Beta agonist application in fish

Rainbow trout
Neurohormone

@IBNU SAHIDHIR
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www.artaquaculture.blogspot.com

1. Introduction

2. Beta agonist ?

3. Action mechanisms ?

4. Application in aquaculture ?

5. Inconsistency of results and side effect ?

6. Conclusion

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HEALTH: FEED EFFICIENCY:
Reduce free radical
Increase muscle mass
Increase glucose intake
PRODUCT: Increase sparing protein
Reduce rate of fish rancidity
Increase protein quality Reduce feed cost

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LIPOLYSIS LYPOGENESIS

Stress response mimic

Catecholamines mimic = beta agonist

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1. Stress response ?
2. Catecholamines ?
3. Beta Agonist ?
4. Beta Agonist receptor ?
5. Action Mechanism ?

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Fight or Flight
A threat like a predator or a mating competitor, animal can respond in two ways. It can
either defend itself, its mate and offspring, or it can flee for safety, hoping to elude a more powerful
foe. This behavioural response to stress was termed the ‘fight or flight’ syndrome by W.B. Cannon in
1932.

This self-preservation response is accompanied by an array of acute physiological
adaptations that mobilize energy and provide it to organ systems involved in this reflex. The
sympathetic portion of the autonomic nervous system and the adrenal glands are largely responsible
for changes in the cardiovascular, respiratory and gastrointestinal systems that mediate the response
to stress. These processes are stimulated by the release of catecholamines such as norepinephrine, a
neurotransmitter in the SNS, and the adrenal gland hormone epinephrine.

This results in the mobilization of lipids and glycogen and their catabolism by lipolysis and
glycogenolysis to provide energy to the animal. In addition, coordinated responses in the
cardiovascular system occur. The rate and strength of heart contractions are increased and
vasoconstriction of blood vessels reduces blood flow to the gastrointestinal tract. Concomitantly,
vasodilation of blood vessels increases blood flow to skeletal muscle, the heart and the brain. In
total, these physiological adaptations ensure that organs involved in response to ‘fight or flight’ stress
receive the energy needed for optimal function.

While one might properly assume that a response to acute stress that involves the
mobilization and use of body energy stores is a process that is counter to the use of energy for
growth, nevertheless, it has been recently found that catecholamine derivatives are useful as agents
to alter food animal body composition and improve production efficiency.
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Hossner 2005. Hormonal Regulation of Farm Animal Growth

1. Stress response ?
Physiological adaptations in stress for organs optimal function

Increase blood plasma glucose
1. Breakdown lipids and glycogen
2. Heart contractions increased
3. Increases blood flow to skeletal muscle, the
heart and the brain.

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“Catecholamines released by adrenal medulla as stress response.”

Catecholamines: epinephrine, norepinephrine

Fight or Flight
1. Heart beat increase
2. Blood flow increase
3. Trigger releasing glucose
4. Increase brain oxygen supply

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Neuroendocrinology of catecholamines
The autonomic nervous system is part of the peripheral nervous system that lies
outside of, but arises from the CNS. The autonomic nervous system is responsible for the
innervation of the skin, visceral organs, blood vessels, smooth muscles and glands of the body and
regulates the involuntary reactions that characterize the functions of these tissues. The autonomic
nervous system is divided into two portions, the SNS and the parasympathetic nervous system.
Parasympathetic neurones originate in the cranio-sacral regions of the spinal cord, while those of
the SNS arise from the thoracolumbar regions of the spinal cord. In contrast to the somatic
nervous system, in which a single continuous nerve fibre extends to innervate muscle, neurones
from the autonomic nervous system form synapses once they have left the CNS.

After leaving the spinal cord, the preganglionic neurones for the autonomic nervous
system terminate in ganglia, clusters of neuronal cell bodies where the synapses occur. The nerve
fibres then continue on to their target tissues as postganglionic neurones. Sympathetic ganglia lie
close to the spinal cord in a distinct chain of neurones, the sympathetic trunk, or they are located
halfway between the spinal cord and the affected organ. In contrast, parasympathetic ganglia are
located within the walls of the affected organ, characterized by a short postganglionic fibre. In
both pre- and postganglionic parasympathetic neurones acetylcholine acts as the
neurotransmitter. On the other hand, the SNS uses acetylcholine as the preganglionic
neurotransmitter but the postganglionic neurotransmitter is norepinephrine, a catecholamine.


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Neuroendocrinology of catecholamines
The adrenal medulla is a specialized modification of the SNS and is part of the
sympathoadrenal system. This system includes the SNS and the catecholamine hormone secretions
of the adrenal medulla. Like the pituitary gland, the adrenal gland is derived from more than one
embryonic source. The outer cortex, source of the glucocorticoids, is of mesodermal origin. The
inner medulla, which synthesizes and secretes the catecholamines, is derived from embryonic
neural crest cells, which arise near the spinal cord.

