β-Agonistic Bronchodilators: Comparison of Dose/Response in Working Rat Hearts

doi:10.1378/chest.117.2.519

Chest

Volume 117, Issue 2, February 2000, Pages 519-529

https://doi.org/10.1378/chest.117.2.519 Get rights and content

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.

Measurements 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.

Conclusions

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.

Section snippets

Animals

The animals used were male Wistar rats that were donated by Hoechst AG (Frankfurt, Germany). They received a standard diet (Altromin pellets; Lage; Lippe, Germany) and drinking water ad libitum. The average weight of the animals was 400 to 450 g.

Chemicals

Buffer substances were purchased as p.a. substances from Merck (Darmstadt, Germany). Laboratory gases were supplied as certified mixtures of O₂/CO₂ 95%/5% and N₂/CO₂ 95%/5% by Messer Griesheim (Frankfurt, Germany). Reproterol was obtained from Asta

Results

Figure 2 shows aortic flow in the rat hearts treated with different concentrations of reproterol. Obviously, there is no systematic concentration-dependent response. There may be a periodicity (see Discussion). The curves, after application of repro-terol, however, generally parallel the control. The lowest concentration (0.001μ mol) shows some depression in its course. At 0.005 μmol, there is a clear-cut improvement compared to the control. At 0.01 μmol, there is further improvement, in

Discussion

In acute exacerbation of asthmatic disease, arterial oxygen tension may fall due to drug-induced pulmonary vascular dilation.¹⁹ Severe pulmonary edema has been reported in women receiving terbutaline for premature labor.²⁰ This agrees with the observation of a distinct fall in Pao₂ due to terbutaline.²¹

Moreover, Criée et al²² have concluded from their extensive data that use of fenoterol and terbutaline may have caused increased risk of death. Contrary to investigations concerning fenoterol,

Acknowledgments

The authors thank Dr. Hanns Ackermann, Department of Biomathematics, University Clinics, Frankfurt/M, for his help in performing the statistical analyses.