Anti-inflammatory effects of beraprost sodium, a stable analogue of PGI(2), and its mechanisms

We examined whether beraprost sodium (beraprost), a stable analogue of PGI(2), has an anti-inflammatory effect on the permeability barrier through endothelial cells in vivo. The injection of collagen (5 mu g/head) plus epinephrine (0.6 mu g/head) showed time-dependently the increased Evans blue dye leakage of the lung in mice for 60 min. Beraprost significantly suppressed this leakage dose-dependently (control; 11.26 +/- 2.64 mu g/lung, beraprost 10 mu g/kg; 7.49 +/- 1.36 mu g/lung, 30 mu g/kg; 5.33 +/- 0.71 mu g/lung, 100 mu g/kg; 5.52 +/- 0.79 mu g/lung). Pulmonary thromboembolism-induced Evans blue dye leakage was also reduced significantly by aspirin (5 mg/kg), but PGE(1) (170 mu g/kg) showed a tendency to potentiate the edematogenic response. One week after the injection of same dosage of collagen plus epinephrine in mice, pulmonary thromboembolism showed the increase of wet-to-dry weight ratio of the lung (normal; 3.84 +/- 0.01, control; 3.96 +/- 0.04) and right ventricular hypertrophy (normal; 28.2 +/- 0.9%, control; 32.3 +/- 0.9%) compared to normal mice. Beraprost significantly suppressed lung edema and hypertrophy dose-dependently, and over 30 mu g/kg/day of beraprost, the effects were statistically significant (beraprost 30 mu g/kg/day; 3.85 +/- 0.02 and 27.8 +/- 1.4 %, 100 mu g/kg/day; 3.85 +/- 0.02 and 27.3 +/- 1.1%). Beraprost significantly reduced 5-hydroxytryptamine (5-HT; 17 nmol/paw)-induced rat paw edema dose-dependently (5-HT alone; 100%, beraprost 10(-13) mol/paw; 91.19 +/- 2.22%, 20(-12) mol/paw; 85.79 +/- 4.85%, 10(-11) mol/paw; 78.49 +/- 3.95 %). 5-HT-induced edema was also suppressed significantly by the co-injection of (-)-isoproterenol (10(-12) mol/paw), but PGE(1) (10(-11) mol/paw) significantly potentiated the edematogenic response. From these results, we propose that the anti-inflammatory effect of beraprost may be contributed, in part, to the permeability barrier through end othelial cells in vivo. (C) 1997 by Elsevier Science Inc.