inhibit the pituitary from releasing LH and to a lesser extent it will inhibit the GnRH.

Do sperm go into the blood stream and feedback to the adenohypophysis?

No. Sperm are ejaculated out of the penis. There is a theoretical chemical that should be providing a negative feedback loop for this to work but physiologists aren’t sure of what it is or how it works. We don’t have a male birth control pill because we aren’t sure how this feedback system works. If we give a guy testosterone everyday, that primarily inhibits the release of LH which means their own testes won’t produce testosterone, but it wont stop the production of FSH that produces sperm. We don’t have a way of stopping the production of sperm. That’s why there’s no male birth control. Body builders could still cause pregnancy. Twenty years ago it might have been a political statement to say that a male birth control pill doesn’t exist because all the physicians are males but that’s not true anymore with the majority of doctors being female.  If a male birth control existed, men would take it.

FSH and LH in women

I highly urge you to review the physiology of the menstrual cycle because it’s important enough to go over again. For women of menstruating age, it’s about the most important system as anything else in the body. Anyway, these hormones work completely differently in women. In women, FSH is released for 2 weeks, LH for 2 weeks. Remember in guys, it releases both at the same time. We also know that at about the age of 50, the menstrual cycle stops in women, this is known as menopause, but menopause is not caused by the pituitary not releasing LH or FSH, in fact a woman releases LH or FSH for their entire life but the ovaries stop responding! The common expression is, “I guess my ovaries are burned out.”  Postmenopausal woman have VERY high levels of LH and FSH because they don’t have the negative feedback loop of the ovaries.

The following is a very quick review of the menstrual cycle and how this ties into what we are learning:

During the ages of 12-50, the pituitary releases FSH and LH cyclically. FSH stimulates the growth of the ovarian follicle in the ovaries, and also the follicle cells around it to release estrogen.  Estrogen is a feminizing hormone that affects the woman’s body, skin, breasts, bone and causes a slight thickening of endometrial lining. This first 2 weeks is known as the preovulatory phase (or the follicular phase). Around day 14, after the first 2 weeks, the adenohypophysis starts secreting increasingly-higher amounts of LH and that causes an egg to pop out. Once an egg pops out into the fallopian tube, now a woman could get pregnant and the egg can live only 3-5 days so there’s only a window of 3-5 days where a woman could get pregnant during the cycle. LH is going to be released for 2 weeks, so then we call the ovarian follicle, a corpus luteum, and the ovarian follicles secrete estrogen and progesterone which causes a very strong thickening of the endometrial lining. This is called the luteal (postovulatory phase) because of the release of LH.  About day 28, LH is going to stop being released. The drop in the LH level causes the corpus luteum to degenerate and this drop leads to the shedding of the endometrial lining. It was the increase of progesterone that caused the thickening and now the drop in its level causes the shedding out the birth canal. The first day a woman notices this, is considered the first day of menstruation and the cycle starts all over again.

If the woman HAD gotten pregnant, the chorionic villi surrounding the embryo will secrete HCG, which mimics LH and stimulates the corpus luteum to keep secreting progesterone so that the hormones from the pituitary are no longer controlling the woman but the baby is.

So to recap, we have GnRH that causes the adenohypophysis to secrete these gonadotropin hormones cyclically. FSH stimulates the ovaries to grow an ovarian follicle and causing the follicle cells to secrete estrogen. What does LH do? LH causes ovulation and follicle cells of the corpus luteum to secrete progesterone. So FSH controls the release of estrogen and LH controls the release of progesterone.

Negative feedback loops:

As estrogen hormone levels rise, that inhibits the release of FSH, because that’s what normally causes the secretion of estrogen.

An increase of progesterone inhibits the release of LH, because that’s what normally causes progesterone to be secreted.

Now the next most logical step would be to go over how birth control works!