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Efeito muscular e nerológico do clenbuterol

 
1: J Pharmacol Sci. 2007 Jun;104(2):146-52. Epub 2007 Jun 8. Related Articles, Links
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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.

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PMID: 17558185 [PubMed - indexed for MEDLINE]

 
2: Neurobiol Aging. 2007 Mar 13; [Epub ahead of print] Related Articles, Links
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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]
 
3: Muscle Nerve. 2007 Feb;35(2):217-23. Related Articles, Links
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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.

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PMID: 17058275 [PubMed - indexed for MEDLINE]

 
4: Indian J Exp Biol. 2006 Jun;44(6):448-58. Related Articles, Links

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.

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PMID: 16784115 [PubMed - indexed for MEDLINE]

 
5: Muscle Nerve. 2006 May;33(5):655-63. Related Articles, Links
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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.

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PMID: 16411205 [PubMed - indexed for MEDLINE]

 
6: Physiol Res. 2006;55(1):97-103. Epub 2005 Apr 26. Related Articles, Links
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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.

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PMID: 15857157 [PubMed - indexed for MEDLINE]

 
7: Bone. 2005 Nov;37(5):622-33. Epub 2005 Sep 12. Related Articles, Links
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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]
 
8: Acta Physiol Scand. 2004 Mar;180(3):271-80. Related Articles, Links
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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]
 
9: Domest Anim Endocrinol. 2004 Jan;26(1):23-31. Related Articles, Links
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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.

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PMID: 14732450 [PubMed - indexed for MEDLINE]

 
10: Eur J Pharmacol. 2002 Jun 20;446(1-3):25-36. Related Articles, Links
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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.

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PMID: 12098582 [PubMed - indexed for MEDLINE]

 
11: Med Sci Sports Exerc. 2002 Feb;34(2):267-73. Related Articles, Links
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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]
 
12: Am J Physiol Endocrinol Metab. 2001 Apr;280(4):E554-61. Related Articles, Links
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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.

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PMID: 11254461 [PubMed - indexed for MEDLINE]

 
13: Muscle Nerve. 2001 Feb;24(2):211-22. Related Articles, Links
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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.

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PMID: 11180204 [PubMed - indexed for MEDLINE]

 
14: Am J Physiol Cell Physiol. 2000 Mar;278(3):C582-8. Related Articles, Links
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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.

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PMID: 10712247 [PubMed - indexed for MEDLINE]

 
15: Am J Physiol. 1997 May;272(5 Pt 1):E941-4. Related Articles, Links
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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.

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PMID: 9176197 [PubMed - indexed for MEDLINE]

 
16: Am J Physiol. 1996 Nov;271(5 Pt 1):E847-54. Related Articles, Links
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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]
 
17: Mol Cell Endocrinol. 1996 Mar 1;117(1):7-16. Related Articles, Links
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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]

 
18: Eur J Appl Physiol Occup Physiol. 1996;73(3-4):304-10. Related Articles, Links

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]

 
19: Pflugers Arch. 1995 Dec;431(2):237-43. Related Articles, Links

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]

 
20: J Anim Sci. 1995 Jun;73(6):1754-65. Related Articles, Links
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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]

 
21: Am J Physiol. 1994 Sep;267(3 Pt 1):E475-84. Related Articles, Links
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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]

 
22: Metabolism. 1994 Sep;43(9):1086-92. Related Articles, Links

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]

 
23: Metabolism. 1994 Sep;43(9):1119-25. Related Articles, Links
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Comparison of the effects of salbutamol and clenbuterol on skeletal muscle mass and carcass composition in senescent rats.

Carter WJ, Lynch ME.

Veterans Administration Medical Center, Little Rock, AR.

