Regulation of Oxygen Distribution in Tissues by Endothelial Nitric Oxide (original) (raw)
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Biphasic modulation of vascular nitric oxide catabolism by oxygen
American Journal of Physiology-Heart and Circulatory Physiology, 2004
Endothelium-derived nitric oxide (NO) plays an important role in the regulation of vascular tone. Lack of NO bioavailability can result in cardiovascular disease. NO bioavailability is determined by its rates of generation and catabolism; however, it is not known how the NO catabolism rate is regulated in the vascular wall under normoxic, hypoxic, and anaerobic conditions. To investigate NO catabolism under different oxygen concentrations, studies of NO and O2consumption by the isolated rat aorta were performed using electrochemical sensors. Under normoxic conditions, the rate of NO consumption in solution was enhanced in the presence of the rat aorta. Under hypoxic conditions, NO consumption decreased in parallel with the O2concentration. Like the inhibition of mitochondrial respiration by NO, the inhibitory effects of NO on aortic O2consumption increased as O2concentration decreased. Under anaerobic conditions, however, a paradoxical reacceleration of NO consumption occurred. This...
Role of endothelial nitric oxide in pulmonary and systemic arteries during hypoxia
Nitric Oxide, 2014
Our aim was to investigate the role played by endothelial nitric oxide (NO) during acute vascular response to hypoxia, as a modulator of both vascular tone (through guanylate cyclase (sGC) activation) and mitochondrial O 2 consumption (through competitive inhibition of cytochrome-c-oxydase (CcO)). Organ bath experiments were performed and O 2 consumption (Clark electrode) was determined in isolated aorta, mesenteric and pulmonary arteries of rats and eNOS-knockout mice. All pre-contracted vessels exhibited a triphasic hypoxic response consisting of an initial transient contraction (not observed in vessels from eNOS-knockout mice) followed by relaxation and subsequent sustained contraction. Removal of the endothelium, inhibition of eNOS (by L-NNA) and inhibition of sGC (by ODQ) abolished the initial contraction without altering the other two phases. The initial hypoxic contraction was observed in the presence of L-NNA+NO-donors. L-NNA and ODQ increases O 2 consumption in hypoxic vessels and increases the arterial tone in normoxia but not in hypoxia. When L-NNA+mitochondrial inhibitors (cyanide, rotenone or myxothiazol) were added, the increase in tone was similar in normoxic and hypoxic vessels, which suggests that inhibition of the binding of NO to reduced CcO restored the action of NO on sGC. CONCLUSION: A complex equilibrium is established between NO, sGC and CcO in vessels in function of the concentration of O 2 : as O 2 falls, NO inhibition of mitochondrial O 2 consumption increases and activation of sGC decreases, thus promoting a rapid increase in tone in both pulmonary and systemic vessels, which is followed by the triggering of NOindependent vasodilator/vasoconstrictor mechanisms.
Tissue Oxygenation Modifies Nitric Oxide Bioavailability
Microcirculation, 1999
Objective: Because changes in blood oxygenation acutely alter vascular tone, we explored a possible modulation of nitric oxide-induced vasodilation (nitrovasodilation) by oxygen. Methods: We studied the effects of manipulation of tissue oxygenation on renal parenchymal nitric oxide (NO) with a selective NO electrode placed in the welloxygenated renal cortex or in the physiologically hypoxemic outer medulla. Results: In the cortex, as expected, NO signals fell in response to the NO synthase (NOS) inhibitor L-NAME. By contrast, in the outer medulla, NO signals paradoxically rose following NOS inhibition, known to intensify local hypoxia. Other manipulations that intensify outer medullary hypoxia (such as indomethacin or radiologic contrast media) increased local NO readings, while measures known to ameliorate outer medullary hypoxia (furosemide, L-arginine, hypotension) reduced regional NO readings.
