The Concentration-dependent Investigation of the Toxic Effects of the Anorectic Agent Sibutramine on the Electrical Activity of the Cardiomyocytes in Metabolic Syndrome Rat Heart

Abstract

Objectives:

Sibutramine (SBT) has been intensely used for losing weight over the past decades. In addition to the known mode of its action through brown adipose tissue thermogenesis, systemic actions reveal some side effects including alterations in cardiac function. Despite various clinical findings, the effect of SBT on cellular levels remains elusive. This study aimed to investigate the possible effects of sibutramine on the electrical activity of the cardiomyocytes from freshly isolated metabolic syndrome (MetS) rat hearts.

Materials and Methods:

Wistar type 2-month-old male rats were used. The animals were fed (20-22 weeks) with tap water containing 32% sucrose in addition to standard feed (20-22 weeks). MetS were confirmed using higher body weight, higher fasting blood glucose, and impaired glucose tolerance test. Heart tissue sections were stained with Masson Trichrome and examined under light microscopy. All patch-clamp experiments were performed in whole-cell mode, but action potentials were recorded in current-clamp configuration and voltage-gated K⁺-channel currents in voltage-clamp configuration from freshly isolated MetS cardiomyocytes. Acute SBT treatment was performed in a concentration-dependent manner (10^-8-10^-5 M) for all cardiomyocytes.

Results:

Histological examinations reveal that MetS hearts are characterized by a marked increase in collagen depositions. Electrophysiological findings show the significant prolongation in action potential duration, indicate pro-arrhythmic action for SBT treatment in a concentration-dependent manner. As voltage-gated K⁺-channel currents (I_K) are responsible for changes in the repolarization of the action potentials (AP) in ventricular cardiomyocytes acute SBT treatment reduced I_K channels significantly.

Conclusion:

This study showed that the effects of SBT on prolongation of action potential and reduction in I_K channel density include pro-arrhythmic and detrimental outcomes in overweighed MetS hearts.