Inhibitory effect of nifedipine on tumor necrosis factor alpha-induced neovascularization in cultured choroidal explants of streptozotocin-diabetic rat.
We have previously reported that the Nepsilon (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) alpha, 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 alpha-induced choroidal neovascularization in the STZ-diabetic rat. TNF alpha (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 alpha antibody (1 : 1000) decreased the neovascularization in the diabetic rat but not in the normal rat. Nifedipine (1 microM) inhibited TNF alpha-induced neovascularization of the normal choroidal explant in a non-competitive manner. Nifedipine (1 microM) also inhibited the diabetic state-induced neovascularization and its inhibitory action was reversed by TNF alpha (1-10 ng/ml). In conclusion, STZ-diabetic state facilitated choroidal neovascularization through the release of TNF alpha. Nifedipine inhibited the action of TNF alpha probably by blocking voltage-dependent Ca2+ channels in the endothelial progenitor cells of the diabetic choroid.
Kobayashi
Shinjiro
S
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Hokuriku University, 3-Ho Kanagawa-machi, Kanazawa 920-1181, Japan. s-kobayashi@hokuriku-u.ac.jp
Fukuta
Mizuki
M
Suzuki
Miho
M
Tsuneki
Hiroshi
H
Kimura
Ikuko
I
D000818:Animals; D002829:Choroid / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D020256:Choroidal Neovascularization / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000517:prevention & control; D008297:Male; D009543:Nifedipine / Q000494:pharmacology* / Q000627:therapeutic use; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000633:toxicity
D014409:Tumor Necrosis Factor-alpha; D009543:Nifedipine