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41.5A: Epinephrine and Norepinephrine - Biology

41.5A: Epinephrine and Norepinephrine - Biology



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Epinephrine and norepinephrine are released during the flight/fight response, causing vasoconstriction of blood vessels in the kidney.

Learning Objectives

  • Describe hormonal control by epinephrine and norepinephrine of osmoregulatory functions

Key Points

  • Epinephrine, produced by the adrenal medulla, causes either smooth muscle relaxation in the airways or contraction of the smooth muscle in arterioles, which results in blood vessel constriction in the kidneys, decreasing or inhibiting blood flow to the nephrons.
  • Norepinephrine, produced by the adrenal medulla, is a stress hormone that increases blood pressure, heart rate, and glucose from energy stores; in the kidneys, it will cause constriction of the smooth muscles, resulting in decreased or inhibited flow to the nephrons.
  • Together, epinephrine and norepinephrine cause constriction of the blood vessels associated with the kidneys to inhibit flow to the nephrons.

Key Terms

  • epinephrine: (adrenaline) an amino acid-derived hormone secreted by the adrenal gland in response to stress
  • norepinephrine: a neurotransmitter found in the locus coeruleus which is synthesized from dopamine
  • catecholamine: any of a class of aromatic amines derived from pyrocatechol that are hormones produced by the adrenal gland
  • adrenergic: containing or releasing adrenaline

Epinephrine and Norepinephrine

Epinephrine

As a hormone and neurotransmitter, epinephrine acts on nearly all body tissues. Its actions vary by tissue type and tissue expression of adrenergic receptors. For example, high levels of epinephrine cause smooth muscle relaxation in the airways, but cause contraction of the smooth muscle that lines most arterioles. Epinephrine acts by binding to a variety of adrenergic receptors. Epinephrine is a nonselective agonist of all adrenergic receptors, including the major subtypes α1, α2, β1, β2, and β3. Epinephrine’s binding to these receptors triggers a number of metabolic changes. Binding to α-adrenergic receptors inhibits insulin secretion by the pancreas, stimulates glycogenolysis (the breakdown of glycogen) in the liver and muscle, and stimulates glycolysis (the metabolic pathway that converts glucose into pyruvate) in muscle. β-Adrenergic receptor binding triggers glucagon secretion in the pancreas, increased adrenocorticotropic hormone (ACTH) secretion by the pituitary gland, and increased lipolysis by adipose tissue. Together, these effects lead to increased blood glucose and fatty acids, providing substrates for energy production within cells throughout the body.

Norepinephrine

Norepinephrine is a catecholamine with multiple roles. It is the hormone and neurotransmitter most responsible for vigilant concentration in contrast to its most-chemically-similar hormone, dopamine, which is most responsible for cognitive alertness. Areas of the body that produce or are affected by norepinephrine are described as noradrenergic. One of the most important functions of norepinephrine is its role as the neurotransmitter released from the sympathetic neurons to affect the heart. An increase in norepinephrine from the sympathetic nervous system increases the rate of contractions in the heart. Norepinephrine also underlies the fight-or-flight response, along with epinephrine, directly increasing heart rate, triggering the release of glucose from energy stores, and increasing blood flow to skeletal muscle. When norepinephrine acts as a drug, it increases blood pressure by increasing vascular tone through α-adrenergic receptor activation. Norepinephrine is synthesized from dopamine by dopamine β-hydroxylase in the secretory granules of the medullary chromaffin cells and is released from the adrenal medulla into the blood as a hormone. It is also a neurotransmitter in the central nervous system and sympathetic nervous system, where it is released from noradrenergic neurons in the locus coeruleus. The actions of norepinephrine are carried out via the binding to adrenergic receptors.

Role of Epinephrine and Norepinephrine in Kidney Function

Epinephrine and norepinephrine are released by the adrenal medulla and nervous system respectively. They are the flight/fight hormones that are released when the body is under extreme stress. During stress, much of the body’s energy is used to combat imminent danger. Kidney function is halted temporarily by epinephrine and norepinephrine. These hormones function by acting directly on the smooth muscles of blood vessels to constrict them. Once the afferent arterioles are constricted, blood flow into the nephrons of the kidneys stops. These hormones go one step further and trigger the renin-angiotensin-aldosterone system, the hormone system that regulates blood pressure and water (fluid) imbalance.


Difference Between Adrenaline and Noradrenaline

Adrenaline vs Noradrenaline

There are number of things that are known by different names but are more or less the same. The most confusing thing is that what the world knows as adrenaline is known as epinephrine by most people in the US. Noradrenalin is known as norepinephrine in the US. What is the difference between the two? Lets us find out:
For starters, adrenalin and Noradrenalin are different from each other chemically. Adrenalin is actually produced by the body when the body modifies noradrenalin. This is what makes it chemically different.

The two substances are used in different areas of the body. The post ganglionic neurons of the nervous system use the Noradrenalin. It is basically used as a neurotransmitter, that is, it is generated by the neurons in the brain.
Adrenaline on the other hand, is mainly produced by the adrenal medulla. Though this structure also produces some Noradrenalin, the main output of the gland is actually adrenaline.

