Posted by jojo on August 6, 2001, at 15:59:43
In reply to Re: Yohimbe trial results » PhoenixGirl, posted by katz on May 6, 2001, at 8:51:10
> >I am on day 5 or 6 of a yohimbe trial and have been getting some very positive results. Energy & mood significantly improved. Libido enhancing properties have unfortunately been negative thus far. Increased energy & mood were noticible with the first dose. I'm taking 8 mg bid.
>
> Does anyone happen to know the mode of action of Yohimbe? Does it act on the dopamine or nor-adrenaline systems? Gaba? My personal experience would indicate that it is a type of stimulant. Any input would be appreciated.
>
> Kathy.
>
> What effects did it have on you?
> >
> > > I don't want the OTC kind, because who knows what's really in it. I most want the generic prescription.
Home > Articles > Elzi VolkFat Loss, alpha2-Adrenoceptors
and Yohimbine, Part IIby Elzi Volk
elzi.volk@thinkmuscle.com
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Subscribe to the free Think Muscle Newsletter!
Find Bodybuilding & Fitness Books at Amazon.com.
Find Health and Fitness Magazines at Enews.com.Part 1: Fat Loss, alpha2-Adrenoceptors and Yohimbine
Part 2: Fat Loss, alpha2-Adrenoceptors and YohimbineIntroduction
In the previous installment of this article, we discovered
the regulatory role of adrenoceptors on lipolysis by action
of the catecholamines. This installment examines the
relevance of the sympathetic nervous system in
mediating levels of catecholamines in the body and the
interactions of this system with adipose tissue. The role
of a 2-adrenoceptors and a pharmacological approach
that mediates these receptors is also discussed.The Sympathetic Nervous System and a
2-AdrenoceptorsIt is widely accepted that lipolysis is modulated by the
sympathetic nervous system (SNS) and possibly the
parasympathetic nervous system (PNS). The SNS and the
PNS are the two arms of the autonomic nervous system
of the body. The SNS, often called the "fight-or-flight"
system, is a network of motor neurons that innervates
smooth muscle, cardiac muscle and glands. The SNS
mobilizes the body during extreme situations such as
stress and exercise. The PNS, sometimes called the
"resting and digesting" system, serves to counterbalance
the effects of the SNS and conserve energy. The SNS
may stimulate a gland to secrete or smooth muscle to
contract, whereas the PNS inhibits that action. Generally,
the SNS and PNS innervate the same organs; although,
the SNS innervates more organs than the PNS. While
adipose tissue is innervated solely by the SNS, the PNS
may indirectly influence lipolysis.Both systems comprise of neurons, and each neuron ends
in a terminal synapse. These synapses mediate the
transfer of information from one neuron to another or to
an effector (target) cell. That information may be in the
form of electrical impulses (flow of ions) or chemicals.
Certain signals are transmitted while others are blocked.
Just inside the terminal are vesicles containing
neurotransmitters, the chemical signals. In response to a
nerve impulse the neurotransmitters are released from the
vesicles into the synaptic cleft, a narrow space between
the presynaptic terminal and the postsynaptic membrane
of a nerve or an effector cell. Neurotransmitters diffuse
across the synaptic cleft and bind to specific receptors on
the effector cell. They may also diffuse into the
bloodstream or be degraded by enzymes. Some
neurotransmitters are taken back up into the presynaptic
neuron to be recycled in a process called re-uptake.The major neurotransmitter of the PNS is acetylcholine
(ACh), which binds to nicotinic and muscarine receptors.
The two neurotransmitters of the SNS are acetylcholine
and norepinephrine (NE). ACh is degraded quickly by
acetylcholinesterase; hence its effects are short-lived.
Stimulation of the SNS increases release of
neurotransmitters inducing a response in the effector
cells, which may be excitatory or inhibitory depending on
the nature of the receptor that binds the neurotransmitter.
