EFFECT OF PROTEIN-KINASE-C INHIBITORS AND 2,3-BUTANEDIONE MONOXIME ONTHE LONG-TERM HYPOTHERMIC PRESERVATION OF ISOLATED RAT HEARTS

1. This study examines the protective effect of staurosporine, chelery thrine, Ro 31-8220 and 2,3-butanedione monoxime in rat hearts during h ypothermic storage. 2. Hearts were microperfused at 4 degrees C for 24 or 48 h with a storage buffer that in some cases contained one of the se protein kinase C inhibitors either alone or in combination with 2,3 -butanedione monoxime. After hypothermic storage, hearts were rewarmed to 37 degrees C with Krebs-Henseleit buffer. Cardiac function was the n assessed in either Langendorff mode or working heart mode.3. Compare d with values from fresh non-stored hearts, hypothermic stored hearts showed a significant decrease in both coronary flow and left ventricul ar developed pressure when the stored hearts were reperfused in Langen dorff mode. The decrease in coronary how and left ventricular develope d pressure was more pronounced in hearts stored for 48 h than in those stored for 24 h. 4. Hearts stored for 24 or 48 h, with or without the protein kinase C inhibitors, and then perfused in working mode genera ted less aortic flow and less cardiac output than fresh unstored heart s. 5. Hearts preserved in solutions containing staurosporine, cheleryt hrine, Ro 31-8220 or 2,3-butanedione monoxime had significantly higher left ventricular developed pressure values on reperfusion than hearts stored without any such drug. 6. Addition of 2,3-butanedione monoxime to storage buffer containing either staurosporine, chelerythrine or R o 31-8220 further improved left ventricular developed pressure, aortic flow and cardiac output values in these stored hearts. The group of h earts stored in a buffer containing 2,3-butanedione monoxime and chele rythrine gave the highest left ventricular developed pressure value se en during reperfusion, 7. The ATP and creatine phosphate concentration s of hearts stored in buffer alone were significantly lower than those of fresh unstored hearts, irrespective of the duration of storage. AT P concentrations were better preserved in hearts stored in a buffer co ntaining 2,3-butanedione monoxime or/and one of the protein kinase C a ntagonists than those stored without such antagonists. A positive corr elation was found between peak cardiac output values and the concentra tions of combined high-energy phosphates in various groups of stored a nd reperfused hearts, 8. The present study showed that inhibition of p rotein kinase C during long-term hypothermic storage significantly inc reased high-energy phosphate concentrations and also improved contract ile function during reperfusion.