Adrenaline and Noradrenalin also differ in their functions. There are number of receptors for adrenaline. For example, the α1 receptors are found in the blood vessels and when stimulated, result in a constriction. However, the β1 receptors located in the heart result in a rise in the force and the rate of the heart contractions.
Noradrenalin on the other hand, has a dominant α effect. It always acts as a stimulator on the brain and increases arousal and alertness.
Noradrenalin and adrenaline are called catecholamine because they have a catechol group. They are derived from the amino acid called tyrosine.

When Noradrenaline acts as a drug, it increases the blood pressure by increasing upon its vascular tone. However, it does not have a direct stimulatory effect on the heart.

A major difference between adrenaline and Noradrenalin is that adrenaline or epinephrine contains a methyl group that is attached to the nitrogen. This is replaced by a hydrogen atom where norepinephrine or Noradrenalin is concerned.
Both adrenaline and noradrenalin are an important part of the fight or flight syndrome in the body that is activated when a person is either too angry or too excited. It prepares the body for a rush of blood through the system. Unfortunately, both these substances are under the direct control of the central nervous system and is therefore not under voluntary control.
Summary:
1. Adrenaline and Noradrenalin are chemically different from each other.
2. They are also used by different parts of the body.
3. Adrenaline has a very weak beta effect, but a strong α effect. NorAdrenaline on the other hand has a less sensitive α effect.
4. Adrenaline has a methyl group attached to the nitrogen. In Noradrenalin, it is replaced by a hydrogen atom.


Although norepinephrine and epinephrine are structurally related, they have differing effects. Noradrenaline has a more specific action working mainly on alpha receptors to increase and maintain blood pressure whereas epinephrine has more wide-ranging effects. Norepinephrine is continuously released into circulation at low levels while epinephrine is only released during times of stress.

Norepinephrine is also known as noradrenaline. It is both a hormone and the most common neurotransmitter of the sympathetic nervous system. Epinephrine is also known as adrenaline. It is mainly made in the adrenal medulla so acts more like a hormone, although small amounts are made in nerve fibers where it acts as a neurotransmitter.

Norepinephrine Vs epinephrine: Synthesis and Actions in the body

Naturally occurring norepinephrine is mostly made inside nerve axons (the shaft of the nerve), stored inside vesicles (small fluid-filled sacs), then released when an action potential (an electrical impulse) travels down the nerve. Noradrenaline travels across the gap between two nerves where it binds to a receptor on the second nerve and stimulates that nerve to respond. This is norepinephrine acting as a neurotransmitter. Norepinephrine causes vasoconstriction (a narrowing of the blood vessels) so is useful for maintaining blood pressure and increasing it in times of acute stress.

Norepinephrine is also made in the adrenal medulla where it synthesized from dopamine and is released into the blood as a hormone.

Epinephrine is made from norepinephrine inside the adrenal medulla (the inner part of the adrenal gland, a small gland associated with the kidneys). Our adrenal medulla helps us to cope with physical and emotional stress. The synthesis of epinephrine increases during times of stress. Epinephrine acts on almost all body tissues, but its effects are different depending on the tissue, for example, epinephrine relaxes the breathing tubes, allowing easier breathing, but contracts the blood vessels (keeping blood pressure up and ensuring brain and heart are perfused with blood). Epinephrine also increases the heart rate and force of contraction, blood flow to the muscles and brain and aids the conversion of glycogen (a stored form of energy) into glucose in the liver.

Epinephrine diffuses through the adrenal medulla into the blood which perfuses the adrenal glands and is then carried throughout the body.

Norepinephrine Vs epinephrine: Epinephrine has a wider range of effects

Norepinephrine acts mostly on alpha receptors, although it does stimulate beta receptors to a certain degree. One of its most important roles is to increase the rate of contractions of the heart, and together with epinephrine, it underlies the fight-or-flight response.

Epinephrine is relatively nonspecific, stimulating both alpha, beta 1, beta 2, and beta 3 receptors more or less equally. By binding to these receptors epinephrine triggers a number of changes, all of which are aimed at either increasing energy use by the body or making more energy available to be used, for example, stimulating glucagon secretion from the alpha cells of the pancreas.

Norepinephrine Vs epinephrine: Use in medicine

In medicine, norepinephrine is used to increase and maintain blood pressure in acute situations where low blood pressure is a feature (such as cardiac arrest, spinal anesthesia, septicemia, blood transfusions, drug reactions). It is usually used in addition to other agents.

Epinephrine is used in medicine to treat low blood pressure associated with septic shock, for the emergency treatment of allergic reactions, and in eye surgery to maintain dilation of the pupil. It is also available in an autoinjector for people with a history of severe allergic reactions.

In medicine, norepinephrine is used to increase or maintain blood pressure during acute medical situations that cause low blood pressure and epinephrine is used in the emergency treatment of allergic reactions, to treat low blood pressure during septic shock, and in eye surgery to maintain dilation of the pupil.

Epinephrine is mainly produced by the adrenal medulla as a hormone, although small amounts are produced in the nerves and act as a neurotransmitter. Noradrenaline is mainly produced in the nerves, although small amounts are also produced in the adrenal medulla. Both norepinephrine and epinephrine are released during a fight-or-flight response.


