Role and possible mechanisms of clenbuterol in enhancing reverse remodelling during mechanical unloading in murine heart failure.
OBJECTIVE
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 beta(2)-adrenoceptor (beta(2)-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 HF.


RESULTS
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 (2 mg/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. 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 (microm): HF + UN + Clen 0.1 +/- 0.01 [50], HF + UN + Sal 0.07 +/- 0.01 [38]; P < 0.001) by normalizing the depressed myofilament sensitivity to Ca(2+) (slope of the linear relationship between Ca(2+) transient and sarcomere shortening hysteresis loop during relaxation (microm/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 HF patients treated with LVADs and also begins to elucidate some of the possible cellular mechanisms responsible for the improvement in LV function.
Soppa
Gopal K R
GK
Heart Science Centre, Imperial College London, National Heart and Lung Institute, Laboratory of Cellular Electrophysiology, Harefield Hospital, Harefield, Middlesex, UK.
Lee
Joon
J
Stagg
Mark A
MA
Felkin
Leanne E
LE
Barton
Paul J R
PJ
Siedlecka
Urszula
U
Youssef
Samuel
S
Yacoub
Magdi H
MH
Terracciano
Cesare M N
CM
D008841:Actin Cytoskeleton / Q000378:metabolism; D000200:Action Potentials; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D048429:Cell Size; D002976:Clenbuterol / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016027:Heart Transplantation; D015918:Infusion Pumps, Implantable; D008297:Male; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D012518:Sarcomeres / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000187:drug effects / Q000378:metabolism; D014463:Ultrasonography; D016277:Ventricular Function, Left / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects*
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D020746:Calcium Channels, L-Type; D020033:Protein Isoforms; D018343:Receptors, Adrenergic, beta-2; D019831:Sodium-Calcium Exchanger; D018995:Myosin Heavy Chains; D002976:Clenbuterol