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

• Published in: PloS one Vol. 9; no. 9; p. 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: Journal Article
• Language: English
• Published: United States Public Library of Science 30.09.2014; Public Library of Science (PLoS)
• 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; Rodents; 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; United Kingdom > UK
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0092909

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.