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The FDA risk statement: No longer a shrug.

Risk Section added Sept. 10, 2020

Let’s digest what the FDA announcement says about risks in this recall:

Risk Statement: Patients being treated for hypothyroidism (underactive thyroid), who receive sub potent Nature-Throid® or WP Thyroid®, may experience signs and symptoms of hypothyroidism (underactive thyroid) which may include, fatigue, increased sensitivity to cold, constipation, dry skin, puffy face, hair loss, slow heart rate, depression, swelling of the thyroid gland and/or unexplained weight gain or difficulty losing weight.

There is reasonable risk of serious injury in newborn infants or pregnant women with hypothyroidism including early miscarriage, fetal hyperthyroidism, and/or impairments to fetal neural and skeletal development.

In elderly patients and patients with underlying cardiac disease toxic cardiac manifestations of hyperthyroidism may occur, such as cardiac pain, palpitations or cardiac arrhythmia.

RLC Labs, Inc. has not received any reports of adverse events related to this recall.

On the symptoms of hypothyroidism, we can be thankful for their inclusion of such a detailed list. It is rare to see people care about listing the symptoms of hair loss and weight gain, two things that can be incredibly damaging to our identity and our social lives.

I’m not sure why they mentioned “fetal hyperthyroidism” and “cardiac manifestations of hyperthyroidism” near the end, because this is a potency DEcrease not an INcrease. It looks like filler text someone plunked in without thinking clearly!

Other risks not mentioned?

Symptoms, maternal risks, and cardiovascular risks. These are stereotypical top 3 things to mention. They have to be covered.

But the simple fact is that if they listed all the risks to all the organs and tissues affected by thyroid hormone levels, they would have a list as long as your leg.

There is no disease or disorder in the body that is immune to the effects of a severe reduction in thyroid hormone receptor signalling. Thyroid hormone is just that essential to everything functioning well.

If you have another autoimmune disease, skin disorder or kidney or liver dysfunction, your symptoms and overall health could get worse when you are hypothyroid.

But woe unto the people who are just coming out of surgery, or fighting for their lives in hospital intensive care, or struggling in the final stages of cancer or a neurological disease. You can’t risk being hypothyroid without adequate T3 supply for recovery if you’re in Nonthyroidal Illness.

What is Nonthyroidal illness syndrome (NTIS)? It is a metabolic derangement that happens in all sorts of acute and chronic illnesses and after surgeries and accidents. Your deiodinase type 3 (D3) dumps your thyroid hormones and depletes T3 to lower your metabolic rate very quickly (See GRAPHIC and discussion: T3 Depletion). But sometimes D3 dumps T3 way too far, and T3 stays low for too long. If your TSH was normal to start with, it stays normal during the acute phase (early phase) like an apathetic observer, because the body isn’t ready yet for a T3 refill.

The body will need a T3 refill from a TSH-driven healthy thyroid (or from a hormone pill) to turn it around just at the right time, to aid your recovery of health. If you can’t get your T3 refill at that crucial turning point (whenever that is…), the risk of morbidity and mortality escalates.

Why “woe unto the people…”? Because people on a thyroid hormone leash — people who depend on pills for their thyroid hormone supply — are going to see a loss in T3 levels, too, just like others with healthy thyroids.

  • The natural way to recover is by TSH stimulating a healthy thyroid, which then rapidly secretes more T3 to fill the T3 hole. TSH rises fast, and as TSH rises, the T3 portion of the T3:T4 ratio of thyroidal secretion escalates significantly to give a T3-refill to the body even while there’s still a hole in the T3 bucket. Eventually enough T3 and T4 are in circulation and you can recover.
  • But you, the thyroid disabled person, will need enough T3 from your hormone pill (plus any residual thyroid tissue you may have) to dig yourself out of the hole and to recover health.

GOOD News: Be thankful you’re on a hormone pill that includes some T3, and do not let them switch you to LT4-Levothyroxine while you are in hospital (they can be sneaky if they are programmed to believe that LT4 is best for you!) Bring your supply of NDT. Tell a family member that if you ever go to hospital, they will need to bring your pills to the hospital.

Scientists and doctors are ignorant about our risk as thyroid patients because, as I’ve pointed out before, Thyroid patients are routinely excluded from low T3 syndrome (NTIS) research. It’s called nonthyroidal illness, and we have an illness that is thyroidal but we’re still at risk. But scientists can be easily tricked by language and definitions, so they routinely eliminate us from most research studies of NTIS. Out of ignorance and blind faith, doctors have been told that all we need is our daily T4 dose and we’re fine. No, you can’t say that with enough research. We have to use science and thyroid physiology to surmise what is risky, and not having a thyroid with adjustable TSH-driven T3 secretion rate is a risk because that’s key to recovery!

Why is LT4 therapy bad for you in hospital? An early study on NTIS treatment showed that when they tried to “help” even healthy-thyroid people out of NTIS T3-depletion using T4 hormone alone, it backfired (Brent & Hershman, 1986). That’s because not only did the T4 dosing reduce the strength of their TSH elevation which meant loss of bonus T3 secretion, but also the body was in a mode of D3 enzyme upregulation, converting T4 quickly to RT3 at the same time as converting T3 to various T2s.