Nitric oxide contribution to vascular wall oxygen consumption in arterioles
Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2006
To study the role of nitric oxide (NO) in regulating oxygen consumption by vessel walls, the oxygen consumption rate of arteriolar walls in rat cremaster muscle was measured in vivo during flow-induced vasodilation and after inhibiting NO synthesis. The oxygen consumption rate of arteriolar was calculated based on the intra- and peri-vascular oxygen tension (P0(2)) values measured by phosphorescence quenching laser microscopy. The peri-vascular PO(2) value of the arterioles during vasodilation was significantly higher than under control conditions, although the intravascular PO(2) values under both conditions were approximately the same. On the other hand, inhibition of NO synthesis caused a significant decrease in both the intra- and peri-vascular P0(2) values of the arterioles. The inhibition of NO synthesis increased the oxygen consumption rate of the walls by 42%, whereas enhancement of flow-induced NO release decreased it by 34%. These results suggest that NO plays an important...
On the Mechanism by Which Vascular Endothelial Cells Regulate Their Oxygen Consumption
Proceedings of The National Academy of Sciences, 1999
Two enzymes, soluble guanylyl cyclase and cytochrome c oxidase, have been shown to be exquisitely sensitive to nitric oxide (NO) at low physiological concentrations. Activation of the soluble guanylyl cyclase by endogenous NO and the consequent increase in the second messenger cyclic GMP are now known to control a variety of biological functions. Cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain, is inhibited by NO. However, it is not clear whether NO produced by the constitutive NO synthase interacts with cytochrome c oxidase, nor is it known what the biological consequences of such an interaction might be. We now show that NO generated by vascular endothelial cells under basal and stimulated conditions modulates the respiration of these cells in response to acute changes in oxygen concentration. This action occurs at the cytochrome c oxidase and depends on inf lux of calcium. Thus, NO plays a physiological role in adjusting the capacity of this enzyme to use oxygen, allowing endothelial cells to adapt to acute changes in their environment.
Diminished NO release in chronic hypoxic human endothelial cells
American Journal of Physiology-Heart and Circulatory Physiology, 2007
The present study addressed whether chronic hypoxia is associated with reduced nitric oxide (NO) release due to decreased activation of endothelial NO synthase (eNOS). Primary cultures of endothelial cells from human umbilical veins (HUVECs) were used and exposed to different oxygen levels for 24 h, after which NO release, intracellular calcium, and eNOS activity and phosphorylation were measured after 24 h. Direct measurements using a NO microsensor showed that in contrast to 1-h exposure to 5% and 1% oxygen (acute hypoxia), histamine-evoked (10 μM) NO release from endothelial cells exposed to 5% and 1% oxygen for 24 h (chronic hypoxia) was reduced by, respectively, 58% and 40%. Furthermore, chronic hypoxia also lowered the amount and activity of eNOS enzyme. The decrease in activity could be accounted for by reduced intracellular calcium and altered eNOS phosphorylation. eNOS Ser1177and eNOS Thr495phosphorylations were reduced and increased, respectively, consistent with lowered e...
Oxygen Metabolism by Endothelial Nitric-oxide Synthase
Journal of Biological Chemistry, 2007
Nitric-oxide synthase (NOS) catalyzes both coupled and uncoupled reactions that generate nitric oxide and reactive oxygen species. Oxygen is often the overlooked substrate, and the oxygen metabolism catalyzed by NOS has been poorly defined. In this paper we focus on the oxygen stoichiometry and effects of substrate/cofactor binding on the endothelial NOS isoform (eNOS). In the presence of both L-arginine and tetrahydrobiopterin, eNOS is highly coupled (>90%), and the measured stoichiometry of O 2 /NADPH is very close to the theoretical value. We report for the first time that the presence of L-arginine stimulates oxygen uptake by eNOS. The fact that nonhydrolyzable L-arginine analogs are not stimulatory indicates that the occurrence of the coupled reaction, rather than the accelerated uncoupled reaction, is responsible for the L-arginine-dependent stimulation. The presence of 5,6,7,8-tetrahydrobiopterin quenched the uncoupled reactions and resulted in much less reactive oxygen species formation, whereas the presence of redox-incompetent 7,8-dihydrobiopterin demonstrates little quenching effect. These results reveal different mechanisms for oxygen metabolism for eNOS as opposed to nNOS and, perhaps, partially explain their functional differences.
