Many professional athletes aim at excelling in their profession sport by increasing their performance through the use of illegal drugs that alters the natural rhythm of the human body, e.g. metabolism. The aim of this article is to determine the properties of Adrenaline (Epinephrine) and Noradrenaline (Norepinephrine) occurring naturally in the human body, their effect on overall metabolism and if using any sympathomimetic agents produce any of the same effects witnessed to occur naturally in the body in times of distress that could possibly enhance sport performance significantly through use.
Functioning as both hormones and a neurotransmitter molecule[1,2,3,4], Adrenaline and Noradrenaline are catecholamines[2,5,6] found in the body that act as non-selective agonists for stimulating all Î±- & Î²-Adrenergic receptors of target tissues.[4,5,6,8] Their task as sympathomimetic agents include the regulation of the sympathetic division of the autonomic nervous system[9,10] by activating the Adrenergic receptors on the cell surface to different extents, due to variations in binding affinity for each receptor. Adrenaline has the highest affinity for Î²2-receptor binding[11,12] with equal or lower binding as compared to Noradrenaline for the other Adrenergic receptors (Table 1). They are also responsible for the well known fight-or-flight reaction.
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Table 1. Binding affinity to Î±- & Î²-Adrenergic receptors by Adrenaline (E) and Noradrenaline(NE)
Both molecules have the same structure, differing only at the N-atom where Adrenaline has a methyl group bound (Figure 1). Both molecules are produced in the specialized neuroendocrine tissue, the Adrenal medulla, on the kidneys and get secreted through the adrenal glands into the bloodstream. Adrenaline is synthesised from Noradrenaline and synthesis is restricted to the Chromaffin granules found in the Adrenal medulla as this is the only location of the special enzyme, phenylethanol N-methyltransferase[3,5,10,36].
Some neurons, e.g. postganglionic sympathetic neurons, produce Noradrenaline, functioning as signal molecules at neuroeffector junctions.[5,10,14]
The synthesis of Adrenaline and Noradrenaline occurs through a 4 step biosynthesis pathway that is shared by all the other catecholamine hormones (Figure 2). Tyrosine is widely accepted as the starting point of synthesis, but in cases where Tyrosine levels are too low Phenylalanine can be converted to Tyrosine by the enzyme phenylalanine hydroxylase .
Figure 1. The chemical structures of Adrenaline(left) & Noradrenaline(right) indicating the extra CH3 group attached at the N-atom of Adrenaline.
Regulation of Synthesis
Studies have determined that the first step in synthesis, Tyrosine hydroxylation by tyrosine hydroxylase, is the rate limiting step in catecholamine synthesis[18,19].
Many theories have been formulated as to how enzyme activity is regulated, but experimental evidence point to activation by several protein kinases as the major control mechanism. Other theories with little or no evidence, due to difficulty and limitations in the determination of catecholamine sample concentrations, include competitive end product feedback inhibition (enzyme activation stimulated by release of Noradrenaline) and second messenger systems.
The four protein kinases found to be associated with regulation of catecholamine synthesis are Protein Kinase A(PKA), Protein Kinase C(PKC), Protein Kinase II(PKII)[25,26] and cGMP-dependant Protein Kinase. Phosphorylation by these kinases at specific serine residues, Ser19 and Ser40, activates the enzyme tyrosine hydroxylase .
Of the four kinases PKA, PKC and cGMP-dependant Protein Kinase are activated by presynaptic receptors, causing increased affinity for cofactors and decreased inhibition by catechols. The influx of Ca2+ during release of Noradrenaline (Figure 3) stimulates PKII, the Ca2+/Calmodium-dependant kinase, causing a rapid response to brief activation of Tyrosine hydroxylase with an increased Vmax. The changes induced by each protein kinase is illustrated in table 2.
Table 2. Effects of Protein Kinases A, C, II & cGMP-dependant Protein Kinase on Tyrosine Hydroxylase
Effect of Phosphorylation
â†“Kmfor cofactors; â†‘KiCatechols
â†“Kmfor cofactors; â†‘KiCatechols
â†“Kmfor cofactors; â†‘KiCatechols
Figure 2. The synthesis of the catecholamine hormones Dopamine, Epinephrine and Norepinephrine
Mechanism of Action & Physiological Response
As mentioned previously the main function of Adrenaline and Noradrenaline secretion is due to a direct response to danger, the well known survival mechanism; the fight-or-flight response
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During the fight-or-flight response as a response to certain stressors, be it physiological stressors: hypoglycaemia, exercise, heart attacks, haemorrhage or emotional stressors: stress, anger or fear[5,14] , high amounts of both adrenaline and noradrenaline gets released in the body by the adrenal glands and neurons. The differences are that the adrenal glands secrete 80% adrenaline and 20% noradrenaline into the blood[3,14] while sympathetic neurons only secrete noradrenaline as a neurotransmitter.
