Role of Slowed Ca2+Transient Decline in Slowed Relaxation During Myocardial Ischemia

Abstract The goal of this study was to test the hypothesis that during myocardial ischemia, slowing of the Ca 2+ transient decline causes slowed relaxation. Our approach was to monitor pressure and Ca 2+ transients in isovolumic rat hearts during control and low flow ischemia conditions. In addition, we experimentally slowed the decline of the Ca 2+ transient using cyclopiazonic acid (CPA) to inhibit the sarcoplasmic reticulum Ca 2+ -ATPase (SERCA, the most important pump for rapidly transporting Ca 2+ out of the cytosol). Using 9 μ m CPA during normoxia, we were able to reproduce the slowed Ca 2+ transient decline and slowed relaxation found during low flow ischemia. The time constants of cytosolic [Ca 2+ ] decline and pressure decline ( τ Ca and τ P respectively) with CPA (78±5 ms and 64±3 ms) were similar to those found with ischemia (89±12 ms and 72±10 ms, mean±SEM, n =7) and were considerably greater than for controls (41±3 and 25±2 ms, mean±SEM, n =14, P τ P v τ Ca with CPA was similar to that found with ischemia. These findings are consistent with the hypothesis that the slowed Ca 2+ transient decline with both CPA and ischemia causes slowed relaxation. Consistent with this conclusion, a simple mathematical model to relate cytosolic [Ca 2+ ] and pressure also suggests that slowed pressure relaxation can be explained by slowing of the Ca 2+ transient decline. This study suggests that impaired Ca 2+ uptake is a major injury causing slowed relaxation during ischemia.

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