Increased functional importance of the Na,Ca-exchanger in contracting failing human myocardium but unchanged activity in isolated vesicles

Abstract

The present study aimed to investigate the hypothesis that the function of the Na,Ca- exchanger (NCX) is of higher importance for contractility and Cal2+-homeostasis in left ventricle from terminally failing than from nonfailing human hearts. The effect of decreasing extracellular [Na]e, (140 to 25 mmol/ L) on force of contraction in isolated left ventricular papillary muscle strips was studied as a reflection of NCX function in multicellular preparations (terminally failing, DCM, dilated cardiomyopathy, NYHA IV, n = 13; nonfailing, NF, donor hearts, n = 10). Decreasing [Na]e has previously been shown to increase contractility in vitro secondary to a decreased Ca2+-extrusion by the NCX. In addition, the NCX activity was measured as Na+-dependent 45Ca2+-uptake into isolated myocardial vesicles as a function of time and Ca2+-concentration (DCM n = 8, NF n = 8). Decreasing [Na]e enhanced the contractility of papillary muscle strips in both DCM and NF, but the contractility of DCM was increased at smaller reductions of [Na]e than NF. The NCX activity in isolated myocardial vesicles was unchanged as a function of time (T1/2: DCM 2.4 ± 0.3 s versus NF 2.5 ± 0.3 s) and as a function of Ca2+ (DCM 0.99 ± 0.08 versus NF 0.96 ± 0.07 nmol/mg protein x 3 s, K1/2: DCM 39.2 μM versus NF 38.3 μM). These results demonstrate a higher sensitivity of the failing human myocardium towards Na,Ca-exchanger mediated positive inotropic effects, suggesting a higher significance of the Na,Ca-exchanger for the extrusion of Ca2+-ions in intact failing versus non-failing human myocardium. Since the activity and the Ca2+-affinity of the Na,Ca- exchanger in isolated vesicles was unchanged, we propose that alterations in Ca2+- and Na+-homeostasis (due to impaired function of the sarcoplasmic reticulum and the Na+, K+- ATPase) or the prolonged action potential are the reason for this observation.