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

Schillinger, W. et al. (2007) Negative inotropy of the gastric proton pump inhibitor pantoprazole in myocardium from humans and rabbits - Evaluation of mechanisms. Circulation, 116(1), pp. 57-66. (doi: 10.1161/CIRCULATIONAHA.106.666008)

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 degrees 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 mu g/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/F-0) were significantly depressed by 10.4 +/- 2.1% at 40 mu g/mL. Intracellular Ca2+ fluxes were assessed in fura 2-loaded, voltage-clamped rabbit ventricular myocytes. Pantoprazole (40 mu g/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,I-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 mu g/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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Smith, Professor Godfrey and Kettlewell, Dr Sarah
• Authors: Schillinger, W., Teucher, N., Sossalla, S., Kettlewell, S., Werner, C., Raddatz, D., Elgner, A., Tenderich, G., Pieske, B., Ramadori, G., Schondube, F., Kogler, H., Kockskamper, J., Maier, L., Schworer, H., Smith, G., and Hasenfuss, G.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health; College of Medical Veterinary and Life Sciences
• Journal Name: Circulation
• ISSN: 0009-7322