Iloprost inhibits neutrophil function in vitro and in vivo and limits experimental infarct size in canine heart

Abstract

The prostacyclin analogue iloprost (ZK 36374) inhibits neutrophil activation in vitro, reduces neutrophil accumulation in inflammatory skin lesions, and reduces ultimate infarct size in an anesthetized open-chest canine model of regional ischemia and reperfusion. Iloprost (0.1-100 μM) inhibited the in vitro production of superoxide anion by canine neutrophils in a concentration-dependent manner. Iloprost (100 ng/kg/min i.v.) inhibited C(5a)-induced neutrophil migration into inflammatory skin lesions as assessed by the neutrophil-specific enzyme marker, myeloperoxidase. The myeloperoxidase activity determined 2 hours after the intradermal administration of C(5a) in each of the groups was control 13.3 ± 1.8 units/g tissue (n = 12) and iloprost 6.5 ± 0.9 units/g (n = 12), p < 0.01. Iloprost was administered to anesthetized open-chest dogs (100 ng/kg/min) 10 minutes after left circumflex coronary artery (LCCA) occlusion and continued during the 90-minute occlusion period and the first 2 hours of reperfusion. Regional myocardial blood flow was similar between treatment groups at baseline, 5 minutes and 80 minutes after LCCA occlusion, and after 1 hour of reperfusion. Infarct size, assessed 6 hours after reperfusion, was reduced by iloprost treatment: 22.4 ± 3.1% of the area at risk (n = 15) compared with 42.4 ± 3.3% of control (n = 13), p < 0.01. Iloprost treatment reduced the accumulation of neutrophils (measured by myeloperoxidase activity) in the ischemic myocardium at the interface between infarcted and noninfarcted tissue: control (n = 9) 9.0 ± 1.8 units/g tissue, iloprost (n = 6) 2.0 ± 0.4 units/g, p < 0.01. The ability of iloprost to reduce infarct size may be related both to a reduction in arterial blood pressure and to a modulation of neutrophil infiltration and activation at the site of tissue injury.