ALTERED INOTROPISM IN THE FAILING HUMAN MYOCARDIUM

beta-adrenoreceptor-cAMP-dependent inotropic interventions lose their effectiveness depending on the degree of myocardial failure. This blun ted effect of beta-adrenoreceptor-dependent stimulation might be due t o a downregulation of beta-adrenoreceptors and an increase of inhibito ry G-proteins leading to decreased intracellular cAMP-concentrations. However, the maximal positive inotropic effect elicited by elevation o f the extracellular [Ca2+] does not differ between failing and nonfail ing human myocardium, indicating that terminally failing human myocard ium is effective to increase force of contraction to the same degree a s nonfailing tissue. Agents which increase force of contraction primar ily via increasing the intracellular [Na+], e.g., cardiac glycosides a nd the Na+-channel activator BDF 9148, exert a higher potency in faili ng myocardium than in nonfailing tissue to increase force of contracti on. This could result from an enhanced protein expression of the Na+/C a2+ exchanger observed in diseased human hearts. Alterations in the in tracellular Ca2+-homeostasis reported in failing myocardium lead to a negative force-frequency-relationship and a prolonged relaxation. As t he protein expression of SERCA IIa and phospholamban seems to be simil iar in NYHA IV and nonfailing tissue, the reduced Ca2+-uptake may resu lt from an altered regulation of these proteins, e.g., reduced phospho rylation of phospholamban or the SERCA IIa. After inhibition of the Ca 2+-ATPase of the sarcoplasmic reticulum with the high specific inhibit or cyclopiazonic acid the former positive force-frequency-relationship became significantly less positive even in the nonfailing tissue and twitch course became similiar to diseased hearts. These findings may b e indicative for the importance of the Ca2+-reuptake mechanism into th e sarcoplasmic reticulum in addition to the regulatory control at the site of the contractile apparatus for the regulation of contraction an d relaxation in human myocardium.