EFFECT OF INOTROPIC INTERVENTIONS ON THE FORCE-FREQUENCY RELATION IN THE HUMAN HEART

In severe human heart failure, an increase in frequency of stimulation is accompanied by a reduced force of contraction in vivo and in vitro . This contrasts the findings in nonfailing human hearts. To investiga te influences of inotropic stimulation on the force-frequency relation ship in human myocardium, the effects of the cAMP-independent positive inotropic agents ouabain (Na+/K+-ATPase inhibitor) and BDF 9148 (Na+- channel modulator) as well as of the beta-adrenoceptor agonist isopren aline on the force-frequency relationship in electrically driven left ventricular papillary muscle strips from nonfailing and terminally fai ling human myocardium were studied. In nonfailing myocardium, force of contraction increased following an increase in stimulation frequency, whereas in failing human myocardium force of contraction gradually de clined following an increase in stimulation frequency, Moderate stimul ation of contractility by isoprenaline reversed the negative force-fre quency relationship in failing myocardium and preserved the positive f orce-frequency relationship in nonfailing myocardium. In the presence of ouabain and BDF 9148 the positive force-frequency relationship was completely restored in failing myocardium. In contrast, in the presenc e of high concentrations of isoprenaline the former positive force-fre quency relationship became negative even in nonfailing myocardium, The negative force-frequency relationship in failing human myocardium is accompanied by alterations in the intracellular Ca2+-homeostasis. The latter may be due to an impaired function of the sarcoplasmic reticulu m (SR) in failing human myocardium. Therefore, the activity of the SR- Ca2+-ATPase (SERCA2) of crude membrane preparations was investigated a nd was significantly reduced in failing compared to nonfailing human m yocardium, It is concluded that the negative force-frequency relations hip may be due to alterations in the intracellular Ca2+-handling cause d by an impaired function of the SERCA2 in failing human myocardium. T he beneficial effects of cAMP-increasing agents on the farce-frequency relationship in failing human hearts could result from an enhanced ph osphorylation status of phospholamban in the presence of beta-adrenoce ptor-stimulation. The effect of the [Na+](i)-modulating agents BDF 914 8 and ouabain demonstrates that the intracellular Na+-homeostasis infl uences intracellular Ca2+-handling as well, Differences observed in fa iling compared to nonfailing myocardium may be due to an altered expre ssion or function of the Na+/Ca2+-exchanger, Na+-channels or the Na+/K +-ATPase in addition to the blunted activity of the SERCA2 in failing myocardium.