Transcription
Okay, now we have finished the fate of acetylcholine. So let's go and see what happens to catecholamine or norepinephrine. Again, we will draw the brain and spinal cord, which sends parasympathetic nerves supplying visceral organs. Let's take a heart for an example. Here, we are going to draw the sympathetic nervous system, which we are going to discuss, and this is its nerve endings. We have finished studying acetylcholine, so now let's shift to another, epinephrine. You already know there are endings of sympathetic that contain norepinephrine, and I have told you before when signals reach these nerve endings, norepinephrine is released. Then it binds to one of the five receptors: you know Alpha One, Alpha Two, Beta 1, Beta 2, and Beta 3. You already know that the heart contains Beta 1, but this is not our concern right now.
After norepinephrine is released and performed its function, most of it undergoes a process called reuptake. Let's agree that there is nothing that can just stand still without purpose; either it has a function or it's broken down immediately. So the remainder of norepinephrine, after performing its function, undergoes a process called reuptake. This reuptake represents about 80 percent of the total amount. Let's just draw a better picture of nerve endings. This is a nerve ending, and this is a sympathetic nerve, and this nerve ending, after norepinephrine is released, is subjected to a process called re-uptake for 80 percent of the total amount. There are two levels of this reuptake process. The first level: it only just enters the cytoplasm after crossing the synaptic space. There is a certain transporter; this transporter enables norepinephrine to enter the cytoplasm of the cell. Then it's immediately stored into vesicles again, just like it was before. We cause the cytoplasm of nerve endings to contain mitochondria, which has a certain enzyme you know from biochemistry called MAO enzyme or monoamine oxidase enzyme. If norepinephrine remains in the cytoplasm and doesn't hide quickly in those vesicles, this MAO enzyme breaks it immediately. That's why norepinephrine can't remain free in this cytoplasm for long periods of time. However, free norepinephrine can be present inside the cytoplasm, but in tiny amounts, because the majority of it must quickly hide from the MAO enzyme.
So what happens if norepinephrine became stubborn and refused to get inside the cell and remained free in the synaptic space? No one would prevent it; however, someone could actually destroy it. This someone is called COMT enzyme. So norepinephrine acts on its receptor and becomes consumed; however, the remaining amount must be removed by recycling. For 80 percent of the remaining amount, the other 20 percent, which refused to enter the vesicles, are destroyed by the MAO and those present in the synaptic space are destroyed by COMT. So 20 percent of the amount is metabolized, and 80 percent of the amount is safely stored inside the vesicles again. Remember that the 20 percent that failed to be stored in the vesicles are destroyed, either by MAO or COMT enzyme. This MAO enzyme has two isoenzymes; one of them is called MAO A, and the other is called MAO B. Monoamine, both of them are present in the central nervous system. MAO A is present in CNS and nerves in general and in the brain; it is also present in the peripheral nervous system. However, MAO B is mostly, mostly not only, but mostly present in the brain. So remember B is for brain, not in peripheral tissue. Both of them, MAO A and MAO B, destroy the amount remaining from norepinephrine which couldn't be stored in the vesicles. Those inside the vesicles are safe, but those free in the cytoplasm are destroyed by monoamine oxidase enzyme, and those free in the synaptic space are destroyed by COMT enzyme.
Now you may wonder why are we studying this part? That's because we are going to study a certain medication in the autonomic nervous system called reserpine. This drug is not commonly used these days; it was essentially used as a treatment for hypertension. If you want to get this drug called reserpine and then be fitting its qualities, it would be called the most scandalous drug ever. Why so? Because its mechanism is based on one of the most treacherous actions in the history of medicine. So let's see together how this drug works. This drug goes to the vesicles and prevents norepinephrine from entering them. In other words, it allows norepinephrine to be released, perform its function on the receptor, and the remaining part to come back; it lets them come back and enter the cytoplasm; however, the scoundrel prevents them from entering the vesicles, which leads to a lottery. Since the thug, MAO, is waiting for them out in the cytoplasm, by the time you take this drug, more and more norepinephrine is destroyed by this enzyme, depleting the body from epinephrine. And when your body has no epinephrine, the sympathetic system ceases to function, so blood pressure is lowered. This drug is not commonly used these days because it leads to what is known as medical sympathectomy, and sympathectomy means cutting the sympathetic nerve; it becomes out of action because it no longer has transmitters in it.
