Efeito muscular e
nerológico do clenbuterol
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Beta2-agonist clenbuterol induced changes in the
distribution of white blood cells in rats.
Shirato K,
Tanihata J,
Motohashi N,
Tachiyashiki K,
Tomoda A,
Imaizumi K.
Laboratory of Physiological Sciences, Faculty of Human Sciences, Waseda
University, 2-579-15 Mikajima, Tokorozawa 359-1192, Japan.
Clenbuterol [CLE: 4-amino-alpha(t-butyl-amino)methyl-3,5-dichlorobenzyl
alcohol] is well known as a potent beta2-adrenergic agonist and
non-steroidal anabolic drug, and thus it is generally used for sports doping
and asthma therapy. Although the functions of immune cells such as white
blood cells (WBCs) have shown to be modulated through beta2-adrenoceptors,
the effects of CLE on immune-responsive systems have not been elucidated
systematically. Therefore, the effects of CLE on the number of WBCs were
studied in rats. Male adult rats were divided into CLE-administered group
and the control group to compare the number of total WBCs, neutrophils,
monocytes, lymphocytes, eosinophils, and basophils. The administration (dose
= 1.0 mg . kg(-1) body weight . day(-1), s.c.) of CLE was maintained for 30
days. CLE did not change the number of total WBCs during the experimental
period. However, CLE increased significantly the number of neutrophils and
monocytes, while CLE decreased drastically the number of lymphocytes and
eosinophils. There was no significant change in the number of basophils
between both groups. These results suggest that the administration of CLE
induces drastic redistribution of WBCs in circulation without changing the
number of total WBCs, and these responses of WBCs during the administration
of CLE are sustained for at least 30 days.
Publication Types:
PMID: 17558185 [PubMed - indexed for MEDLINE]
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beta2 adrenergic agonist, clenbuterol, enhances working
memory performance in aging animals.
Ramos BP,
Colgan LA,
Nou E,
Arnsten AF.
Yale University School of Medicine, Department of Neurobiology, SHM C-300,
333 Cedar Street, New Haven, CT 06510, USA.
Previous studies using a mixed beta1 and beta2 adrenergic antagonist,
propanolol, have indicated that beta adrenoceptors have little effect on the
cognitive functioning of the prefrontal cortex. However, recent studies have
suggested that endogenous stimulation of beta1 adrenoceptors impairs working
memory in both rats and monkeys. Since propanolol has no effect on cognition,
we hypothesized that activation of beta2 adrenoceptors might improve
performance in a working memory task. We tested this hypothesis by observing
the effects of the beta2 agonist, clenbuterol, on spatial working memory
performance. Clenbuterol was either infused directly into the prefrontal
cortex (rats) or administered systemically (monkeys). Results demonstrated
that clenbuterol improved performance in many young and aged rats and
monkeys who performed poorly under control conditions. Actions at beta2
adrenoceptors were confirmed by challenging the clenbuterol response with
the beta2 adrenergic antagonist, ICI 118,551. The effects of clenbuterol
were not universal and depended on the cognitive status of the animal: the
drug moderately improved only a subset of animals with working memory
impairment.
PMID: 17363115 [PubMed - as supplied by publisher]
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Anabolic effects of a non-myotoxic dose of the
beta2-adrenergic receptor agonist clenbuterol on rat plantaris muscle.
Burniston JG,
McLean L,
Beynon RJ,
Goldspink DF.
Muscle Physiology and Proteomics Laboratory, Research Institute for Sport
and Exercise Sciences, Liverpool John Moores University, Webster Street,
Liverpool L3 2ET, UK. j.burniston@ljmu.ac.uk
Previous investigations of the effects of clenbuterol have used
suprapharmacological doses that induce myocyte death, alter muscle phenotype,
and do not approximate the proposed therapeutic dose for humans. Recently,
we reported that smaller doses of clenbuterol induce muscle growth without
causing myocyte death. In the present study we used histochemical and
proteomic techniques to investigate the molecular effects of this dose. Male
Wistar rats (n = 6, per group) were infused with saline or 10 microg/kg/day
clenbuterol via subcutaneously implanted osmotic pumps. After 14 days the
animals' plantaris muscles were isolated for histochemical and proteomic
analyses. Clenbuterol induced significant muscle growth with concomitant
protein accretion and preferential hypertrophy of fast oxidative glycolytic
fibers. Clenbuterol reduced the optical density of mitochondrial staining in
fast fibers by 20% and the glycogen content of the muscle by 30%.
Differential analysis of two-dimensional gels showed that heat shock protein
72 and beta-enolase increased, whereas aldolase A, phosphogylcerate mutase,
and adenylate kinase decreased. Only heat shock protein 72 has previously
been investigated in clenbuterol-treated muscles. The clenbuterol-induced
increase in muscle growth was concomitant with qualitative changes in the
muscle's proteome that need to be considered when proposing therapeutic uses
for this agent.
Publication Types:
PMID: 17058275 [PubMed - indexed for MEDLINE]
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Histological evidences of reparative and regenerative
effects of beta-adrenoceptor agonists, clenbuterol and isoproterenol, in
denervated rat skeletal muscle.
