Reduced sodium pump alpha(1), alpha(3), and beta(1)-isoform protein levelsand Na+,K+-ATPase activity but unchanged Na+-Ca2+ exchanger protein levelsin human heart failure

Background-Cardiac glycosides initiate an increase in force of contraction by inhibiting the sarcolemmal sodium pump (Na+,K+-ATPase), thereby decreasi ng Ca2+ extrusion by the Na+-Ca2+ exchanger, which increases the cellular c ontent of Ca2+. In patients with heart failure the sensitivity toward cardi ac glycosides is enhanced. Methods and Results-Because the inotropic effect of cardiac glycosides may be a function of the sodium pump and Na+-Ca2+ exchanger (NCE) expression le vels, the present study aimed to investigate protein expression of both tra nsporters (immunoblot with specific antibodies against the sodium pump cata lytic alpha(1)-, alpha(2)-, alpha(3)-, and glycoprotein beta(1)-isoforms an d against NCE) in left ventricle from failing (heart transplantations, New York Heart Association class IV, n=21) compared with nonfailing (donor hear ts, NF, n=22) human myocardium. The density of H-3-ouabain-binding sites (B -max) and the Na+,K+-ATPase activity were also measured. In NYHA class IV, protein levels of Na+,K+-ATPase alpha(1)- (0.62+/-0.06 of control), alpha(3 )- (0.70+/-0.09), and beta(1)- (0.61+/-0.04) but not alpha(2)-isoforms were significantly reduced (P<0.01), whereas levels of NCE (0.92+/-0.13 of cont rol) and calsequestrin (0.98+/-0.06) remained unchanged. Both Na+,K+-ATPase activity (NF: 1.9+/-0.29; NYHA class IV: 1.1+/-0.17 mu mol ATP/min per mil ligram of protein) and the H-3-ouabain binding sites (B-max NF: 15.9+/-1.9 pmol/mg protein; NYHA class IV: 9.7+/-1.5) were reduced in NYHA class IV an d correlated significantly to each other (r(2)=0.73; P<0.0001), as did beta (1)-subunit expression. In left ventricular papillary muscle strips from NY HA class IV compared with nonfailing tissue the Na+-channel modulator BDF 9 198 exerted an increase in force of contraction with unchanged effectivenes s but enhanced potency. Conclusions-The enhanced sensitivity of failing human myocardium toward car diac glycosides may be, at least in part, attributed to a reduced protein e xpression and activity of the sarcolemmal Na+,K+-ATPase without a change in Na+-Ca2+ exchanger protein expression.