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Updated: Aug 21, 2026
Histological Quantification of Chronic Myocardial Infarct in Rats
Published on: December 11, 2016
Quantitative estimation of myocardial fibrosis based on receptor occupancy for beta2-adrenergic receptor agonists in
Satoru Tanaka1, Yasunori Momose, Masaru Tsutsui
1Division of Toxicological Research, Kissei Pharmaceutical Co. Ltd., 2320-1 Ohaza Maki, Hotaka-machi, Minamiazumi-gun, Nagano 399-8305, Japan.
Abstract:
To develop beta2-adrenergic receptor (AR) agonists with higher selectivity, it is essential to evaluate the cardiac side effects which are the most serious side effects of this class of drugs. We studied receptor occupancy of beta1-ARs in rats as a possible cause for the side effect of beta2-AR agonists, namely myocardial fibrosis. Myocardial fibrosis in rats was observed on Day 7 after the administration of salbutamol and terbutaline, both of which are selective beta2-AR agonists, at higher dose levels. To evaluate receptor occupancy, plasma concentrations of (R)-salbutamol and (R)-terbutaline, plasma protein binding and the EC50 for chronotropic effects in rats were determined. Based on the plasma concentrations, the plasma protein binding and EC50, receptor occupancy-time profiles were constructed. The relationship between the receptor occupancy-time profile under the curve, the AUCphi, and the degree of myocardial fibrosis was evaluated with a multiple correlation analysis. Myocardial fibrosis was significantly correlated (r2 > 0.78) to the AUCphi with the threshold above approximately 50%, but not to plasma concentrations. These results indicate that the receptor occupancy theory is also useful for the evaluation of the chronotropic side effects of beta2-AR agonists.
Insights
Beta2-adrenergic receptor (AR) agonists can cause myocardial fibrosis. This study shows that beta1-AR occupancy, not plasma concentration, predicts this cardiac side effect, aiding safer drug development.
Area of Science:
- Pharmacology
- Cardiovascular Research
- Drug Safety Evaluation
Background:
- Beta2-adrenergic receptor (AR) agonists are crucial for treating respiratory diseases.
- Cardiac side effects, particularly myocardial fibrosis, are serious concerns with beta2-AR agonists.
- Understanding the mechanism of beta2-AR agonist-induced cardiotoxicity is essential for developing safer drugs.
Purpose of the Study:
- To investigate the role of beta1-AR occupancy in mediating myocardial fibrosis caused by beta2-AR agonists.
- To establish a correlation between receptor occupancy and the incidence of myocardial fibrosis.
- To evaluate the utility of receptor occupancy theory in predicting cardiac side effects of beta2-AR agonists.
Main Methods:
- Administration of selective beta2-AR agonists (salbutamol, terbutaline) to rats.
- Measurement of plasma drug concentrations, plasma protein binding, and EC50 for chronotropic effects.
- Construction of receptor occupancy-time profiles and calculation of AUCphi.
- Correlation analysis between AUCphi and the degree of myocardial fibrosis.
Main Results:
- Myocardial fibrosis was observed in rats treated with higher doses of salbutamol and terbutaline.
- Myocardial fibrosis showed a significant correlation (r2 > 0.78) with AUCphi, with a threshold around 50%.
- No significant correlation was found between myocardial fibrosis and plasma drug concentrations.
Conclusions:
- Beta1-AR occupancy, rather than plasma concentration, is a key determinant of myocardial fibrosis induced by beta2-AR agonists.
- Receptor occupancy theory provides a valuable framework for predicting and evaluating cardiac side effects of beta2-AR agonists.
- These findings can guide the development of more selective and safer beta2-AR agonists with reduced cardiotoxicity.
