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

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.

• Authors: Hiroshi Tsuneyoshi, Wnimunk Oriyanhan, Hideo Kanemitsu, Reiko Shiina, Takeshi Nishina, Satoshi Matsuoka, Tadashi Ikeda, Masashi Komeda
• Journal: Circulation (Circulation) Vol. 112 Issue 9 Suppl Pg. I51-6 (Aug 30 2005) ISSN: 1524-4539 [Electronic] United States
• PMID: 16159865 (Publication Type: Comparative Study, Journal Article)

Chemical References

• 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

Topics

• Adrenergic beta-Agonists (pharmacology, therapeutic use)
• Animals
• Atrophy
• Calcium-Transporting ATPases (biosynthesis, genetics)
• Caspase 3
• Caspases (biosynthesis, genetics)
• Clenbuterol (pharmacology, 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, pathology, physiopathology)
• Isoproterenol (pharmacology)
• Male
• Myocardial Contraction (drug effects)
• Myocardium (pathology)
• Myosin Heavy Chains (biosynthesis, genetics)
• Organ Size
• Papillary Muscles (drug effects, physiopathology)
• Protein Isoforms (biosynthesis, genetics)
• RNA, Messenger (biosynthesis, genetics)
• Random Allocation
• Rats
• Rats, Inbred Lew
• Receptors, Adrenergic, beta-1 (biosynthesis, genetics)
• Receptors, Adrenergic, beta-2 (biosynthesis, drug effects, genetics)
• Sarcoplasmic Reticulum Calcium-Transporting ATPases
• Stress, Mechanical
• Transplantation, Heterotopic
• Transplantation, Isogeneic
• Ventricular Function, Left (drug effects)