Impact of combined clenbuterol and metoprolol therapy on reverse remodelling during mechanical unloading

Clenbuterol (Cl), a β2 agonist, is associated with enhanced myocardial recovery during left ventricular assist device (LVAD) support, and exerts beneficial remodelling effects during mechanical unloading (MU) in rodent heart failure (HF). However, the specific effects of combined Cl+β1 blockade duri...

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Published in:	PloS one 2014-09, Vol.9 (9), p.e92909-e92909
Main Authors:	Navaratnarajah, Manoraj, Siedlecka, Urszula, Ibrahim, Michael, van Doorn, Carin, Soppa, Gopal, Gandhi, Ajay, Shah, Adarsh, Kukadia, Punam, Yacoub, Magdi H, Terracciano, Cesare M
Format:	Article
Language:	eng
Subjects:	Adrenergic beta-1 Receptor Antagonists - pharmacology Adrenergic beta-2 Receptor Agonists - pharmacology Adrenergic receptors Animals Atrophy Biology and Life Sciences Calcium (reticular) Calcium - metabolism Calcium signalling Cardiovascular disease Chronic effects Clenbuterol Clenbuterol - pharmacology Contraction Coronary artery Coupling Cytology Drug therapy Drug Therapy, Combination Excitation Contraction Coupling - drug effects Gene expression Heart diseases Heart failure Heart Failure - drug therapy Heart Failure - metabolism Heart Failure - pathology Heart Failure - physiopathology Heart Rate - drug effects Heart Transplantation Hypertrophy Laboratory animals Male Mechanical unloading Medicine and Health Sciences Metoprolol Metoprolol - pharmacology Myocardium - metabolism Myocardium - pathology Ostomy Physiology Rats Rats, Inbred Lew Receptors, Adrenergic, beta-1 - metabolism Receptors, Adrenergic, beta-2 - metabolism Recovery Remodeling Research and Analysis Methods Sarcoplasmic reticulum Science Stroke Volume - drug effects Structure-function relationships Studies Tachycardia Therapy Transplantation Transplantation, Heterotopic Unloading Ventricle Ventricular Function, Left - drug effects Ventricular Remodeling - drug effects
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Summary:	Clenbuterol (Cl), a β2 agonist, is associated with enhanced myocardial recovery during left ventricular assist device (LVAD) support, and exerts beneficial remodelling effects during mechanical unloading (MU) in rodent heart failure (HF). However, the specific effects of combined Cl+β1 blockade during MU are unknown. We studied the chronic effects (4 weeks) of β2-adrenoceptor (AR) stimulation via Cl (2 mg/kg/day) alone, and in combination with β1-AR blockade using metoprolol ((Met), 250 mg/kg/day), on whole heart/cell structure, function and excitation-contraction (EC) coupling in failing (induced by left coronary artery (LCA) ligation), and unloaded (induced by heterotopic abdominal heart transplantation (HATx)) failing rat hearts. Combined Cl+Met therapy displayed favourable effects in HF: Met enhanced Cl's improvement in ejection fraction (EF) whilst preventing Cl-induced hypertrophy and tachycardia. During MU combined therapy was less beneficial than either mono-therapy. Met, not Cl, prevented MU-induced myocardial atrophy, with increased atrophy occurring during combined therapy. MU-induced recovery of Ca2+ transient amplitude, speed of Ca2+ release and sarcoplasmic reticulum Ca2+ content was enhanced equally by Cl or Met mono-therapy, but these benefits, together with Cl's enhancement of sarcomeric contraction speed, and MU-induced recovery of Ca2+ spark frequency, disappeared during combined therapy. Combined Cl+Met therapy shows superior functional effects to mono-therapy in rodent HF, but appears inferior to either mono-therapy in enhancing MU-induced recovery of EC coupling. These results suggest that combined β2-AR simulation +β1-AR blockade therapy is likely to be a safe and beneficial therapeutic HF strategy, but is not as effective as mono-therapy in enhancing myocardial recovery during LVAD support.
ISSN:	1932-6203 1932-6203