Constructive priming of myocardium against ischemia-reperfusion injury.
Ischemia and ischemic stress hormones induce endogenous cardiac protection against ischemia-reperfusion (I/R) injury. Although ischemia and ischemic stress hormones are accompanied by increased [Ca2+], it is unknown whether either opening of the sarcoplasmic reticular ryanodine Ca2+ channel (SR RyR) or inhibition of Ca2+ uptake by the sarcoendoplasmic reticular Ca(2+)-ATPase (SERCA) prior to I/R can similarly induce post-I/R functional protection. To study this, isolated, crystalloid perfused Sprague-Dawley rat hearts were used to assess the effects of inducing a pre-ischemic [Ca2+]i load by either priming the SR RyR with ryanodine (Ry, 5 nM/2 min) or by transient blockade of the SERCA 10 min prior to global I/R (20 min). A pre-ischemic Ca2+ load by either SR RyR activation or SERCA blockade improved post-ischemic myocardial functional recovery (developed pressure, end diastolic pressure, coronary flow, heart rate, and left ventricular creatine kinase activity). We conclude that 1) Ca(2+)-induced myocardial functional protection involves the SR Ca2+ source, 2) a pre-ischemic Ca2+ load induced with either Ry or thapsigargin constructively primes against myocardial I/R injury, and 3) Ca(2+)-induced cardioadaptation to I/R injury may have important therapeutic implications prior to planned ischemic events such as cardiac allograft preservation and cardiac bypass surgery.
Department of Surgery, University of Colorado Health Sciences Center, Denver 80262, USA.
D R
DR
Meldrum
J C
JC
Cleveland
M B
MB
Mitchell
R T
RT
Rowland
A
A
Banerjee
A H
AH
Harken
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000187:drug effects / Q000378:metabolism; D003326:Coronary Circulation / Q000187:drug effects; D003402:Creatine Kinase / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009124:Muscle Proteins / Q000187:drug effects / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012433:Ryanodine / Q000494:pharmacology*; D019837:Ryanodine Receptor Calcium Release Channel; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology*
D015220:Calcium Channels; D004791:Enzyme Inhibitors; D009124:Muscle Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D012433:Ryanodine; D019284:Thapsigargin; D003402:Creatine Kinase; D000252:Calcium-Transporting ATPases; D002118:Calcium