Nordihydroguaiaretic acid elevates osteoblastic intracellular Ca2+ |
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Authors: | Wang J L Chang H J Tseng L L Liu C P Lee K C Chou K J Cheng J S Lo Y K Su W Law Y P Chen W C Chan R C Jan C R |
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Institution: | Department of Rehabilitation, Kaohsiung Veterans General Hospital, 386 Ta Chung 1st Road, Taipei, Taiwan 813. |
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Abstract: | Nordihydroguaiaretic acid (NDGA) is widely used as a pharmacological tool to inhibit lipoxygenases; however, recent evidence suggests that it increases renal intracellular Ca2+]i via novel mechanisms. Here the effect of NDGA on Ca2+ signaling in MG63 osteoblastic cells was explored using fura-2 as a Ca2+ indicator. NDGA (2-50 microM) increased Ca2+]i in a concentration-dependent manner. The signal comprised an initial rise and an elevated phase over a time period of 4 min. Removing extracellular Ca2+ reduced 2-50 microM NDGA-induced signals by 62+/-2%. After incubation with 50 microM NDGA in Ca2+-free medium for several minutes, addition of 3 mM CaCl2 induced an increase in Ca2+]i. NDGA (50 microM)-induced Ca2+]i increases were not changed by pretreatment with 10 microM of verapamil, diltiazem, nifedipine, nimodipine and nicardipine. In Ca2+-free medium, pretreatment with the endoplasmic reticulum Ca2+ pump inhibitor thapsigargin (1 microM) inhibited 50 microM NDGA-induced Ca2+]i increases by 69+/-3%. Inhibition of phospholipase C with 2 microM U73122 had little effect on 50 microM NDGA-induced Ca2+ release. Several other lipoxygenase inhibitors had no effect on basal Ca2+]i. At a concentration that did not increase basal Ca2+]i, NDGA (1 microM) did not alter 10 microM ATP- or 1 microM thapsigargin-induced Ca2+]i increases. Alteration of protein kinase C activity with 1 nM phorbol 12-myristate 13-acetate or 2 microM GF 109203X did not affect 50 microM NDGA-induced Ca2+]i increases. Together, the results show that NDGA increased Ca2+]i in osteoblasts in a lipoxygenase-independent manner, by releasing stored Ca2+ in a fashion independent of phospholipase C activity, and by causing Ca2+ influx. |
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