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(Circulation. 2005;112:I-51 – I-56.)
© 2005 American Heart Association, Inc.

Cardiac Transplantation and Surgery for Congestive Heart Failure

Does the ß₂-Agonist Clenbuterol Help to Maintain Myocardial Potential to Recover During Mechanical Unloading?

Hiroshi Tsuneyoshi, MD; Wnimunk Oriyanhan, MD; Hideo Kanemitsu, MD; Reiko Shiina, BS; Takeshi Nishina, MD, PhD; Satoshi Matsuoka, MD, PhD; Tadashi Ikeda, MD, PhD; Masashi Komeda, MD, PhD

From the Department of Cardiovascular Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Correspondence to Masashi Komeda, Department of Cardiovascular Surgery, Graduate School of Medicine, Kyoto University, 4 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Japan, 606-8507. E-mail masakom{at}kuhp.kyoto-u.ac.jp

Objective— Chronic mechanical unloading induces left ventricular (LV) atrophy, which may impair functional recovery during support with an LV-assist device. Clenbuterol, a ß₂-adrenergic receptor (AR) agonist, is known to induce myocardial hypertrophy and might prevent LV atrophy during LV unloading. Furthermore, ß₂-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 1o f 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 ß-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 ß₁-AR mRNA expression between the 2 groups. In contrast, ß₂-AR mRNA was significantly decreased in the clenbuterol-treated, unloaded heart. This indicates that clenbuterol may downregulate ß₂-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, ß-MHC) and ß-adrenergic responsiveness and potentially prevented myocardial apoptosis. However, chronic administration of clenbuterol may be associated with downregulation of ß₂-ARs.

Key Words: cardiomyopathy • heart-assist device • heart failure • inotropic agents • receptors, adrenergic, beta