Thus, the SNS regulates energy intake and expenditure
according to genetic and environmental influence.SNS stimulation increases plasma levels of the
catecholamines by inducing secretion of NE from
postganglionic terminals and release of epinephrine (E)
from the adrenal medulla. Although NE lingers in the
synaptic cleft for a longer period of time than ACh, NE
has several fates. A portion of the NE diffuses out of the
synaptic cleft into the bloodstream. Enzymes such as
monoamine oxidase and catechol-O-methyltransferase
(COMT) degrade a portion of NE. Much of the
neurotransmitter is actively transported back into the
terminal that released it and recycled. This re-uptake is
moderated by a -adrenoceptors.a 2-Adrenoceptors are found in the cell membrane of the
neuron axon terminals and mediate rate neurotransmitter
release. Some evidence shows that a 1-adrenoreceptors
may be present on presynaptic membranes as well, but
their existence is still disputed (1). When NE is released
from the vesicles of the terminals, they come into contact
with and stimulate the a 2-adrenoceptors, inhibiting
further release of these same neurotransmitters. Such is
the feedback system for NE release in the SNS.Many pharmaceuticals interact with presynaptic a
-adrenoceptors interfering with NE-mediated regulation
of NE release and re-uptake. a 2-Antagonists are
compounds that block the inhibiting effect of the a
2-adrenoceptors and, therefore, interfere with re-uptake
of the synaptic NE. This allows NE to linger longer in
synaptic clefts producing excessive stimulation and
diffusion of excess NE into the bloodstream. a
2-Antagonists reserpine and yohimbine enhance NE
release and inhibit NE re-uptake.a 2-Adrenoceptors are present on many tissues and
mediate a variety of functions. Pre- and postsynaptic a
2-adrenoceptors found on central and peripheral neural
terminals mediate noradrenergic, cholinergic and
serotonergic receptors. Recall that activation of these a
2-adrenoceptors inhibits release of neurotransmitters.
Thus, blockage of the adrenoceptors will increase
neurotransmitter release. As well, a 2-adrenoceptors are
located on many other tissues and have important
pharmacological implications. Some of these are
discussed further when we address use of
pharmaceuticals targeting the a 2-adrenoceptors for fat
loss and their possible side effects.a 2-Adrenoceptor Subtypes
Receptor-binding studies have demonstrated that several
subtypes exist for alpha-adrenoceptors types, depending
on species and tissue (2,3). In addition to genetic coding,
pharmacological response to agonists and antagonists
determine the classifications depending on their binding
potency to the receptors. The most common probes used
in these studies are agonists, such as clonidine, and
antagonists: yohimbine and yohimbine-like compounds
such as rauwolscine, corynanthine. Each of these
compounds has various binding affinities for the
alpha-adrenoceptors types. Some, such as yohimbine,
exhibit weak binding to a 1-adrenoceptors as well as high
affinity for the a 2-adrenoceptors.As mentioned previously, species and tissue differences
exist in a 2-adrenoceptor subtypes. For instance, human
brain cortex presynaptic a 2-adrenoceptors are classified
as a 2A or a 2D (4). Primarily a 2A-adrenoceptors mediate
vascular effects, such as changes in blood pressure (5).
Whereas, human kidney presynaptic a 2-adrenoceptors
are classified as a 2C (6), further binding studies
established that human adipocytes express only the a
2A-adrenoceptor subtype (7, 8).These a 2-adrenoceptor subtypes are differentially
regulated by their affinity for the physiological
catecholamines and sensitivity to downregulation. The
functional roles for the a 2-adrenoceptors continue to be
explored. Pharmaceutical agonists and antagonists are
being developed with greater selectivity for the individual
subtypes. They may be used as therapeutics for treating
glaucoma, hypertension, non-insulin dependent diabetes
and as adjuncts to general anesthesia.The SNS, a 2-Adrenoceptors and the Catecholamines
Catecholamines stimulate the adipocyte adrenoceptors on
the basis of their relative affinity for each type of
adrenoceptor. These hormones preferentially recruit the a
2-adrenoceptor at lower catecholamine levels than the
beta-adrenoceptors, especially in tissues where a
2-adrenoceptors predominate (9,10). Consequently, the a
