Printed in U.S.A. DISSOCIATION OF THE POSITIVE INOTROPIC AC- TION OF DIGITALIS FROM INHIBITION OF SODIUM- AND POTASSIUM-ACTIVATED ADENOSINE TRI-

.Acc(l)ted for fflhl)lirtt ion December 21. 1972 OKITA, GEow;E T.. FLORENCE RICHARDSON AND BARBARA F. ROTH-SCHECHTEII: Dissociation of the positive inotropic action of (ligitalis from inhlbition of sodium-an(l p0t15si11fl1-l(ti\te(l adenosine t ril)hosl)llatase..1. Pharmacol. Exp. Ther. 185: 1-11, 1973. Experimellts were undertaken to test the hypothesis that the mechanism of the positive inot ropic art ion of (ligitalis Is the result of inhibit ion of the transport enzyme. Na , activate(l adenosine triphosphatase (Na, K-ATPase). Initial studies utilizing strophan-thidin-3-bronioacetate indicate(l indirert evidence for the dissociation of the short duration of the posit ive inot ropic act ion from the long persist ent inhibition in vitro of the transport enZyme. In an attempt to oI)tain direct evi(lence for this observed dis-sociation. c.r lila j)harnlacolOgic a11(l l)iochemical studies were conducted on isolated Langendorfi ral)l)lt hea rt ut ilizing st rophant hidin-3-bromoacet ate. st ropha nt Ili(hn and onabain. After positive inot ropic effects with each of the cardiac st eroids in the Langendorff hearts were oi)tained. the l)erfusate was changed to a drug-free buffer solution in or(ler to effect “washout ’ of all )harmacologic effect. After return of con-tract ile force to control levels, t he hearts were ext ract e(l for Na, K-ATPase and assayed for enzyme activity. Up to 39Y inhibition of Na, K-ATPase activity was noted in eoml)arison to control values. Since the transport enzyme was inhibited when positive inotropic effect was no longer l)reseilt. these findings indicate that inhibit ion of Na, K-ATPase may not be resl uonsil)l e for t he positive inot ropic act ion of the cardiac steroids. (‘urrentlv one of the proposed theories for the mode of the positive inotropic action of cardiac steroids is based on their ability to inhibit Received for publication June 14, 1971. ‘This investigation was supported in part I)