Olanzapine-mediated cardiotoxicity is associated with altered energy metabolism in isolated rat hearts

  • Patrik Gulac 1Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovak Republic; 2Department of Cardiovascular Surgery, Inselspital, Bern University Hospital and Department for BioMedical Research, University of Bern, Bern, Switzerland https://orcid.org/0000-0003-1446-4538
  • Maria Arnold Department of Cardiovascular Surgery, Inselspital, Bern University Hospital and Department for BioMedical Research, University of Bern, Bern, Switzerland https://orcid.org/0000-0003-4146-404X
  • Marian Grman Institute of Clinical and Translational Research, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovak Republic
  • Thierry Carrel Department of Cardiovascular Surgery, Inselspital, Bern University Hospital and Department for BioMedical Research, University of Bern, Bern, Switzerland
  • Sarah Longnus Department of Cardiovascular Surgery, Inselspital, Bern University Hospital and Department for BioMedical Research, University of Bern, Bern, Switzerland https://orcid.org/0000-0001-8489-917X
  • Tatiana Stankovicova Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovak Republic
  • Lenka Tomasova 1Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovak Republic, 2Institute of Clinical and Translational Research, Biomedical Research Center, University Science Park for Biomedicine, Slovak Academy of Sciences, Bratislava, Slovak Republic https://orcid.org/0000-0002-1943-0858

Abstract

Olanzapine is an antipsychotic drug routinely used for the treatment of schizophrenia. Although the olanzapine treatment is associated with disturbed electrical heart activity, the exact mechanism underlying this severe adverse effect remains unclear. Recently, olanzapine administration was demonstrated to be associated with elevation of blood glucose and lower levels of free fatty acids. Therefore, we investigated the effect of acute olanzapine administration on pathways regulating the cardiac energy metabolism in an isolated heart. Electrical activity and contractile parameters were recorded in isolated, spontaneously beating, adult male rat hearts, perfused with either olanzapine (100 nmol/l) or the vehicle for 10 min. Regulation of key signalling molecules was evaluated by immunoblotting and ATP levels were measured spectrophotometrically. Olanzapine prolonged the QTc intervals and induced a higher number of premature ventricular beats. Furthermore, olanzapine significantly decreased the coronary flow, the rate-pressure product and the contractility (+dP/dt and –dP/dt). These changes were associated with an increased acetyl-CoA carboxylase phosphorylation and tissue ATP levels. We also found a trend for lower phosphorylation levels of Akt and its downstream products AS160, a key regulator of GLUT4 trafficking and glycogen synthase kinase‑3ß in olanzapine‑treated hearts when compared to vehicle-treated controls. These data should contribute to the elucidation of mechanisms that underlie the adverse cardiac effects of olanzapine.

Published
2020-01-30
Section
Articles