title: 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 Ca(2+)-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 Ca(2+)-extrusion by the NCX. In addition, the NCX activity was measured as Na(+)-dependent (45)Ca(2+)-uptake into isolated myocardial vesicles as a function of time and Ca(2+)-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 (T(1/2): DCM 2.4 +/- 0.3 s versus NF 2.5 +/- 0.3 s) and as a function of Ca(2+) (DCM 0.99 +/- 0.08 versus NF 0.96 +/- 0.07 nmol/mg protein x 3 s, K(1/2): DCM 39.2 microM versus NF 38.3 microM). 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 Ca(2+)-ions in intact failing versus nonfailing human myocardium. Since the activity and the Ca (2+)-affinity of the Na,Ca-exchanger in isolated vesicles was unchanged, we propose that alterations in Ca(2+)-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.
authors.affiliation: Clinic III for Internal Medicine, University of Cologne, Cologne, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Diedrichs
authors.forename: Konrad
authors.initials: K
authors.lastname: Frank
authors.forename: Christian A
authors.initials: CA
authors.lastname: Schneider
authors.forename: Volker
authors.initials: V
authors.lastname: Burst
authors.forename: Jens
authors.initials: J
authors.lastname: Hagemeister
authors.forename: Carsten
authors.initials: C
authors.lastname: Zobel
authors.forename: Jochen
authors.initials: J
authors.lastname: Müller-Ehmsen
mesh_terms: D002118:Calcium / Q000378:metabolism*; D005260:Female; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000502:physiology*
chemical_list: D019831:Sodium-Calcium Exchanger; D012964:Sodium; D002118:Calcium