The causal relationships between cytosolic free-Ca2+ concentration ([Ca2+]i) increases and production of nitric oxide (NO) have been investigated mostly with indirect methods and remain unclear. Here we demonstrate, by direct real-time measurements of [NO] with a porphyrinic microsensor, that Ca2+ entry, but not an increase in [Ca2+]i, is required for triggering of NO production in human endothelial cells. Histamine, ranging from 0.1 to 100 μM, increased both NO production and [Ca2+]i when given in a single dose. However, histamine caused increased NO release but induced progressively smaller [Ca2+]i changes when cumulatively added. In the absence of a transmembrane Ca2+ gradient, no significant NO release was detectable, despite the marked Ca2+ peak induced by histamine. Inhibition of Ca2+ entry by SK&F 96365 abolished histamine-elicited NO production but only reduced the transient [Ca2+]i rise. The suppression of the sustained [Ca2+]i response under these two conditions suggests that NO release was closely associated with Ca2+ entry from the extracellular space. In addition, membrane depolarization, achieved by increasing the extracellular K+ concentration from 5 to 130 mM, reduced both the amplitude of histamine-induced sustained [Ca2+]i elevation and NO production. These results lead us to propose that the availability of numerous Ca2+ ions around the internal side of the plasma membrane would promote the association between nitric oxide synthase and calmodulin, thereby activating the enzyme.
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March 1998
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Research Article|
March 01 1998
Nitric oxide production in human endothelial cells stimulated by histamine requires Ca2+ influx Available to Purchase
Frédérique LANTOINE;
Frédérique LANTOINE
†Laboratoire d'Electrochimie et de Chimie Analytique, URA CNRS 216, Ecole Nationale Supérieure de Chimie Paris, 11 rue Pierre et Marie Curie, 75231 Paris Cedex 05, France
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Lahcen IOUZALEN;
Lahcen IOUZALEN
*Pharmacology, URA CNRS 1482, Paris V University, Necker Medical School, 156 rue de Vaugirard, 75015, Paris, France
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Marie-Aude DEVYNCK;
Marie-Aude DEVYNCK
*Pharmacology, URA CNRS 1482, Paris V University, Necker Medical School, 156 rue de Vaugirard, 75015, Paris, France
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Elisabeth MILLANVOYE-van BRUSSEL;
Elisabeth MILLANVOYE-van BRUSSEL
*Pharmacology, URA CNRS 1482, Paris V University, Necker Medical School, 156 rue de Vaugirard, 75015, Paris, France
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Monique DAVID-DUFILHO
Monique DAVID-DUFILHO
1
*Pharmacology, URA CNRS 1482, Paris V University, Necker Medical School, 156 rue de Vaugirard, 75015, Paris, France
1To whom correspondence should be addressed.
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Publisher: Portland Press Ltd
Received:
September 08 1997
Revision Received:
October 27 1997
Accepted:
November 03 1997
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 1998
1998
Biochem J (1998) 330 (2): 695–699.
Article history
Received:
September 08 1997
Revision Received:
October 27 1997
Accepted:
November 03 1997
Citation
Frédérique LANTOINE, Lahcen IOUZALEN, Marie-Aude DEVYNCK, Elisabeth MILLANVOYE-van BRUSSEL, Monique DAVID-DUFILHO; Nitric oxide production in human endothelial cells stimulated by histamine requires Ca2+ influx. Biochem J 1 March 1998; 330 (2): 695–699. doi: https://doi.org/10.1042/bj3300695
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