Cardiac preconditioning with calcium: clinically accessible myocardial protection.
Cardiac preconditioning is mediated by protein kinase C. Although endogenous calcium is a potent stimulus of protein kinase C, it remains unknown whether preischemic administration of exogenous calcium can induce protein kinase C-mediated myocardial protection against ischemia-reperfusion injury. To study this, calcium chloride was administered retrogradely through the aorta at a rate 5 nmol/min for 2 minutes to isolated perfused rat hearts 10 minutes before a 20-minute ischemia and 40-minute reperfusion insult. Calcium-mediated cardioadaptation was then linked to protein kinase C by means of the protein kinase C inhibitor chelerythrine (20 mumol.L-1.2 min-1). To determine whether exogenous calcium administration induces protein kinase C translocation and activation, immunohistochemical staining for the calcium-dependent protein kinase C isoform alpha was performed on adjacent 5 microns myocardial sections with and without calcium chloride treatment. Results indicated that preischemic calcium chloride administration improved myocardial functional recovery, as determined by enhanced developed pressure, improved coronary flow, reduced end-diastolic pressure, and decreased creatine kinase leakage during reperfusion. Beneficial effects of calcium chloride were eliminated by concurrent protein kinase C inhibition. Immunohistochemical staining for the alpha isoform of protein kinase C demonstrated that calcium chloride induces translocation of this isoform from the cytoplasm to the sarcolemma, indicating that exogenous calcium administration activates this isoform. These results suggest that calcium chloride, a safe and routinely administered agent, can induce protein kinase C-mediated cardiac preconditioning. Calcium-induced cardioadaptation to ischemia-reperfusion injury may be promising as a clinically feasible therapy before planned ischemic events such as cardiac allograft preservation and elective cardiac operations.
Meldrum
D R
DR
Department of Surgery, University of Colorado Health Sciences Center, Denver 80262, USA.
Cleveland
J C
JC
Sheridan
B C
BC
Rowland
R T
RT
Banerjee
A
A
Harken
A H
AH
D000470:Alkaloids; D000818:Animals; D001011:Aorta; D053119:Benzophenanthridines; D002122:Calcium Chloride / Q000008:administration & dosage / Q000627:therapeutic use*; D006348:Cardiac Surgical Procedures; D003326:Coronary Circulation / Q000187:drug effects; D003402:Creatine Kinase / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D017558:Elective Surgical Procedures; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005240:Feasibility Studies; D006321:Heart / Q000187:drug effects; D006324:Heart Arrest, Induced; D006339:Heart Rate / Q000187:drug effects; D007150:Immunohistochemistry; D007261:Infusions, Intra-Arterial; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009926:Organ Preservation; D010617:Phenanthridines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012508:Sarcolemma / Q000378:metabolism; D017725:Ventricular Pressure / Q000187:drug effects
D000470:Alkaloids; D053119:Benzophenanthridines; D004791:Enzyme Inhibitors; D010617:Phenanthridines; C016299:chelerythrine; D011493:Protein Kinase C; D003402:Creatine Kinase; D002122:Calcium Chloride