Within seconds of sensing danger the Amygdala in the CNS triggers the signal for release of Adrenaline and Noradrenaline via the Sympathetic neurons which stimulate the Adrenal glands and target tissues. Sympathetic neurons at the neuroeffector junction secrete Noradrenaline as signalling molecules (Figure 3) whereas sympathetic neurons affecting the Adrenal medulla secrete Acetylcholine. During high stimulation, Noradrenaline can also diffuse from the neurojunction to the blood.
Figure 3. Sympathetic neuron terminal at the neuroeffector junction of a targeted tissue
After release into the bloodstream and at neuroeffector junctions, Adrenaline and Noradrenaline bind to all the Adrenergic receptors on target tissues and organs. Binding is achieved either through interaction of the amine group with aspartate residues in the third transmembrane domain, hydrogen bonds between serine residues in the fifth transmembrane domain or aromatic amino acid residues forming Ï€-bonds in the sixth transmembrane domain.(Figure 4)
Figure 4. Binding of a Noradrenaline (top molecule) to the different residues in the transmembrane domains of the Adrenergic receptors
Binding to the Adrenergic receptors activates the G-coupled proteins in the cell membrane which in turn activates the Adenyl cyclase signalling pathway. Intracellular ATP gets converted to cAMP, a second messenger, that activates the Protein Kinase cascade by binding Protein kinase A and activating it. Depending on the target tissue Protein kinase A then further phosphorylates the following protein in the cascade and produces a cellular response. Phosphodiesterase degrades second messenger cAMP and terminates further activation of the Protein Kinase cascade. (Figure 5)
Figure 5. The activation of a cellular response due to binding of ligands to the Adrenergic receptors
After the release of Adrenaline and Noradrenaline into circulation and activation of the signalling pathways due to binding of the Adrenergic receptors, the main effects on metabolism induced by adrenaline and noradrenaline in the body are:
â†‘ Cardiac output : â†‘ Heart rate, Blood pressure [3,5,14]
â†‘ Blood flow: Skeletal muscle, heart & brain
â†“Blood flow: Peripheral tissues, skin/mucus membranes/digestive track.[3,14]
â†‘ Glycogenolysis in the liver[6,7,12]
â†‘ Blood glucose concentration
â†‘ O2 supply, due to bronchiole dilation
Both molecules have similar effects on the body, but the main targets for Adrenaline are the Î²2-receptors of the lungs, heart and muscles.[10,35] Noradrenaline is also different in it being a psychoactive hormone, affecting the CNS and increases alertness, affects mood and behaviour.[3,12]
Figure 6 and 7 illustrate the three mechanisms by which signal termination is achieved. These are recycling, degradation of diffusion away from the receptor. Mostly 90% of Noradrenaline is taken back up by high affinity membrane carriers at the neuron terminal[13,15,36], but can be blocked by substrates like cocaine (figure 3). Monoamine oxidase on the membrane of mitochondria and catechol-O-methyltransferase degrade the catecholamines into inactive metabolites and gets transported.
Figure 6. Sympathetic neuron illustrating signal termination via re-uptake and degradation.
Figure 7. Degradation of the catecholamines, Epinephrine and Norepinephrine, by Monoamine oxidase and Catechol-O-methyltransferase.
Stimulants in Sport: Analogues & Mimetics
Chemical compounds in this class used as drugs by athletes to achieve the same activation of the Adrenergic receptors as the catecholamines, by either by stimulating the sympathetic nervous system directly or indirectly, are classified as stimulants. Mimetics mimic the action of catecholamines whereas analogues are synthetically produced to structurally look like the original molecule..
One of the Methylxanthines (Figure 8), caffeine is one of the most daily used drugs that stimulate the CNS, heart, lungs and relaxes the smooth muscles of the bronchioles. Its chemical structure is similar to that of adenosine (e.g. cAMP), sharing the same fused carbon/nitrogen rings and electrostatic potential, it acts as a competitive inhibitor of cAMP-binding by being a non-selective antagonist that binds the adenosine receptors without activation[40,41,42].
Catabolism of caffeine by cytochrome P450 found in the liver results in the formation of the dimethylxanthines metabolites theophylline, theobromine and paraxanthine. All three these metabolites have the same stimulation effects as caffeine.
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Figure 8. The chemical structures of the Methylxanthines resembling Adenine
Its mechanism of action for stimulating the adrenergic receptors is indirect through inhibition of cAMP breakdown by e.g. phospodiesterase (figure 5)[40,43] thus promoting prolonged Protein kinase A activation by increased second messenger cAMP concentrations which induces the cellular response. Caffeine consumption also directly increases adrenaline secretion into the blood. The use of caffeine will thus enhance the effects of the adrenaline and noradrenaline signalling and response.
