Inhibitory Effect of Nifedipine on Tumor Necrosis Factor α-Induced Neovascularization in Cultured Choroidal Explants of Streptozotocin-Diabetic Rat

  • Kobayashi Shinjiro
    Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Hokuriku University Department of Pharmacology, Faculty of Pharmaceutical Sciences, Hokuriku University
  • Fukuta Mizuki
    Department of Pharmacology, Faculty of Pharmaceutical Sciences, Hokuriku University
  • Suzuki Miho
    Department of Pharmacology, Faculty of Pharmaceutical Sciences, Hokuriku University
  • Tsuneki Hiroshi
    Department of Clinical Pharmacology, Graduate School of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University
  • Kimura Ikuko
    Department of Clinical Pharmacology, Graduate School of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University

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タイトル別名
  • Inhibitory Effect of Nifedipine on Tumor Necrosis Factor .ALPHA.-Induced Neovascularization in Cultured Choroidal Explants of Streptozotocin-Diabetic Rat
  • Inhibitory Effect of Nifedipine on Tumor Necrosis Factor アルファ Induced Neovascularization in Cultured Choroidal Explants of Streptozotocin Diabetic Rat

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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.

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