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The favorable kinetics and balance of nebivolol-stimulated nitric oxide and peroxynitrite release in human endothelial cells

Mason, R Preston ; Jacob, Robert F ; Corbalan, J Jose ; Szczesny, Damian ; Matysiak, Kinga ; Malinski, Tadeusz

BMC pharmacology & toxicology, 2013-09, Vol.14 (1), p.48-48, Article 48 [Periódico revisado por pares]

England: BioMed Central Ltd

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The favorable kinetics and balance of nebivolol-stimulated nitric oxide and peroxynitrite release in human endothelial cells
Autor: Mason, R Preston ; Jacob, Robert F ; Corbalan, J Jose ; Szczesny, Damian ; Matysiak, Kinga ; Malinski, Tadeusz
Assuntos: Adenosine Triphosphate - metabolism ; Adrenergic beta-3 Receptor Antagonists - pharmacology ; Benzopyrans - pharmacology ; Biosensing Techniques - instrumentation ; Biosensing Techniques - methods ; Cell Culture Techniques ; Endothelial Cells - drug effects ; Endothelial Cells - metabolism ; Endothelium ; Ethanolamines - pharmacology ; Evaluation ; Human Umbilical Vein Endothelial Cells ; Humans ; Hypertension ; Kinetics ; Nebivolol ; Nitric oxide ; Nitric Oxide - secretion ; Oxidases ; Peroxynitrous Acid - secretion ; Receptors, Purinergic P2Y - metabolism ; Superoxide ; Time Factors
É parte de: BMC pharmacology & toxicology, 2013-09, Vol.14 (1), p.48-48, Article 48
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
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Descrição: Nebivolol is a third-generation beta-blocker used to treat hypertension. The vasodilation properties of nebivolol have been attributed to nitric oxide (NO) release. However, the kinetics and mechanism of nebivolol-stimulated bioavailable NO are not fully understood. Using amperometric NO and peroxynitrite (ONOO⁻) nanosensors, β₃-receptor (agonist: L-755,507; antagonists: SR59230A and L-748,337), ATP efflux (the mechanosensitive ATP channel blocker, gadolinium) and P2Y-receptor (agonists: ATP and 2-MeSATP; antagonist: suramin) modulators, superoxide dismutase and a NADPH oxidase inhibitor (VAS2870), we evaluated the kinetics and balance of NO and ONOO⁻ stimulated by nebivolol in human umbilical vein endothelial cells (HUVECs). NO and ONOO⁻ were measured with nanosensors (diameter ~ 300 nm) placed 5 ± 2 μm from the cell membrane and ATP levels were determined with a bioluminescent method. The kinetics and balance of nebivolol-stimulated NO and ONOO⁻ were compared with those of ATP, 2-MeSATP, and L-755,507. Nebivolol stimulates endothelial NO release through β₃-receptor and ATP-dependent, P2Y-receptor activation with relatively slow kinetics (75 ± 5 nM/s) as compared to the kinetics of ATP (194 ± 10 nM/s), L-755,507 (108 ± 6 nM/s), and 2-MeSATP (105 ± 5 nM/s). The balance between cytoprotective NO and cytotoxic ONOO- was expressed as the ratio of [NO]/[ONOO⁻] concentrations. This ratio for nebivolol was 1.80 ± 0.10 and significantly higher than that for ATP (0.80 ± 0.08), L-755,507 (1.08 ± 0.08), and 2-MeSATP (1.09 ± 0.09). Nebivolol induced ATP release in a concentration-dependent manner. The two major pathways (ATP efflux/P2Y receptors and β₃ receptors) and several steps of nebivolol-induced NO and ONOO⁻ stimulation are mainly responsible for the slow kinetics of NO release and low ONOO⁻. The net effect of this slow kinetics of NO is reflected by a favorable high ratio of [NO]/[ONOO⁻] which may explain the beneficial effects of nebivolol in the treatment of endothelial dysfunction, hypertension, heart failure, and angiogenesis.
Editor: England: BioMed Central Ltd
Idioma: Inglês

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The favorable kinetics and balance of nebivolol-stimulated nitric oxide and peroxynitrite release in human endothelial cells

Mason, R Preston ; Jacob, Robert F ; Corbalan, J Jose ; Szczesny, Damian ; Matysiak, Kinga ; Malinski, Tadeusz

England: BioMed Central Ltd

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