Cardiovascular Research Advance Access [Accepted Manuscript] published online on January 4, 2008
Cardiovascular Research, doi:10.1093/cvr/cvm106
Role and Possible Mechanisms of Clenbuterol in Enhancing Reverse Remodelling During Mechanical Unloading in Murine Heart Failure
Imperial College London, NHLI, Heart Science Centre, Harefield Hospital, Harefield, UB9 6JH, United Kingdom
Corresponding author: Dr Cesare M.N. Terracciano, Senior Lecturer, Imperial College London, National Heart & Lung Institute, Heart Science Centre, Laboratory of Cellular Electrophysiology, Harefield Hospital, Harefield, Middlesex, UB9 6JH, United Kingdom, tel. +44 (0)1895 453 874, fax. +44 (0)1895 828 900, email: c.terracciano{at}imperial.ac.uk
Aims: Combined left ventricular assist device (LVAD) and pharmacological therapy has been proposed to favour myocardial recovery in patients with end-stage heart failure (HF). Clenbuterol (Clen), a β2 adrenoceptor (β2-AR) agonist, has been used as a part of this strategy. In this study, we investigated the direct effects of clenbuterol on unloaded myocardium in heart failure.
Methods: Left coronary artery ligation or sham operation was performed in male Lewis rats. After 4-6 weeks, heterotopic abdominal transplantation of the failing hearts into normal recipients was performed to induce LV unloading (UN). Recipient rats were treated with saline (Sal) or clenbuterol (2mg/kg/day) via osmotic minipumps (HF+UN+Sal or HF+UN+Clen) for 7 days. Non-transplanted HF animals were treated with Sal (Sham+Sal, HF+Sal) or clenbuterol (HF+Clen). LV myocytes were isolated and studied using optical, fluorescence and electrophysiological techniques.
Results: Clenbuterol treatment improved in-vivo LV function measured with echocardiography (LVEF (%): HF 35.9±2 [16], HF+Clen 52.1±1.4 [16]; p<0.001; mean±SEM [n]). In combination with unloading, clenbuterol increased sarcomere shortening (amplitude (µm): HF+UN+Clen 0.1 ±0.01 [50], HF+UN+Sal 0.07±0.01 [38]; p<0.001) by normalising the depressed myofilament sensitivity to Ca2+ (slope of the linear relationship between Ca2+ transient and sarcomere shortening hysteresis loop during relaxation (µm/ratio unit): HF+UN+Clen 2.13±0.2 [52], HF+UN+Sal 1.42±0.13 [38]; p<0.05).
Conclusions: Clenbuterol treatment of failing rat hearts, alone or in combination with mechanical unloading, improves LV function at the whole-heart and cellular levels by affecting cell morphology, excitation-contraction coupling, and myofilament sensitivity to calcium. This study supports the use of this drug in the strategy to enhance recovery in heart failure patients treated with LVADs and also begins to elucidate some of the possible cellular mechanisms responsible for the improvement in LV function.
KEYWORDS clenbuterol; unloading; calcium; myofilament sensitivity; heart failure
Time for primary review: 21
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