Aging decreases skeletal muscle mass and strength, making elderly subjects particularly vulnerable to catabolic effects of age-related diseases. Clenbuterol, a muscle anabolic beta 2-adrenergic agonist, has reduced or restored skeletal muscle losses in experimental catabolic states. However, the doses of clenbuterol used to prevent or reverse muscle wasting in most animal models have exceeded the estimated safe dose in man. Recently, another beta 2-adrenergic agonist, salbuamol (albuterol), has been shown to increase muscle weight and protein content in young rats at a dose similar to that used clinically. In contrast to clenbuterol, salbutamol is currently approved for human use as a bronchodilator in the United States. This study has compared the muscle and protein anabolic effects of salbutamol at a clinically relevant dose with those of clenbuterol at a dose typically used in animal models of muscle wasting. Salbutamol and clenbuterol were administered by implanted osmotic minipumps to Fisher-344 rats aged 3 and 24 months at doses of 1.03 mg and 600 micrograms per kilogram per 24 hours for 3 weeks. The weights of five hindlimb muscles, as well as carcass protein and fat content, were determined. Salbutamol and clenbuterol increased combined hindlimb muscle weight 19% and 28% in young rats, with 19% and 25% increases in old rats. Similarly, these drugs increased gastrocnemius weight and protein content 19% and 24% in young rats, with 19% and 23% increases in old rats. Salbutamol and clenbuterol increased carcass protein content 20% and 30% in young rats, with 12% and 21% increases in old rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Publication Types:


PMID: 7916118 [PubMed - indexed for MEDLINE]

 
24: J Gerontol. 1994 Jul;49(4):B162-8. Related Articles, Links

Effect of clenbuterol on recovery of muscle mass and carcass protein content following dietary protein depletion in young and old rats.

Carter WJ, Lynch ME.

Veterans Administration Medical Center, Little Rock, Arkansas.

There is a need for new therapeutic agents designed to prevent or restore skeletal muscle loss in frail, elderly subjects resulting from injury or disease and associated catabolic stresses such as malnutrition. Since the beta 2-adrenergic agonist clenbuterol increases skeletal muscle mass in rats, the effect of this agent on recovery of muscle mass and carcass protein content following protein malnutrition was studied in young and old rats. The 3-week period of severe dietary protein restriction reduced body weight 21%, hind-limb muscle weight 24 and 15%, and carcass protein content 31 and 19%, respectively, in 3- and 24-month-old rats. During the 3-week recovery period induced by feeding a complete diet, 10 mg clenbuterol per kg diet increased hind-limb muscle weight 34 and 30% and carcass protein content 27 and 25%, respectively, in 3- and 24-month-old rats. Restoration was complete in animals of both ages fed clenbuterol and incomplete in animals fed the control diet. These observations suggest that clenbuterol or similar beta 2-adrenergic agonists may be useful in hastening the recovery of muscle mass and body protein stores lost because of malnutrition in frail, elderly humans.

Publication Types:


PMID: 8014387 [PubMed - indexed for MEDLINE]

 
25: Burns. 1993 Feb;19(1):26-34. Related Articles, Links

Clenbuterol, a beta 2-adrenergic agonist, reverses muscle wasting due to scald injury in the rat.

Martineau L, Little RA, Rothwell NJ, Fisher MI.

Department of Physiological Sciences, University of Manchester, UK.

The effects of clenbuterol, a beta 2-adrenergic agonist, on body weight, tissue masses, and protein and RNA contents were studied following scald injury (30 per cent TBSA) in the rat. While the masses of heart, liver and epididymal fat pads remained unaffected, significant reductions in gastrocnemius, plantaris and soleus muscle masses (approximately 11 per cent; P < 0.01) were observed following injury, none of which were mimicked by pair-feeding or could be attributed to dehydration. This muscle wasting was accompanied by significant reductions in protein and/or RNA content. Oral administration of clenbuterol (4 mg/kg diet) had no anabolic effects, either in the scalded animals or their pair-fed controls. While clenbuterol (12 mg/kg diet) did not affect the masses of heart and fat pads, increases in the wet weights (approximately 20 per cent), RNA (approximately 30 per cent) and protein content (approximately 20 per cent) of the gastrocnemius and plantaris muscles were observed in all animals; the magnitude of these effects was greater (P < 0.05) in the scalded animals than in their pair-fed controls. Clenbuterol had no effect on body weight but increased (P < 0.001) carcass water content. These data indicate that there is a selective mobilization of muscle protein and sparing of fat in the early phase following burn injury, and that beta 2-adrenergic agonists, such as clenbuterol, may be of therapeutic value in inhibiting or reversing muscle atrophy associated with thermal injury.

