Augmentation of eicosanoids in ischemic heart muscle in dogs: its role in the deterioration of the ischemic lesion.
The dissolution of infarcted myocardium occurs after the infiltration of leukocytes. In the search for a mechanism of the leukocyte infiltration, we measured the production of lipoxygenase metabolites of arachidonic acid in the canine myocardium after ligation of the circumflex branch of the left coronary artery. At least 2 lipoxygenase products, namely 5- and 12-hydroxyeicosatetraenoic acids (HETEs), were augmented in myocardium subjected to ischemia lasting more than 6 hours, with levels of the latter being raised much more than the former. Augmentation of the HETEs in ischemic myocardium appeared to occur prior to any significant infiltration of leukocytes. More than 12 hours after coronary ligation, the infiltration of leukocytes became prominent and an increase in 12-HETE was observed. Calcium content in the infarcted myocardium appeared to be increased several hours before the increase in 12-HETE. These data suggest that the initial increment in 12-HETE may result from it being a product of infarcted myocardium, where Ca2+ is accumulated in the cell, and that the increased HETEs work as a leukocyte chemoattractant in infarcted myocardium. This hypothesis is supported by the independent experiment which showed that cultured cardiomyocytes produced lipoxygenase metabolites of arachidonic acid, including 12-HETEs etc, which exhibited neutrophil-chemoattractant activity when they were challenged by calcium ionophore and/or arachidonic acid. Azelastine-HCl, a lipoxygenase inhibitor, attenuated not only the above production of HETEs from the cardiomyocytes, but also production of HETEs and infiltration of neutrophils in ischemic myocardium, resulting in attenuation of the fibrous scar of infarcted myocardium.
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003327:Coronary Disease / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D004285:Dogs; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis*; D007962:Leukocytes / Q000473:pathology; D016859:Lipoxygenase Inhibitors; D009206:Myocardium / Q000378:metabolism*; D010793:Phthalazines / Q000494:pharmacology
D006893:Hydroxyeicosatetraenoic Acids; D016859:Lipoxygenase Inhibitors; D010793:Phthalazines; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D002118:Calcium; C020976:azelastine