PT691. Haloperidol aggravates heart failure induced by pressure overload in mice through inhibition of sigma1-receptor

Abstract

Haloperidol was commonly used for schizophrenia patients as D2 receptor antagonist. It has been known that haloperidol-induced cardiac sudden death is serious adverse event for schizophrenia patients. Haloperidol antagonizes not only D2 receptor but also σ₁-receptor (σ₁R), and we previously reported that σ₁R stimulation ameliorates cardiac dysfunction by restoring mitochondrial Ca²⁺ mobilization in transverse aortic constriction (TAC) mice. In the cardiomyocytes, σ₁R is associated with IP₃ receptor in the sarcoplasmic reticulum (SR) and promotes mitochondrial Ca²⁺ mobilization from SR. Here we found that haloperidol impairs mitochondrial Ca²⁺ mobilization and promotes cardiac hypertrophy via σ₁R inactivation in primary cultured cardiomyocytes. The σ₁R inactivation by haloperidol also aggravated Ang II-induced impaired mitochondrial Ca²⁺ mobilization and ATP production. Inversely, σ₁R agonist SA4503 ameliorated Ang II-induced impaired mitochondrial Ca²⁺ mobilization and ATP production. Our observations suggest that haloperidol promotes progression of heart failure via impairment of σ₁R-induced mitochondrial ATP production.