So what is the resultant compound of breaking down norepinephrine by monoamine oxidase and COMT enzyme? Norepinephrine is transformed into two substances: one of them is called metanephrine, the other is called VMA, or vanillylmandelic acid. These are two major metabolites of catecholamine. Remember that catecholamines are amines involving adrenaline or epinephrine and others, but it mostly refers to adrenaline and norepinephrine. The result of metabolism of catecholamines are metanephrine and vanillylmandelic acid. We need to understand this as we have many diseases that can be diagnosed by these two metabolites. So if I may ask you, since these are metabolites of norepinephrine, can you tell me what increases their level, or what can raise the level of metanephrine and VMA in blood? And by the way, they can be measured in blood or in urine. Can you tell me what increases their level? In other words, if I take a sample from your blood and measure their levels and they were raised, what can cause such a case? You would tell me, since their levels are high, then my body is releasing much norepinephrine. That's correct, but what are the reasons? The first reason: the first reason my body is producing so much norepinephrine is stress. Nervous people, or people under prolonged stress—you even know from physiology that nervous people's sympathetic is dominating over the parasympathetic system—can't sleep, can't eat well, and so on. Therefore, his body is releasing much more norepinephrine and catecholamines that are metabolized, raising the level of metanephrine and vanillylmandelic acid. But what is a normal level of metanephrine and vanillylmandelic acid? Catecholamines' blood level shouldn't exceed 10 nanograms per liter. So each liter of your blood doesn't have more than 10 nanograms of catecholamines. This stress can elevate the level 10-fold. So if you are feeling tense right now, your blood level of catecholamine will reach 100 nanograms per liter—a 10-fold increase. This is the first reason. Let's shift to the next reason. The second reason behind increased blood level of metanephrine and vanillylmandelic acid is external epinephrine administration as medication, for example, by injection. If someone gives you intravenous adrenaline bolus or parenteral adrenaline, the level of metanephrine rises 100-fold. And the third reason, which is rare but also very important, is a tumor. I have told you before that the suprarenal gland has a single nerve supply only from the sympathetic system, and this suprarenal gland, situated above the kidney, is responsible for releasing adrenaline and norepinephrine. However, it releases adrenaline more than norepinephrine because it has an enzyme that converts norepinephrine into epinephrine. So now this is a gland responsible for releasing catecholamine or adrenaline. Imagine if a tumor occurs in this gland. These cells that release catecholamine are called chromaffin cells. So if a tumor arises from chromaffin cells, catecholamine blood level increases, and when catecholamine blood level increases, catecholamine metabolites level also increases this time thousands-fold. So stress raises it 10-fold, injection raises it 100-fold, and pheochromocytoma raises it thousands-fold. So remember, pheochromocytoma is a tumor arising from suprarenal glands; mostly it is unilateral—90 percent of cases are unilateral—and 90 percent of cases are benign, not malignant. Its incidence is five per million; from every million humans, only five experience this tumor. But how can we diagnose this tumor? What do you think? When someone has a suprarenal gland tumor releasing high levels of adrenaline and/or norepinephrine, what do you think of his blood pressure? Of course, it's very high. So when someone suffers from high blood pressure without any apparent reason, and you measure the level of metanephrine or vanillylmandelic acid in plasma or urine and find out they are elevated, then you start to doubt one of the three reasons: stress, external medication, or pheochromocytoma. That's why you order a CT scan. This is a picture of a CT scan. This CT scan shows a suprarenal gland tumor and proves your diagnosis. So the three reasons behind increased levels of norepinephrine or catecholamines are stress, external medication, or the rarest but most dangerous, pheochromocytoma. Let's just clear this board to have some more space after we have finished this part.
