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(Circulation. 2007;116:57-66.)
© 2007 American Heart Association, Inc.

Heart Failure

Negative Inotropy of the Gastric Proton Pump Inhibitor Pantoprazole in Myocardium From Humans and Rabbits

Evaluation of Mechanisms

Wolfgang Schillinger, MD^*; Nils Teucher, MD^*; Samuel Sossalla, MS; Sarah Kettlewell, PhD; Carola Werner, PhD; Dirk Raddatz, MD; Andreas Elgner, MS; Gero Tenderich, MD; Burkert Pieske, MD; Giuliano Ramadori, MD; Friedrich A. Schöndube, MD; Harald Kögler, MD; Jens Kockskämper, PhD; Lars S. Maier, MD; Harald Schwörer, MD; Godfrey L. Smith, PhD; Gerd Hasenfuss, MD

From the Herzzentrum, Kardiologie und Pneumologie, Universitaet Goettingen, Goettingen, Germany (W.S., S.S., A.E., B.P., H.K., J.K., L.S.M., G.H.); Herzzentrum, Thorax-, Herz-, und Gefaesschirurgie, Universitaet Goettingen, Goettingen, Germany (N.T., F.A.S.); Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, UK (S.K., G.L.S.); Medizinische Statistik, Universitaet Goettingen, Goettingen, Germany (C.W.); Gastroenterologie und Endokrinologie, Universitaet Goettingen, Goettingen, Germany (D.R., G.R., H.S.); and Herz- und Diabeteszentrum Nordrhein-Westfalen, Klinik fuer Thorax- und Kardiovaskularchirurgie, Bad Oeynhausen, Germany (G.T.).

Correspondence to Wolfgang Schillinger, MD, Herzzentrum, Kardiologie und Pneumologie, Georg-August Universitaet Goettingen, Robert-Koch Strasse 40, 37099 Goettingen, Germany. E-mail schiwolf{at}med.uni-goettingen.de

Received September 25, 2006; accepted May 1, 2007.

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.

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