Does the beta2-agonist clenbuterol help to maintain myocardial potential to recover during mechanical unloading?

Circulation. 2005 Aug 30;112(9 Suppl):I51-6. doi: 10.1161/CIRCULATIONAHA.104.525097.

Abstract

Objective: Chronic mechanical unloading induces left ventricular (LV) atrophy, which may impair functional recovery during support with an LV-assist device. Clenbuterol, a beta2-adrenergic receptor (AR) agonist, is known to induce myocardial hypertrophy and might prevent LV atrophy during LV unloading. Furthermore, beta2-AR stimulation is reported to improve Ca2+ handling and contribute to antiapoptosis. However, there is little information on the effects of clenbuterol during LV unloading.

Methods and results: We investigated LV atrophy and function after LV unloading produced by heterotopic heart transplantation in isogenic rats. After transplantation, rats were randomized to 1 of 2 groups (n=10 each). The clenbuterol group received 2 mg.kg(-1).d(-1) of the drug for 2 weeks; the control group received normal saline. The weight of unloaded control hearts was 48% less than that of host hearts after 2 weeks of unloading. Clenbuterol significantly increased the weight of the host hearts but did not prevent unloading-induced LV atrophy. Papillary muscles were isolated and stimulated, and there was no difference in developed tension between the 2 groups. However, the inotropic response to the beta-AR agonist isoproterenol significantly improved in the clenbuterol group. The mRNA expression of myocardial sarco(endo)plasmic reticulum Ca2+-ATPase 2a (SERCA2a) and fetal gene shift (myosin heavy chain [MHC] mRNA isozyme) was also significantly improved by clenbuterol treatment. There was no difference in beta1-AR mRNA expression between the 2 groups. In contrast, beta2-AR mRNA was significantly decreased in the clenbuterol-treated, unloaded heart. This indicates that clenbuterol may downregulate beta2-ARs. In the evaluation of apoptosis, mRNA expression of caspase-3, which is the central pathway for apoptosis, tended to be better in the clenbuterol group.

Conclusions: During complete LV unloading, clenbuterol did not prevent myocardial atrophy but improved gene expression (SERCA2a, beta-MHC) and beta-adrenergic responsiveness and potentially prevented myocardial apoptosis. However, chronic administration of clenbuterol may be associated with downregulation of beta2-ARs.

Publication types

  • Comparative Study

MeSH terms

  • Adrenergic beta-Agonists / pharmacology
  • Adrenergic beta-Agonists / therapeutic use*
  • Animals
  • Atrophy
  • Calcium-Transporting ATPases / biosynthesis
  • Calcium-Transporting ATPases / genetics
  • Caspase 3
  • Caspases / biosynthesis
  • Caspases / genetics
  • Clenbuterol / pharmacology
  • Clenbuterol / therapeutic use*
  • Down-Regulation / drug effects
  • Drug Evaluation, Preclinical
  • Enzyme Induction / drug effects
  • Gene Expression Regulation / drug effects
  • Heart / drug effects*
  • Heart Transplantation
  • Heart Ventricles / drug effects
  • Heart Ventricles / pathology
  • Heart Ventricles / physiopathology
  • Isoproterenol / pharmacology
  • Male
  • Myocardial Contraction / drug effects
  • Myocardium / pathology
  • Myosin Heavy Chains / biosynthesis
  • Myosin Heavy Chains / genetics
  • Organ Size
  • Papillary Muscles / drug effects
  • Papillary Muscles / physiopathology
  • Protein Isoforms / biosynthesis
  • Protein Isoforms / genetics
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Random Allocation
  • Rats
  • Rats, Inbred Lew
  • Receptors, Adrenergic, beta-1 / biosynthesis
  • Receptors, Adrenergic, beta-1 / genetics
  • Receptors, Adrenergic, beta-2 / biosynthesis
  • Receptors, Adrenergic, beta-2 / drug effects
  • Receptors, Adrenergic, beta-2 / genetics
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Stress, Mechanical
  • Transplantation, Heterotopic
  • Transplantation, Isogeneic
  • Ventricular Function, Left / drug effects

Substances

  • Adrenergic beta-Agonists
  • Protein Isoforms
  • RNA, Messenger
  • Receptors, Adrenergic, beta-1
  • Receptors, Adrenergic, beta-2
  • Casp3 protein, rat
  • Caspase 3
  • Caspases
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Myosin Heavy Chains
  • Calcium-Transporting ATPases
  • Isoproterenol
  • Clenbuterol