Angioprotective action of calcium dobesilate against reactive oxygen species-induced capillary permeability in the rat.
Calcium dobesilate possesses antioxidant properties in vitro, but the in vivo significance and putative angioprotective role of these properties are undefined. Here, calcium dobesilate was tested in a newly developed in vivo model of microvascular permeabilization induced by reactive oxygen species in the rat peritoneal cavity. In this model, microvascular permeabilization is equated to the rate of Evans blue extravasation toward the peritoneal cavity. Basal Evans blue extravasation (rate constant values ke = 0.0176 +/- 0.0015 h-1) was markedly and significantly increased by reactive oxygen species generated in situ, with: (i) phenazine methosulfate/NADH (delta ke(phenazine methosulfate) = 0.0419 +/- 0.0043 h-1) and (ii) xanthine/xanthine oxidase (delta ke(xo) = 0.0383 +/- 0.0010x h-1). These actions of reactive oxygen species were abolished by locally injected superoxide dismutase (i.p., 300 units/kg). Intraperitoneally given calcium dobesilate (100 mg/kg) inhibited 75-100% of reactive oxygen species-induced Evans blue extravasation. By the intravenous route, calcium dobesilate i.v. (1-50 mg/kg) dose dependently inhibited phenazine methosulfate-induced Evans blue extravasation with an ID50 of 2-5 mg/kg (full inhibition was reached at 20-50 mg/kg). After single oral administration, calcium dobesilate (5-500 mg/kg) dose dependently inhibited phenazine methosulfate-dependent Evans blue extravasation with an ID50 of 50-100 mg/kg (81% inhibition at 500 mg/kg, P < 0.003). After 7 days of oral calcium dobesilate (50 mg/kg once/day) phenazine methosulfate-induced Evans blue peritoneal extravasation was significantly reduced by half. These effects of calcium dobesilate were similar to those observed with a comparative antioxidant molecule, rutin. In conclusion, rat peritoneal microvascular permeability was strongly increased by reactive oxygen species, an effect that was significantly reduced by intraperitoneal, intravenous and oral calcium dobesilate. These results support the hypothesis that the antioxidant properties of calcium dobesilate could play a role in its angioprotective properties in vivo.
Brunet
J
J
INSERM U400, Faculté de Médecine, Créteil, France.
Farine
J C
JC
Garay
R P
RP
Hannaert
P
P
D000284:Administration, Oral; D000818:Animals; D002123:Calcium Dobesilate / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002199:Capillary Permeability / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D005070:Evans Blue; D005119:Extravasation of Diagnostic and Therapeutic Materials / Q000503:physiopathology / Q000517:prevention & control; D006490:Hemostatics / Q000494:pharmacology* / Q000627:therapeutic use; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008297:Male; D010529:Peritoneal Cavity / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000502:physiology*
D006490:Hemostatics; D017382:Reactive Oxygen Species; D005070:Evans Blue; D002123:Calcium Dobesilate