© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Gingerol, isoproterenol and ouabain normalize impaired post-rest behavior but not force–frequency relation in failing human myocardium
aGeorg-August-Universität Göttingen, Abteilung Kardiologie und Pneumologie, Zentrum Innere Medizin, Robert-Koch-Str. 40, 37075 Göttingen, Germany
bHerzzentrum Nordrhein-Westfalen, Bad Oeynhausen, Germany
* Corresponding author. Tel.: +49-551-39-8925; fax: +49-551-39-8925 pieske{at}med.uni-goettingen.de
Objective: Rest- and stimulation frequency-dependent potentiation of contractile force is blunted in failing human myocardium. These alterations have been related to reduced sarcoplasmic reticulum (SR) Ca2+-reuptake and enhanced transsarcolemmal Ca2+-elimination by Na+/Ca2+-exchange. We investigated whether inotropic interventions that enhance SR Ca2+-uptake, or reduce Ca2+-elimination by Na+/Ca2+-exchange, normalize impaired post-rest and force–frequency behavior in left ventricular muscle strips from failing human hearts. Methods: We tested the influence of [10]-gingerol which activates SR Ca2+-ATPase (10 µmol/l; n=13), and isoproterenol which activates cAMP-dependent pathways (0.01, 0.1, 1 µmol/l; n=40) on post-rest and force–frequency behavior. Ouabain which blocks Na+/K+-ATPase (0.03 µmol/l; n=16) was used to test the effects of inhibiting Ca2+-elimination by Na+/Ca2+-exchange. For comparison, the effects of blocking SR Ca2+-uptake by thapsigargin (10 µmol/l; n=14) were tested. In addition, Ca2+-uptake in myocardial homogenates was measured for gingerol (10 µmol/l; n=6). Results: Gingerol, isoproterenol (0.1, 1 µmol/l) and ouabain exerted significant positive inotropic effects under basal experimental conditions and normalized post-rest behavior. In contrast, force–frequency relation was only slightly improved by gingerol and isoproterenol (0.01 µmol/l). Ouabain and isoproterenol (1 µmol/l) further deteriorated force–frequency relation due to frequency-dependent significant increases in diastolic tension. Thapsigargin exerted negative inotropic effects and significantly deteriorated post-rest and force–frequency behavior. In addition, gingerol increased SR Ca2+-uptake significantly in myocardial homogenates. Conclusions: Inotropic interventions that stimulate SR Ca2+-ATPase or inhibit Na+/Ca2+-exchange normalize impaired post-rest behavior. Force–frequency behavior is only slightly improved by stimulation of SR Ca2+-ATPase but not by inhibition of Na+/Ca2+-exchange. This dissociation between post-rest and force–frequency behavior results from diastolic dysfunction at high stimulation rates.
KEYWORDS Contractile function; E–C coupling; Heart failure; Inotropic agents
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