Potentiation of beta-adrenergic inotropic response by pyruvate in failing human myocardium.
BACKGROUND
Pyruvate has been shown to increase contractile function in isolated myocardium and to improve hemodynamics in patients with congestive heart failure. We tested the hypothesis that pyruvate potentiates the inotropic response to beta-adrenergic stimulation and to elevated extracellular calcium, since this may be of potential therapeutic value in the clinical setting of acute heart failure in order to circumvent deleterious effects on energy demand as can occur during catecholamine therapy.


RESULTS
We investigated isometrically contracting isolated multicellular muscle preparations from terminal failing human hearts at 37 degrees C, pH 7.4, and a stimulation frequency of 1 Hz. At an extracellular calcium concentration of 1.25 mM, pyruvate (10 mM) alone increased developed force (F(dev)) from 9.0+/-2.3 to 21.1+/-4.3 mN/mm(2) (n=9, P<0.001) and isoproterenol (1 microM) alone increased F(dev) from 9.5+/-2.0 to 31.3+/-5.4 mN/mm(2) (P<0.001), whereas the combination of pyruvate and isoproterenol increased F(dev) over-proportionally from 9.0+/-2.3 to 47.4+/-6.4 mN/mm(2) (P<0.01). In a separate series we assessed the combination of pyruvate and calcium. Although F(dev) did not increase from 12 to 16 mM [Ca(2+)](o), 10 mM pyruvate further increased F(dev) from 25.8+/-5.0 to 30.6+/-4.7 mN/mm(2) (P<0.01). Rapid cooling contractures revealed that altered myofilament responsiveness and/or sarcoplasmic reticulum (SR) calcium load must underlie the positive inotropic effect of pyruvate.


CONCLUSIONS
A combination of pyruvate and beta-adrenergic stimulation may be of therapeutic value in acute heart failure by reducing the concentrations of potential deleterious catecholamines that are currently necessary to maintain adequate tissue perfusion.
Hermann
Hans Peter
HP
Abteilung Kardiologie und Pneumologie, Georg-August-Universität Göttingen, Robert-Koch-Str. 40, D-37075 Göttingen, Germany. phermann@med.uni-goettingen.de
Zeitz
Oliver
O
Lehnart
Stephan E
SE
Keweloh
Boris
B
Datz
Nicolin
N
Hasenfuss
Gerd
G
Janssen
Paul M L
PM
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000368:Aged; D000704:Analysis of Variance; D002118:Calcium / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D019289:Pyruvic Acid / Q000494:pharmacology*; D018709:Statistics, Nonparametric; D013268:Stimulation, Chemical
D000318:Adrenergic beta-Agonists; D019289:Pyruvic Acid; D007545:Isoproterenol; D002118:Calcium