title: Impact of combined clenbuterol and metoprolol therapy on reverse remodelling during mechanical unloading.
abstract: 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.
  
  
  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.
authors.affiliation: Harefield Heart Science Centre, Imperial College London, National Heart and Lung Institute, Laboratory of Cellular Electrophysiology, Harefield Hospital, Harefield, Middlesex, United Kingdom.
authors.forename: Manoraj
authors.initials: M
authors.lastname: Navaratnarajah
authors.affiliation: Harefield Heart Science Centre, Imperial College London, National Heart and Lung Institute, Laboratory of Cellular Electrophysiology, Harefield Hospital, Harefield, Middlesex, United Kingdom.
authors.forename: Urszula
authors.initials: U
authors.lastname: Siedlecka
authors.affiliation: Harefield Heart Science Centre, Imperial College London, National Heart and Lung Institute, Laboratory of Cellular Electrophysiology, Harefield Hospital, Harefield, Middlesex, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Ibrahim
authors.affiliation: Harefield Heart Science Centre, Imperial College London, National Heart and Lung Institute, Laboratory of Cellular Electrophysiology, Harefield Hospital, Harefield, Middlesex, United Kingdom.
authors.forename: Carin
authors.initials: C
authors.lastname: van Doorn
authors.affiliation: Harefield Heart Science Centre, Imperial College London, National Heart and Lung Institute, Laboratory of Cellular Electrophysiology, Harefield Hospital, Harefield, Middlesex, United Kingdom.
authors.forename: Gopal
authors.initials: G
authors.lastname: Soppa
authors.affiliation: Harefield Heart Science Centre, Imperial College London, National Heart and Lung Institute, Laboratory of Cellular Electrophysiology, Harefield Hospital, Harefield, Middlesex, United Kingdom.
authors.forename: Ajay
authors.initials: A
authors.lastname: Gandhi
authors.affiliation: Harefield Heart Science Centre, Imperial College London, National Heart and Lung Institute, Laboratory of Cellular Electrophysiology, Harefield Hospital, Harefield, Middlesex, United Kingdom.
authors.forename: Adarsh
authors.initials: A
authors.lastname: Shah
authors.affiliation: Harefield Heart Science Centre, Imperial College London, National Heart and Lung Institute, Laboratory of Cellular Electrophysiology, Harefield Hospital, Harefield, Middlesex, United Kingdom.
authors.forename: Punam
authors.initials: P
authors.lastname: Kukadia
authors.affiliation: Harefield Heart Science Centre, Imperial College London, National Heart and Lung Institute, Laboratory of Cellular Electrophysiology, Harefield Hospital, Harefield, Middlesex, United Kingdom.
authors.forename: Magdi H
authors.initials: MH
authors.lastname: Yacoub
authors.affiliation: Harefield Heart Science Centre, Imperial College London, National Heart and Lung Institute, Laboratory of Cellular Electrophysiology, Harefield Hospital, Harefield, Middlesex, United Kingdom.
authors.forename: Cesare M
authors.initials: CM
authors.lastname: Terracciano
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000494:pharmacology*; D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002976:Clenbuterol / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D056966:Excitation Contraction Coupling / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D016027:Heart Transplantation; D008297:Male; D008790:Metoprolol / Q000494:pharmacology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D013318:Stroke Volume / Q000187:drug effects; D016042:Transplantation, Heterotopic; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D058666:Adrenergic beta-2 Receptor Agonists; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D008790:Metoprolol; D002118:Calcium; D002976:Clenbuterol