The preganglionic neurones that regulate the adrenal medulla arise from the spinal cord
and terminate in the adrenal medulla. Unlike other sympathetic nerves, however, there is no
postganglionic nerve fibre and the adrenal medulla, instead, secretes its products, the
catecholamine hormones, directly into the bloodstream. The primary catecholamine produced and
secreted by the adrenal medulla of most mammals is epinephrine, a hormone closely related to
norepinephrine, the neurotransmitter of postganglionic sympa-thetic nerves. Epinephrine is
released in response to preganglionic nerve stimulation from the SNS and influences adrenergic
receptors throughout the body.

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Neurohormones-producing tissues

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Group of nerves

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Types of catecholamines hormone
In mammals, the most abundant catecholamines are adrenaline (also called
epinephrine), noradrenaline (norepinephrine) and dopamine. The catecholamines are amino
acid derivatives that are synthesized from tyrosine. This involves an initial hydroxylation of
tyrosine to form dihydroxyphenylalanine (DOPA), followed by a decarboxylation resulting in
dopamine formation. Hydroxylation of dopamine produces norepinephrine, which is then
methylated to form epinephrine. The presence of the amino methyl group on epinephrine
distinguishes it from norepinephrine (the pre-fix ‘nor’, means ‘without’).

Epinephrine, norepinephrine and dopamine are found in the circulation in very low
levels which are quite variable between species. Although norepinephrine and dopamine are
found in the circulation, they are primarily neurotransmitters that function within the nervous
system. Very high concentrations of norepinephrine are needed to induce a response in
endocrine target organs. For example, in humans, norepinephrine concentrations above 1800
pg/ml are needed to stimulate metabolic and cardiovascular events. Dopamine acts primarily
within the brain, via specific dopamine receptors and is not considered a hormone. Circulating
concentrations of norepinephrine and dopamine are, in most mammals, considered to result
from ‘spillover’ into the blood during sympathetic activation.

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Cathecholamines and instant energy
Catecholamines function as the primary mediators of the response to real or
perceived stress from internal or external sources. The direct connection of the adrenal medulla
to the CNS means that these compounds are rapidly released in response to external stressors.
The release of catecholamines from the adrenal medulla serves to integrate the CNS and SNS
with the endocrine system.

In response to events that reduce blood glucose, such as sudden stress, fasting and
exercise, epinephrine acts to rapidly mobilize energy reserves by increasing glycogenolysis and
gluconeogenesis in the liver and glycogeno-lysis in skeletal muscle. This results in a rapid
increase in blood glucose. Epinephrine treatment also suppresses pancreatic insulin release and
induces glucagon secretion. These effects combine to assure that a high level of blood glucose is
maintained for use as an energy source. In addition, lipolysis of adipose tissue is enhanced,
providing free fatty acids and glycerol that can be metabolized for energy production or used to
produce additional glucose by the process of gluconeogenesis.


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Dopamine, norepinephrine/noradrenalin,
epinephrine/adrenalin

Terbutaline

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Glucogenesis
Beta oxidation Glycolisis
Glycogenolisis and
Lipolysis (Glycogen breakdown)
Lipogenesis
(lipid breakdown)

Beta agonist Chatecholamines
=
(Salbutamol, terbutaline, clenbutarol) (adrenalin, noradrenalin)

Approved for bronchodilatation and tocolysis agents

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Beta agonist

Receptor Beta

Lipid
Glycogen
Free fatty acid
Plasma glucose

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Epinephrine action mechanism
K.L. Hossner 2005. Hormonal Regulation of Farm Animal Growth

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1. Terrestrial animal performances
2. Fish performances
3. Evidences in metabolites:Fatty acid, Glycerol, Glucose,
4. Evidences in gene-related actions

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2. Performances of fish

“Ractopamine have no main effects on growth”
Moccia et al, 1998 @IBNU SAHIDHIR
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“Ractopamine have no main effects on carcass composition”

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Evidence in Action Mechanisms

1. Energy Fatty acid Beta oxidation
Lypolisis
Glycerol Energy
Glycogenolisis
Glucose Glycolysis

2. Structures
Lipogenesis Protein synthesis

Protein degradation

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1. Increase free fatty acid plasma
(Dunshea, 1993)

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2. Increase glycerol release (Dunshea, 1993)

Epinephrine

Clenbuterol

Concentration (M)

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3. Increasing plasma glucose
in rainbow trout fed ractopamine
(Vandenberg, 1998)

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4. Activity in gene level relate to protein turnover
The three major proteolytic pathways (calpains, cathepsins , proteasome)
vs
Synthesis of myofibrillar proteins MCH and the cytoskeletal protein β-actin

1) The calpain/calpastatin proteinase pathway :
the catalytic subunits of μ-calpain (Capn1) and m-calpain (Capn2), the calpain
regulatory subunit (cpns), the calpastat in long isoform (CAST-L ) and the
calpastatin short isoform (CAST-S)

2) The proteasome multicatalytic pathway:
proteasome subunits alpha, beta, N3 and regulatory subunit

3) The cathepsin proteolytic pathway: cathepsins -L and -D;

4) The BAA receptor β2-AR, ACase , ATF-1, s-MHC, f-MHC and β -actin.

