Background: Clenbuterol (Cl), a b2 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+b1 blockade during MU are unknown.
Methods and Results: We studied the chronic effects (4 weeks) of b2-adrenoceptor (AR) stimulation via Cl (2 mg/kg/day)
alone, and in combination with b1-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 MUinduced
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 b2-
AR simulation +b1-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.