Prostacyclin and Its Analogues: Reduction of Myocardial Reperfusion Injury By Inhibition of Neutrophil Function.

Prostacyclin (PGI$\\sb2$; 50 ng/kg/min) was administered to open chest anesthetized dogs subjected to 90 min left circumflex coronary artery (LCCA) occlusion. PGI$\\sb2$ reduced infarct size (by 59%) measured after 6 hr reperfusion. The PGI$\\sb2$ analogue, SC39902 failed to reduce infarct size. PGI$\\sb2$ and SC39902 reduced blood pressure to the same extent. PGI$\\sb2$ caused no increase in regional myocardial blood flow (radiolabelled microsphere technique) to the ischemic myocardium. Furthermore, administration of PGI$\\sb2$ to anesthetized dogs reduced the amount of neutrophil infiltrate, measured with myeloperoxidase (MPO; a neutrophil marker enzyme), into inflammatory skin lesions induced by intradermal injection of the complement activation product C5a. Isolated canine neutrophils were activated with the phagocytic stimulus opsonized zymosan (OZ). Prostacyclin pretreatment (5 min) decreased the superoxide anion production by 27% at $10\\sp{-7}$M and by 55% at $10\\sp{-4}$M. SC 39902 failed to effectively inhibit neutrophil activation. Taken together, these data indicate that PGI$\\sb2$ reduces myocardial infarct size by virtue of its inhibitory effects on the activation of neutrophils. Subsequent studies employed another PGI$\\sb2$ analogue, iloprost in the same experimental model. Iloprost (100 ng/kg/min) reduced infarct size by 47% compared to controls. Dogs that had been treated with iloprost had only 22% of the MPO at the border between infarcted and non-infarcted myocardium. Iloprost (100 ng/kg/min) reduced MPO accumulation in dermal lesions by 51% (2 hr after injection of C5a). Iloprost inhibited canine neutrophil activation by OZ by 15% at $10\\sp{-7}$M and by 52% at $10\\sp{-4}$M. Another set of experiments examined the effects of iloprost on myocardial infarcts after 90 min of ischemia in open chest dogs followed by 72 hr of reperfusion. Iloprost (100 ng/kg/min) administered during occlusion and for 2 hr after reperfusion failed to reduce myocardial infarct size $(57.6\\pm 5.2\\%)$ compared to control $(48.7\\pm 5.6\\%)$. However, iloprost administered over the same time course plus at 25 ng/kg/min beginning 1 hr after reperfusion and continued until 48 hr after reperfusion, reduced myocardial infarct size by 54% compared to controls. Depletion of circulating neutrophils with specific antibodies reduced infarct size to 32.1 $\\pm$ 5.0%. The beneficial treatment window for therapies that suppress neutrophil activation is defined to between 2 hr after reperfusion and 48 hr after reperfusion. (Abstract shortened with permission of author.)PhDPharmacologyUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/161460/1/8712210.pd