Publication Types:


PMID: 7679579 [PubMed - indexed for MEDLINE]

 
26: Am J Physiol. 1992 Jul;263(1 Pt 1):E50-6. Related Articles, Links
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Anabolic effects of clenbuterol on skeletal muscle are mediated by beta 2-adrenoceptor activation.

Choo JJ, Horan MA, Little RA, Rothwell NJ.

Department of Physiological Sciences, University of Manchester Medical School, United Kingdom.

The potent anabolic effects of the beta 2-adrenoceptor agonist clenbuterol on skeletal muscle have been reported to be independent of actions on beta-adrenoceptors. In the present study clenbuterol, presented to rats in the diet (4 mg/kg), caused significant increases in gastrocnemius muscle mass, protein, and RNA content and a decrease in epididymal fat pad mass. These effects were not mimicked by oral administration of the beta 2-adrenoceptor agonist salbutamol even at high dose (52 mg/kg diet), and the effects of clenbuterol were not inhibited by addition of DL-propranolol (200 mg/kg diet). However, the selective beta 2-antagonist ICI-118,551 (200 mg/kg diet) reversed the anabolic effects of clenbuterol, and a high dose of DL-propranolol (1,000 mg/kg diet) also inhibited these actions of clenbuterol. Furthermore, continuous infusion of salbutamol (1.15 mg.kg body wt-1.day-1) via miniosmotic pumps did cause significant increases in muscle mass, protein, and RNA content. These results indicate that the anabolic effects of clenbuterol are dependent on interaction with the beta 2-adrenoceptor. However, a long duration of action appears to be required to induce the anabolic effects of beta 2-agonists.

Publication Types:


PMID: 1322047 [PubMed - indexed for MEDLINE]

 
27: Naunyn Schmiedebergs Arch Pharmacol. 1991 Oct;344(4):449-53. Related Articles, Links

Effects of clenbuterol, ICI118551 and sotalol on the growth of cardiac and skeletal muscle and on beta 2-adrenoceptor density in female rats.

Sillence MN, Matthews ML, Spiers WG, Pegg GG, Lindsay DB.

CSIRO Division of Tropical Animal Production, Tropical Cattle Research Centre, Queensland, Australia.

The aim of the present study was to determine whether the anabolic effects of clenbuterol in rat skeletal muscle are mediated by beta 2-adrenoceptor stimulation. Female rats were treated with clenbuterol, alone or in combination with either the nonselective beta 1/beta 2-adrenoceptor antagonist sotalol, or the beta 2-adrenoceptor-selective antagonist ICI118551. Clenbuterol caused an increase in muscle growth, accompanied by a reduction in beta 2-adrenoceptor density in the rat hind-limb. Both actions were attenuated by sotalol. However, at the dose tested ICI118551 was the more effective antagonist of the muscle growth response, and when given alone, ICI118551 caused significant muscle atrophy. An increase in the weight of the heart was also observed in clenbuterol-treated rats, and again while this effect was attenuated by sotalol, it was reversed by ICI118551. It is concluded that beta 2-adrenoceptors mediate the anabolic effects of clenbuterol in cardiac and skeletal muscle, and that they play an important physiological role in the growth and maintenance of muscle mass in the rat hind-limb.

