Study objectives: Different β-agonists are compared
with regard to their cardiodepressive side effects.
Design: The metaphenolic bronchodilators reproterol,
salbutamol, fenoterol, and terbutaline were introduced at a dosage of
0.0005 μmol to a maximum of 10 μmol per gram of heart tissue into
the isolated working rat heart under hypoxic conditions, and the
response was observed during subsequent reoxygenation. As an index of
external heart work, aortic flow was measured. Heart rate, coronary
flow, and developed pressure were recorded. At the end of heart
perfusion, mitochondria were isolated and analyzed for adenosine
triphosphatase activity, adenosine triphosphate (ATP) synthesis, and
membrane fluidity. Moreover, intact mitochondria and lipid peroxidation
were investigated using a model system.
and results: Compared to controls, reproterol gave the most
favorable results, with an increase of 25 to 30% of aortic flow during
reoxygenation at a concentration of 10 μmol/g heart tissue. In
contrast, both fenoterol and salbutamol at a concentration of 1μ
mol/g heart tissue decreased aortic flow during reoxygenation,
whereas terbutaline had a negative influence on aortic flow at 0.01 to
0.1 μmol/g heart tissue. Mitochondria of these hearts were isolated
at the end of the experiment. Mitochondrial ATP synthesis was increased
above controls at nearly all concentrations of reproterol. ATP
synthesis was decreased at 1 μmol and 10 μmol fenoterol. As little
as 0.0005 μmol terbutaline decreased ATP synthesis by 50%. In intact
mitochondria, adenosine diphosphate (ADP) to oxygen ratios were found
to be increased with terbutaline and fenoterol, indicating ADP
consumption by myokinase activation. Lipid peroxidation was increased
in a model system between concentrations of 0.002 μmol/mg and 0.04μ
mol/mg phosphatidylcholine by fenoterol and terbutaline, whereas a
decrease was noted with reproterol. Membrane fluidity was found
increased after addition of reproterol, which supports the evidence of
efficient ATP synthesis by this compound.
Cardiodepressive side effects and greater toxicity of fenoterol and
terbutaline were found under the conditions of our experiment.
Salbutamol and, in particular, reproterol appear much better tolerated.
In addition to partial β-adrenergic agonism, reproterol may exert an
inhibitory influence on adenosine receptor sites and phosphodiesterase,
which could result in membrane stabilization by saving cyclic adenosine
monophosphate or ATP.