EFFECT OF CYCLOPIAZONIC ACID ON THE FORCE-FREQUENCY-RELATIONSHIP IN HUMAN NONFAILING MYOCARDIUM

The present study investigated the functional role of the sarcoplasmic reticulum Ca++-ATPase in contraction and relaxation, intracellular Ca ++-transients, as well as on the force-frequency relationship in human myocardium, The Ca++-ATPase activity of membrane vesicles isolated fr om sarcoplasmic reticulum (SR) obtained from nonfailing donor hearts ( n = 7) was measured in the presence of cyclopiazonic acid (CPA, 0-30 m u M), a highly specific inhibitor of the Ca++-ATPase of the SR (SERCA) . The effects of CPA on parameters of contraction and relaxation, forc e-frequency relationship and [Ca++](i) transients (with fura-2) were s tudied on isolated left ventricular muscle strips from human nonfailin g myocardium, CPA concentration-dependently inhibited SERCA activity o f isolated SR vesicles, in the presence of CPA (30 mu M) the former po sitive force-frequency relationship in human left ventricular nonfaili ng myocardium became negative. Especially at high frequencies of stimu lation, CPA decreased developed tension, peak rate of tension rise and systolic fura-2-light emission, whereas time to peak tension, time to peak [Ca++](i), time to 95% relaxation, diastolic tension and diastol ic Ca++ levels were increased, Peak rate oi tension decay and time to half-relaxation and half-decay of [Ca++](i) were not altered significa ntly after treatment with CPA, These findings provide evidence that th e SERCA plays a functional role in the frequency-dependent increase in farce of contraction in human myocardium, Because an impaired functio n of the SERCA is predominantly followed by alterations of inotropic a nd to a lesser degree of lusitropic function, other important factors to lower [Ca++](i), and influence relaxation may be present in human m yocardium to compensate for the reduced SERCA activity, e.g., Na+-Ca+ exchanger.