Gingerol, isoproterenol and ouabain normalize impaired post-rest behavior but not force-frequency relation in failing human myocardium

Objective: Rest- and stimulation frequency-dependent potentiation of contra ctile force is blunted in failing human myocardium. These alterations have been related to reduced sarcoplasmic reticulum (SR) Ca2+-reuptake and enhan ced 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 hea rts. Methods: We tested the influence of [10]-gingerol which activates SR C a2+-ATPase (10 mu mol/l; n=13), and isoproterenol which activates cAMP-depe ndent pathways (0.01, 0.1, 1 mu mol/l; n=40) on post-rest and force-frequen cy behavior. Ouabain which blocks Na+/K+-ATPase (0.03 mu mol/l; n=16) was u sed to test the effects of inhibiting Ca2+-elimination by Na+/Ca2+-exchange . For comparison, the effects of blocking SR Ca2+-uptake by thapsigargin (1 0 mu mol/l; n=14) were tested. In addition, Ca2+-uptake in myocardial homog enates was measured for gingerol (10 mu mol/l; n=6). Results: Gingerol, iso proterenol (0.1, 1 mu mol/l) and ouabain exerted significant positive inotr opic effects under basal experimental conditions and normalized post-rest b ehavior. In contrast, force-frequency relation was only slightly improved b y gingerol and isoproterenol (0.01 mu mol/l). Ouabain and isoproterenol (1 mu mol/l) further deteriorated force-frequency relation due to frequency-de pendent significant increases in diastolic tension. Thapsigargin exerted ne gative inotropic effects and significantly deteriorated post-rest and force -frequency behavior. In addition, gingerol increased SR Ca2+-uptake signifi cantly in myocardial homogenates. Conclusions: Inotropic interventions that stimulate SR Ca2+-ATPase or inhibit Na+/Ca2+-exchange normalize impaired p ost-rest behavior. Force-frequency behavior is only slightly improved by st imulation of SR Ca2+-ATPase but not by inhibition of Na+/Ca2+-exchange. Thi s dissociation between post-rest and force-frequency behavior results from diastolic dysfunction at high stimulation rates. (C) 2000 Elsevier Science B.V. All rights reserved.