Katoch SS,
Garg A,
Sharma S.
Department of Biosciences, Himachal Pradesh University, Summer Hill, Shimla
171 005, India.
The aim of this study was to determine the contribution of beta-adrenoceptor
activation in the reconstruction of the structural and functional
organization of denervated skeletal muscle. beta-agonists, clenbuterol (1.2
mg/kg body weight) and isoproterenol (2 mg/kg body weight), administration (daily
oral administration; maximum 7 days) to normal innervated rats as well as
denervated animals caused muscle hypertrophy. An increase in mean fiber
diameter confirmed this stimulated growth both in normal innervated and
denervated rat gastrocnemius muscle. Examination of muscle nuclei from
treated but normal innervated rat gastrocnemius exhibited features like
large size, active nucleoplasm and an increase in their number per fiber
cross section and per mm mean fiber length indicating towards an elevated
biosynthetic activity in tissue in the presence of beta adrenoceptor
agonists. Administration of drugs to normal innervated animals resulted in
an emergence of central muscle nuclei. The hyperactive and enlarged muscle
nuclei ultimately organized themselves into unusually elongated nuclear
streaks. beta agonist treatment to denervated rats resulted in amelioration
of atrophic state of tissue characterized by hypertrophy of muscle fibers
thus lending to a restoration of structural organization of tissue. Bizarre
shapes of nuclei in denervated muscle tend to recover to that characteristic
to normal innervated muscle in presence of clenbuterol and isoproterenol
hydrochloride. All observations were confirmed by administering butoxamine,
a beta-adrenoceptor antagonist along with beta-agonists. The results
suggests that both clenbuterol and isoproterenol hydrochloride are capable
of mimicking normal innervation functions in skeletal muscle and thus play
important role in the structural and functional reorganization of tissue.
Amelioration of denervation atrophy in rat gastrocnemius in the presence of
beta-agonists supports this.
Publication Types:
PMID: 16784115 [PubMed - indexed for MEDLINE]
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Dose-dependent separation of the hypertrophic and
myotoxic effects of the beta(2)-adrenergic receptor agonist clenbuterol in
rat striated muscles.
Burniston JG,
Clark WA,
Tan LB,
Goldspink DF.
Research Institute for Sport & Exercise Sciences, Liverpool John Moores
University, Webster Street, Liverpool L3 2ET, UK. j.burniston@ljmu.ac.uk
Muscle growth in response to large doses (milligrams per kilogram) of
beta(2)-adrenergic receptor agonists has been reported consistently. However,
such doses may also induce myocyte death in the heart and skeletal muscles
and hence may not be safe doses for humans. We report the hypertrophic and
myotoxic effects of different doses of clenbuterol. Rats were infused with
clenbuterol (range, 1 microg to 1 mg.kg(-1)) for 14 days. Muscle protein
content, myofiber cross-sectional area, and myocyte death were then
investigated. Infusions of >or=10 microg.kg(-1).d(-1) of clenbuterol
significantly (P<0.05) increased the protein content of the heart (12%-15%),
soleus (12%), plantaris (18%-29%), and tibialis anterior (11%-22%) muscles,
with concomitant myofiber hypertrophy. Larger doses (100 microg or 1 mg)
induced significant (P<0.05) myocyte death in the soleus (peak 0.2+/-0.1%
apoptosis), diaphragm (peak 0.15+/-0.1% apoptosis), and plantaris (peak
0.3+/-0.05% necrosis), and significantly increased the area fraction of
collagen in the myocardium. These data show that the low dose of 10 microg.kg(-1).d(-1)
can be used in rats to investigate the anabolic effects of clenbuterol in
the absence of myocyte death.
Publication Types:
PMID: 16411205 [PubMed - indexed for MEDLINE]
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Tissue specific and variable collagen proliferation in
Swiss albino mice treated with clenbuterol.
Patiyal SN,
Katoch SS.
Department of Biosciences, Himachal Pradesh University, Summer Hill, Shimla-171
005, India. snpatiyal@yahoo.co.in
Chronic administration of clenbuterol, a beta-adrenoceptor agonist (2 mg/kg
body weight/day for 30 days) to mice resulted in an increased body mass.
Measurement of dry tissue mass suggested a protein anabolic effect in the
gastrocnemius and heart. Quantitative estimation of collagen content, a
non-contractile element as calculated from hydroxyproline assay revealed its
proliferation in the gastrocnemius, cardiac ventricle, intestine and to some
extent also in the kidney. Clenbuterol did not induce collagen proliferation
in non-muscle tissues such as the lungs and liver. Histopathological
examination of sections from treated ventricles showed an extensive collagen
infiltration in the subendocardium and at myonecrosis sites.
Publication Types:
PMID: 15857157 [PubMed - indexed for MEDLINE]
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Severe bone alterations under beta2 agonist treatments:
bone mass, microarchitecture and strength analyses in female rats.
Bonnet N,
Benhamou CL,
Brunet-Imbault B,
Arlettaz A,
Horcajada MN,
Richard O,
Vico L,
Collomp K,
Courteix D.