2-adrenoceptors will be recruited before the
beta-adrenoceptors.One study demonstrates that a 2-adrenoceptors modulate
lipolysis at rest, whereas lipolysis is modulated by the
beta-adrenoceptors during exercise (9). During physical
activity, increased levels of E in the extracellular fluid
maximally stimulate the beta-adrenoceptors and mask the
inhibitory effect of the a 2-adrenoceptors. a
2-Adrenoceptors may exert a permanent inhibition on
lipolysis, contributing to a tonic inhibitory component
influenced by catecholamines on 'basal lipolysis' (11). In
vitro studies support this observation by demonstration
that many G proteins have a significant level of basal
activity in the absence of an agonist (12). Therefore, the
a 2-adrenoceptors could be considered the major
lipolysis-regulating adrenoceptor on adipocytes.To illustrate the regulatory mechanism of the dual
adrenoceptors on the fat cells, let us consider the a
2-adrenoceptor as a 'brake' on lipolysis in the cell. At
rest the a 2-adrenoceptors apply a slight pressure to the
brakes on lipolysis even in the absence of an agonist, a
compound which binds and stimulates the receptor. A
slight rise in extracellular norepinephrine, such as seen in
mild SNS stimulation (sitting at the computer typing all
day), will increase the number of a 2-adrenoceptors being
activated with a small number of beta-receptors activated
as well. Since the a 2-adrenoceptors outnumber the
beta-receptors in humans, this will apply the breaks to
lipolysis harder, decreasing-lipolysis. During exercise,
concentrations of NE and E from the SNS and the
adrenal gland increase in the blood and fat tissue
extracellular fluid. These higher levels of catecholamines
increase stimulation of the beta-adrenoceptors, which
then overshadow the a 2-adrenoceptor-induced activity.
Basically, stimulated beta-adrenoceptors cut the brake
cable on lipolysis and start the train of events promoting
and increasing fat breakdown in fat cells.Adipocytes are only one of the many tissues within the
body that have adrenergic receptors. Thus, response to
activation of the SNS will vary between tissues
depending on the adrenoceptor types present on the cells,
the relative proportion and the second messenger system
within the cell. For instance, skeletal muscle blood vessel
wall cells have both a 1- and b 2-adrenoceptors with the a
1-adrenoceptors lying close to the sympathetic nerve
terminals. The b 2-adrenoceptors are on the endothelial
surface of the blood vessels. Therefore, SNS activation
usually produces predominantly vasoconstriction
mediated by the a 1-adrenoceptors, whereas an increase
in E activates the b 2-adrenoceptors causing vasodilation.
Another important organ with dual adrenergic regulation
is the pancreas. This interaction is explained when we
examine a pharmaceutical approach that blocks the a
2-adrenoceptors.a 2-Adrenoceptors and Blood Flow
SNS activity has an additional catecholamine-mediated
effect on lipolysis in adipose tissue: blood flow. A
coordination of local blood flow and metabolism carries
away by-products of lipolysis and supplies energy
substrates to tissues and organs in times of increased
demand. Changes in blood flow can facilitate or inhibit
movement of substrates, such as glycerol and
non-esterified fatty acids (NEFA), that arise from
lipolysis. Consequently, stimulation of the SNS increases
lipolysis and blood flow; low SNS activity (such as during
rest) inhibits lipolysis and blood flow. However, the
increase in blood flow is not in proportion to rising
concentrations of NEFA and glycerol. During strenuous
exercise, adipose tissue blood flow does not increase
sufficiently to remove all NEFAs released by lipolysis
(13). A feedback system probably exists; however, it is
not well understood. Vascular adrenoceptors that affect
vasoconstriction and vasodilation may be responsible for
this feedback. Studies using microdialysis have shown
that the interplay of a 2- and b 2-adrenoceptors mediate
vascular blood flow in adipose tissue (14,15).Up until several years ago, in vitro and in vivo
investigations on plasma circulating metabolites limited
measurements of metabolism in adipose tissue. A
technique called microdialysis allows for local
manipulation and in situ studies of adipose tissue (16,17).
It can be applied to individual subcutaneous deposits
enabling investigation of specific-site metabolism.
