228 EQUINE VETERINARY EDUCATION / AE / June 2007

Evidence-based Clinical Question Does clenbuterol positively affect racing horses? L. CARLOS* AND M. DAVIS† College of Agriculture; and †Department of Physiological Sciences, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, Oklahoma 74078, USA.

Introduction healthy horses, nonelastic resistance of the lung or pulmonary resistance significantly decreased, with 33.6% reduction at

Clenbuterol, a β2-sympathomimetic agent, is a synthetic 10 min post clenbuterol, and a return to normal values after hormone with similar physiological functions to the 3 h (Shapland et al. 1981). Premedication of normal catecholamines, epinephrine and norepinephrine. Clenbuterol racehorses with i.v. clenbuterol at the recommended dosage is one of a large group of compounds that are selective does not alter pulmonary mechanical and gas exchange β2-adrenergic agonists. Other drugs in this class include properties during exercise (Slocombe et al. 1992). Likewise, albuterol (salbutamol), pirbuterol and fenoterol. At low i.v. administration of clenbuterol to Thoroughbred horses 30 doses, clenbuterol preferentially activates β2-adrenoceptors, min before exercising on a treadmill does not improve oxygen but at higher doses it begins to activate β1-adrenoceptors consumption or cardiovascular function. Because the plasma (Robinson 2000). concentration resulting from the same oral dose would be Clenbuterol is sometimes used for its bronchodilatatory lower, it is even less likely that acute oral administration effect in horses suffering from chronic obstructive pulmonary (using the currently available veterinary product) would have disease (COPD or ‘heaves’) and other forms of respiratory any effect on oxygen consumption (Robinson 2000). Thus, distress. Its main action in the lung is relaxation of airway while clenbuterol may help return the diseased horse to smooth muscle. Clenbuterol is also widely believed to have normal function, it fails to enhance performance efficacy as bronchodilator in normal racing horses, and in demonstrably in healthy individuals, at least by standard some countries, it has been common to use it illegally in an statistical analyses. effort to improve air delivery to the lungs (Slocombe et al. 1992). Because it is both a bronchodilator and a repartitioning Clenbuterol and muscle agent, i.e. it redirects dietary energy away from fat deposition in the direction of lean muscle tissue production, clenbuterol Chronic clenbuterol administration is believed to be ergogenic has been used in an effort to enhance performance in horses. through the production of increased muscle mass, but paradoxically, this effect appears to impair exercise capacity. Clenbuterol and the respiratory system Clenbuterol results in significant repartitioning in horses when administered at the recommended doses, both alone and in Clenbuterol is used as a bronchodilator to relieve combination with exercise. When caloric intake is controlled, bronchospam. The main action of clenbuterol in the equine exercise alone and clenbuterol administration alone result in a lung is relaxation of airway smooth muscle. When the drug decrease in total body fat mass and percentage body fat in binds to β2-adrenoceptors, it activates adenyl cyclase, which healthy horses, and the combination of exercise and leads to an increase in the intracellular concentration of the clenbuterol administration has an additive effect on these second messenger cyclic adenosine monophosphate (cAMP) parameters (Kearns et al. 2001). Both exercise and clenbuterol and activation of protein kinase A (PKA). In the administration increase fat-free body mass, but the tracheobronchial tree (as well as in the uterus), β2-agonists, combination of exercise and clenbuterol administration cAMP and PKA inhibit smooth muscle contraction by opening seemed to attenuate partially the effect of clenbuterol alone + K channels and downregulate myosin light chain kinase on treatment-induced increases in fat-free body mass. activity (Robinson 2000). Clenbuterol decreases the time to fatigue in horses (Kearns Acute administration of clenbuterol to healthy horses and McKeever 2002) and rats (Suzuki et al. 1997); i.e. animals does not improve pulmonary function during exercise. treated with clenbuterol fatigue sooner than animals without Following clenbuterol administration (0.8 µg/kg bwt i.v.) in clenbuterol treatment. Treated horses developed a power output 11% greater than the control group, and the muscle *Author to whom correspondence should be addressed. mass was approximately 16% greater. However, the power EQUINE VETERINARY EDUCATION / AE / June 2007 229