Inserm U 658, CTI and ATOSEP, Orleans Regional Hospital and University of
Orleans, 1, rue porte Madeleine, France. nicolas.bonnet15@wanadoo.fr
AIMS: Beta2 adrenergic agonists are widely used in therapeutics and as
doping agents by athletes. However, their effects on bone tissue, especially
bone microarchitecture, remain poorly understood. Using three-dimensional
(3D) microtomography, dual-energy X-ray absorptiometry, biomechanical
testing and enzyme-linked immunosorbent assay, we evaluated the effects of
two beta2 agonists, clenbuterol and salbutamol, on bone in growing rats.
METHODS: Twelve-week-old Wistar female rats (N = 39), divided in 3 groups,
received during 6 weeks either salbutamol (4 mg/kg/day), clenbuterol (2
mg/kg/day) or normal saline (0.5 ml/kg/day) by subcutaneous injections.
RESULTS: After 6 weeks, the salbutamol and clenbuterol groups displayed
lower bone mineral content (BMC), femoral length and cortical width than
controls. Clenbuterol treatment further reduced bone mineral density. Bone
microarchitecture was clearly altered by clenbuterol, as evidenced by lower
trabecular number (-40.40%; P < 0.001), connectivity and trabecular bone
volume (-42.85%; P < 0.001), leading to lower ultimate force. Clenbuterol
significantly increased muscle mass (P < 0.01) and reduced fat mass when
compared to controls. Salbutamol did not seem to have any effect on bone
microarchitecture or body composition. Both beta2 agonists increased the
bone resorption marker (C-terminal collagen crosslinks) without any change
of a bone formation marker. At the end of the treatment, a drop in leptin
was seen in the clenbuterol group only. Leptin levels were correlated with
BMC (r = 0.69, P = 0.003). CONCLUSION: These results confirm the deleterious
effect of beta2 agonists on bone mass and show the negative effects of
clenbuterol on trabecular bone microarchitecture. Bone loss occurred
independently from muscle mass but was related to fat mass. A
leptin-mediated effect on bone tissue seems likely. These pathophysiological
effects may have important consequences in human therapeutics and doping.
PMID: 16157516 [PubMed - indexed for MEDLINE]
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Clenbuterol treatment affects myosin heavy chain isoforms
and MyoD content similarly in intact and regenerated soleus muscles.
Bricout VA,
Serrurier BD,
Bigard AX.
Department of Human Factors, Centre de recherches du service de santé des
armées, La Tronche Cedex, France.
AIMS: Pharmacological treatment with the beta2-adrenoceptor agonist
clenbuterol is known to induce a slow-to-fast fibre type and myosin heavy
chain (MHC) isoform transition in intact muscle. This study examined the
sensitivity of regenerated soleus muscle to 4 weeks of clenbuterol treatment
(2 mg kg-1 day-1). METHODS: Female Wistar rats were divided into two groups:
vehicle treated (n = 8) and clenbuterol treated (n = 8). The clenbuterol
effects on MHC and MyoD expression were examined in soleus muscles either
intact, or previously degenerated by venom of the Notechis scutatus scutatus
snake. RESULTS: Post-treatment body weights and skeletal muscle weights were
not affected by clenbuterol treatment. Muscle protein concentration was
higher, and body fat lower in clenbuterol-treated rats than in
vehicle-treated animals (P < 0.05). Polyacrylamide gel electrophoresis of
soleus myofibrillar protein indicated a clenbuterol-induced decrease in the
relative percentage of type I MHC with a concomitant increase in type IIa
MHC (31%, P < 0.001). No degeneration effect was observed after 28 days of
recovery on the MHC isoform content, and regenerated soleus muscles
exhibited the same phenotypical profile as intact soleus muscles, whether or
not they were treated with clenbuterol. In intact and in regenerated soleus
muscles, MyoD protein levels were significantly increased by clenbuterol
treatment (90 and 77%, respectively, P < 0.001). CONCLUSION: These results
show that regenerated soleus muscles, comprising a homogeneous population of
fibres deriving from satellite cells, have a similar response to clenbuterol
as intact muscle arising from at least two discrete populations of myotubes;
it is suggested that the activity of signalling pathways involved in the
effects of clenbuterol on MHC transitions is not related to the
developmental history of myofibres.
PMID: 14962009 [PubMed - indexed for MEDLINE]
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beta-Adrenergic receptor agonists increase apoptosis of
adipose tissue in mice.
Page KA,
Hartzell DL,
Li C,
Westby AL,
Della-Fera MA,
Azain MJ,
Pringle TD,
Baile CA.