Maternal risks

We should be very thankful to them for noticing that risk to fetal life is real. To some people on the borderline of hypothyroidism, a small difference is enough to push them under.

The risk here is very present with REDUCED potency in the T4 portion of desiccated thyroid (NDT). Some women on NDT therapy are superconverters and have a very low FT4 level, hovering near the bottom end of reference, while their FT3 is much higher in range and compensates for the lower FT4.

Pregnancy demands more thyroid hormones in circulation, in general, and FT4 / TT4 (total and free) is the hormone that naturally elevates (even above reference) in people who are pregnant with healthy thyroid glands. (But please do not try to elevate your FT4 above reference using NDT just to mimic their T4 levels! Because of your medication type, your FT3 would be super-high above your FT4 and you’d be overdosed! Just try to keep your FT4 in range bare minimum and half way up the range would be nice, trying to keep your FT3 from spiking too high above reference.)

The risk is that you may already be in your 1st trimester not knowing that you are pregnant, and the fetus really, really needs your maternal hormones in the first trimester. So if you are trying to get pregnant you cannot risk hypothyroidism.

The stablest hormone with the largest supply in blood is T4, and the placenta (which expresses a lot of D3 enzyme) does the labor of filtering the T4 down to levels that the fetus needs. The placenta converts a lot of your T4 to RT3 and only gives the fetus a trickle, and that’s what they need, just enough.

The older studies of fetal risk during pregnancy (1964 to 1970s by Dr. Evelyn Man and associates) focused on UNDERdosed people on desiccated thyroid (Proloid brand) versus women who were dosed with enough T4 supply (the T4 was measured by BEI, Butanol Extracted Iodine, before there was a reliable T4 hormone test. They did not have the technology to measure T3).

  • The women who had enough T4 hormone in circulation while on NDT had perfectly healthy babies with normal mental development by 7 years old. The underdosed women’s children did not fare well.

I don’t have room here to give links to all 10 of these old articles on desiccated thyroid in pregnancy, and most are not fully online anyway. But here is Dr. Man’s most recent article on the topic, in 1991, after a rat study was done by Escobar-Morreale and team, which confirmed some of what Man’s team had found many years previously:

  • Man, E. B., Brown, J. F., & Serunian, S. A. (1991). Maternal hypothyroxinemia: Psychoneurological deficits of progeny. Annals of Clinical & Laboratory Science, 21(4), 227–239. http://www.annclinlabsci.org/content/21/4/227

About heart rate / arrhythmias.

Yes, having hypothyroidism will overall slow the heart rate down (bradycardia). The risk with bradycardia can happen when your heart rate goes down naturally at night, especially if you already have sleep apnea. (Read about bradycardia in this US News & World Report article.)

But there are risks beyond slow heart rate in hypothyroidism that many doctors are not aware of:

  • Hypothyroidism (especially low T3) can also cause intermittent spikes in heart rate.
  • Low T3 can also cause heart rhythm problems like atrial fibrillation.

Fluctuating heart rate in hypothyroidism appears to happen because our adrenal hormones (catecholamines) try to compensate for loss of T3 activity in receptors, and they kick in to keep our heart rate going.

“Thyrotoxic patients have normal plasma norepinephrine (NE) levels, while hypothyroid patients have elevated plasma NE levels, perhaps to compensate for reduced adrenergic sensitivity […]

Epinephrine levels were not different in hyperthyroid or hypothyroid patients compared with normal […]

Catecholamines [such as norepinephrine, etc. secreted from the adrenals] increase T4 to T3 conversion, by stimulating activity of a specific deubiquitinase that acts on the D2 protein, upregulates D2 activity, and increases T3 levels in the nucleus. […] (Mullur et al, 2014)

What is the effect of higher norepinephrine in hypothyhroidism? A tachycardia rush (high heart rate)!

“Norepinephrine, produced by the adrenal medulla, is a stress hormone that increases blood pressure, heart rate, and glucose from energy stores in the kidneys, it will cause constriction of the smooth muscles, resulting in decreased or inhibited flow to the nephrons.”

(Biology LibreTexts, 41.5A Epinephrine and Norepinephrine)

How quickly does norepinephrine cause a heart rate spike? pretty fast.

Catecholamines

During stress or a need for increased cardiac output, the adrenal glands release a hormone called norepinephrine into the bloodstream at the same time that the sympathetic nervous system is also triggered to increase your heart rate. This hormone causes the heart to beat faster, and unlike the sympathetic nervous system that sends an instantaneous and short-lived signal, norepinephrine released into the bloodstream increases the heart rate for several minutes or more.

(Michigan Medicine, Electrical System of the Heart, 2019)

I experienced these erratic tachycardia flares myself when I was in my final 3 months on Synthroid as a poor converter. My FT3 was far below reference (2.9 in a ref range of 3.5 to 6.5), and I was in nonthyroidal illness with a high RT3 of 33 (8-25) and a FT4 at mid range or higher. That kind of biochemistry is high risk (see graph below).

