Received July 13, 2006
Revised August 4, 2006
Accepted after revision September 4, 2006

¹ Liverpool John Moores University
² University of Leeds

^* To whom correspondence should be addressed. E-mail: j.burniston{at}ljmu.ac.uk.

	Abstract

The ₂-adrenoceptor (₂-AR) agonists clenbuterol and fenoterol have similar beneficial effects in animal models of heart failure. However, large doses of clenbuterol can induce cardiomyocyte death and it is not known which of these agents has the most favourable therapeutic profile. We have investigated the cardiotoxicity of clenbuterol and fenoterol alongside that of isoproterenol, and compared their haemodynamic effects. Wistar rats (n=6, per group) were subcutaneously injected with each -agonist (0.003 mmol kg^-1 to 3 mmol kg^-1) or saline and cardiomyocyte apoptosis was detected by caspase 3 immunohistochemistry. In a separate experiment rats (n=4) were given equivalent doses to those used in the myotoxicity studies, in a randomised crossover design, and their blood pressure recorded via radio telemetry. Injection of 0.3 mmol kg^-1 fenoterol or isoproterenol, but not clenbuterol, induced significant cardiomyocyte apoptosis (0.4±0.05%; P<0.05). At 3 mmol kg^-1, all agonists induced apoptosis (fenoterol 1.1±0.1%; isoproterenol 0.9±0.8%; clenbuterol 0.4±0.07%; P<0.05). ₁-AR antagonism (10 mg kg^-1 bisoprolol) prevented (92%; P<0.05) apoptosis induced by all 3 agonists, but clenbuterol-induced apoptosis could also be prevented (96%; P<0.05) by ₂-AR antagonism (10 mg kg^-1 ICI118551). Clenbuterol decreased diastolic (1.3-1.6 fold; P<0.05) and systolic (1.3 fold; P<0.05) blood pressure and doses >0.3 mmol kg^-1 increased heart rate (1.4 fold; P<0.05). Fenoterol increased heart rate (1.2-1.4 fold; P<0.05) and doses >0.3 mmol kg^-1 decreased diastolic blood pressure (1.3 fold; P<0.05). In conclusion, the cardiotoxicity of fenoterol was similar to isoproterenol and greater than clenbuterol, and fenoterol had less desirable haemodynamic effects.

Key Words: Adrenoceptor, Blood pressure, Isoprenaline

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