Department of Animal and Dairy Science, University of Georgia, Athens, GA
30602, USA.
beta-Adrenergic receptor (beta-AR) agonists increase muscle mass and
decrease body fat in rodents and livestock. With oral administration,
however, the effects of beta1-AR and beta2-AR can be different, depending on
the species tested. We tested the effects of clenbuterol, a beta2-AR agonist,
and ractopamine, a beta1/beta2-AR agonist, on growth, adiposity and adipose
tissue apoptosis in male and female mice by feeding diets containing control,
200 ppm clenbuterol, or 200 or 800 ppm ractopamine. Food intake (FI) was
measured daily; body weight (BW) and temperatures (BT) were measured on days
0, 3, 7, 10, 14, 17, and 20. On day 21 mice were sacrificed, body
composition was determined using PIXImus densitometry, and muscle and
adipose tissues were collected. There were no treatment effects on BT, FI,
BW, feed efficiency or body composition. Retroperitoneal (Rp) and epididymal/parametrial
(Epi/Par) fat pad masses were reduced in both 800 ppm ractopamine (40+/-3mg
and 207+/-20mg, respectively) and clenbuterol (35+/-7 mg and 211+/-22 mg)
treated mice compared to control (66+/-8 mg and 319+/-30 mg, P<0.05). Brown
adipose tissue (BAT) mass was greater (P<0.05) in clenbuterol treated mice
compared to other treatments. Adipose tissue apoptosis (% DNA fragmentation)
was increased in Epi/Par fat pads in clenbuterol (5.2+/-1.1%) and 800 ppm
ractopamine (4.1+/-0.8%) treated mice compared to control (1.7+/-0.4%, P<0.05).
These findings show that WAT apoptosis can be induced by activation of
beta-AR in mice, although the mechanism is unknown.
Publication Types:
PMID: 14732450 [PubMed - indexed for MEDLINE]
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Stimulation of beta-adrenoceptors activates astrocytes
and provides neuroprotection.
Junker V,
Becker A,
Hühne R,
Zembatov M,
Ravati A,
Culmsee C,
Krieglstein J.
Institut für Pharmakologie und Toxikologie, Fachbereich Pharmazie der
Philipps-Universität Marburg, Ketzerbach 63, 35032, Marburg, Germany.
Our previous studies established that induction of growth factor synthesis
and neuroprotection by the beta(2)-adrenoceptor agonist clenbuterol in vitro
and in vivo was associated with the activation of astrocytes, the major
source of trophic factors in the brain. In the present study, we further
investigated the specificity of beta(2)-adrenoceptor-mediated effects on
astrocyte activation and neuroprotection. In mixed hippocampal cultures
neuroprotection against glutamate-induced cell death by clenbuterol (1
microM) was blocked by the beta(1/2)-adrenoceptor antagonist propranolol and
the specific beta(2)-adrenoceptor antagonists 1-[2,3-(Dihydro-7-methyl-1H-inden-4-yl)-oxy]-3-[(1-methylethyl)-amino]-2-butanol
(ICI 118,551, 10 microM) and butoxamine (10 microM), while the beta(1)-adrenoceptor-selective
antagonist metoprolol (10 microM) showed no effect. The beta(2)-adrenoceptor
agonists clenbuterol (1-100 microM) and salmeterol (0.01-1 microM) induced
profound morphological changes of cultured astrocytes which transformed into
activated astroglia with pronounced dendrite-like processes. This phenomenon
was blocked by butoxamine (1 mM) and propranolol (10 microM), but not by
metoprolol (10 microM). However, similar morphological changes in astrocytes
were also observed after stimulation of beta(1)-adrenoceptors by dobutamine
(1-10 microM) and norepinephrine (1-10 microM). This effect was blocked by
propranolol (10 microM) and metoprolol (10 microM) but not by butoxamine (1
mM), suggesting that stimulation of either beta(1)- or beta(2)-adrenoceptors
was sufficient to induce activation of astrocytes. In addition, beta(1)-adrenoceptor
stimulation by dobutamine (1-10 microM) protected hippocampal neurons
against glutamate toxicity. In a model of focal cerebral ischemia in mice
the cerebroprotective effect of clenbuterol (0.3 mg/kg) was blocked by
propranolol (5 mg/kg) and butoxamine (5 mg/kg). Interestingly, the infarct
size was reduced after co-treatment with clenbuterol (0.3 mg/kg) and
metoprolol (5 mg/kg) as compared to clenbuterol treatment (0.3 mg/kg) alone.
In conclusion, activation of astrocytes and neuroprotection can be achieved
by stimulation of either beta(1)- or beta(2)-adrenoceptors in vitro, whereas
in vivo neuroprotection is preferentially mediated through beta(2)-adrenoceptors.
Publication Types:
PMID: 12098582 [PubMed - indexed for MEDLINE]
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Inhibited longitudinal growth of bones in young male rats
by clenbuterol.
Kitaura T,
Tsunekawa N,
Kraemer WJ.
