Negative inotropy of the gastric proton pump inhibitor pantoprazole in myocardium from humans and rabbits: evaluation of mechanisms.
BACKGROUND
Proton pump inhibitors are used extensively for acid-related gastrointestinal diseases. Their effect on cardiac contractility has not been assessed directly.


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 microg/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 microg/mL. Intracellular Ca2+ fluxes were assessed in fura 2-loaded, voltage-clamped rabbit ventricular myocytes. Pantoprazole (40 microg/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 (Kd) of sarcoplasmic reticulum Ca2+ adenosine triphosphatase: control, Kd=358+/-15 nmol/L; 40 microg/mL pantoprazole, Kd=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.
Schillinger
Wolfgang
W
Herzzentrum, Kardiologie und Pneumologie, Georg-August Universitaet Goettingen, Robert-Koch Strasse 40, 37099 Goettingen, Germany. schiwolf@med.uni-goettingen.de
Teucher
Nils
N
Sossalla
Samuel
S
Kettlewell
Sarah
S
Werner
Carola
C
Raddatz
Dirk
D
Elgner
Andreas
A
Tenderich
Gero
G
Pieske
Burkert
B
Ramadori
Giuliano
G
Schöndube
Friedrich A
FA
Kögler
Harald
H
Kockskämper
Jens
J
Maier
Lars S
LS
Schwörer
Harald
H
Smith
Godfrey L
GL
Hasenfuss
Gerd
G
D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000009:adverse effects / Q000494:pharmacology*; D008841:Actin Cytoskeleton / Q000187:drug effects*; D000814:Aniline Compounds / Q000032:analysis; D000818:Animals; D000897:Anti-Ulcer Agents / Q000009:adverse effects / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D003864:Depression, Chemical; D003971:Diastole; D005260:Female; D005452:Fluoresceins / Q000032:analysis; D005456:Fluorescent Dyes / Q000032:analysis; D006325:Heart Atria / Q000187:drug effects; D006333:Heart Failure / Q000503:physiopathology; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D017136:Ion Transport / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000201:enzymology; D032383:Myocytes, Cardiac / Q000187:drug effects; D010070:Oxalates / Q000494:pharmacology; D000077402:Pantoprazole; D018408:Patch-Clamp Techniques; D016133:Polymerase Chain Reaction; D054328:Proton Pump Inhibitors; D017494:Proton Pumps / Q000032:analysis; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000187:drug effects; D013599:Systole; D014966:Xanthenes / Q000032:analysis
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000814:Aniline Compounds; D000897:Anti-Ulcer Agents; D020746:Calcium Channels, L-Type; D005452:Fluoresceins; D005456:Fluorescent Dyes; D010070:Oxalates; D054328:Proton Pump Inhibitors; D017494:Proton Pumps; D014966:Xanthenes; C059715:Fluo-3; C043829:2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein; D000077402:Pantoprazole; D002118:Calcium