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


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.
Tsuneyoshi
Hiroshi
H
Department of Cardiovascular Surgery, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan.
Oriyanhan
Wnimunk
W
Kanemitsu
Hideo
H
Shiina
Reiko
R
Nishina
Takeshi
T
Matsuoka
Satoshi
S
Ikeda
Tadashi
T
Komeda
Masashi
M
D000318:Adrenergic beta-Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001284:Atrophy; D000252:Calcium-Transporting ATPases / Q000096:biosynthesis / Q000235:genetics; D053148:Caspase 3; D020169:Caspases / Q000096:biosynthesis / Q000235:genetics; D002976:Clenbuterol / Q000494:pharmacology / Q000627:therapeutic use*; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004790:Enzyme Induction / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D016027:Heart Transplantation; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000473:pathology; D018995:Myosin Heavy Chains / Q000096:biosynthesis / Q000235:genetics; D009929:Organ Size; D010210:Papillary Muscles / Q000187:drug effects / Q000503:physiopathology; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011897:Random Allocation; D051381:Rats; D011917:Rats, Inbred Lew; D018342:Receptors, Adrenergic, beta-1 / Q000096:biosynthesis / Q000235:genetics; D018343:Receptors, Adrenergic, beta-2 / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013314:Stress, Mechanical; D016042:Transplantation, Heterotopic; D014185:Transplantation, Isogeneic; D016277:Ventricular Function, Left / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D020033:Protein Isoforms; D012333:RNA, Messenger; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D018995:Myosin Heavy Chains; D000252:Calcium-Transporting ATPases; D007545:Isoproterenol; D002976:Clenbuterol