CHRONIC ORAL DEFIBROTIDE STIMULATES VASCULAR PGI2 AND INHIBITS ATHEROSCLEROTIC PLAQUE FORMATION IN CHOLESTEROL-FED RABBITS
Defibrotide (DEF) is a polydeoxyribonucleotide fraction from bovine lung, possessing profibrinolytic and PGI2 stimulating properties. Male rabbits were fed for 4 months a standard laboratory diet (150 g/day) without (A) or with (B) DEF or a cholesterol (1%) supplemented diet without (C) or with (D) DEF (60 mg/kg x day) was administered orally (drinking water) and withdrawn 24-36 h prior to the acute experiments.DEF did not change the elevated serum cholesterol: 18 ± 2 (C) vs. 26 ± 5 (D) mM but significantly reduced the plaque formation in the aorta from 4.5 ± 0.3 (C) to 3.3 ± 0.2 (D) (subjective score). Collagen induced (0.6 pg/ml) thromboxane formation and ATP release was significantly reduced by DEF: 55+2 (C) vs. 42 ± 2 (D) ng/ml TXB2; 152 ± 11 (C) vs. 74±5 (D) AU ATP (platelet rTch plasma). DEF significantly increased the basal and bradykinin (Bk, 30 nM) stimulated PGI2 release from rabbit aorta preparations in Krebs buffer, while the PGI2 forming capacity (arachidonic acid, AA, 30 pg/ml) was unchanged Furthermore, the iloprost (30 nM) stimulated cAMP was significantly elevated by DEF in both control: 115 ± 10 (A) vs. 155 ± 18 (B) pmoles/1 and cholesterol-fed rabbits: 120 ± 14 (C) vs. 172 ± 9 (D). DEF, directly added to the platelets in vitro did not inhibit platelet activation up to 100 pg/ml.The data demonstrate a 2-3-fold stimulation of basal and hormone (Bk) induced PGI2 formation of control and sclerotic rabbit aorta after 4 months DEF treatment while the atherosclerosis per se does not significantly change these parameters. DEF treatment also significantly reduces platelet hyperreactivity at unchanged serum ch() lesterol. Both properties might be useful to prevent complication’s of atherosclerosis, such as myocardial infarction and stroke.