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

Article

关键词: FAILING HUMAN MYOCARDIUM;    OMEPRAZOLE;    PH;    CA2+-ATPASE;    EXPRESSION;    ATPASE;    HEART;   

DOI  :  10.1161/CIRCULATIONAHA.106.666008

来源: SCIE

【 摘 要 】

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.

【 授权许可】

Free