Endothelial protection by defibrotide--a new strategy for treatment of myocardial infarction?
Myocardial ischemia is associated with endothelial injury and an apparently insufficient generation of endothelium-derived vasodilating and platelet and white cell inhibitory mediators, such as prostacyclin (PGI2) and EDRF. This paper reviews some recent findings of our laboratory on cardioprotective effects of defibrotide, a PGI2 stimulating agent, in experimental myocardial ischemia and its possible sites of action in several in vitro assay systems. Defibrotide (32 mg/kg x h) reduced the infarct size by 50% in pigs, subjected to 1 h of coronary artery ligation followed by 3 h of reperfusion. This was associated with significant inhibition of neutrophil activation during the reperfusion period and a two-to threefold increase in cardiocoronary PGI2 generation. In vitro studies on PAF- and calcium ionophore-stimulated human granulocytes confirmed a dose-dependent (10-1000 micrograms/ml) antineutrophil effect of defibrotide (inhibition of lysosomal enzyme release) which was independent of the type of stimulus. Defibrotide (0.1 mg/ml) also inhibited superoxide anion generation from PAF stimulated neutrophils in Langendorff-perfused guinea pig hearts and was equipotent to a specific PAF antagonist (BN 52021). Defibrotide (0.1 mg/ml) did not stimulate PGI2 release from cultured porcine aortic endothelial cells but enhanced PGI2 release four- to fivefold above control if endothelial cells were coincubated with platelets. These data demonstrate a considerable cardioprotective potential of defibrotide which appears to involve endothelial protection from granulocyte-derived noxious compounds and a long-lasting stimulation of PGI2 production.
Schrör
K
K
Institut für Pharmakologie, Heinrich-Heine-Universität Düsseldorf, FRG.
Ackermann
G
G
Hohlfeld
T
T
Löbel
P
P
Ney
P
P
Schröder
H
H
Strobach
H
H
D000818:Animals; D002478:Cells, Cultured; D003326:Coronary Circulation / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects*; D011464:Epoprostenol / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000008:administration & dosage*; D005609:Free Radicals; D006098:Granulocytes / Q000187:drug effects; D006168:Guinea Pigs; D009203:Myocardial Infarction / Q000188:drug therapy*; D009504:Neutrophils / Q000187:drug effects; D010477:Perfusion; D011089:Polydeoxyribonucleotides / Q000008:administration & dosage*; D013481:Superoxides / Q000378:metabolism; D013552:Swine; D013556:Swine, Miniature
D005343:Fibrinolytic Agents; D005609:Free Radicals; D011089:Polydeoxyribonucleotides; D013481:Superoxides; C036901:defibrotide; D011464:Epoprostenol