Influence of pyruvate on contractile performance and Ca(2+) cycling in isolated failing human myocardium.
BACKGROUND
Application of pyruvate was shown to improve contractile function in isolated animal myocardium and hemodynamics in patients with congestive heart failure. We assessed the influence of pyruvate on systolic and diastolic myocardial function and its subcellular mode of action in isolated myocardium from end-stage failing human hearts.


RESULTS
In muscle strip preparations, concentration-dependent effects of pyruvate on developed and diastolic force (n=6), aequorin light emission reflecting intracellular Ca(2+) transients (n=6), and rapid cooling contractures reflecting sarcoplasmic reticulum (SR) Ca(2+) content (n=11) were measured. Pyruvate resulted in a concentration-dependent increase in developed force and a decrease in diastolic force, with a maximum effect of 155% and 21%, respectively, at 20 mmol/L pyruvate (P<0.05). This was associated with a dose-dependent prolongation of time to peak tension and relaxation time. Pyruvate increased rapid cooling contractures by 51% and aequorin light signals by 85% (at 15 and 20 mmol/L; P<0.05). This indicates increased SR Ca(2+) content and increased intracellular Ca(2+) transients. The inotropic effect of pyruvate was still present after elimination of SR Ca(2+) storage function with 10 micromol/L cyclopiazonic acid and 1 micromol/L ryanodine (n=8). Pyruvate significantly increased intracellular pH from 7.31+/-0.03 to 7.40+/-0.04 by BCECF fluorescence (n=6).


CONCLUSIONS
The present findings indicate that pyruvate improves contractile performance of failing human myocardium by increasing intracellular Ca(2+) transients as well as myofilament Ca(2+) sensitivity. The former seem to result from increased SR Ca(2+) accumulation and release, the latter from increased intracellular pH.
Hasenfuss
Gerd
G
Abteilung Kardiologie und Pneumologie, Zentrum Innere Medizin, Georg-August-Universität Göttingen, Germany. hasenfus@med.uni-goettingen.de
Maier
Lars S
LS
Hermann
Hans-Peter
HP
Lüers
Claus
C
Hünlich
Mark
M
Zeitz
Oliver
O
Janssen
Paul M L
PM
Pieske
Burkert
B
D000331:Aequorin / Q000737:chemistry; D002118:Calcium / Q000378:metabolism*; D003080:Cold Temperature; D046508:Culture Techniques; D004305:Dose-Response Relationship, Drug; D005260:Female; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology*; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D019289:Pyruvic Acid / Q000494:pharmacology*; D012433:Ryanodine / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000187:drug effects; D013268:Stimulation, Chemical
D007211:Indoles; D012433:Ryanodine; D000331:Aequorin; D019289:Pyruvic Acid; D002118:Calcium; C000543:cyclopiazonic acid