Microdialysis allows infusing adrenergic-active agents,
such as beta- and alpha-agonists or antagonists, to
manipulate adrenergic control and monitoring adipose
tissue metabolites and local blood flow. Recent studies
elucidate further the role of the catecholamines on
regulation of adipose tissue metabolism, especially
pertaining to regional and gender differences.E and NE stimulate blood flow in adipose tissue by
activation of the b -adrenoceptors on the walls of the
blood vessels causing vasodilation. Stimulation of the a 1-
and a 2-adrenoceptors, also on blood vessel walls,
promote vasoconstriction. The distribution of these two
types of alpha-adrenoceptors and their subtypes within
the blood vessel walls mediate their sensitivity to
vascular controls. Some vascular beds, such as the renal
bed, respond primarily to a 1-adrenoceptor modulation
(5). Whereas other beds, such as in cutaneous circulation,
respond primarily to a 2-adrenoceptors (19,18). SNS
regulation of local blood flow in the various adipose
deposits may have important implications for lipolysis
(20).Results from in vitro and in vivo studies have had
contradicting results depending on techniques utilized
and physiological status of subjects. Without question, in
vitro and in vivo results show that a 2-adrenoceptors
predominate in the femoral vascular bed (in the lower
body) by using various antagonists for the specific
alpha-adrenoceptors (21-23). Microdialysis studies
confirm a higher concentration of glycerol in
gluteofemoral than abdominal adipose deposits possibly
due to reduced local blood flow in gluteofemoral sites
during resting basal conditions despite lower basal
lipolysis rates (14,20).Experiments using microdialysis have shown that
perfusing adipose tissue with clonidine, an a 2-agonist,
promoted an increase in extracellular glycerol
concentrations. Vasoconstriction by stimulation of
vascular a 2-adrenoceptors may be the primary
determinant in glycerol and NEFA mobilization (20,24).
Vasodilating agents infused via microdialysis produced a
decrease in the removal of glycerol from the extracellular
space of adipose tissue (24). The resulting decrease in
blood flow may reduce the net removal of lipolysis
metabolites from the extracellular fluid of adipose tissue.NEFAs produced by lipolysis within the adipocytes may
be more sensitive to change in blood flow. Glycerol is
water-soluble and diffuses out of the adipocytes to move
freely within extracellular fluid. NEFAs are not
water-soluble and must be bound to protein carriers to
move out of adipocytes and into the intracellular space.
Newly NEFAs will therefore linger in the interstitial
space surrounding adipocytes and possibly be reutilized
(re-esterified) by surrounding adipocytes. Indeed, it has
been shown that reduced blood flow in adipose tissue
delayed NEFA and glycerol mobilization (25,26).
Therefore, vasodilation induced by an antagonist that
specifically blocks the a 2-adrenoceptors in the blood
vessels of adipose tissue could increase lipolysis
metabolite mobilization.In vitro and in vivo studies suggest obesity may modify
the response to the catecholamines due to differences in
fat cell size, adrenoceptor populations and circulation
(27-31). Continued investigation is needed to explain
controversies in changes of regulatory mechanisms seen
in altered physiological states. Additionally, physical
exercise modifies changes in adipose tissue response to
SNS. Gender differences are apparent during exercise,
such as higher glycerol levels in circulating blood supply
and in adipose tissue of women than in men.
Microdialysis investigations report higher lipid
mobilization from subcutaneous abdominal adipose tissue
in women (9,32). Explanations for this gender response
may be differences in adrenergic receptor population and
activity. Glycerol levels in men were enhanced by a
-adrenoceptor blockage. However, whether this was
induced by direct blockage of adipocyte
alpha-adrenoceptors or those of the vascular bed was not
examined.The Sympathetic Nervous System, a 2-Adrenoceptors
and YohimbineThus far, this article has addressed the basic physiology
of lipolysis and the interaction of the SNS and
alpha-adrenoceptors. As alluded to throughout the
preceding sections, manipulation of the SNS will have
direct impact on lipolysis. It is useful to remember,
however, that insulin is the main regulator of lipolysis.
