Key result
Combined clenbuterol and metoprolol therapy improved ejection fraction in a rodent heart failure model, but worsened mechanical unloading-induced myocardial atrophy and was inferior to monotherapy for excitation-contraction coupling recovery.
Why the study?
Does combined clenbuterol and metoprolol therapy improve reverse remodelling during mechanical unloading in a rodent heart failure model?
Does combined clenbuterol and metoprolol therapy improve reverse remodelling during mechanical unloading in a rodent heart failure model?
Combined beta-2 agonist and beta-1 blocker therapy is beneficial in rodent heart failure but inferior to mono-therapy for enhancing myocardial recovery during mechanical unloading.
Combined β2 agonism plus β1 blockade may aid function in rodent HF; leaves open optimal strategy during LVAD unloading.
BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.
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Navaratnarajah et al. (2014) studied Heart failure and mechanical unloading (n=72). Combined Clenbuterol and Metoprolol vs. Clenbuterol alone, Metoprolol alone, or no drug treatment was evaluated on Reverse remodelling and myocardial recovery (ejection fraction, myocardial atrophy, and excitation-contraction coupling). Combined clenbuterol and metoprolol therapy improved ejection fraction in a rodent heart failure model, but worsened mechanical unloading-induced myocardial atrophy and was inferior to monotherapy for excitation-contraction coupling recovery.
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