Abstract 10240: Clenbuterol Affects Cardiomyocyte Contractility Via A β2-Adrenoceptor Independent Pathway
Clenbuterol (CL) has been employed in combination with other pharmacological agents and left ventricular assist devices (LVAD) to treat patients with severe heart failure. Chronic administration of CL increases expression of Ca2+ regulatory proteins in isolated cardiomyocytes (CMs) and improves contractility, while acute administration decreases contractility and Ca2+ current, mainly through Gi protein activation. CL has been classified as a β2-adrenoceptor (AR) agonist. However, our previous study could not demonstrate the involvement of β2-ARs in CL's acute action in rat CMs.
We investigated chronic and acute effects of CL on heart and isolated CM function in β2-AR knockout (KO) mice compared with control (WT). After 7 days of CL treatment (2mg/kg/day) hearts were explanted and CMs isolated. No difference in heart/body weight ratio between KO and WT mice was seen, however, % increase in diastolic left ventricle posterior wall thickness was smaller in KO (WT: 49.0 ± 2.7 n=4 vs KO: 21.4 ± 6.9 n=4, p<0.01). Also KO CMs were smaller (WT: 45010 ± 2003µm3 n=65 vs KO: 33610 ± 1521µm3 n=75, p<0.001). CL increased ejection fraction in WT ((%): day0: 80.6 ± 0.7 vs day7: 86.7 ± 1.0 n=4, p<0.001) but not in KO mice.
We also studied contractility and Ca2+ handling in CMs. CM contractility was similar in both groups, including peak amplitude (PA), time to peak (TTP) and time to 50% relaxation (T50). Ca2+ transients also did not differ between groups in terms of PA or TTP but T50 was longer in KO cells ((ms) WT: 104.7 ± 6.0, n=10 vs KO: 129.8 ± 7.3 n=19, p<0.05). Ca2+ sparks were smaller in KO cells (spark peak (F/Fo): WT: 1.9 ± 0.06 n=21 vs KO: 1.6 ± 0.03 n=15, p<0.001).
Acute effects of CL on CM contractility were not different between groups. CL induced a similar strong negative inotropic effect in WT and KO CMs (sarcomere shortening (% of control) at 30µM CL - WT: 36.3 ± 4.1 n=27 vs KO: 43.7 ± 2.3 n=5).
Our results suggest that β2-ARs are involved in chronic hypertrophic and inotropic effects of CL at the whole heart level. However, cellular mechanisms involved in CL's acute effects are not eliminated in the KO, suggesting that CL affects CM contractility via a β2-AR independent route. This pathway may be important for the role of CL when associated with LVADs and requires further studies.
- Beta-adrenergic receptor agonists
- Cardiac hypertrophy
- Myocyte electrophysiology
- Ventricular assist devices
- © 2011 by American Heart Association, Inc.