Publication Types:


PMID: 1685013 [PubMed - indexed for MEDLINE]

 
28: Metabolism. 1991 Aug;40(8):855-60. Related Articles, Links

Effects of clenbuterol on skeletal muscle mass, body composition, and recovery from surgical stress in senescent rats.

Carter WJ, Dang AQ, Faas FH, Lynch ME.

Veterans Administration Medical Center, Little Rock, AR.

Aging decreases skeletal muscle mass and strength, which may be exacerbated by age-related diseases. There is a need for therapeutic agents to prevent or restore loss of skeletal muscle in elderly subjects with muscle wasting disorders. Clenbuterol, a beta 2-adrenergic agonist, dramatically increases skeletal muscle mass in young animals and partially prevents or restores muscle loss in experimental models of muscle wasting. However, the protein anabolic and fat catabolic effects of clenbuterol have not been studied in senescent animals. To determine whether this drug has potential for preventing or repairing muscle loss in elderly subjects, we have examined its effects in young and old rats. Clenbuterol was administered by implanted osmotic minipumps to Fischer-344 rats ages 3, 12, and 23 months, at a dose of 1.5 mg/kg/24 h for 3 weeks. The weights of five hindlimb muscles and carcass protein and fat content were determined. Clenbuterol treatment increased the weight of skeletal muscles 22% to 39% in 3-month-old rats, 19% to 35% in 12-month-old rats, and 22% to 25% in 23-month-old animals. Likewise, clenbuterol increased carcass protein content 19% in 3-month-old rats, 16% in 12-month-old rats, and 24% in 23-month-old animals. Conversely, the drug reduced carcass fat content 36% in 3-month-old rats, 32% in 12-month-old rats, and 38% in 23-month-old rats. Therefore, clenbuterol had similar anabolic and catabolic effects in all age groups. In addition, clenbuterol stimulated recovery of skeletal muscle protein lost following pump implantation in senescent rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Publication Types:


PMID: 1861634 [PubMed - indexed for MEDLINE]

 
29: Br J Nutr. 1991 Mar;65(2):115-29. Related Articles, Links
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Action and interaction of growth hormone and the beta-agonist, clenbuterol, on growth, body composition and protein turnover in dwarf mice.

Bates PC, Pell JM.

Nutrition Research Unit, London School of Hygiene, London.

The responses of dwarf mice to dietary administration of clenbuterol (3 mg/kg diet), daily injections of growth hormone (15 micrograms/mouse per d) or both treatments combined were investigated and their actions, and any interactions, on whole-body growth, composition and protein metabolism, and muscle, liver and heart growth and protein metabolism, were studied at days 0, 4 and 8 of treatment. Growth hormone, with or without clenbuterol, induced an increase in body-weight growth and tail length growth; clenbuterol alone did not affect body-weight or tail length. Both growth hormone and clenbuterol reduced the percentage of whole-body fat and increased the protein:fat ratio. They also increased protein synthesis rates of whole body and muscle, although the magnitude of the increase was greater in response to growth hormone than to clenbuterol. Clenbuterol specifically induced growth of muscle, with a decrease in liver protein content, whereas growth hormone exhibited more general anabolic effects on tissue protein. Previous reports have suggested that effects of clenbuterol on skeletal muscle are mediated, at least in part, via decreased rates of protein degradation; we could find little evidence of any decrease in whole-body or tissue protein degradation and anabolic effects were largely due to increases in protein synthesis rates. However, small increases in muscle protein degradation rate were observed in response to growth hormone. Growth hormone induced a progressive increase in serum insulin-like growth factor-1 concentration, whereas there was no change with clenbuterol administration. Anabolic effects on whole-body and skeletal muscle protein metabolism, therefore, appear to be initially via independent mechanisms but are finally mediated by a common response (increased protein synthesis) in dwarf mice.

PMID: 2043598 [PubMed - indexed for MEDLINE]
 
30: J Trauma. 1991 Mar;31(3):365-70. Related Articles, Links

Clenbuterol decreases catabolism and increases hypermetabolism in burned rats.

