Stimulation of vascular prostacyclin and inhibition of platelet function by oral defibrotide in cholesterol-fed rabbits.
The effect of chronic oral defibrotide on platelet function, vascular PGI2 generation, atherosclerotic plaque formation and serum lipids was studied in rabbits. The animals were fed for 4 months a standard laboratory diet (150 g/day) with or without defibrotide (60 mg/kg/day) or a cholesterol-rich (1%) diet with or without defibrotide. Defibrotide significantly reduced the platelet reactivity ex vivo against collagen and ADP. This included a reduced aggregation response, thromboxane release and ATP secretion. Furthermore, the inhibition of platelet function and stimulation of platelet cAMP by iloprost, were significantly improved by defibrotide treatment. This was associated with an increased number of prostacyclin binding sites and enhanced PGI2 affinity in platelet membranes from these animals. Bradykinin stimulated PGI2 generation of segments of the thoracic aorta about 2-fold above control in both normo- and hypercholesterolemic rabbits. There was no difference in basal values between these groups but a more than 2-fold increase in either group by defibrotide treatment. Atherosclerotic plaque formation, determined by a subjective score, was found to be significantly reduced by defibrotide although the compound did not alter serum cholesterol levels. The data suggest potent and potentially valuable antiatherosclerotic effects of oral defibrotide: (i) normalization of platelet function by reduction of platelet hyperreactivity and improvement of the sensitivity towards prostacyclin, and (ii) stimulation of vascular PGI2 production.
Löbel
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P
Institut für Pharmakologie, Heinrich-Heine-Universität Düsseldorf, F.R.G.
Schrör
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D000284:Administration, Oral; D000818:Animals; D001161:Arteriosclerosis / Q000097:blood* / Q000188:drug therapy / Q000209:etiology; D004036:Diet, Atherogenic; D011464:Epoprostenol / Q000096:biosynthesis*; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D008055:Lipids / Q000097:blood; D008297:Male; D015539:Platelet Activation / Q000187:drug effects*; D011089:Polydeoxyribonucleotides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits
D005343:Fibrinolytic Agents; D008055:Lipids; D011089:Polydeoxyribonucleotides; C036901:defibrotide; D011464:Epoprostenol