I would be doing nothing, like sitting as a passenger in a car, not feeling stressed, when all of a sudden I’d have a painful squeeze in one of my arteries or areas of my chest. Then my HR would spike up to 115 and be erratically jumping around with odd jaggedy shapes on the heartbeat visualization line as I put my finger on the phone and did a heart rate test.

There is a stereotype out there that heart problems are only seen in hyperthyroidism, and that’s simply not true. Being hypothyroid is not good for people with cardiovascular risks.

There is an “U shaped” risk profile — meaning that the risk is high on both ends, low thyroid hormone and high thyroid hormone. However, it matters what hormone you are low in.

Atrial fibrillation risk in particular

Being low in T3 is the biggest risk, followed by high-normal Free T4.

If you are taking a desiccated thyroid pill, the good news is that you likely do not have a “low T3 high T4” profile like many poor converters on LT4 monotherapy.

Instead, you’d likely have the reverse, with higher FT3 than FT4. Your ratio of FT3:FT4 is far healthier for the heart as long as you are not overdosing yourself.


Epinephrine, norepinephrine, and cortisol concentrations in cannulated seawater-acclimated rainbow trout (Oncorhynchus mykiss) following black-box confinement and epinephrine injection

Department of Biological Sciences, Simon Fraser University, Burnaby, British Columbia, Canada V5A 1S6.

Department of Biology, University of Ottawa, Ottawa, Ontario, Canada K1N 6N5

EVS Environment Consultants, 195 Pemberton Ave., North Vancouver, B.C. Canada V7P 2R4.

Department of Zoology, University of Cambridge, Downing Street, Cambridge CB2 3EJ

Department of Biology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4J1

Department of Biological Sciences, Simon Fraser University, Burnaby, British Columbia, Canada V5A 1S6.

Department of Biology, University of Ottawa, Ottawa, Ontario, Canada K1N 6N5

EVS Environment Consultants, 195 Pemberton Ave., North Vancouver, B.C. Canada V7P 2R4.

Department of Zoology, University of Cambridge, Downing Street, Cambridge CB2 3EJ


Trimeric Gs Protein Links β-Adrenergic Receptors and Adenylyl Cyclase

Having described which parts of GPCRs are necessary for interacting with ligand and their associated G protein, we now explain how G proteins function in signal transduction. Again, we focus our attention on β-adrenergic receptors, which are coupled to Gs, or stimulatory G protein. As noted above, the initial response following binding of epinephrine to β-adrenergic receptors is an elevation in the intracellular level of cAMP. The increase in cAMP results from activation of adenylyl cyclase, which converts ATP to cAMP and pyrophosphate (PPi). This membrane-bound enzyme has two catalytic domains on the cytosolic face of the plasma membrane that can bind ATP in the cytosol (Figure 20-15). The link between hormone binding to an exterior domain of the receptor and activation of adenylyl cyclase is provided by Gs, which functions as a signal transducer.

Figure 20-15

Schematic diagram of mammalian adenylyl cyclases. The membrane-bound enzyme contains two similar catalytic domains on the cytosolic face of the membrane and two integral membrane domains, each of which is thought to contain six transmembrane α (more. )

Cycling of Gsbetween Active and Inactive Forms

The G proteins that transduce signals from the β-adrenergic receptor and other GPCRs contain three subunits designated α, β, and γ. As explained earlier, these GTPase switch proteins alternate between an “on” state with bound GTP and an “off” state with bound GDP (see Figure 20-5a). For example, when no ligand is bound to a β-adrenergic receptor, the α subunit of Gs protein (G) is bound to GDP and complexed with the β and γ subunits (Figure 20-16). Binding of a hormone or agonist to the receptor changes its conformation, causing it to bind to the trimeric Gs protein in such a way that GDP is displaced from G and GTP is bound. The G·GTP complex, which dissociates from the G complex, then binds to and activates adenylyl cyclase. This activation is short-lived, however, because GTP bound to G hydrolyzes to GDP in seconds, leading to the association of G with G and inactivation of adenylyl cyclase. The G subunit thus relays the conformational change in the receptor triggered by hormone binding to adenylyl cyclase.

Figure 20-16

Activation of adenylyl cyclase following binding of an appropriate hormone (e.g., epinephrine, glucagon) to a Gs protein –𠁜oupled receptor. Following ligand binding to the receptor, the Gs protein relays the hormone signal to (more. )

Important evidence supporting this model has come from studies with a nonhydrolyzable analog of GTP called GMPPNP, in which a P – NH – P replaces the terminal phosphodiester bond in GTP:

Although this analog cannot be hydrolyzed, it binds to G as well as GTP does. The addition of GMPPNP and an agonist to an erythrocyte membrane preparation results in a much larger and longer-lived activation of adenylyl cyclase than occurs with an agonist and GTP. Once the GDP bound to G is displaced by GMPPNP, it remains permanently bound to G. Because the G · GMPPNP complex is as functional as the normal G · GTP complex in activating adenylyl cyclase, the enzyme is in a permanently active state.

