beta-agonistic bronchodilators - Comparison of dose/response in working rat hearts

Study objectives: Different beta-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 mu mol to a maximum of 10 mu mol per gram of heart tissue into the isolated working rat heart u nder hypoxic conditions, and the response was observed during subsequent re oxygenation. 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 membra ne fluidity. Moreover, intact mitochondria and Lipid peroxidation were inve stigated using a model system. Measurements and results: Compared to controls, reproterol gave the most fa vorable results, with an increase of 25 to 30% of aortic flow during reoxyg enation at a concentration of 10 mu mol/g heart tissue, In contrast, both f enoterol and salbutamol at a concentration of 1 mu mol/g heart tissue decre ased aortic flow during reoxygenation, whereas terbutaline had a negative i nfluence on aortic now at 0.01 to 0.1 mu mol/g heart tissue. Mitochondria o f these hearts mere isolated at the end of the experiment. Mitochondrial AT P synthesis was increased above controls at nearly all concentrations of re proterol. ATP synthesis was decreased at 1 mu mol and 10 mu mol fenoterol. As little as 0.0005 mu mol terbutaline decreased ATP synthesis by 50%. In i ntact 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 syste m between concentrations of 0.002 mu mol/mg and 0.04 mu mol/mg phosphatidyl choline by fenoterol and terbutaline, whereas a decrease was noted with rep roterol, Membrane fluidity was found increased after addition of reproterol , which supports the evidence of efficient ATP synthesis by this compound. Conclusions: Cardiodepressive side effects and greater toxicity of fenotero l and terbutaline were found under the conditions of our experiment. Salbut amol and, in particular, reproterol appear much better tolerated. In additi on to partial beta-adrenergic agonism, reproterol may exert an inhibitory i nfluence on adenosine receptor sites and phosphodiesterase, which could res ult in membrane stabilization by saving cyclic adenosine monophosphate or A TP.