Analysis of Resibufogenin on Cardiac conduction reveals a species difference in the cardiac electrophysiology: Rats versus guinea pigs.

Highlights

• Resibufogenin derived from Chan Su had great potential in influencing the activities of the cardiac electrophysiology.

• Resibufogenin showed potential in controlling arrhythmia of rats, however, Resibufogenin triggered arrhythmia of guinea pigs.

• The species-difference drug effect is likely to be associated with different distribution of ion channels.

• Resibufogenin triggered arrhythmias of guinea pigs, which may be due to the lack of the I_to on the myocardial membrane.

Abstract

Resibufogenin (RBG) is a chemical ingredient of Chan Su. In our research, we found RBG affected cardiac rhythm in a negative chronotropic way in vivo. The cardiac Mapping system ex vivo and the patch clamp in vitro were used to explore how RBG influenced the cardiac electrophysiological properties. The negative chronotropic action of RBG at 100 μM might be attribute to prolongation in the atrioventricular conduction time and reduction in the ventricular conduction velocity. Using whole-cell patch clamp in ventricular myocytes of adult rats, we found that RBG prolonged the action potential duration (APD) in APD₂₀, APD₅₀, and APD₉₀ at 100 μM and inhibited calcium currents (I_Ca), total outward potassium currents (I_K), and transient outward potassium current (I_to) in a concentration-dependent manner, but not on the inward rectifying potassium current (I_K1). Notably, RBG had a potent proarrhythmic action ex vivo in the isolated perfused guinea pig hearts at 10 μM, but not in rats. To avoid the potential cardiotoxicity derived from the distributional differences of ion channels among species, the effect of RGB on I_Kr in hERG-HEK293 cells was detected. The IC₅₀ of RGB on I_Kr was more than 100 μM. In summary, all these results indicated that the negative chronotropic action of RBG relied on the blocking activities on multiple ion channels, and the species-difference of proarrhythmic effects might result from lack of the I_to on the myocardial membrane of guinea pigs. Anyhow, the cardiotoxicity observed in guinea pigs required further detailed studies to mitigate the potential risks in the clinical application of Chan Su.