Amplification of Hormone Signal

The cellular responses triggered by cAMP may require tens of thousands or even millions of cAMP molecules per cell. Thus the hormone signal must be amplified in order to generate sufficient second messenger from the few thousand β-adrenergic receptors present on a cell. Amplification is possible because both receptors and Gs proteins can diffuse rapidly in the plasma membrane. A single receptor-hormone complex causes conversion of up to 100 inactive Gs molecules to the active form. Each active G · GTP, in turn, probably activates a single adenylyl cyclase molecule, which then catalyzes synthesis of many cAMP molecules during the time Gs · GTP is bound to it. Although the exact extent of this amplification is difficult to measure, binding of a single hormone molecule to one receptor molecule can result in the synthesis of at least several hundred cAMP molecules per receptor-hormone complex before the complex dissociates and activation of adenylyl cyclase ceases.

Termination of Cellular Response

Successful cell-to-cell signaling also requires that the response of target cells to a hormone terminate rapidly once the concentration of circulating hormone decreases. Termination of the response to hormones recognized by β-adrenergic receptors is facilitated by a decrease in the affinity of the receptor that occurs when Gs is converted from the inactive to active form. When the GDP bound to G is replaced with a GTP following hormone binding, the KD of the receptor-hormone complex increases, shifting the equilibrium toward dissociation. The GTP bound to G is quickly hydrolyzed, reversing the activation of adenylyl cyclase and terminating the cellular response unless the concentration of hormone remains high enough to form new receptor-hormone complexes. Thus, the continuous presence of hormone is required for continuous activation of adenylyl cyclase. We discuss signal termination in more detail later in this chapter.


Contents

Catecholamines have the distinct structure of a benzene ring with two hydroxyl groups, an intermediate ethyl chain, and a terminal amine group. Phenylethanolamines such as norepinephrine have a hydroxyl group on the ethyl chain. [ citation needed ]

Location Edit

Catecholamines are produced mainly by the chromaffin cells of the adrenal medulla and the postganglionic fibers of the sympathetic nervous system. Dopamine, which acts as a neurotransmitter in the central nervous system, is largely produced in neuronal cell bodies in two areas of the brainstem: the ventral tegmental area and the substantia nigra, the latter of which contains neuromelanin-pigmented neurons. The similarly neuromelanin-pigmented cell bodies of the locus coeruleus produce norepinephrine. Epinephrine is produced in small groups of neurons in the human brain which express its synthesizing enzyme, phenylethanolamine N-methyltransferase [8] these neurons project from a nucleus that is adjacent (ventrolateral) to the area postrema and from a nucleus in the dorsal region of the solitary tract. [8]

Biosynthesis Edit

Dopamine is the first catecholamine synthesized from DOPA. In turn, norepinephrine and epinephrine are derived from further metabolic modification of dopamine. The enzyme dopamine hydroxylase requires copper as a cofactor (not shown in the diagram) and DOPA decarboxylase requires PLP (not shown in the diagram). The rate limiting step in catecholamine biosynthesis through the predominant metabolic pathway is the hydroxylation of L-tyrosine to L-DOPA. [ citation needed ]

Catecholamine synthesis is inhibited by alpha-methyl-p-tyrosine (AMPT), which inhibits tyrosine hydroxylase. [ citation needed ]

The amino acids phenylalanine and tyrosine are precursors for catecholamines. Both amino acids are found in high concentrations in blood plasma and the brain. In mammals, tyrosine can be formed from dietary phenylalanine by the enzyme phenylalanine hydroxylase, found in large amounts in the liver. Insufficient amounts of phenylalanine hydroxylase result in phenylketonuria, a metabolic disorder that leads to intellectual deficits unless treated by dietary manipulation. [ citation needed ] Catecholamine synthesis is usually considered to begin with tyrosine. The enzyme tyrosine hydroxylase (TH) converts the amino acid L-tyrosine into 3,4-dihydroxyphenylalanine (L-DOPA). The hydroxylation of L-tyrosine by TH results in the formation of the DA precursor L-DOPA, which is metabolized by aromatic L-amino acid decarboxylase (AADC see Cooper et al., 2002 [ citation needed ] ) to the transmitter dopamine. This step occurs so rapidly that it is difficult to measure L-DOPA in the brain without first inhibiting AADC. [ citation needed ] In neurons that use DA as the transmitter, the decarboxylation of L-DOPA to dopamine is the final step in formation of the transmitter however, in those neurons using norepinephrine (noradrenaline) or epinephrine (adrenaline) as transmitters, the enzyme dopamine β-hydroxylase (DBH), which converts dopamine to yield norepinephrine, is also present. In still other neurons in which epinephrine is the transmitter, a third enzyme phenylethanolamine N-methyltransferase (PNMT) converts norepinephrine into epinephrine. Thus, a cell that uses epinephrine as its transmitter contains four enzymes (TH, AADC, DBH, and PNMT), whereas norepinephrine neurons contain only three enzymes (lacking PNMT) and dopamine cells only two (TH and AADC). [ citation needed ]

Degradation Edit

Catecholamines have a half-life of a few minutes when circulating in the blood. They can be degraded either by methylation by catechol-O-methyltransferases (COMT) or by deamination by monoamine oxidases (MAO).

