Impact of Combined Clenbuterol and Metoprolol Therapy on Reverse Remodelling during Mechanical Unloading

Abstract

BackgroundClenbuterol (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 ResultsWe 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.ConclusionsCombined 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.

Rat Heterotopic Heart Transplantation Model to Investigate Unloading-Induced Myocardial Remodeling

“…Metoprolol, not Clenbuterol, prevented unloading-induced myocardial atrophy, with increased atrophy occurring during combined therapy. Unloading-induced recovery of Ca 2+ transient amplitude, speed of Ca 2+ release and sarcoplasmic reticulum Ca 2+ content was enhanced equally by each monotherapy, but these benefits, together with Clenbuterols enhancement of sarcomeric contraction speed, and unloading-induced recovery of Ca 2+ spark frequency disappeared during combined therapy ( 40 ).…”

Effects of carvedilol and metoprolol on the myocardium during mechanical unloading in a rat heterotopic heart transplantation model

“…The β 2 -agonist clenbuterol has been tested in a rat model of mechanical unloading. 4,6,7 Moreover, the β 1 -blocker metoprolol has been investigated in various studies and has been shown to have a positive effect on apoptosis prevention in rat hearts subjected to mechanical unloading. 7,8 For treating cases of heart failure, the nonselective β-blocker carvedilol is a representative drug that has cardioprotective effects similar to those of metoprolol.…”

Computational analysis of the hemodynamic characteristics under interaction influence of β-blocker and LVAD

“…This indicates that β-blocker, alone, likely does not have any effects on promoting reverse cardiac remodeling [ 33 ], emphasizing that much of unloading is due to LVAD. Nevertheless, the combination of LVAD and β-blocker has attracted more and more interest due to its exciting effects on improving cardiac function [ 19 , 34 ]. However, the mechanism and pathway of β-blocker in the therapy is still unclear.…”