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“Reducing protein degradation
by increasing CAST (calpastatin) activity
(reduce calpain proteosome)”

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4b. Proteolytic activity decrease

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Cathepsin proteosome activity insignificant different

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“Increase protein synthesis”

MHC = major histocompatibility complex
AR = adrenergic receptor
Acase = adenylate cyclase
ATF-1 = activating transcriptional factor 1

“No shift to muscle type”

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Inconsistence denotes variable levels of effects of BAAs
depending on:
1. Experimental animals (mammals > poultry > fish)

2. Age (older > younger)

3. Dose (optimum)

4. Length of the treatment (optimum)

5. Type of beta agonist (beta 1, beta 2, strong attach to receptor)

6. Feed composition (protein level)

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Intoxicity Clenbuterol in Portugal

Barbosa et al (2005)

1. Gross tremors of the extremities

2. Tachycardia
A heart rate that exceeds the normal range for a resting heart rate
( inactive or sleep)

3. Nausea
Discomfort in the upper stomach with an involuntary urge to vomit

4. Headaches

5. Dizziness
An impairment in spatial perception and stability

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1. Beta agonist increase releasing energy storage

2. Beta agonist reduce protein catalysis and induce protein synthesis

3. Although beta agonist proven effective in terrestrial animal, it had
not improved yet rainbow trout performance

4. Consumption of product with residual beta agonist can make
health problem

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Metabolic activity of beta agonist
1. Anderson, D.B., D.E. Moody, and D.L. Hancock. 2005. Beta Adrenergic Agonists (WG Pond and AW Bell, Eds.).
Encyclopedia of Animal Science 1: 104–107.
2. D’Mello, J.P.F. 2000. Farm animal metabolism and nutrition. CABI.
3. Dunshea, F.R. 1993. Effect of metabolism modifiers on lipid metabolism in the pig. J ANIM SCI 71(7): 1966–1977.
4. Reeds, P.J., and H.J. Mersmann. 1991. Protein and energy requirements of animals treated with beta-adrenergic
agonists: a discussion. J ANIM SCI 69(4): 1532–1550.
5. Smith, D.J. 1998. The pharmacokinetics, metabolism, and tissue residues of beta-adrenergic agonists in livestock. J
ANIM SCI 76(1): 173–194.

Beta agonist ractopamine in rainbow trout
1. Moccia, R.D., R.M. Gurure, J.L. Atkinson, and G.W. Vandenberg. 1998. Effects of the repartitioning agent
ractopamine on the growth and body composition of rainbow trout, Oncorhynchus mykiss (Walbaum), fed three
levels of dietary protein. Aquaculture Research 29(9): 687–694.
2. Salem, M., H. Levesque, T.W. Moon, C.E. Rexroad, and J. Yao. 2006. Anabolic effects of feeding β2-adrenergic
agonists on rainbow trout muscle proteases and proteins. Comparative Biochemistry and Physiology - Part A:
Molecular & Integrative Physiology 144(2): 145–154.
3. Vandenberg, G.W., J.F. Leatherland, and R.D. Moccia. 1998. The effects of the beta‐agonist ractopamine on growth
hormone and intermediary metabolite concentrations in rainbow trout, Oncorhynchus mykiss (Walbaum).
Aquaculture Research 29(2): 79–87.

Illegal use of beta agonist
1. Kuiper, H.A., M.Y. Noordam, M.M. van Dooren-Flipsen, R. Schilt, and A.H. Roos. 1998. Illegal use of beta-adrenergic
agonists: European Community. J ANIM SCI 76(1): 195–207.
2. Barbosa, J., C. Cruz, J. Martins, J.M. Silva, C. Neves, C. Alves, F. Ramos, and M.I.N. Da Silveira. 2005. Food poisoning
by clenbuterol in Portugal. Food Addit Contam 22(6): 563–566.
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Appendix 1. Simplification of Beta agonist action mechanism

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Appendix 2. Fat deposition and breakdown

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Appendix 3. Energy sparing protein

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Appendix 4. Glucose regulation in liver

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Appendix 5. Glucose utilization in liver and muscle

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Appendix 6. General pathway of metabolism

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Beta agonist application in fish

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