title: Oxytocin does not directly alter cardiac repolarization in rabbit or human cardiac myocytes.
abstract: Oxytocin, a nine amino acid peptide, is highly conserved in placental mammals, including humans. Oxytocin has a physiological role in parturition and parenteral administration of the synthetic peptide is used to induce labor and control postpartum hemorrhage. Endogenous levels of oxytocin before labor are ∼20 pg/mL, but pharmacological administration of the peptide can achieve levels of 110 pg/mL (0.1 nmol/L) following intravenous administration. Cardiac arrhythmia and premature ventricular contractions have been associated with oxytocin administration in addition to QTc interval prolongation. In the conscious rabbit model, intravenous oxytocin produced QT and QTc prolongation. The mechanism of oxytocin-induced QTc prolongation is uncertain but could be the result of indirect changes in autonomic nervous tone, or a direct effect on the duration of cardiomyocyte repolarization. The purpose of this study was to examine the ability of oxytocin to alter cardiac repolarization directly. Two conventional models were used: QTc interval evaluation in the isolated rabbit heart (IRH) and assessment of action potential duration (APD) in human ventricular myocytes (HVM). Oxytocin did not prolong QTc intervals in IRH or APD in HVM when tested at suprapharmacological concentrations, for example, up to 1 μmol/L. The results indicate that oxytocin has very low risk for eliciting QTc and APD prolongation directly, and infer that the QTc changes observed in vivo may be attributed to an indirect mechanism.
authors.affiliation: Safety and Exploratory Pharmacology, Toxicology Sciences, Amgen Inc. Thousand Oaks, CA, 91320.
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Qu
authors.affiliation: Safety and Exploratory Pharmacology, Toxicology Sciences, Amgen Inc. Thousand Oaks, CA, 91320.
authors.forename: Mei
authors.initials: M
authors.lastname: Fang
authors.affiliation: Safety and Exploratory Pharmacology, Toxicology Sciences, Amgen Inc. Thousand Oaks, CA, 91320.
authors.forename: BaoXi
authors.initials: B
authors.lastname: Gao
authors.affiliation: Neuroscience, Amgen Inc. Thousand Oaks, CA, 91320.
authors.forename: Shanti
authors.initials: S
authors.lastname: Amagasu
authors.affiliation: Zenas Technologies LLC New Orleans, LA 70006.
authors.forename: William J
authors.initials: WJ
authors.lastname: Crumb
authors.affiliation: Safety and Exploratory Pharmacology, Toxicology Sciences, Amgen Inc. Thousand Oaks, CA, 91320.
authors.forename: Hugo M
authors.initials: HM
authors.lastname: Vargas
keywords: APD90; Action potential duration; QT; QTc; human ventricular myocytes; ion channels; isolated rabbit heart; oxytocin; ventricular repolarization