output expressed per gram of muscle was approximately the Clenbuterol and performance same in both groups. Since the relative power output in both groups was the same, a difference in rate of fatigue can be Exercise training is expected to increase maximal aerobic attributed to some inherent change within the muscle. capacity (VO2max) in horses, and this increase is associated The mechanism of increased fatigueability secondary to with increased plasma volume (presumably permitting greater chronic clenbuterol administration is unclear. The cardiac output). However, even minimal therapeutic administration of clenbuterol at ≥1 µg/kg bwt in rats induces concentrations of clenbuterol adversely affect aerobic apoptosis in skeletal muscle (Burniston et al. 2005). In performance, high-intensity exercise capacity and the horse’s addition, there was a cumulative myocyte death over 8 days ability to recover from exercise (Kearns and McKeever 2002). after administration of clenbuterol at a 48 h interval in rats. Horses treated with clenbuterol and exercise training Apoptosis alone was observed at low clenbuterol doses; in demonstrated a reduction in VO2max (-10%) and plasma most cases apoptotic myocytes lysed and became necrotic, volumes (-10%). Interestingly, no significant changes in and the magnitude of necrosis was greater than that of VO2max (-3.5%) or plasma (3.0%) of the clenbuterol-treated apoptosis. Clenbuterol provokes a shift in myosin heavy chain horses without exercise training were found, suggesting the (MHC) composition toward the fast-twitch isoforms in the antiergogenic effect of chronic clenbuterol administration in soleus muscle of rats (Dodd et al. 1996) and in middle gluteal athletic horses is a result of interaction with exercise. muscles of Standardbred mares (Beekley et al. 2003). This study also suggested that aerobic exercise might not be able Conclusion to reverse these effects. Given that fast-twitch fibre (i.e. Type II muscle fibres) are more easily fatigued than Type I muscle Clenbuterol has effects in multiple body systems and tissues fibres, it is likely that these MHC shifts are detrimental to directly relevant to exercise performance, including the prolonged exercise performance. respiratory system, cardiovascular system, and skeletal muscle. Some of these effects, such as bronchodilation and increased Clenbuterol and cardiac function muscle mass, could potentially be ergogenic. However, numerous studies in horses have failed to demonstrate a clear Undesirable effects of chronic clenbuterol administration on ergogenic benefit of clenbuterol, and in some cases, have cardiac function may also contribute to impaired athletic demonstrated impaired exercise capacity. Thus, the current performance, but the current data are not consistent. In one body of evidence supports the use of clenbuterol only as a study, no changes were found in heart rate response to specific treatment for horses with chronic airway disease, but exercise 2 h after clenbuterol administration (Kallings et al. not in healthy horses as a performance-enhancing drug. 1991). In addition, clenbuterol treatment did not affect blood lactate concentration or arterial oxygen tension during References exercise. However, in another study, chronic clenbuterol administration caused cardiac remodelling and adversely Beekley, M.D., Ideus, J.M., Brechue, W.F., Kearns, C.F. and McKeever, affected cardiac function (Sleeper et al. 2002). Horses treated K.H. (2003) Chronic clenbuterol administration alters myosin heavy chain composition in standardbred mares. Vet. J. 165, 234-239. with clenbuterol had substantially elevated cardiac output (Q) Burniston, J.G., Chester, N., Clark, W.A., Tan, L.B. and Goldspink, D.F. and stroke volume (SV) immediately after a standardised (2005) Dose-dependent apoptotic and necrotic myocyte death exercise test when compared to untreated horses, suggesting induced by the beta2-adrenergic receptor agonist, clenbuterol. lower cardiovascular efficiency for a given workload. After Muscle Nerve 32, 767-774. 8 weeks, horses receiving clenbuterol, with or without Cubria, J.C., Reguera, R., Balana-Fouce, R., Ordonez, C. and Ordonez, concurrent exercise training, had a significantly elevated SV D. (1998) Polyamine-mediated heart hypertrophy induced by immediately after maximal exercise due to increased left clenbuterol in the mouse. J. Pharm. Pharmacol. 50, 91-96. ventricular dimension (LVD). Other increases included Dodd, S.L., Powers, S.K., Vrabas, I.S., Criswell, D., Stetson, S. and intraventricular septal wall thickness (IVS) at end diastole, IVS Hussain, R. (1996) Effects of clenbuterol on contractile and biochemical properties of skeletal muscle. Med. Sci. Sports Exerc. at end systole immediately after exercise, and left ventricular 28, 669-676. posterior wall systolic thickness. Absolute aortic root diameter Duncan, N.D., Williams, D.A. and Lynch, G.S. (2000) Deleterious immediately after exercise was larger in both horses with effects of chronic clenbuterol treatment on endurance and sprint exercise and without exercise after treatment with clenbuterol, exercise performance in rats. Clin. Sci. (Lond) 98, 339-347. suggesting increased risk of aortic rupture. Chronic Kallings, P., Ingvast-Larsson, C., Persson, S., Appelgren, L.E., Forster, clenbuterol treatment has been shown to cause cardiac H.J. and Rominger, K.L. (1991) Clenbuterol plasma concentrations hypertrophy in many other species, including rats (Petrou et al. after repeated oral administration and its effects on cardio- respiratory and blood lactate responses to exercise in healthy 1995; Wong et al. 1998; Duncan et al. 2000), and mice Standardbred horses. J. vet. Pharmacol. Ther. 14, 243-249. (Cubria et al. 1998), in some cases associated with evidence of Kearns, C.F. and McKeever, K.H. (2002) Clenbuterol diminishes aerobic myocardial damage (Cubria et al. 1998; Duncan et al. 2000). performance in horses. Med. Sci. Sports Exerc. 34, 1976-1985. Although not conclusive, the current data suggest that chronic Kearns, C.F., McKeever, K.H., Malinowski, K., Struck, M.B. and Abe, T. clenbuterol administration may have adverse effects on (2001) Chronic administration of therapeutic levels of clenbuterol cardiac function in healthy horses. acts as a repartitioning agent. J. appl. Physiol. 91, 2064-2070. 230 EQUINE VETERINARY EDUCATION / AE / June 2007