Faculty of Pharmaceutical Sciences, University of Kanazawa, Kakuma, Kanazawa
920-1192, Japan. kitaura@dbs.p.kanazawa-u.ac.jp
PURPOSE: Clenbuterol is one of the beta-2 adrenergic receptor agonists with
potent anabolic properties in muscles, yet the concomitant effects on muscle
and bone in young animals remain to be resolved. Therefore, the purpose of
this study was to determine the effects of clenbuterol administration on
muscles and bones of young rats. METHODS: Twelve male Sprague-Dawley rats
(9-wk-old) were randomly assigned to either a control (CON, N = 6) or
clenbuterol group (CLE, N = 6). Clenbuterol of 2 mg x kg body wt x d(-1) was
administered subcutaneously for 4 wk. After treatment, the soleus (SOL),
extensor digitorum longus (EDL), and ventricle (VENT) muscles and the femurs
(FE) and tibiae (TI) bones were excised and analyzed. The bone mineral
content (BMC), area, and bone mineral density (BMD) of FE and TI were
measured by dual-energy x-ray absorptiometry (DXA). The longitudinal lengths
of bones were measured with the Vernier calipers. RESULTS: CLE showed
smaller body weight than CON (P < 0.05) after the treatment. The muscle wet
weights in CLE tended (P = 0.08) to be higher than CON in SOL (9%) and EDL
(12%), but the ratio of muscle wet weight-to-body weight were higher (SOL: P
< 0.05, EDL: P < 0.01) than CON. VENT of CLE showed increases in both the
wet weight and the ratio (P < 0.01). FEs in CLE showed smaller values in BMC
(P < 0.01), area (P < 0.01), and length (P < 0.05) than CON but not in BMD.
TIs showed significant decreases (P < 0.01) in BMC, area, and length but not
in BMD. CONCLUSION: These results indicated that clenbuterol induced the
muscular hypertrophy but inhibited the longitudinal growth of bones in young
male rats, which may be a serious concern in any ergogenic use.
PMID: 11828236 [PubMed - indexed for MEDLINE]
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Effects of clenbuterol on insulin resistance in conscious
obese Zucker rats.
Pan SJ,
Hancock J,
Ding Z,
Fogt D,
Lee M,
Ivy JL.
Exercise Physiology and Metabolism Laboratory, Department of Kinesiology and
Health Education, University of Texas at Austin, Austin, TX 78712, USA.
The present study was conducted to determine the effect of chronic
administration of the long-acting beta(2)-adrenergic agonist clenbuterol on
rats that are genetically prone to insulin resistance and impaired glucose
tolerance. Obese Zucker rats (fa/fa) were given 1 mg/kg of clenbuterol by
oral intubation daily for 5 wk. Controls received an equivalent volume of
water according to the same schedule. At the end of the treatment, rats were
catheterized for euglycemic-hyperinsulinemic (15 mU insulin. kg(-1).
min(-1)) clamping. Clenbuterol did not change body weight compared with the
control group but caused a redistribution of body weight: leg muscle weights
increased, and abdominal fat weight decreased. The glucose infusion rate
needed to maintain euglycemia and the rate of glucose disappearance were
greater in the clenbuterol-treated rats. Furthermore, plasma insulin levels
were decreased, and the rate of glucose uptake into hindlimb muscles and
abdominal fat was increased in the clenbuterol-treated rats. This increased
rate of glucose uptake was accompanied by a parallel increase in the rate of
glycogen synthesis. The increase in muscle glucose uptake could not be
ascribed to an increase in the glucose transport protein GLUT-4 in
clenbuterol-treated rats. We conclude that chronic clenbuterol treatment
reduces the insulin resistance of the obese Zucker rat by increasing
insulin-stimulated muscle and adipose tissue glucose uptake. The
improvements noted may be related to the repartitioning of body weight
between tissues.
Publication Types:
PMID: 11254461 [PubMed - indexed for MEDLINE]
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Clenbuterol reduces soleus muscle fatigue during disuse
in aged rats.
Chen KD,
Alway SE.
Department of Anatomy, College of Medicine, University of South Florida,
Tampa, Florida, USA.
High levels of clenbuterol have been shown to preserve muscle mass and
function during disuse. In this study we report that a low dose of
clenbuterol (10 microg/kg per day) lessened the loss of in situ soleus
muscle isometric force normalized to wet muscle weight (P(o)/g wet weight)
by 8% and reduced isometric fatigue by approximately 30% in senescent rats
after 21 days of hindlimb suspension (HS). Clenbuterol did not reduce the
loss of relative force in the soleus of adult rats or the plantaris of old
or adult rats. Furthermore, clenbuterol failed to improve muscle force or
isometric fatigue in the soleus of adult rats or in the plantaris of either
age group after HS. We conclude that low levels of clenbuterol reduce muscle
fatigue in slow muscles during disuse and this beta-agonist may also have
therapeutic value for reducing fatigue in slow muscles (e.g., postural
muscles) in the elderly during disuse.
Publication Types:
PMID: 11180204 [PubMed - indexed for MEDLINE]
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Effects of beta(2)-agonist clenbuterol on biochemical and
contractile properties of unloaded soleus fibers of rat.
Ricart-Firinga C,
Stevens L,
Canu MH,
Nemirovskaya TL,
Mounier Y.
Laboratory of Neuromuscular Plasticity, University of Sciences and
Technologies of Lille, F-59655 Villeneuve d'Ascq, France.
The effects of clenbuterol beta(2)-agonist administration were investigated
in normal and atrophied [15-day hindlimb-unloaded (HU)] rat soleus muscles.
