Diminished posttetanic potentiation in failing human myocardium

Abstract

In heart failure a decreased function of SERCA 2 has been demonstrated. The present study aimed at investigating the relation between sarcoplasmic reticulum-Ca2+-load (SR-Ca2+-load) and the activity of the SERCA 2. SR-Ca2+ load was evaluated by measuring posttetanic potentiation (PTP) in human nonfailing (NF, n = 10) and endstage failing myocardium (DCM, n = 11). In addition, the effect of cyclopiazonic acid (CPA), a specific inhibitor of SERCA 2, on PTP was studied in both NF and DCM. In crude membrane preparations from the same hearts the maximal SERCA 2 activity was determined and correlated with the PTP. In failing myocardium the PTP was significantly reduced compared to nonfailing myocardium (13.7+/-0.75 mN/mm2 vs. 17.1+/-1.55 mN/mm2, p<0.05, +/- SEM). When PTP was studied in the presence of increased extracellular Ca2+-concentrations, the difference between NF and DCM was further pronounced. CPA decreased PTP in both nonfailing and failing human tissue. The maximal SERCA 2 activity was significantly reduced in failing myocardium (NF 267+/-18.5 nmol ATP/mg protein x min(-1) vs. DCM 191+/-13.4 nmol ATP/mg protein x min(-1), p<0.05, +/- SEM). Correlation of the PTP and maximal SERCA 2 activity revealed a close correlation between both parameters in NF and DCM. In summary, the presented results suggest that reduced SERCA 2 activity in DCM influences posttetanic force potentiation probably through a reduced SR-Ca2+-load.