Chance WT, von Allmen D, Benson D, Zhang FS, Fischer JE.

Department of Surgery, University of Cincinnati Medical Center, Ohio 45267-0558.

Following a 30% body surface area full-thickness open-flame burn, rats exhibited hypermetabolism, body weight loss, and muscle catabolism. Twenty-one days of treatment of one group of burned rats with the selective beta 2-adrenergic agonist, clenbuterol, increased resting energy expenditure and normalized body weight gain, muscle mass, and muscle protein content. Conversely, similar treatment of another group of burned rats with the long-acting beta-adrenergic antagonist, nadolol, reduced muscle mass, while having no effect on resting energy expenditure, body weight gain, or muscle protein content. These results demonstrate that hypermetabolism does not invariably result in loss of lean body mass and suggest that clenbuterol may be useful in preserving muscle mass and protein in catabolic diseases.

Publication Types:


PMID: 2002523 [PubMed - indexed for MEDLINE]

 
31: J Surg Res. 1991 Jan;50(1):1-5. Related Articles, Links
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Decreased myofibrillar protein breakdown following treatment with clenbuterol.

Benson DW, Foley-Nelson T, Chance WT, Zhang FS, James JH, Fischer JE.

Department of Surgery, University of Cincinnati Medical Center, Ohio 45267.

Daily treatment of Fischer-344 rats for 14 days with the beta 2-adrenergic agonist, clenbuterol, increased gastrocnemius muscle mass and protein content. Coadministration with the beta-adrenergic antagonist, nadolol, significantly reduced these anabolic effects of clenbuterol. Although clenbuterol treatment reduced food intake during the first 4 days, clenbuterol-treated rats were hyperphagic during the second week of drug administration. Nadolol treatment also blocked these effects of clenbuterol on feeding. In a second experiment, in vitro incubation of extensor digitorum longus muscles taken from post weaning food-deprived rats demonstrated decreased release of 3-methylhistidine by clenbuterol-treated rats, suggesting decreased breakdown of myofibrillar protein. Protein synthesis was not increased in vitro in the soleus muscles taken from these rats. These experiments demonstrate that the anabolic effect of clenbuterol is due in part to beta-adrenergic activity and may involve reduced myofibrillar protein degradation. These results appear to have direct application to nutrition and protein repletion in various catabolic diseases.

Publication Types:


PMID: 1670961 [PubMed - indexed for MEDLINE]

 
32: Biochem J. 1989 Dec 1;264(2):573-9. Related Articles, Links
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Effects of clenbuterol and propranolol on muscle mass. Evidence that clenbuterol stimulates muscle beta-adrenoceptors to induce hypertrophy.

MacLennan PA, Edwards RH.

Department of Medicine, Liverpool University, U.K.

1. A single subcutaneous injection of clenbuterol hydrochloride (0.125 mg/kg body wt.) to female Wistar rats produced a rapid increase in muscle cyclic AMP and lactate concentrations and a decrease in muscle glycogen concentrations. These changes are characteristic of muscle beta-adrenoceptor stimulation and were abolished by intraperitoneal injection of propranolol (12.5 mg/kg) 15 min before clenbuterol administration. 2. When this dose of clenbuterol was injected twice daily, the changes in muscle metabolite concentrations which followed its acute administration persisted until day 7 of treatment, and were accompanied by increases in muscle mass, body weight and muscle protein synthesis rate (ks). When the clenbuterol injections were preceded by propranolol injections (12.5 mg/kg administered according to the protocol described above), or if animals were treated with propranolol only, the values of these variables were not significantly different from those of sham-injected controls. 3. In rats fed on a semi-synthetic diet (PW3) supplemented with 2 mg of clenbuterol/kg of diet for 7 days, the muscle mass was greater than that of rats fed on unsupplemented PW3. The increased muscle mass was accompanied by increased muscle lactate and decreased muscle glycogen concentrations. When PW3 was supplemented with 2 mg of clenbuterol/kg and 200 mg of propranolol/kg, the increase in muscle mass remained, but decreased muscle glycogen concentrations and increased muscle lactate concentrations were also observed. 4. These data are consistent with the hypothesis that clenbuterol influences muscle growth via beta-adrenoceptor stimulation.

