Delayed protection by 7-oxo-PGI2 against cardiac transmembrane ion shifts and early morphological changes due to ischemia and reperfusion

Abstract

In previous experiments on dogs subjected to local myocardial ischemia, we have shown a late and prolonged anti-ischemic and anti-arrhythmic effect of a single injection of the stable prostacyclin analogue, 7-oxo-PgI2. The protection was dependent on dose and time. Maximal effects were observed 48 hours after an optimal intramuscular dose of 50/micrograms/kg. To study the mechanism of this protective effect we have followed the time-dependent changes in transmembrane cation homeostasis induced by ischemia and reperfusion by measuring the intracellular potassium, sodium and calcium ion concentrations in Langendorff guinea pig heart preparations isolated from untreated control animals and from animals receiving a single intramuscular injection of 50/micrograms/kg 7-oxo-PgI2 48 hours before preparation. Global ischemia was produced by stopping perfusion for 25 minutes and was followed by reperfusion. In a second series, similarly treated and untreated hearts were fixed for electron microscopy after 25 minutes' global ischemia as well as after 15 minutes' reperfusion. Ischemia and reperfusion evoked a rapid loss of intracellular potassium and gain of sodium as well as an accumulation of calcium in the reperfusion phase. Pretreatment with 7-oxo-PgI2 prevented all these changes. It also prevented the shortening of the sarcomers and swelling of mitochondria induced by ischemia and the deposition of calcium-dense granules in mitochondria appearing after reperfusion. The findings support the hypothesis that 7-oxo-PgI2 has a delayed cytoprotective action which preserves normal transmembrane ion transport and normal structure of myocardial cells under conditions of ischemic and reperfusion injury.