POSTISCHEMIC FUNCTION AND PROTEIN-KINASE-C SIGNAL-TRANSDUCTION

Background. The protective effects of myocardial preconditioning may o ccur by way of multiple mechanisms, with G-protein-mediated protein ki nase C (PKC) translocation as a final common pathway. In this study we investigate the pharmacologic induction of preconditioning, by PKC tr anslocation, using PKC agonists/antagonists to reveal its effects on c ontractile function after myocardial ischemia. Methods. Langendorff-pe rfused rabbit hearts received: (1) control; (2) dimethyl sulfoxide (ve hicle); (3) acetylcholine (0.55 mmol/L; PKC agonist); (4) 1,2-s,n-dioc tanoylglycerol (DOG; 22 mmol/L; PKC agonist); (5) chelerythrine (0.8 m mol/L; PKC antagonist); or (6) DOG-chelerythrine followed by a 2-hour ischemic period, using modified St. Thomas cardioplegia and a 45-minut e reperfusion period. The period of ischemia was chosen so as to allow for improvement by appropriate agonists. To observe metabolic changes , tissue nucleotides and nucleosides were measured. Membrane and cytos olic fractions of PKC were determined by an anti-PKC antibody directed against the PKC delta isozyme. Lactate levels and myocardial pH were measured. Results. The PKC agonists DOG and acetylcholine showed the g reatest recovery of developed pressure (68% +/- 2%, 60% +/- 9%, respec tively). Although pH, lactate, and nucleotide levels were similar betw een groups at all times, myocyte PKC translocation demonstrated 25% of PKC delta isoforms on cell membrane sites during baseline, which shif ted to 67% +/- 17% with unprotected ischemia. DOG mimicked this shift with 58% +/- 12% of PKC delta isoforms on membranes, which was also bl ocked by chelerythrine to 35% +/- 7%. Conclusions. These data demonstr ate that PKC translocation results in improved postischemic function, not by alteration of energetics or metabolism, and deserves further in vestigation. (C) 1998 by The Society of Thoracic Surgeons.