Anti-inflammatory effects of beraprost sodium, a stable analogue of PGI2, and its mechanisms.
We examined whether beraprost sodium (beraprost), a stable analogue of PGI2, has an anti-inflammatory effect on the permeability barrier through endothelial cells in vivo. The injection of collagen (5 micrograms/head) plus epinephrine (0.6 microgram/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 +/- 1.64 micrograms/lung, beraprost 10 micrograms/kg; 7.49 +/- 1.36 micrograms/lung, 30 micrograms/kg; 5.33 +/- 0.71 micrograms/lung, 100 micrograms/kg; 5.52 +/- 0.79 micrograms/lung). Pulmonary thromboembolism-induced Evans blue dye leakage was also reduced significantly by aspirin (5 mg/kg), but PGE1 (170 micrograms/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 micrograms/kg/day of beraprost, the effects were statistically significant (beraprost 30 micrograms/kg/day; 3.85 +/- 0.02 and 27.8 +/- 1.4%, 100 micrograms/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%, 10(-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 PGE1 (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.
Ueno
Y
Y
Toray Industries, Inc., Basic Research Laboratories, Kanagawa, Japan.
Koike
H
H
Annoh
S
S
Nishio
S
S
D000527:Alprostadil / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology; D002463:Cell Membrane Permeability / Q000187:drug effects; D003094:Collagen / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000188:drug therapy; D004730:Endothelium, Vascular / Q000166:cytology; D004837:Epinephrine / Q000494:pharmacology; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology; D008168:Lung / Q000033:anatomy & histology; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D011655:Pulmonary Embolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D012701:Serotonin; C048081:beraprost; D003094:Collagen; D011464:Epoprostenol; D000527:Alprostadil; D001241:Aspirin; D004837:Epinephrine