Noradrenaline: everything you need to know

We know that neurotransmitters are very important in several functions of both the central nervous system, including the brain, and the peripheral nervous system.

And, therefore, we have several posts about neurotransmitters, such as:  dopamine ,  adrenaline and serotonin .

Today, we are going to talk about norepinephrine, a neurotransmitter and a very important hormone in our body.

Who is norepinephrine?

The norepinephrine , also known as norepinephrine , or NOR, is a hormone / neurotransmitter present in our organism and that perform essential functions.

For example, when you are faced with a situation of fear or danger, a series of reactions occurs in our organism, in order to prepare our body to face such a situation.

These reactions are mediated by substances such as norepinephrine, which acts on the well-known sympathetic autonomic system.

Who produces norepinephrine?

Norepinephrine is produced in different locations: mainly in noradrenergic neurons and in the adrenal medulla , therefore, it is a neurotransmitter and hormone.

The noradrenergic neurons are the major source of noradrenaline in our body. It is produced from tyrosine and, after some reactions, is then formed, as seen in the image below.

Norepinephrine is released into the synaptic cleft by noradrenergic neurons and acts on receptors, thus promoting direct sympathetic stimulation.

Figure 1: Noradrenaline Synthesis

Although the production is mainly in the noradrenergic neurons, there is also the production of noradrenaline in the medulla of the adrenal gland . When there is a stimulus, that is, a situation of fear / danger, it stimulates the adrenal gland to stimulate the catecholamines (adrenaline, about 80%, and norepinephrine, about 20%).

This norepinephrine is released into the circulation and acts on several receptors. The advantage of noradrenaline as a hormone, released by a gland in the circulation and performing its effects at a distance, is that this action lasts longer than direct sympathetic stimulation.

Norepinephrine storage

The norepinephrine produced in noradrenergic neurons is stored in vesicles in the neuron itself , and this storage is maintained by the vesicular monoamine transporter.

Noradrenaline release

The release of NOR vesicles occurs when a nervous impulse arrives and, thus, the influx of calcium occurs and the consequent increase in intracellular calcium, and this stimulates a series of reactions so that the vesicles are released (you can read more about the synapses and the process of releasing neurotransmitters at chemical synapses ).

End of norepinephrine effect

For the norepinephrine effect to end, it must be captured and degraded.

When we think of norepinephrine released by norepinephrine neurons, which acts there, on the postsynaptic receptors, this capture occurs mainly by the norepinephrine transporter (NET) present in the neuronal membrane, selective for norepinephrine, and which makes this capture quickly. .

After being captured, norepinephrine is metabolised, mainly, by the MAO enzyme (monoamine oxidase), an enzyme that performs catecholamine metabolism and is mainly present in norepinephrine nerve endings.

The final product of the degradation is 3-methoxy-4-hydroxyphenyl glycol and this, after being conjugated, is released into the urine in the form of vanillmandelic acid (VMA).

When we think of circulating norepinephrine, the one released by the adrenal gland medulla , the main responsible for the capture is the extraneuronal monoamine transporter (EMT), present in non-neuronal cell membranes, and the metabolism is by MAO , and also by the enzyme COMT (catechol-O-methyl transferase), and the final product is the same.

Noradrenaline and Sympathetic Nervous System

Norepinephrine is the neurotransmitter involved in direct activation of the sympathetic autonomic nervous system. It is produced in noradrenergic neurons, and when released, it acts on post synaptic receptors, producing a series of important effects on the fight or flight response.

Norepinephrine released into the bloodstream by the adrenal medulla acts as a hormone, producing the same effects on Organs effector organs, the sympathomimetic effects.

But what is this system? The autonomic nervous system consists of an efferent system, which stimulates the striated cardiac muscle, smooth muscle and glands.

This stimulus is involuntary – you cannot interfere with the speed at which your heart “beats”, for example. The performance of this system is made possible by the action of two neurons, which will unite the central nervous system to the effector organ (which can be, striated cardiac muscle, smooth muscle or glands).

These neurons are known as pre- and post-ganglionic. Pre-ganglion neurons are located in the thoracolumbar region.

The autonomic nervous system, both sympathetic and parasympathetic, acts in our body in balance. However, throughout the day and in our activities, one can prevail over the other, and in situations of danger or fear, the action of the sympathetic system predominates.

This action is mediated by neurotransmitters, with norepinephrine being the most important of them, as we mentioned earlier.

And what are the functions of norepinephrine acting on the sympathetic nervous system?

First information you need to know is the receivers NORA operates on: α1, α2 and  β 1. Now let’s talk about NORA’s role in each of these receivers.

Noradrenaline in α1

When acting on α1, one of the most important actions and one that you cannot forget is that NORA promotes an important vasoconstriction and, thus, can cause an important increase in blood pressure .

