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The activation of nitric oxide synthase by copper ion is mediated by intracellular Ca 2+ mobilization in human pulmonary arterial endothelial cells
Author(s) -
Demura Yoshiki,
Ishizaki Takeshi,
Ameshima Shingo,
Okamura Seitarou,
Hayashi Takio,
Matsukawa Shigeru,
Miyamori Isamu
Publication year - 1998
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0702197
Subject(s) - nitric oxide , chemistry , extracellular , nitrendipine , dihydropyridine , enos , agonist , nitric oxide synthase type iii , endocrinology , nifedipine , medicine , receptor , intracellular , nitric oxide synthase , calcium , biochemistry , pharmacology , biology , organic chemistry
1 The aim of the study was to elucidate the vasodilatory mechanism due to Cu 2+ by assessing nitric oxide (NO) production as determined by NOx (NO, NO 2 − , and NO 3 − ) that is released from human pulmonary arterial endothelial cell (HPAEC) monolayers using a NO chemiluminescence analyzer, and also to assess Ca 2+ movement using 45 Ca and fura 2 in HPAEC. 2 Cu 2+ (10 −6 –10 −4 m ) significantly increased NO production in a dose‐dependent manner when extracellular Ca 2+ was present. 3 45 Ca influx into the adherent cells was dose‐dependently enhanced by Cu 2+ (10 −6 –10 −4 m ), but not by Mn 2+ , Zn 2+ or Fe 2+ . 4 [Ca 2+ ] i , measured by monitoring the fluorescence changes of fura 2, was significantly elevated in the presence of Cu 2+ . 5 The increase in [Ca 2+ ] i induced by Cu 2+ was inhibited by either diethyldithiocarbamate (DDC) or the depletion of extracellular Ca 2+ . 6 The dihydropyridine receptor agonist, BayK8644, significantly attenuated the Cu 2+ ‐induced increase in [Ca 2+ ] i in a dose dependent manner and nitrendipine or nifedipine, the dihydropyridine receptor antagonists, dose‐dependently inhibited a Cu 2+ ‐induced increase in [Ca 2+ ] i . 7 These results suggest that Cu 2+ activates eNOS through the mechanism of [Ca 2+ ] i elevation due to Ca 2+ influx into HPAEC and that the Cu 2+ ‐induced [Ca 2+ ] i elevation in HPAEC is likely due to activation of the dihydropyridine‐like receptors.British Journal of Pharmacology (1998) 125 , 1180–1187; doi: 10.1038/sj.bjp.0702197