Let's illustrate some of the exceptions, and remember to leave exceptions for the last when you are explaining any topic. Always start with the common, then progress to the exceptions. So here, what are the exceptions? This is the spinal cord, which sends a pair of sympathetic fibers. Let's give this fiber a blue color, and this is sympathetic. And I have told you that most organs in your body have dual supply; however, some organs receive single supply, like the suprarenal gland that has only sympathetic supply, sweat glands that have only sympathetic supply, and most of the blood vessels have only sympathetic supply. The three—suprarenal gland, sweat glands, and most of the blood vessels—don't forget this was mentioned before. So now I want to tell you that this suprarenal gland, receiving sympathetic supply, and its nerve endings are expected to have norepinephrine as any other organ supplied by the sympathetic system; however, nerve endings here don't have norepinephrine but acetylcholine, and this is one of the exceptions because, although it is supplied by the sympathetic system, the chemical transmitter inside it is acetylcholine. So in this case, the nerve reaching the suprarenal gland is termed a sympathetic cholinergic nerve; it is a sympathetic nerve, part of the sympathetic system; however, its chemical transmitter is acetylcholine. Theoretically, if I give you an injection of acetylcholine—this is impossible, of course, but let's imagine if we can—one of its effects inside your body is to act on the receptor on the suprarenal gland and releases adrenaline. How strange that adrenaline from the suprarenal gland is released by acetylcholine. The same scenario occurs in sweat glands, which receive sympathetic nerves; its nerve endings are expected to have norepinephrine as a transmitter, but no, it also has acetylcholine. Also, a little amount of blood vessels—little amount, little, not many—all the same as these two have sympathetic, however cholinergic, so they have sympathetic nerves but are controlled by acetylcholine. Okay, remember we are pharmacologists, not physiologists, so we need to understand the effect of drugs, not the effect of sympathetic nerve stimulation, and as long as the chemical transmitter that controls something—like here where acetylcholine is responsible for the function of organs—we are concerned with acetylcholine's effects as a drug, not by sympathetic effect on the body.
Now I want to tell you about skeletal muscle; an autonomic organ. When you move your hand, is it an autonomic or voluntary function? Of course, voluntary or motor, not concerned with the autonomic nervous system. So the nerve supply in skeletal muscle is a motor nerve, not an autonomic nerve. Correct, indeed. We are; however, the chemical transmitter at the nerve ending is also acetylcholine, and when it is released, it acts on a receptor on the muscle. This receptor is like a gate, such as the one I have told you about in the ganglia in the previous video. I have told you about a gate inside ganglia called the nicotinic acetylcholine receptor, which is a gate opened by acetylcholine, resulting in sodium ions influx, causing depolarization with an action potential leading to muscle contraction. The gate within the ganglia, which are the same as the ones in the muscle, is called the nicotinic acetylcholine receptor, and takes the letter N, short for neuronal; however, the same gate in muscle takes the letter M, short for muscular. So we have two types of nicotinic acetylcholine receptors: one in the ganglia, termed neuronal, and the other in muscles, termed muscular. These receptors are completely different in both structure and function from receptors inside normal tissue, like M1, M2, and M3, which we are going to talk about in the next video.
Before we finish this video, I want to tell you about something important. In the 90s, there were bacteria from a family called Clostridium, which release a certain toxin, a neurotoxin, because it causes paralysis. This toxin is present in improperly canned food. You sometimes hear about people who die after eating expired canned food because canned food is a perfect medium for anaerobic bacteria that doesn't need oxygen, like the Clostridium family. This bacteria releases certain toxins; if it reaches nerves, it can cause paralysis throughout the whole body. So how can someone die from this toxin? Because it causes paralysis of respiratory muscles, and that's because this toxin can inhibit the release of acetylcholine from nerve endings. But this toxin specifically inhibits acetylcholine release at the neuromuscular junction, this part of the muscle; that's why it causes paralysis. Now we are using this toxin in cosmetics, however, in very tiny amounts. This toxin that causes inhibition of acetylcholine release is termed botulinum toxin. Since this toxin can cause paralysis of skeletal muscle, then we can use it in very tiny concentrations for medical purposes. How can we use such a toxin in medicine? Imagine if someone is experiencing spasms of certain muscles in his neck; this spasm can be so severe that it can cause terrible pain. So imagine if we locally inject the muscle with tiny concentrations of this toxin; it will cause paralysis of this muscle and relieve the spasms; however, if it was delivered in higher concentration, it can kill the patient.
