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Circulation Research. 1995;76:1049-1056

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(Circulation Research. 1995;76:1049-1056.)
© 1995 American Heart Association, Inc.


Articles

Postischemic Changes in Cardiac Sarcoplasmic Reticulum Ca2+ Channels

A Possible Mechanism of Ischemic Preconditioning

Riccardo Zucchi, Simonetta Ronca-Testoni, Gongyuan Yu, Paola Galbani, Giovanni Ronca, Mario Mariani

From Scuola Superiore S. Anna (R.Z.), Istituto di Cardiologia (R.Z., M.M.), and Istituto di Chimica Biologica (S.R.-T., G.Y., P.G., G.R.), University of Pisa (Italy).

Correspondence to R. Zucchi, MD, Scuola Superiore S. Anna, via Carducci 40, I-56100 Pisa, Italy.

Abstract We investigated the modifications of cardiac ryanodine receptors/sarcoplasmic reticulum Ca2+ release channels occurring in ischemic preconditioning. In an isolated rat heart model, the injury produced by 30 minutes of global ischemia was reduced by preexposure to three 3-minute periods of global ischemia (preconditioning ischemia). The protection was still present 120 minutes after preconditioning ischemia but disappeared after 240 minutes. Three 1-minute periods of global ischemia did not provide any protection. In the crude homogenate obtained from ventricular myocardium, the density of [3H]ryanodine binding sites averaged 372±18 fmol/mg of protein in the control condition, decreased 5 minutes after preconditioning ischemia (290±15 fmol/mg, P<.01), was still significantly reduced after 120 minutes (298±17 fmol/mg, P<.05), and recovered after 240 minutes (341±21 fmol/mg). Three 1-minute periods of ischemia did not produce any change in ryanodine binding. The Kd for ryanodine (1.5±0.3 nmol/L) was unchanged in all cases. In parallel experiments, the crude homogenate or a microsomal fraction was passively loaded with 45Ca, and Ca2+-induced Ca2+ release was studied by the quick filtration technique. In both preparations, the rate constant of Ca2+-induced Ca2+ release decreased 5 and 120 minutes after preconditioning ischemia (homogenate values: 19.7±1.4 and 18.9±0.9 s-1 vs a control value of 25.4±1.7 s-1, P<.05 in both cases) and recovered after 240 minutes (23.0±1.9 s-1). The Ca2+ dependence of Ca2+-induced Ca2+ release was not affected by preconditioning ischemia. In conclusion, changes in sarcoplasmic reticulum Ca2+-release channels occur after brief ischemia and reperfusion, are closely correlated with the development of myocardial protection versus sustained ischemia, and might play a role in the pathogenesis of ischemic preconditioning.


Key Words: sarcoplasmic reticulum • Ca2+ • ischemia • reperfusion




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