MAOIs bind to MAO, thereby preventing it from breaking down catecholamines and other monoamines.

Catabolism of catecholamines is mediated by two main enzymes: catechol-O-methyltransferase (COMT) which is present in the synaptic cleft and cytosol of the cell and monoamine oxidase (MAO) which is located in the mitochondrial membrane. Both enzymes require cofactors: COMT uses Mg 2+ as a cofactor while MAO uses FAD. The first step of the catabolic process is mediated by either MAO or COMT which depends on the tissue and location of catecholamines (for example degradation of catecholamines in the synaptic cleft is mediated by COMT because MAO is a mitochondrial enzyme). The next catabolic steps in the pathway involve alcohol dehydrogenase, aldehyde dehydrogenase and aldehyde reductase. The end product of epinephrine and norepinephrine is vanillylmandelic acid (VMA) which is excreted in the urine. Dopamine catabolism leads to the production of homovanillic acid (HVA). [9]

Modality Edit

Two catecholamines, norepinephrine and dopamine, act as neuromodulators in the central nervous system and as hormones in the blood circulation. The catecholamine norepinephrine is a neuromodulator of the peripheral sympathetic nervous system but is also present in the blood (mostly through "spillover" from the synapses of the sympathetic system). [ citation needed ]

High catecholamine levels in blood are associated with stress, which can be induced from psychological reactions or environmental stressors such as elevated sound levels, intense light, or low blood sugar levels. [ citation needed ]

Extremely high levels of catecholamines (also known as catecholamine toxicity) can occur in central nervous system trauma due to stimulation or damage of nuclei in the brainstem, in particular, those nuclei affecting the sympathetic nervous system. In emergency medicine, this occurrence is widely known as a "catecholamine dump".

Extremely high levels of catecholamine can also be caused by neuroendocrine tumors in the adrenal medulla, a treatable condition known as pheochromocytoma.

High levels of catecholamines can also be caused by monoamine oxidase A (MAO-A) deficiency, known as Brunner syndrome. As MAO-A is one of the enzymes responsible for degradation of these neurotransmitters, its deficiency increases the bioavailability of these neurotransmitters considerably. It occurs in the absence of pheochromocytoma, neuroendocrine tumors, and carcinoid syndrome, but it looks similar to carcinoid syndrome with symptoms such as facial flushing and aggression. [10] [11]

Acute porphyria can cause elevated catecholamines. [12]

Effects Edit

Catecholamines cause general physiological changes that prepare the body for physical activity (the fight-or-flight response). Some typical effects are increases in heart rate, blood pressure, blood glucose levels, and a general reaction of the sympathetic nervous system. [ citation needed ] Some drugs, like tolcapone (a central COMT-inhibitor), raise the levels of all the catecholamines. Increased catecholamines may also cause an increased respiratory rate (tackypnoea) in patients. [13]

Catecholamine is secreted into urine after being broken down, and its secretion level can be measured for the diagnosis of illnesses associated with catecholamine levels in the body. [14] Urine testing for catecholamine is used to detect pheochromocytoma.

Function in plants Edit

"They have been found in 44 plant families, but no essential metabolic function has been established for them. They are precursors of benzo[c]phenanthridine alkaloids, which are the active principal ingredients of many medicinal plant extracts. CAs have been implicated to have a possible protective role against insect predators, injuries, and nitrogen detoxification. They have been shown to promote plant tissue growth, somatic embryogenesis from in vitro cultures, and flowering. CAs inhibit indole-3-acetic acid oxidation and enhance ethylene biosynthesis. They have also been shown to enhance synergistically various effects of gibberellins." [15]

Catecholamines are secreted by cells in tissues of different systems of the human body, mostly by the nervous and the endocrine systems. The adrenal glands secrete certain catecholamines into the blood when the person is physically or mentally stressed and this is usually a healthy physiological response. [16] However, acute or chronic excess of circulating catecholamines can potentially increase blood pressure and heart rate to very high levels and eventually provoke dangerous effects. Tests for fractionated plasma free metanephrines or the urine metanephrines are used to confirm or exclude certain diseases when the doctor identifies signs of hypertension and tachycardia that don't adequately respond to treatment. [17] [18] Each of the tests measure the amount of adrenaline and noradrenaline metabolites, respectively called metanephrine and normetanephrine.

Blood tests are also done to analyze the amount of catecholamines present in the body.

Catecholamine tests are done to identify rare tumors at the adrenal gland or in the nervous system. Catecholamine tests provide information relative to tumors such as: pheocromocytoma, paraganglioma, and neuroblastoma. [19] [20]


Acetylcholine

The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system (PNS) and central nervous system (CNS) in many organisms including humans.

The term cholinergic is used to describe parts of the body that use acetylcholine in stimulation, and anticholinergic if it is used to decrease activity. Acetylcholine is the primary neurotransmitter in the parasympathetic nervous system. It also functions as a transmitter in the sympathetic nervous system. In the brain, acetylcholine functions as both a neurotransmitter and a neuromodulator. It is one of several chemicals that act to regulate diverse populations of neurons with effects that last significantly longer than the normal short-term nerve action.

