CELLULAR BASIS FOR THE NEGATIVE INOTROPIC EFFECTS OF TUMOR-NECROSIS-FACTOR-ALPHA IN THE ADULT MAMMALIAN HEART

To define the mechanism(s) responsible for the negative inotropic effe cts of tumor necrosis factor-alpha (TNFalpha) in the adult heart, we e xamined the functional effects of TNFalpha in the intact left ventricl e and the isolated adult cardiac myocyte. Studies in both the ventricl e and the isolated adult cardiac myocyte showed that TNFalpha exerted a concentration- and time-dependent negative inotropic effect that was fully reversible upon removal of this cytokine. Further, treatment wi th a neutralizing anti-TNFalpha antibody prevented the negative inotro pic effects of TNFalpha in isolated myocytes. A cellular basis for the above findings was provided by studies which showed that treatment wi th TNFalpha resulted in decreased levels of peak intracellular calcium during the systolic contraction sequence; moreover, these findings di d not appear to be secondary to alterations in the electrophysiologica l properties of the cardiac myocyte. Further studies showed that incre ased levels of nitric oxide, de novo protein synthesis, and metabolite s of the arachidonic acid pathway were unlikely to be responsible for the TNFalpha-induced abnormalities in contractile function. Thus, thes e studies constitute the initial demonstration that the negative inotr opic effects of TNFalpha are the direct result of alterations in intra cellular calcium homeostasis in the adult cardiac myocyte.