We showed that clenbuterol had a specific effect on muscle tissue, since it
reduces soleus atrophy induced by HU. The study of Ca(2+) activation
properties of single skinned fibers revealed that clenbuterol partly
prevented the decrease in maximal tension after HU, with a preferential
effect on fast-twitch fibers. Clenbuterol improved the Ca(2+) sensitivity in
slow- and fast-twitch fibers by shifting the tension-pCa relationship toward
lower Ca(2+) concentrations, but this effect was more marked after HU than
in normal conditions. Whole muscle electrophoresis indicated slow-to-fast
transitions of the myosin heavy chain isoforms for unloaded and for
clenbuterol-treated soleus. The coupling of the two latter conditions did
not, however, increase these phenotypical transformations. Our findings
indicated that clenbuterol had an anabolic action and a beta(2)-adrenergic
effect on muscle fibers and appeared to counteract some effects of unloading
disuse conditions.
Publication Types:
PMID: 10712247 [PubMed - indexed for MEDLINE]
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Clenbuterol increases the expression of myogenin but not
myoD in immobilized rat muscles.
Delday MI,
Maltin CA.
Rowett Research Institute, Bucksburn, Aberdeen, United Kingdom.
Immobilization of one hindlimb of young rats in plantar flexion for 3 days
led to changes in the plantaris muscles. These comprised a loss of muscle
mass and a reduction in protein and RNA content, but no change in the
transcript levels of the myogenic regulatory factors myogenin and myoD.
Dietary administration of the beta-adrenoceptor agonist clenbuterol (2 mg/kg
diet), which has been shown to ameliorate muscle wasting in a wide range of
atrophic conditions, also limited muscle wasting in terms of weight, protein,
and RNA in the immobilized plantaris muscles. In addition, drug treatment in
immobilized plantaris muscles was associated with a marked increase in the
steady-state levels of mRNA for myogenin (approximately 360% increase over
control) but not myoD. These data provide the first evidence for independent
changes in these two myogenic regulatory factors in immobilized muscle and
suggest that the action of clenbuterol on these factors may depend on the
mechanistic basis for the atrophic response.
Publication Types:
PMID: 9176197 [PubMed - indexed for MEDLINE]
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Interaction of exercise training and clenbuterol on GLUT-4
protein in muscle of obese Zucker rats.
Kuo CH,
Ding Z,
Ivy JL.
Department of Kinesiology, University of Texas at Austin 78712, USA.
Chronic administration of clenbuterol, a beta 2-adrenergic agonist,
attenuates the exercise training-induced improvement in muscle insulin
resistance of the obese Zucker rat. The present study was conducted to
determine whether clenbuterol also attenuates the increase in muscle GLUT-4
protein that occurs with exercise training and whether the action of
clenbuterol is related to its ability to downregulate the beta-adrenergic
receptors. Female obese Zucker rats were randomly assigned to one of the
following four groups: control (CON, n = 7), clenbuterol (CL, n = 8),
exercise training (TR, n = 8), and clenbuterol with exercise training (CL+TR,
n = 8). Rats assigned to the training groups were run on a rodent
motor-driven treadmill for 6-7 wk. Rats receiving clenbuterol were intubated
with 0.8 mg/kg body weight 30 min before running each day. Red quadriceps (RQ)
and white quadriceps (WQ) GLUT-4 protein concentrations of TR rats were
significantly greater than those of CON and CL+TR rats. The RQ GLUT-4
protein concentration of the CL+TR rats was significantly greater than that
of CON rats, but this difference did not occur in the WQ. GLUT-4 protein
concentrations were not different between the CON and CL rats. The patterns
of RQ and WQ GLUT-4 mRNA were similar to those of their respective GLUT-4
proteins. Rats receiving daily injections of propranolol (30 mg/kg body wt),
a beta-adrenergic receptor antagonist, demonstrated no increase in GLUT-4
protein in RQ or WQ after 6 wk of exercise training. These results indicate
that 1) clenbuterol can attenuate the increase in muscle GLUT-4 protein
associated with exercise training and 2) this effect is likely mediated by a
downregulation of the beta-adrenergic receptors.
PMID: 8944671 [PubMed - indexed for MEDLINE]
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Effect of selective beta-adrenoceptor stimulation on UCP
synthesis in primary cultures of brown adipocytes.
Puigserver P,
Picó C,
Stock MJ,
Palou A.
Dept. de Biologia Fonamental i Ciències de la Salut, Universitat de les
Illes Balears, Palma de Mallorca, Spain.
Given the co-existence of the three beta-adrenoceptor (beta AR) subtypes
(beta 1AR, beta 2AR and beta 3AR) in brown adipocytes, the present study was
undertaken to determine the relative importance of these in the induction of
UCP synthesis in mouse BAT precursor cells in primary culture. Cells at
different stages of differentiation were exposed to different beta AR
agonists: prenalterol (a selective beta 1AR agonist), salbutamol or
clenbuterol (selective beta 2AR agonists), or BRL 37344 (a selective beta
3AR agonist). As with the endogenous agonist, noradrenaline, and the
non-selective beta AR agonist, isoprenaline, all four beta AR agonists
induced UCP in the confluent stage of the cells, but with different
potencies, and with the highest induction being seen after clenbuterol or
BRL 37344 treatment. Cells in the confluent stage of development were the
most sensitive to the effects of the agonists, although clenbuterol and BRL
37344 induced a weak UCP synthesis in pre-confluent cells. None of these
beta AR agonists were able to induce UCP synthesis in the post-confluent
period. The responses to prenalterol and salbutamol were inhibited by
propranolol at relatively low concentrations, suggesting their effects were
mediated by beta 1AR and beta 2AR, respectively. However, propranolol was a
particularly weak antagonist of BRL 37344 and, unexpectedly, of the
clenbuterol UCP responses, which suggests that both induce UCP synthesis via
the beta 3AR. In summary, the beta 3AR is the most important adrenoceptor
coupled to the induction of UCP synthesis, although both beta 1AR and beta
2AR activation may make a contribution. However, all three beta AR subtypes
do not become fully functional until cultured cells become confluent.
