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 Ca²⁺), 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 pH_i. Ca²⁺ transients recorded from field-stimulated fluo 3-loaded myocytes (F/F₀) were significantly depressed by 10.4±2.1% at 40 µg/mL. Intracellular Ca²⁺ fluxes were assessed in fura 2-loaded, voltage-clamped rabbit ventricular myocytes. Pantoprazole (40 µg/mL) caused an increase in diastolic [Ca²⁺]_i by 33±12%, but peak systolic [Ca²⁺]_i was unchanged, resulting in a decreased Ca²⁺ transient amplitude by 25±8%. The amplitude of the L-type Ca²⁺ current (I_Ca,L) was reduced by 35±5%, and sarcoplasmic reticulum Ca²⁺ content was reduced by 18±6%. Measurements of oxalate-supported sarcoplasmic reticulum Ca²⁺ uptake in permeabilized cardiomyocytes indicated that pantoprazole decreased Ca²⁺ sensitivity (K_d) of sarcoplasmic reticulum Ca²⁺ adenosine triphosphatase: control, K_d=358±15 nmol/L; 40 µg/mL pantoprazole, K_d=395±12 nmol/L (P<0.05). Pantoprazole also acted on cardiac myofilaments to reduced Ca²⁺-activated force.

Conclusions--Pantoprazole depresses cardiac contractility in vitro by depression of Ca²⁺ signaling and myofilament activity. In view of the extensive use of this agent, the effects should be evaluated in vivo.