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 from sarcoplasmic reticulum (SR) obtained from nonfailing donor hearts (n = 7) was measured in the presence of cyclopiazonic acid (CPA, 0-30 microM), a highly specific inhibitor of the Ca++-ATPase of the SR (SERCA). The effects of CPA on parameters of contraction and relaxation, force-frequency relationship and [Ca++]i transients (with fura-2) were studied on isolated left ventricular muscle strips from human nonfailing myocardium. CPA concentration-dependently inhibited SERCA activity of isolated SR vesicles. In the presence of CPA (30 microM) the former positive force-frequency relationship in human left ventricular nonfailing myocardium became negative. Especially at high frequencies of stimulation, 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 diastolic Ca++ levels were increased. Peak rate of tension decay and time to half-relaxation and half-decay of [Ca++]i were not altered significantly after treatment with CPA. These findings provide evidence that the SERCA plays a functional role in the frequency-dependent increase in force of contraction in human myocardium. Because an impaired function of the SERCA is predominantly followed by alterations of inotropic and to a lesser degree of lusitropic function, other important factors to lower [Ca++]i and influence relaxation may be present in human myocardium to compensate for the reduced SERCA activity, e.g., Na+-Ca++ exchanger.
Schwinger
R H
RH
Klinik III für Innere Medizin der Universität zu Köln, Germany.
Brixius
K
K
Bavendiek
U
U
Hoischen
S
S
Müller-Ehmsen
J
J
Bölck
B
B
Erdmann
E
E
D000328:Adult; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects*; D012519:Sarcoplasmic Reticulum / Q000201:enzymology; D019831:Sodium-Calcium Exchanger / Q000032:analysis
D004791:Enzyme Inhibitors; D007211:Indoles; D019831:Sodium-Calcium Exchanger; D000252:Calcium-Transporting ATPases; D002118:Calcium; C000543:cyclopiazonic acid