Publication Types:
PMID: 8734469 [PubMed - indexed for MEDLINE]
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Clenbuterol has a greater influence on untrained than on
previously trained skeletal muscle in rats.
Murphy RJ,
Béliveau L,
Seburn KL,
Gardiner PF.
Département d'Education Physique, Université de Montréal, Canada.
The effects of clenbuterol, a selective beta 2-adrenergic agonist, and of
exercise training on the properties of skeletal muscle were studied in the
hindlimb of sedentary and trained rats. A 2-week training programme,
consisting of climbing on a grid with a load attached to the tail, did not
increase the muscle mass of the soleus, the plantaris and the gastrocnemius
muscles or modify the isometric in situ contractile properties of the medial
gastrocnemius muscle. The only change observed in a 12-week training regimen
was a significant increase in contractile forces (expressed in grams per
gram of muscle) of the medial gastrocnemius muscle at sub-tetanic
stimulating frequencies (twitch 42%, 25Hz 45% and 50Hz 47%). Both training
programmes significantly increased fatigue resistance of the medial
gastrocnemius muscle. A 2-week oral treatment with clenbuterol significantly
increased the muscle mass of the soleus (19.8%), plantaris (16.9%) and
gastrocnemius (15.3%) muscles in all animals treated with the agonist.
However, clenbuterol had different effects in animals beginning their
training programme than in animals that had been trained for the previous 10
weeks. Specifically, clenbuterol caused a significant increase in
gastrocnemius muscle mass in the former group but not in the latter. These
results suggest that the responses to the combination of clenbuterol and
training in previously trained skeletal muscles are not as marked as those
observed in untrained muscles.
Publication Types:
PMID: 8781861 [PubMed - indexed for MEDLINE]
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Effects of clenbuterol and ICI118551, a selective beta 2-antagonist,
on the growth of skeletal muscle of suckling rats.
Morton RH,
Agbenyega ET,
Hatton PA,
Wareham AC.
School of Health Sciences, University of Wolverhampton, UK.
The beta 2-adrenergic agonist, clenbuterol, was administered to lactating
rats (4 mg/kg diet) from post-partum day 1 to day 19, or directly injected
into neonate rats (0.1 and 1.0 mg/kg body weight) from post-partum day 3
until day 15. Changes in body weight and the skeletal muscles soleus (SOL)
and extensor digitorum longus (EDL) were studied in both dams and suckling
offspring. Drug treatment consistently increased body weight in dams whilst
significantly reducing the growth of their suckling pups. In dams treated
with clenbuterol (4 mg/kg of diet) muscle weights and protein contents were
significantly increased. Total protein content increased by 16% in SOL and
47% in EDL after 19 days of treatment. In contrast, in their suckling pups,
there was a 22% and 26% reduction in protein content of SOL and EDL
respectively. Administration of the beta 2-antagonist ICI118551 to these
pups failed to prevent these reductions in body and muscle weights. Hence,
if clenbuterol did reach the pups via the milk from treated mothers it did
not act via conventional beta 2-receptors. Injection of pups with
clenbuterol (1.0 mg/kg every 12 h) from litters suckling from untreated dams
also resulted in significant reductions in muscle weights and protein
contents. Protein content was reduced by 10% in SOL and 13% in EDL after 12
days of treatment. No alteration in fibre type proportion in SOL or EDL
resulted from this treatment. Further work is required to determine whether
the growth suppression in the two situations occurs via the same mechanism.
Publication Types:
PMID: 9026784 [PubMed - indexed for MEDLINE]
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Cardiovascular effects of clenbuterol are beta 2-adrenoceptor-mediated
in steers.
Hoey AJ,
Matthews ML,
Badran TW,
Pegg GG,
Sillence MN.
Tropical Beef Centre, Rockhampton, Queensland, Australia.
The mechanism through which the repartitioning agent clenbuterol increases
heart rate was investigated. First, the relative importance of the beta 1-
and beta 2-adrenoceptors was established in rat and bovine right atria in
vitro. The positive chronotropic and inotropic effects of (+/-)isoproterenol
in rat and bovine right atria, respectively, were markedly antagonized (P <
.001) by the beta 1-adrenoceptor antagonist CGP 20712A but were antagonized
less by the beta 2-adrenoceptor antagonist ICI 118 551 in rat (P < .01), but
not in bovine atria, indicating a major role of the beta 1-adrenoceptors.
