Midkine inhibits bradykinin-stimulated Ca(2+) signaling and nitric oxide production in endothelial cells.
Effects of the heparin-binding growth factor midkine (MK) were investigated on endothelial Ca(2+) signaling and nitric oxide (NO) production. Bradykinin (10 nM) and thapsigargin (1 microM) provoked large Ca(2+) influxes under fura-2/AM fluoroscopy. Pretreatment with human MK dose-dependently (1-500 ng/ml) inhibited the Ca(2+) response to bradykinin but not that to thapsigargin. Anti-MK antibody prevented this effect. In Ca(2+)-free medium, MK greatly inhibited intracellular Ca(2+) store release by bradykinin and not that by thapsigargin, which effect was prevented by the antibody. Bradykinin increased NO production by 6.7-fold, which was inhibited 6, 44, 79, and 90% by MK at 1, 10, 100, and 500 ng/ml, respectively. MK did not affect thapsigargin-induced NO production. Our data clearly indicate that MK inhibits bradykinin-induced Ca(2+) response and NO production from endothelial cells.
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Department of Internal Medicine III, Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, 3600 Handa-cho, Hamamatsu, 431-3192, Japan.
Watanabe
H
H
Le
H Y
HY
Yang
J
J
Takeuchi
K
K
Kadomatsu
K
K
Muramatsu
T
T
Ohashi
K
K
D000818:Animals; D001011:Aorta; D001920:Bradykinin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002352:Carrier Proteins / Q000494:pharmacology*; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D016257:Fura-2 / Q000378:metabolism; D000078792:Midkine; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000378:metabolism; D013552:Swine; D019284:Thapsigargin / Q000494:pharmacology
D002352:Carrier Proteins; D016207:Cytokines; D000078792:Midkine; D009569:Nitric Oxide; D019284:Thapsigargin; D000252:Calcium-Transporting ATPases; D001920:Bradykinin; D002118:Calcium; D016257:Fura-2