In the central nervous system, acetylcholine has many important functions in the brain. For example, it has an important role in the enhancement of alertness when we wake up, in sustaining attention, and in learning and memory.

Acetylcholine wiki
Nerve cellChemical neurotransmitters
Index


Other Hormonal Controls for Osmoregulation

The renin-angiotensin-aldosterone system (RAAS) stabilizes blood pressure and volume via the kidneys, liver, and adrenal cortex.

Learning Objectives

Describe hormonal control by the renin-angiotensin-aldosterone system

Key Takeaways

Key Points

  • Renin, a hormone produced by the juxtaglomerular apparatus in the kidneys, converts angiotensinogen (which is made in the liver) to angiotensin I.
  • Angiotensin I is then converted to angiotensin II by the angiotensin converting enzyme (ACE), increasing blood pressure by causing vasoconstriction of the blood vessels.
  • Angiotensin II causes the release of aldosterone which is produced by the adrenal cortex it functions to maintain both sodium and water levels (osmotic balance) in the blood.
  • Angiotensin II also causes the release of antidiuretic hormone (ADH) which functions to conserve water in the body when volume is low it does this by inserting aquaporins in the collecting duct of the nephron to promote water reabsorption.
  • The atrial natriuretic peptide (ANP) is another hormone that is produced to function as a vasodilator and lower blood pressure by preventing sodium reabsorption.

Key Terms

  • renin: a circulating enzyme released by mammalian kidneys that converts angiotensinogen to angiotensin-I that plays a role in maintaining blood pressure
  • aquaporin: any of a class of proteins that form pores in the membrane of biological cells
  • angiotensin: any of several polypeptides that narrow blood vessels and thus regulate arterial pressure

Renin-Angiotensin-Aldosterone

The renin-angiotensin-aldosterone system (RAAS) is a hormone system that regulates blood pressure and water (fluid) balance. This system proceeds through several steps to produce angiotensin II, which acts to stabilize blood pressure and volume. Renin is secreted by a part of the juxtaglomerular complex and produced by the granular cells of the afferent and efferent arterioles. Renin is a circulating enzyme that acts on angiotensinogen, which is made in the liver, converting it to angiotensin I. Defective renin production can cause a continued decrease in blood pressure and cardiac output. After renin facilitates the production of angiotensis I, angiotensin converting enzyme (ACE) then converts angiotensin I to angiotensin II. Angiotensin II raises blood pressure by constricting blood vessels and also triggers the release of the mineralocorticoid aldosterone from the adrenal cortex. This, in turn, stimulates the renal tubules to reabsorb more sodium. Angiotensin II also triggers the release of anti-diuretic hormone (ADH) from the hypothalamus, leading to water retention in the kidneys. It acts directly on the nephrons, decreasing glomerular filtration rate. Thus, via the RAAS, the kidneys control blood pressure and volume directly. Medically, blood pressure can be controlled by drugs that inhibit ACE (called ACE inhibitors).

Renin-angiotensin-aldosterone system: The renin-angiotensin-aldosterone system increases blood pressure and volume. The hormone ANP has antagonistic effects.

Mineralocorticoids

Mineralocorticoids are hormones synthesized by the adrenal cortex that affect osmotic balance. One type of mineralocorticoid, known as aldosterone, regulates sodium levels in the blood. Almost all of the sodium in the blood is reclaimed by the renal tubules under the influence of aldosterone. As sodium is always reabsorbed by active transport and water follows sodium to maintain osmotic balance, aldosterone manages not only sodium levels, but also the water levels in body fluids. Aldosterone also stimulates potassium secretion concurrently with sodium reabsorption. By contrast, absence of aldosterone means that no sodium is reabsorbed in the renal tubules all of it is excreted in the urine. In addition, the daily dietary potassium load is not secreted retention of potassium ions (K+) can cause a dangerous increase in plasma K+ concentration. Patients who have Addison’s disease have a failing adrenal cortex and cannot produce aldosterone. They constantly lose sodium in their urine if the supply is not replenished, the consequences can be fatal.

Antidiurectic Hormone

Antidiuretic hormone or ADH (also called vasopressin) helps the body conserve water when body fluid volume, especially that of blood, is low. It is formed by the hypothalamus, but is stored and released from the posterior pituitary gland. It acts by inserting aquaporins in the collecting ducts, promoting reabsorption of water. ADH also acts as a vasoconstrictor (constricting blood vessels) and increases blood pressure during hemorrhaging.

Atrial Natriuretic Peptide Hormone

The atrial natriuretic peptide (ANP) hormone lowers blood pressure by acting as a vasodilator (dilating or widening blood vessels). It is released by cells in the atrium of the heart in response to high blood pressure and in patients with sleep apnea. ANP affects salt release because water passively follows salt to maintain osmotic balance, it also has a diuretic effect. ANP also prevents sodium reabsorption by the renal tubules, decreasing water reabsorption (thus acting as a diuretic) and lowering blood pressure. Its actions suppress the actions of aldosterone, ADH, and renin.