Interrelated In Vitro Mechanisms of Sibutramine-Induced Cardiotoxicity


ALYU ALTINOK F., OLĞAR Y., DEĞİRMENCİ S., TURAN B., ÖZTÜRK Y.

CARDIOVASCULAR TOXICOLOGY, vol.21, no.4, pp.322-335, 2021 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 21 Issue: 4
  • Publication Date: 2021
  • Doi Number: 10.1007/s12012-020-09622-1
  • Journal Name: CARDIOVASCULAR TOXICOLOGY
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, EMBASE, MEDLINE
  • Page Numbers: pp.322-335
  • Keywords: Sibutramine, Patch-clamp techniques, Langendorff-perfused heart, Reactive oxygen species, Fluorescence microscopy, CELL-DERIVED CARDIOMYOCYTES, INTRACELLULAR PH, RAT-HEART, ANTIARRHYTHMIC ACTIONS, DIMETHYL-SULFOXIDE, MASS-SPECTROMETRY, POTASSIUM CURRENT, HUMAN PLASMA, K+ CURRENTS, CONTRACTILITY
  • Anadolu University Affiliated: Yes

Abstract

Consumption of illicit pharmaceutical products containing sibutramine has been reported to cause cardiovascular toxicity problems. This study aimed to demonstrate the toxicity profile of sibutramine, and thereby provide important implications for the development of more effective strategies in both clinical approaches and drug design studies. Action potentials (APs) were determined from freshly isolated ventricular cardiomyocytes with whole-cell configuration of current clamp as online. The maximum amplitude of APs (MAPs), the resting membrane potential (RMP), and AP duration from the repolarization phases were calculated from original records. The voltage-dependent K+-channel currents (I-K) were recorded in the presence of external Cd2+ and both inward and outward parts of the current were calculated, while their expression levels were determined with qPCR. The levels of intracellular free Ca2+ and H+ (pH(i)) as well as reactive oxygen species (ROS) were measured using either a ratiometric micro-spectrofluorometer or confocal microscope. The mechanical activity of isolated hearts was observed with Langendorff-perfusion system. Acute sibutramine applications (10(-8)-10(-5) M) induced significant alterations in both MAPs and RMP as well as the repolarization phases of APs and I-K in a concentration-dependent manner. Sibutramine (10 mu M) induced Ca2+-release from the sarcoplasmic reticulum under either electrical or caffeine stimulation, whereas it depressed left ventricular developed pressure with a marked decrease in the end-diastolic pressure. pH(i) inhibition by sibutramine supports the observed negative alterations in contractility. Changes in mRNA levels of different I-K subunits are consistent with the acute inhibition of the repolarizing I-K, affecting AP parameters, and provoke the cardiotoxicity.