Therefore, as previously mentioned in Part 1 of this
article, lowering insulin levels will allow for optimal
manipulation of the SNS. Low levels of insulin increase
plasma levels of catecholamines, stimulating lipolysis and
loss of body fat. The SNS can also be manipulated by
pharmaceuticals and naturally occurring substances. We
will discover one such approach: mediation of the a
2-adrenoceptors.Sympathomimetic compounds mimic the action of the
SNS and release NE and E in addition to possessing
direct b -adrenergic properties. Examples of these
compounds are amphetamines, ephedrine and its various
isomers. Isomers are compounds with the same formula
but different molecular structure or different spatial
arrangements. These differences greatly affect the
activity/potency of the compound and the responses they
elicit, as we will discover shortly.Sympatholytic compounds inhibit adrenergic nerve
activity in the SNS and some have direct postsynaptic
adrenoceptor-blockage activity. Physiological responses
of these compounds depend on several factors: chemical
structure, type and subtype of adrenergic receptors
(ARs), second messenger system (including G protein
complex), and tissue site. Other factors include
administration route of the compound, which influences
absorption and metabolism, and dosage. To present a
detailed discussion of pharmacology is beyond the scope
of this article; therefore, only necessary details pertaining
to the ensuing discussion are included.Considered a sympatholytic, yohimbine has been used in
herbal medicine for centuries. Yohimbine is one of a
large family of indole alkaloids called yohimbanes. Indole
alkaloids are naturally-occurring heterocylic amines
derived from botanical sources. Yohimbine is the
principal alkaloid found in extracts from the bark of the
Pausinystlia yohimbe tree that grows in tropical West
Africa and the Congo. It is structurally similar to
reserpine and can also be isolated from the roots of
Rauwolfia. Typical of many alkaloids, the yohimbanes
have diverse pharmacological properties.The basic yohimbane molecular structure contains five
asymmetric carbons; yohimbine is one of 32 isomers
within this family. The yohimbane alkaloids include
antagonists that are selective for the alpha-AR. The
selectivity of the various yohimbane alkaloids depends on
the stereochemical configuration of the five carbon
centers. That is, the shape and position of the various
components of the compound determine how they
interact with the receptors and potency of their response.
Not only do they have differential activity at the
alpha-AR types (a 1- versus a 2), but also within the
subtypes (3,15,33).Recall from the previous discussion on the a 2-AR
subtypes that differences in their affinity for agonists and
antagonists mediate the cell's response. This interaction
of yohimbane compounds and the AR subtypes
determine their use as pharmacological tools and
therapeutic agents. Therefore, the effects of the various
yohimbanes will vary, as we shall see in our examination
of the use of yohimbine.Synthesized yohimbine and its isomer rauwolscine have
been used as pharmacological tools to differentiate the
alpha-ARs due to their selectivity as antagonists for the a
2-AR. Another isomer, corynanthine, is used for its
selectivity for the a 1-AR. They have served as probes for
classification of AR types and to assess a 2 adrenergic
functions in man for several decades. Herbal preparations
from plant parts, however, have been used as
aphrodisiacs and euphorics for centuries. Recently,
yohimbine has been promoted as a dietary supplement to
enhance athletic performance and fat loss. This and
various clinical applications will be examined in this
article.Early investigations demonstrate the activity of
yohimbine as an a 2-antagonist that increases NE release
and induces a hyperadrenergic state (33). Pharmaceutical
studies show that yohimbine has high selectivity for the a
2-AR and weak affinity for the a 1-receptors. Its isomer
rauwolscine has higher selectivity for the a 2-AR with
little or no selectivity for the a 1 type. Later tissue and
cells studies explained the mechanisms of various effects
of yohimbine when administered to humans and other
species by revealing the presence of a 2-AR and their
functions at several sites within the body. Differential
affinity of yohimbine and its isomers for the a 2-AR
subtypes may also explain variability in tissue-specific
responses.Clinically, yohimbine has been administered to induce
anxiety in psychiatric patients, orthostatic hypotension
and other autonomic failure conditions, adjunct therapy
for opiate withdrawal, and male organic impotence
(15,34). It is widely used by veterinarians to reverse
sedation or anesthesia in animals. Other therapeutical
applications currently under research are as a
glucose-dispersal agent for treatment of non-insulin
dependent diabetes and to treat adverse effects of
anti-depressants.
NOTE: This is only half of the article. Possibly you can link to the full article and its 60 references.
Fat Loss, alpha2-Adrenoceptors
and Yohimbine, Part IIby Elzi Volk
elzi.volk@thinkmuscle.com
Please send us your feedback on this article.
Subscribe to the free Think Muscle Newsletter!
Copyright © 2001 Meso-Rx. All rights reserved.
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poster:jojo
thread:61036
URL: http://www.dr-bob.org/babble/20010804/msgs/73828.html