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.
Meldrum
D R
DR
Department of Surgery, University of Colorado Health Sciences Center, Denver 80262, USA.
Cleveland
J C
JC
Mitchell
M B
MB
Rowland
R T
RT
Banerjee
A
A
Harken
A H
AH
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