Clenbuterol was only a partial agonist in rat right atria, increasing heart
rate at high concentrations through stimulation of beta 1-adrenoceptors. In
studies in vivo, clenbuterol decreased the plasma potassium concentration (P
< .05) and increased the plasma glucose concentration (P < .05). Clenbuterol
also reduced diastolic blood pressure (P < .01) and increased heart rate (P
< .001). The increase in heart rate was not due to direct stimulation of
cardiac beta 1-adrenoceptors by clenbuterol but was consistent with a reflex
response to beta 2-adrenoceptor-mediated hypotension. This would have caused
the activation of baroreceptors, which in turn would have resulted in both
the release of norepinephrine to stimulate cardiac beta 1-adrenoceptors and
the inhibition of cholinergic input to the heart. Thus, the effects of
clenbuterol could be eliminated completely by ICI 118 551 or reduced by
approximately 50% using CGP 20712A. The combination of treatment of
clenbuterol and CGP 20712A could be useful. It may allow the full
repartitioning effects seen with the beta 2-agonist alone, but with a
markedly attenuated effect on the heart. Such a treatment regimen may also
help reduce the increased energy expenditure and loss of appetite seen
following the initial administration of clenbuterol.
Publication Types:
PMID: 7673070 [PubMed - indexed for MEDLINE]
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Anabolic effects of the beta 2-adrenoceptor agonist
salmeterol are dependent on route of administration.
Moore NG,
Pegg GG,
Sillence MN.
Department of Chemistry, University of Central Queensland, Rockhampton,
Australia.
It is reported that a long duration of action is required for beta 2-adrenoceptor
agonists to evoke an anabolic response. In the present study, we compare the
potency of clenbuterol with that of the new long-acting compound salmeterol,
when given at equimolar doses to female Wistar rats by different routes of
administration. Given orally for 10 days, salmeterol had no effect on growth
at a dose of 120 micrograms/day, whereas at 2.4 mg/day the drug caused
significant increases in body and carcass weight and in the mass of the
mixed-fiber gastrocnemius/plantaris and tibialis anterior muscles, but there
were no increases in the slow-twitch soleus muscles. A similar growth
response was seen when clenbuterol was given orally at a dose of only 97
micrograms/day, with an additional response seen in soleus muscle at 1.9 mg/day.
Thus clenbuterol was more potent than salmeterol when given by this route of
administration. When the drugs were infused by osmotic minipump, both
salmeterol (130 micrograms/day) and clenbuterol (100 micrograms/day) caused
increases in body weight gain and in the weights of the mixed-fiber muscles,
with the most dramatic effect of infusion being to greatly increase the
anabolic effect of salmeterol in soleus muscle. A single intraperitoneal
injection of salmeterol (53 micrograms) or clenbuterol (40 micrograms)
caused a similar rapid increase in the concentration of adenosine 3',5'-cyclic
monophosphate in gastrocnemius muscle. These results indicate that the
potency of salmeterol in vivo is dependent on its route of administration
and that slow-twitch muscles are less sensitive than mixed-fiber muscles to
the anabolic effects of beta 2-adrenoceptor agonists.
Publication Types:
PMID: 7943228 [PubMed - indexed for MEDLINE]
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Anabolic effects of clenbuterol after long-term treatment
and withdrawal in t the rat.
Cartañà J,
Segués T,
Yebras M,
Rothwell NJ,
Stock MJ.
Department de Bioquímica i Biotecnologia, Facultat de Ciències Químiques,
Universitat Rovira i Virgili, Tarragona, Spain.
Injection of rats with the beta 2-adrenoceptor agonist clenbuterol (1
mg/kg/d for 15 days) stimulated an increase in body weight (9%) and protein
(8%) and water (7%) content, but reduced food intake (4%) and epididymal fat
pad mass (39%). Nine days after termination of treatment, ex-clenbuterol
rats were heavier (5%) and had a greater protein (7%) and water (6%) content
and lower fat pad mass (32%) than controls. Clenbuterol-fed rats (2 mg/kg
diet for 10 days, providing an average of 0.04 mg clenbuterol/kg/d)
increased body weight (7%), muscle mass (15% to 21%), and muscle protein
content (9% to 26%), whereas epididymal fat pad weight and muscle glycogen
content were reduced. During the withdrawal period, the greater body weight
of ex-clenbuterol rats was sustained overall (ANOVA, P < .00005), but by day
10 this difference was no longer significant. At this point, gastrocnemius
muscle mass was still higher (11%) when compared with that of control
animals, but soleus muscle mass, muscle glycogen concentration, and
epididymal fat pad weight had reverted to control values. These results were
corroborated in a subsequent experiment using older rats. It was concluded
that, unlike other beta-adrenoceptor-mediated effects, muscle protein
accumulated during clenbuterol treatment can be maintained in certain
muscles after removal of the drug for a period of time that is at least
equivalent to the duration of treatment. This could have implications for
the potential therapeutic use of this class of compound, and differences in
the response observed between muscle types may help to elucidate the
mechanisms responsible for the muscle protein deposition induced by
clenbuterol.
Publication Types:
PMID: 8084283 [PubMed - indexed for MEDLINE]
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