Petrou, M., Wynne, D.G., Boheler, K.R. and Yacoub, M.H. (1995) the effect of clenbuterol pretreatment on them. Aust. vet. J. Clenbuterol induces hypertrophy of the latissimus dorsi muscle and 69, 221-225. heart in the rat with molecular and phenotypic changes. Suzuki, J., Gao, M., Xie, Z. and Koyama, T. (1997) Effects of the beta Circulation 92, II483-II489. 2-adrenergic agonist clenbuterol on capillary geometry in cardiac Robinson, N.E. (2000) Clenbuterol and the horse. Proc. Am. Ass. and skeletal muscles in young and middle-aged rats. Acta Physiol. equine Practnrs. 46, 229-233. Scand. 161, 317-326. Shapland, J.E., Garner, H.E. and Hatfield, D.G. (1981) Wong, K., Boheler, K.R., Bishop, J., Petrou, M. and Yacoub, M.H. Cardiopulmonary effects of clenbuterol in the horse. J. vet. Pharmacol. Ther. 4, 43-50. (1998) Clenbuterol induces cardiac hypertrophy with normal functional, morphological and molecular features. Cardiovasc. Res. Sleeper, M.M., Kearns, C.F. and McKeever, K.H. (2002) Chronic 37, 115-122. clenbuterol administration negatively alters cardiac function. Med. Sci. Sports Exerc. 34, 643-650. Slocombe, R.F., Covelli, G. and Bayly, W.M. (1992) Respiratory If you have a submission for a future Clinical Question to be included mechanics of horses during stepwise treadmill exercise tests, and in EVE, please contact David Ramey at [email protected]