This vasoconstriction is both arterial, leading to an increase in peripheral vascular resistance (PVR), and venous, thus increasing venous return.

There are effects on the bronchi as well, where NORA binds to the α1 receptor and reduces bronchial secretion , which allows more air to pass through.

There is also contraction of the sphincters of the gastrointestinal tract (TGI), reducing the emptying of the TGI.

There is also a contraction of the bladder sphincter and a contraction of the ureter , which leads to reduced urination.

And the glands? They suffer from the effect of vasoconstriction and, in general, reduce their secretion, and, another change, is the increase in the concentration of secretions.

Thus, sweat, for example, becomes more viscous and odorous, and occurs mainly on the extremities (hands and feet), face, armpits, and genital region.

There is also the contraction of glands present in the male reproductive system, such as the prostate and seminal vesicles, and this contraction causes ejaculation (penile erection is mediated by the action of another system, which is the opposite, the parasympathetic system ).

Α2 norepinephrine

When NORA acts on α2, it can act both in the presynaptic region and in the post-synaptic region.

The most important action occurs in the presynaptic region, where NORA binds to α2 and promotes inhibitory self-regulation, that is, it reduces the release of neurotransmitters and, in this case, reduces the release of norepinephrine .

Post-synaptic effects may also be noted, but these are less important. These effects are vasoconstriction and reduced insulin release (which leads to increased blood glucose).

Noradrenaline in β 1

NORA also acts on β 1 receptors , leading to cardiac stimulation.

By acting on this receptor present in the heart, NORA promotes increased inotropism (increased contraction force), increased heart rate and increased conduction speed.

All of this leads to an increase in cardiac output (Cardiac Output = Stroke Volume x Heart Rate) and an increase in blood pressure (Arterial Pressure = Cardiac Output x Peripheral Vascular Resistance).

An important piece of information is that NORA acts on these receptors, but there are other substances, such as adrenaline, that stimulate these receptors more intensely.

NORA also binds to β 1 receptors in the justaglomerular apparatus, located in the kidneys, which, by means of NaCl sensors, promote the control of renal blood flow and blood volume in general.

When stimulating this receptor, there is an increase in renin secretion , and renin activates the renin angiotensin aldosterone system, and what occurs is vasoconstriction mediated by the action of angiotensin II and the action of aldosterone, which leads to sodium and water retention, promoting an increase in blood volume.

And another action when acting on β 1 is to reduce intestinal motility (which is important because, remember, the sphincters are closed).

Summary of actions on the sympathetic nervous system :

Table 1: Actions of noradrenaline of the sympathetic nervous system

Noradrenaline and the Sleep Wake Cycle

The sleep-wake cycle , in which we spend an awake period and another sleeping period, has several mechanisms, several substances, that regulate it, some of which stimulate sleep while others stimulate wakefulness.

Norepinephrine is part of a system involved with wakefulness, the ascending monoaminergic activating system , a system composed of adrenergic monoamines such as adrenaline, norepinephrine , histamine and serotonin, and these perform cortical activation and induce wakefulness.

Noradrenaline and the Depression

Another function of noradrenaline is to participate in brain biochemistry, along with other neurotransmitters, such as serotonin and dopamine. These substances, in their normal concentrations, maintain our normal reward system .

A deregulation of this system, due to the reduction of some of these substances, can cause disorders such as depression.

The fall in noradrenaline in the brain nerve endings may be responsible for depressive conditions.

When the neurotransmitter that is reduced is norepinephrine, some treatment lines for depression involve inhibition of the norepinephrine transporter: NET, remember it? !!

When it is inhibited, neuronal reuptake does not happen and, thus, the effect is not finished, because noradrenaline remains in the synaptic cleft, interacting with the receptors.

Clinical use of noradrenaline

Noradrenaline, due to its many effects, can be used to work around some emergency situations.

A use of NORA in the emergency is in hyperdynamic shocks , also called “hot”, where the PVR is low . Subtypes of these shocks are septic shock and neurogenic shock. The septic shock or inflammatory, progresses with vasodilation, hypovolemia and myocardial depression.

But the neurogenic shock is given by the interruption of sympathetic efferent pathways to the vessels and the heart, that is, that acting “baseline” of the sympathetic system fails to occur and thus there is an intense arterial vasodilation, reducing RVP; venous vasodilation, reducing venous return; in addition to bradycardia and reduced cardiac contraction strength.

In these cases, norepinephrine is used in order to increase PVR and blood pressure, in order to maintain blood flow to noble organs (heart and brain).

NORA can also be used in circulatory shock , caused by the loss of large blood volume. In these cases, NORA is used after volume replacement, in order to perform vasoconstriction, to maintain perfusion and blood pressure.

Our conversation about norepinephrine is coming to an end. I hope you have learned a little about this substance so important for the homeostasis of our organism and to react to situations that may occur, which require an increase in various activities and functions of our organism …

 

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