Publication Types:


PMID: 2481447 [PubMed - indexed for MEDLINE]

 
33: Biochem Pharmacol. 1989 Sep 15;38(18):2957-65. Related Articles, Links
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Effects of the beta 2-adrenoceptor agonist clenbuterol on tyrosine and tryptophan in plasma and brain of the rat.

Edwards DJ, Sorisio DA, Knopf S.

Department of Pharmacology-Physiology, University of Pittsburgh School of Dental Medicine, PA 15261.

The beta 2-adrenoceptor agonist, clenbuterol (initially 5 mg/kg), was found to significantly reduce plasma tyrosine and raise brain tryptophan levels (P less than 0.01). By comparison, decreases in plasma tryptophan and increases in brain tyrosine were small and often nonsignificant. Amino acid levels measured in different brain regions revealed that the elevations were similar among the cerebellum, striatum, and cortex. These effects were partially blocked by propanolol but not by atenolol. The ED50 was estimated from dose-response curves to be about 0.05 mg/kg for both the decrease in plasma tyrosine and the increase in brain tryptophan. The effects of low doses of clenbuterol were prevented completely by propranolol. Peripheral organs displayed strikingly different patterns of change in amino acid concentrations. Only the spleen had any accumulation of tryptophan, but that was much less than in brain. In contrast, tyrosine and tryptophan were decreased in heart and unaltered in liver; tyrosine was decreased in lung. The elevation in brain tryptophan levels was attenuated by the beta 2-antagonist, ICI 118,551, but not by the beta 1-antagonist, betaxolol; but the reduction in plasma tyrosine was unaffected by either drug. The serotonin antagonist, methysergide, failed to block the effects of clenbuterol. We conclude that changes in amino acid concentrations produced by clenbuterol are mediated by beta 2-adrenoceptor stimulation. Although the increases in brain tyrosine and tryptophan were similar to increases in the plasma ratios of these amino acids to the sum of the other large neutral amino acids competing for transport into the brain, the disparity between the effects of ICI 118,551 in brain and plasma suggests that clenbuterol may also have a direct action in brain to regulate levels of aromatic amino acids. Since clenbuterol has been purported to have an antidepressant effect and since other antidepressants also increase brain tryptophan, this may be a common feature of antidepressant drug action.

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PMID: 2551300 [PubMed - indexed for MEDLINE]

 
34: Brain Res Bull. 1988 Sep;21(3):491-7. Related Articles, Links
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Behavioral consequences of activation of beta adrenergic receptors by clenbuterol: evidence for mediation by the central nervous system.

O'Donnell JM.

Life Sciences Division, Los Alamos National Laboratory, NM 87545.

The centrally acting beta adrenergic agonist clenbuterol has been shown to produce specific effects on behavior maintained under differential-reinforcement-of-low-rate and multiple fixed-interval/fixed-ratio schedules. In the present study, experiments were carried out to determine whether these effects of clenbuterol were mediated by beta adrenergic receptors in the brain or in the periphery. This was accomplished by comparing the antagonistic potencies of the beta adrenergic antagonists propranolol and CGP-12177, following systemic administration. These compounds were found to exhibit similar affinities for beta adrenergic receptors in vitro. They also inhibited 125I-pindolol binding, in vivo, to rat heart and lung with similar potencies. By contrast, CGP-12177, being hydrophilic relative to propranolol, was approximately 100-fold less potent than propranolol at inhibiting 125I-pindolol binding in cerebral cortex and cerebellum, in vivo. The potencies of propranolol and CGP-12177 for antagonizing the behavioral effects of clenbuterol also were determined. CGP-12177 was about 40-fold less potent than propranolol at antagonizing the behavioral effects of clenbuterol. These results suggest that the changes in the goal-oriented behaviors produced by clenbuterol were predominantly a result of activation of central, rather than peripheral, beta adrenergic receptors. For this reason, it appears that centrally acting beta adrenergic agonists like clenbuterol may be useful pharmacological tools to study the relationship between activation of central beta adrenergic receptors and behavior.