The biological lifetime of nitric oxide: Implications for the perivascular dynamics of NO and O 2
Proceedings of the National Academy of Sciences, 2001
Endothelial nitric oxide (nitrogen monoxide) is synthesized at the intravascular/extravascular interface. We previously have reported the intravascular half-life of NO, as a result of consumption by erythrocytes, as approximately 2 ms. We report here studies designed to estimate the lifetime of NO in the parenchymal (extravascular) tissue and describe the implications of these results for the distribution of NO and oxygen concentration gradients away from the blood vessel. The rate of consumption of NO by parenchymal cells (hepatocytes) linearly depends on both NO and O 2 concentration. We estimate that the extravascular half-life of NO will range from 0.09 to > 2 s, depending on O 2 concentration and thus distance from the vessel. Computer modeling reveals that this phenomenon, coupled with reversible NO inhibition of cellular mitochondrial oxygen consumption, substantially extends the zone of adequate tissue cellular oxygenation away from the blood vessel, with an especially dr...
Antioxidants & Redox Signaling, 2008
Nitric oxide (NO) affects two key aspects of O 2 supply and demand: It regulates vascular tone and blood flow by activating soluble guanylate cyclase (sGC) in the vascular smooth muscle, and it controls mitochondrial O 2 consumption by inhibiting cytochrome c oxidase. However, significant gaps exist in our quantitative understanding of the regulation of NO production in the vascular region. Large apparent discrepancies exist among the published reports that have analyzed the various pathways in terms of the perivascular NO concentration, the efficacy of NO in causing vasodilation (EC 50 ), its efficacy in tissue respiration (IC 50 ), and the paracrine and endocrine NO release. In this study, we review the NO literature, analyzing NO levels on various scales, identifying and analyzing the discrepancies in the reported data, and proposing hypotheses that can potentially reconcile these discrepancies. Resolving these issues is highly relevant to improving our understanding of vascular biology and to developing pharmaceutical agents that target NO pathways, such as vasodilating drugs.
Regulation of bovine endothelial constitutive nitric oxide synthase by oxygen
Journal of Clinical Investigation, 1995
Oxygen (02) may regulate pulmonary vascular resistance through changes in endothelial nitric oxide (NO) production. To determine whether constitutive NO synthase (cNOS) is regulated by 02, we assessed cNOS expression and activity in bovine pulmonary artery endothelial cells exposed to different concentrations of 02-In a time-dependent manner, changes in 02 concentration from 95 to 3% produced a progressive decrease in cNOS mRNA and protein levels resulting in 4.8and 43-fold reductions after 24 h, respectively. This correlated with changes in cNOS activity as determined by nitrite measurements. Compared with 20% 02, cNOS activity was increased 1.5-fold in 95% 02 and decreased 1.9-fold in 3% 02. A decrease in 02 concentration from 95 to 3% shortened cNOS mRNA half-life from 46 to 24 h and caused a 20-fold repression of cNOS gene transcription. Treatment with cycloheximide produced a threefold increase in cNOS mRNA at all 02 concentrations, suggesting that cNOS mRNA expression is negatively regulated under basal condition. We conclude that 02 upregulates cNOS expression through transcriptional and posttranscriptional mechanisms. A decrease in cNOS activity in the presence of low 02 levels, therefore, may contribute to hypoxia-induced vasoconstriction in the pulmonary circulation. (J. Clin. Invest. 1995Invest. . 96:2661Invest. -2666