Negative inotropy of the gastric proton pump inhibitor pantoprazole in myocardium from humans and rabbits: Evaluation of mechanisms

Abstract

BACKGROUND - Proton pump inhibitors are used extensively for acid-related gastrointestinal diseases. Their effect on cardiac contractility has not been assessed directly. METHODS AND RESULTS - Under physiological conditions (37°C, pH 7.35, 1.25 mmol/L Ca), there was a dose-dependent decrease in contractile force in ventricular trabeculae isolated from end-stage failing human hearts superfused with pantoprazole. The concentration leading to 50% maximal response was 17.3±1.3 μg/mL. Similar observations were made in trabeculae from human atria, normal rabbit ventricles, and isolated rabbit ventricular myocytes. Real-time polymerase chain reaction demonstrated the expression of gastric H/K-adenosine triphosphatase in human and rabbit myocardium. However, measurements with BCECF-loaded rabbit trabeculae did not reveal any significant pantoprazole-dependent changes of pHi. Ca transients recorded from field-stimulated fluo 3-loaded myocytes (F/F0) were significantly depressed by 10.4±2.1% at 40 μg/mL. Intracellular Ca fluxes were assessed in fura 2-loaded, voltage-clamped rabbit ventricular myocytes. Pantoprazole (40 μg/mL) caused an increase in diastolic [Ca]i by 33±12%, but peak systolic [Ca]i was unchanged, resulting in a decreased Ca transient amplitude by 25±8%. The amplitude of the L-type Ca current (ICa,L) was reduced by 35±5%, and sarcoplasmic reticulum Ca content was reduced by 18±6%. Measurements of oxalate-supported sarcoplasmic reticulum Ca uptake in permeabilized cardiomyocytes indicated that pantoprazole decreased Ca sensitivity (Kd) of sarcoplasmic reticulum Ca adenosine triphosphatase: control, Kd=358±15 nmol/L; 40 μg/mL pantoprazole, Kd=395±12 nmol/L (P<0.05). Pantoprazole also acted on cardiac myofilaments to reduced Ca-activated force. CONCLUSIONS - Pantoprazole depresses cardiac contractility in vitro by depression of Ca signaling and myofilament activity. In view of the extensive use of this agent, the effects should be evaluated in vivo. © 2007 American Heart Association, Inc.