Publication Types:


PMID: 2850845 [PubMed - indexed for MEDLINE]

 
2: J Biochem Mol Biol. 2007 Jul 31;40(4):525-31. Related Articles, Links
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Clenbuterol inhibits SREBP-1c expression by activating CREB1.

Zhou L, Li Y, Nie T, Feng S, Yuan J, Chen H, Yang Z.

Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Life Science and Technology, Huazhong Agricultural University, Wuhan, 430070, P. R. China.

As a beta(2)-adrenergic agonist, clenbuterol decreases body fat, but the molecular mechanism underlying this process is unclear. In the present study, we treated 293T and L-02 cells with clenbuterol and found that clenbuterol downregulates SREBP-1c expression and upregulates CREB1 expression. Considering SREBP-1c has the function of regulating the transcription of several lipogenic enzymes, we considered that the downregulation of SREBP-1c is responsible for body fat reduction by clenbuterol. Many previous studies have found that clenbuterol markedly increases intracellular cAMP levels, therefore, we also investigated whether CREB1 is involved in this process. The data from our experiments indicate that CREB1 overexpression inhibits SREBP-1c transcription, and that this action is antagonized by CREB2, a competitive inhibitor of CREB1. Furthermore, since PPARs are able to repress SREBP-1c transcription, we investigated whether clenbuterol and CREB1 function via a pathway involving PPAR activation. However, our results showed that clenbuterol or CREB1 overexpression suppressed PPARs transcription in 293T and L-02 cells, which suggested that they impair SREBP-1c expression in other ways.

Publication Types:


PMID: 17669268 [PubMed - in process]

 
3: J Pharmacol Sci. 2007 Jun;104(2):146-52. Epub 2007 Jun 8. Related Articles, Links
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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]

 
4: Endocrinology. 2007 Jul;148(7):3441-8. Epub 2007 Apr 19. Related Articles, Links
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An increase in murine skeletal muscle peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) mRNA in response to exercise is mediated by beta-adrenergic receptor activation.

Miura S, Kawanaka K, Kai Y, Tamura M, Goto M, Shiuchi T, Minokoshi Y, Ezaki O.

Nutritional Science Program, National Institute of Health and Nutrition, 1-23-1, Toyama, Shinjuku-ku, Tokyo 162-8636, Japan. shinjim@nih.go.jp

A single bout of exercise increases expression of peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha mRNA, which may promote mitochondrial biogenesis in skeletal muscle. In brown adipose tissue, cold exposure up-regulates PGC-1alpha expression via adrenergic receptor (AR) activation. Because exercise also activates the sympathetic nervous system, we examined whether exercise-induced increase in PGC-1alpha mRNA expression in skeletal muscle was mediated via AR activation. In C57BL/6J mice, injection of the beta2-AR agonist clenbuterol, but not alpha-, beta1-, or beta3-AR agonists, increased PGC-1alpha mRNA expression more than 30-fold in skeletal muscle. The clenbuterol-induced increase in PGC-1alpha mRNA expression in mice was inhibited by pretreatment with the beta-AR antagonist propranolol. In ex vivo experiments, direct exposure of rat epitrochlearis to beta2-AR agonist, but not alpha-, beta1-, and beta3-AR agonist, led to an increase in levels of PGC-1alpha mRNA. Injection of beta2-AR agonist did not increase PGC-1alpha mRNA expression in beta1-, beta2-, and beta3-AR knockout mice (beta-less mice). PGC-1alpha mRNA in gastrocnemius was increased 3.5-fold in response to running on a treadmill for 45 min. The exercise-induced increase in PGC-1alpha mRNA was inhibited by approximately 70% by propranolol or the beta2-AR-specific inhibitor ICI 118,551. The exercise-induced increase in PGC-1alpha mRNA in beta-less mice was also 36% lower than that in wild-type mice. These data indicate that up-regulation of PGC-1alpha expression in skeletal muscle by exercise is mediated, at least in part, by beta-ARs activation. Among ARs, beta2-AR may mediate an increase in PGC-1alpha by exercise.