These are drugs that are analogues of adrenaline and has the same ability to stimulate the sympathetic nervous system. Examples of commonly used drugs include methamphetamine(Tik) and Ephedrine(Figure 9)
Figure 9. The chemical Structures of the Amphetamines compared to Adrenaline
Amphetamine and methamphetamine are powerful CNS stimulators and affects both the Î±- & Î²-Adrenergic receptors indirectly by causing the release of noradrenaline which triggers the sympathetic nervous system and these effects lasts longer than that of adrenaline..
Ephephrine affects the sympathetic nervous system directly by being a sympathomimetic agent that bind and stimulate both Î±- & Î²-Adrenergic receptors. The duration of stimulation to enhance cardiovascular output by Ephedrine is considered to be up to 10x longer than that of adrenaline and the drug stimulates the CNS to a greater extent.
Effects of Stimulants on Sport Performance
In sport the focus lies on the stimulation of Î²2-Adrenergic receptors in the human body, as these receptors mainly target the heart, muscles and lungs. Athletes hope to potentially improve their overall performance through the usage of these drugs that alter the natural rhythm of their metabolism. Their attention is drawn to anabolic gains caused by the inhibition of protein degradation[48,49,50], anti-inflammatory properties, increased cardiac output, the bronchodilator effect that increases air intake and exchange and increased muscle contraction speed and power output. 
Illegal Analogs & Performance
The usage of stimulants are found in sports where short explosive bursts are needed, though studies have shown that the gains from using sympathomimetics or analogues are minimal[46,51]. Thought to be effective in sports where short quick bursts of energy and power are needed, the short lasting effect of these agents used by trained athletes did not significantly improve sport performance.
In one study the effect of amphetamine was tested for enhancing sport performance in different exercises. The results(Figure 10) concluded that there was no significant increase in sport performance. Another study found the gains from using amphetamines to be 0.59%-1.16% for swimming, 1.5% for running and 3%-4% for power sports.
Figure 10. The study showing the results on athletic performance after addition of Amphetamines
Other studies have found that the usage of super doses (800Âµg) of salbutamol caused but a small endurance increase of cyclists whereas the same dose had no effect on the performance of triathletes. Swimmers administered these drugs just before the race where able to save a small amount of race time due to increased respiratory function.
Clenbuterol and Zilpaterol are known to have anabolic effects through the inhibition of protein degradation. This is accompanied by reduced body fat due to an increase in muscles mass, but negative side effects from using these drugs are increased fatigue.
Caffeine & Performance
Caffeine related studies showed that exercise times was increased by 19% after high doses in endurance sports as well as an increase of 44% in running pace in runners and 51% increase in the endurance of cyclists after caffeine doses of 9mg/kg.
Dangers vs. Gains
Amphetamines and other sympathomimetics can have very adverse effects on the human body. These include addiction, loss of judgement and possible injury, cardiac arrhythmias and cardiac damage and cerebral haemorrhage with increased doses.
As stated, the aim of this article was to determine the properties of Adrenaline and Noradrenaline and if using any sympathomimetic agents produce any of the same effects witnessed to occur naturally in the body that could possibly enhance sport performance significantly.
Adrenaline and noradrenaline are hormones in the body that produce the fight-or-flight response. During this response there is an increase in cardiac output due to an increase in heart rate and blood pressure. Glucose gets released from liver glycogen stores and lipolysis in adipose tissues release FFA into the bloodstream. Bronchioles in the lungs dilate and blood flow containing high amounts of fuel molecules gets transferred to the skeletal muscles, heart and brain.
This is the metabolic state athletes attempt to produce by using the illegal analogues as it can in theory improve their sport performance, though experimental data has proved that there is no significant increases in performance by using adrenaline analogues. A possible explanation for these results could be that during the endurance sporting events secretion of naturally occurring adrenaline is already at a maximum high, binding all the receptors and causing the maximal cellular response. Increasing these concentrations can't further enhance the stimulating effect to increase performance, but as the results for caffeine studies has shown, performance is somewhat achieved. Possibly due to the prolonged duration of stimulation caused by caffeine.
Also the duration of the effects of the "adrenaline rush" is short lived. This could be a possible explanation why the test athletes in the power sports and swimming events showed the increase of performance right after receiving the drugs whereas the prolonged endurance test athletes reaped minimal benefits. Though small as they may be, Using these drugs is illegal as it may give an unfair advantage to the athlete, e.g. increased muscle mass as a result of the anabolic effects gained from using them.
It is therefore my opinion that athletes should try and focus on being the best they can be, though not as fast or strong as that somebody else, since there will always be someone better, and be proud of what they achieved. Not many people can say they achieved their maximum potential. The dangers of using these drugs far outweigh the minimal benefits gained from them and in the long-term will cause detrimental effects to the body since athletes will need to overdose with increasing tolerance to these drugs.