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

The goal of this study was to test the hypothesis that during myocardial ischemia, slowing of the Ca2+transient decline causes slowed relaxation. Our approach was to monitor pressure and Ca2+transients in isovolumic rat hearts during control and low flow ischemia conditions. In addition, we experimentally slowed the decline of the Ca2+transient using cyclopiazonic acid (CPA) to inhibit the sarcoplasmic reticulum Ca2+-ATPase (SERCA, the most important pump for rapidly transporting Ca2+out of the cytosol). Using 9 μ m CPA during normoxia, we were able to reproduce the slowed Ca2+transient decline and slowed relaxation found during low flow ischemia. The time constants of cytosolic [Ca2+] decline and pressure decline (τCaand τPrespectively) 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<0.01). Furthermore, the relationship of τPvτCawith CPA was similar to that found with ischemia. These findings are consistent with the hypothesis that the slowed Ca2+transient decline with both CPA and ischemia causes slowed relaxation. Consistent with this conclusion, a simple mathematical model to relate cytosolic [Ca2+] and pressure also suggests that slowed pressure relaxation can be explained by slowing of the Ca2+transient decline. This study suggests that impaired Ca2+uptake is a major injury causing slowed relaxation during ischemia.