Publication Types:


PMID: 17446185 [PubMed - in process]

 
5: Conn Med. 2007 Feb;71(2):89-91. Related Articles, Links

Clenbuterol toxicity: an emerging epidemic. A case report and review.

Bilkoo P, Thomas J, Riddle CD, Kagaoan G.

University of Connecticut, Hoffman Heart Institute, St. Francis Hospital and Medical Center, Hartford, USA.

A 55-year-old Hispanic male found unresponsive at home was brought to our emergency department. The patient was found to have rapid atrial fibrillation and acute inferior ST-elevation myocardial infarction on electrocardiogram. Cardiac catheterization failed to reveal any significant stenotic lesions in the coronary arteries. Initial laboratory studies revealed leukocytosis, hypokalemia, hyperglycemia, an anion-gap metabolic acidosis, as well as an osmolal-gap. Initial toxicology screen was negative. The patient was admitted to the Cardiac Intensive Care Unit. After 24 hours of appropriate medical management the clinical picture had improved. Further blood analysis revealed the presence of clenbuterol. Clenbuterol is a long-acting B-2 agonist used in veterinary medicine. Several patients in the Northeast have recently presented with a similar constellation of symptoms attributed to use of heroin adulterated with clenbuterol.

Publication Types:


PMID: 17393901 [PubMed - indexed for MEDLINE]

 
6: Neurobiol Aging. 2007 Mar 13; [Epub ahead of print] Related Articles, Links
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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]

Am J Physiol Endocrinol Metab 263: E50-E56, 1992;
0193-1849/92 $5.00
 

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AJP - Endocrinology and Metabolism, Vol 263, Issue 1 E50-E56, Copyright © 1992 by American Physiological Society

 

ARTICLES

Anabolic effects of clenbuterol on skeletal muscle are mediated by beta 2-adrenoceptor activation

J. J. Choo, M. A. Horan, R. A. Little and N. J. Rothwell
Department of Physiological Sciences, University of Manchester Medical School, United Kingdom.

The potent anabolic effects of the beta 2-adrenoceptor agonist clenbuterol on skeletal muscle have been reported to be independent of actions on beta-adrenoceptors. In the present study clenbuterol, presented to rats in the diet (4 mg/kg), caused significant increases in gastrocnemius muscle mass, protein, and RNA content and a decrease in epididymal fat pad mass. These effects were not mimicked by oral administration of the beta 2-adrenoceptor agonist salbutamol even at high dose (52 mg/kg diet), and the effects of clenbuterol were not inhibited by addition of DL-propranolol (200 mg/kg diet). However, the selective beta 2-antagonist ICI-118,551 (200 mg/kg diet) reversed the anabolic effects of clenbuterol, and a high dose of DL-propranolol (1,000 mg/kg diet) also inhibited these actions of clenbuterol. Furthermore, continuous infusion of salbutamol (1.15 mg.kg body wt-1.day-1) via miniosmotic pumps did cause significant increases in muscle mass, protein, and RNA content. These results indicate that the anabolic effects of clenbuterol are dependent on interaction with the beta 2-adrenoceptor. However, a long duration of action appears to be required to induce the anabolic effects of beta 2-agonists.