In vivo analysis of acute eletropharmacological effects of proton pump inhibitors using halothane-anesthetized dogs: a translational study of cardiovascular adverse events

• Published in: Journal of toxicological sciences 2023, Vol.48(7), pp.375-385
• Main Authors: Kambayashi, Ryuichi, Goto, Ai, Izumi-Nakaseko, Hiroko, Takei, Yoshinori, Sugiyama, Atsushi
• Format: Article
• Language: English
• Subjects: Blood pressure; Cardiac output; Cardiovascular adverse effects; Dogs; Halothane; Heart rate; Hypomagnesemia; Inhibitors; Muscle contraction; Omeprazole; Prolongation; Proton pump inhibitor; Proton pump inhibitors; Protons; QT prolongation; Refractory period; Ventricle; Ventricular arrhythmias; Ventricular effective refractory period
• ISSN: 0388-1350; 1880-3989
• DOI: 10.2131/jts.48.375

Long-term use of proton pump inhibitors (PPIs) is known to clinically induce hypomagnesemia, increasing the risk toward QT-interval prolongation and lethal ventricular arrhythmias, whereas PPIs can directly modulate cardiac ionic currents in the in vitro experiments. In order to fill the gap between those information, we assessed acute cardiohemodynamic and electrophysiological effects of sub- to supra-therapeutic doses (0.05, 0.5 and 5 mg/kg/10 min) of typical PPIs omeprazole, lansoprazole and rabeprazole, using halothane-anesthetized dogs (n = 6 for each drug). The low and middle doses of omeprazole and lansoprazole increased or tended to increase the heart rate, cardiac output and ventricular contraction, whereas the high dose plateaued and decreased them. Meanwhile, the low and middle doses of omeprazole and lansoprazole decreased the total peripheral vascular resistance, whereas the high dose plateaued and increased it. Rabeprazole decreased the mean blood pressure in a dose-related manner; moreover, its high dose decreased the heart rate and tended to reduce the ventricular contractility. On the other hand, omeprazole prolonged the QRS width. Omeprazole and lansoprazole tended to prolong the QT interval and QTcV, and rabeprazole mildly but significantly prolonged them in a dose-related manner. High dose of each PPI prolonged the ventricular effective refractory period. Omeprazole shortened the terminal repolarization period, whereas lansoprazole and rabeprazole hardly altered it. In effects, PPIs can exert multifarious cardiohemodynamic and electrophysiological actions in vivo, including mild QT-interval prolongation; thus, PPIs should be given with caution to patients with reduced ventricular repolarization reserve.