Abstract
BackgroundNebivolol 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.MethodsUsing 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.ResultsNebivolol 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.ConclusionThe 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.
Highlights
Nebivolol is a third-generation beta-blocker used to treat hypertension
Using nanonsensor technology, we measured in situ, near-real time nitric oxide (NO) and ONOO- released from human umbilical vein endothelial cells (HUVECs) following the acute administration of nebivolol, L-755, 507, 2-MeSATP or ATP over a range of concentrations
Representative amperograms collected from endothelial cells treated with nebivolol, L-755,507, 2-MeSATP, and ATP are shown in the Figure 1
Summary
Nebivolol is a third-generation beta-blocker used to treat hypertension. The vasodilation properties of nebivolol have been attributed to nitric oxide (NO) release. Arterial endothelial cells modulate vascular tone through release of nitric oxide (NO), a potent vasodilator that regulates regional blood flow [1,2]. NO has various vascular benefits that reduce the risk for cardiovascular disease. An uncoupling of endothelial nitric oxide synthase (eNOS) along with reduced endothelial-dependent NO release and generation of peroxynitrite (ONOO-) has been linked to atherogenesis and its clinical manifestations [4,5]. Agents that enhance NO bioavailability have been shown to reduce cardiovascular events, as well as central arterial blood pressure, in patients with hypertension [4,5]. Peroxynitrite, a major component of nitroxidative stress, is cytotoxic and can trigger a cascade of events leading to vasoconstriction, dysfunction of the endothelium, and apoptosis
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