Now to the interesting part: don't all people get wrinkles on their face, or what's known as frontline on the front of the face, that makes one look older? And where do those wrinkles come from? They are the result of the aging process and overactivity of these muscles. When the frontalis muscle and muscles surrounding the eye are overactive, it causes wrinkles that people dislike. How can we do this? We can simply administer botulinum toxin in very tiny concentrations here in the forehead and here around the eye and here around the mouth. This results in controlled paralysis in these muscles; thus, these muscles become relaxed, and when these muscles are relaxed, wrinkles go away, and one can look so much younger. This is what you may know as Botox. So if someone asks you about Botox injection, you now understand how this medication works. To summarize, Botox is botulinum toxin, which is a neurotoxin found in poorly canned food. Companies are producing it through genetic engineering; then it undergoes processes of purification, and only a tiny concentration is used. About 50 units are injected to the face, can make you look so much younger, and of course, it's very expensive, not because these bacteria growing on rotten food are, but because of how this toxin is produced. A single unit of Botox costs around 10 dollars, and an average treatment of about 50 units can cost about 600 dollars. So it's expensive.
After we have finished the main bulk of this topic, we are clarifying some more other points. May I ask you, do you think that life is only about sympathetic and parasympathetic? Because many fresh students think all autonomic is about the sympathetic or parasympathetic system only; however, there is a third system present in the intestine. Imagine if this were a cross-section in the intestine; here we have a third division called the enteric nervous system, composed of a collection of neurons inside the Meissner plexus of nerves present inside the intestine. Indeed, the intestine receives both sympathetic and parasympathetic; however, if you cut a loop of intestine devoid of these nerves, you'll note that this loop still undergoes peristalsis. Where does this peristalsis come from? This loop has a local control system called the enteric nervous system. Both sympathetic and parasympathetic are merely regulating it; however, if you cut them both, the intestine can still work. You may find an MCQ question asking about the third division of the autonomic nervous system; the answer is the enteric nervous system. Another fact you need to know: although the system is called the enteric nervous system and is a third part of the autonomic nervous system, nerves controlling this system neither release acetylcholine nor norepinephrine. So how do these neurons work? They act through other transmitters. Don't you ever think that acetylcholine and norepinephrine are the only transmitters we have? We have uncountable numbers of transmitters, such as ATP, purines, angiotensin, histamine, serotonin, substance P, nitric oxide—all of these are transmitters, but they are not specific for sympathetic nor parasympathetic; they are general transmitters. These systems that are similar to the enteric nervous system, which doesn't follow the sympathetic-parasympathetic rule, are sometimes called the NANC system, short for non-adrenergic non-cholinergic. But are these transmitters considered primary transmitters? Our primary transmitters are acetylcholine in the parasympathetic and norepinephrine in the sympathetic. These transmitters are termed co-transmitters; co- means cooperative. So these are cooperative transmitters, not primary transmitters. The basic autonomic control in our body is either sympathetic or parasympathetic. Many organs have a local control system; this local control system is termed the NANC system. This NANC system is controlled through transmitters other than acetylcholine and norepinephrine, termed co-transmitters.
The last point in this video is the significance of this system. Sometimes this nerve is sympathetic; this means it releases norepinephrine, and this nerve here is parasympathetic, releasing acetylcholine; those are the primary transmitters. Sometimes there are transmitters at nerve endings, either sympathetic or parasympathetic, other than primary transmitters. There is no nerve ending that has only one transmitter; surprisingly, any nerve ending has one primary transmitter and others that are co-transmitters, helping the primary transmitter. So in case of the parasympathetic system, the primary transmitter is acetylcholine, and others that help with it are co-transmitters. What are these co-transmitters here? They are ATP, purines, angiotensin, histamine, serotonin, substance P, nitric oxide, dopamine, and many others. But do these co-transmitters have their own receptors? Yes, they have; however, its function is to regulate the motion of primary transmitters. To summarize, any nerve in your body, either sympathetic or parasympathetic, may have other transmitters than the primary transmitters called co-transmitters; their function is to regulate the primary transmitter. And if I have a tissue with no sympathetic or parasympathetic control, is that possible? Yes, and it's called the NANC system, such as the enteric nervous system in the intestine, that doesn't have acetylcholine, epinephrine, or norepinephrine, but is controlled by these co-transmitters. See you in the next video where we will discuss cholinergic receptors in detail: M1, M2, M3, also adrenergic receptors: Alpha 1, Alpha 2, Beta 1, Beta 2, Beta 3; their sites and function is going to be our base to understand how drugs work, and then we start pharmacologic.