Role of slowed Ca(2+) 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 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 microm 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 (tau(Ca) and tau(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<0.01). Furthermore, the relationship of tau(P) v tau(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.
Halow
J M
JM
The Medical Service (Cardiology), San Francisco General Hospital Medical Center, San Francisco, California 94110, USA.
Figueredo
V M
VM
Shames
D M
DM
Camacho
S A
SA
Baker
A J
AJ
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D003600:Cytosol / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012519:Sarcoplasmic Reticulum / Q000201:enzymology
D000889:Anti-Arrhythmia Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D000252:Calcium-Transporting ATPases; D002118:Calcium; C000543:cyclopiazonic acid