Inhibitory effect of nifedipine on tumor necrosis factor α-induced neovascularization in cultured choroidal explants of streptozotocin-diabetic rat

Abstract

We have previously reported that the Nε-(carboxymethyl) lysine (CML) adduct, a major structure of an advanced glycation end product, facilitates proliferation of CD34+ endothelial progenitor cells budded from cultured choroidal explants and produces immature vessel-like structures in fibrin gel. The CML adduct is accumulated and facilitates immature neovascularization in cultured choroidal explants of streptozotocin (STZ)-induced diabetic rat. The CML-enhanced neovascularization activity is associated with the actions of tumor necrosis factor (TNF) α, vascular endothelial growth factor and platelet-derived growth factor released from the choroidal explant (Kobayashi et al., Biol. Pharm. Bull., 27, 1382-1387 (2004); 27, 1565-1571 (2004)). The present study was investigated an inhibitory effect of a dihydropyridine calcium antagonist nifedipine on TNF α-induced choroidal neovascularization in the STZ-diabetic rat. TNF α(1-100 ng/ml) increased neovascularization of cultured choroidal explants in the age-matched normal rat but did not increase it in the diabetic rat. Anti-TNF α antibody (1:1000) decreased the neovascularization in the diabetic rat but not in the normal rat. Nifedipine (1 μM) inhibited TNF α-induced neovascularization of the normal choroidal explant in a non-competitive manner. Nifedipine (1 μM) also inhibited the diabetic state-induced neovascularization and its inhibitory action was reversed by TNF α (1-10 ng/ml). In conclusion, STZ-diabetic state facilitated choroidal neovascularization through the release of TNF α. Nifedipine inhibited the action of TNF α probably by blocking voltage-dependent Ca2+ channels in the endothelial progenitor cells of the diabetic choroid. © 2005 Pharmaceutical Society of Japan.