Myocardial protection with prostacyclin after lethal endotoxemia

A previous study of endotoxemia in dogs demonstrated that exogenous prostacyclin (PGI₂), normally a product of vascular endothelium, restored the cardiac index to normal and improved survival. To account for these results, a study was undertaken to test whether PGI₂ would alter isolated rat or dog cardiac mitochondrial function following incubation with plasma from endotoxemic animals. A group of five animals served as anesthetized controls. A second group of seven mongrel dogs was given 1.75 mg Escherichia coli endotoxin/kg and was observed for 5 hours without treatment. Anesthesia did not alter cardiopulmonary function; however, 30 minutes after endotoxin administration, the cardiac index decreased from 148 ± 25 ( ± SD) to 111 ± 12 ml/kg · min (P < 0.05) and further decreased to 89 ± 20 ml/kg · min after 4 hours. Dog plasma obtained 2 to 5 hours after endotoxin infusion, incubated with rat or dog myocardial mitochondria, decreased succinate dehydrogenase (SDH) activity (P < 0.05) and depressed mitochondrial respiration in the presence of the substrate succinate and adenosine diphosphate (ADP) from 180 to 87 Natoms oxygen/mg protein · min (P < 0.05). There was no change in oxygen consumption when substrate alone was present, nor did plasma alter the amount of ADP phosphorylation as a function of oxygen consumption. A third group of seven animals, 30 minutes after administration of 7.75 mg endotoxin/kg, was treated with 100 ng/kg · min PGI₂ for 3 hours. PGI₂ infusion in this group prevented the decrease in cardiac index. Plasma obtained during and after PGI₂ infusion did not decrease mitochondrial SDH activity, which remained higher than that in controls (P < 0.001); mitochondrial respiration was also not altered. A correlation was observed between cardiac index and SDH activity (r = 0.58, P < 0.001) and between cardiac index and mitochondrial respiration (r = 0.67, P < 0.001). In PGI₂-treated dogs cardiac mitochondria were functionally and structurally normal in contrast to the depression and disruption produced by endotoxemia, as observed by enzymatic assay as well as electron microscopy. These results suggest that endotoxemia depresses cardiac mitochondrial respiration, an event related to the decrease in cardiac index. In contrast, cardiac function and mitochondrial respiration are maintained with PGI₂ treatment.