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

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.

Antipsychotics cardiotoxicity: What's known and what's next

“…The use of captopril, an angiotensin-converting enzyme inhibitor, significantly protected against the above clozapine-induced effects in rats[ 103 ]. In a rat model, olanzapine-induced cardiotoxicity was reported to be associated with increased acetyl-CoA carboxylase phosphorylation and tissue ATP levels and lower phosphorylation levels of Akt and its downstream product AS160[ 104 ]. These generally descriptive studies reinforced the mitochondria-involved mechanisms and implied that inflammatory cell death might be critically involved in antipsychotic cardiotoxicity.…”

Mapping the Knowledge of Antipsychotics-Induced Sudden Cardiac Death: A Scientometric Analysis in CiteSpace and VOSviewer

“…A study based on zebrafish embryos has shown that, clozapine can increase the levels of reactive oxygen species and a lipid peroxidation marker leading to oxidative and inflammation, thus resulting in cardiotoxicity ( 8 ). Another study based on male rats showed that, in the rat heart, olanzapine can increase the level of acetyl-CoA carboxylase phosphorylation and tissue ATP level, also reduce the level of Akt and its downstream products AS160, which may be involved with the mechanism for the adverse cardiac effects ( 9 ). Data from a Italian study showed that the elderly frail subjects were more likely to be prescribed second-generation antipsychotics and this may be involved in cardiometabolic disorders and other comorbidities ( 10 ).…”

Efeitos do antipsicótico olanzapina na reatividade in vitro da aorta torácica de ratos

“…Patrik Gulac e colaboradores (2020), relata que a incidência de morte súbita cardíaca em pacientes tratados com olanzapina é duas vezes maior do que em não usuários, mas o mecanismo subjacente aos efeitos cardíacos adversos graves permanece pouco compreendido (BEAUCHEMIN; GEGUCHADZE; GUNTUR; NEVOLA et al, 2020;GULAC;ARNOLD;GRMAN;CARREL et al, 2020). Fonte: Próprio autor.…”