Potency of authentic nitric oxide in inducing aortic relaxation

Yan, Qingtao; Liu, Qihui; Zweíer, Jay L.; Li, Xiaoping

doi:10.1016/j.phrs.2007.01.001

Cited by 14 publications

(21 citation statements)

References 18 publications

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“…EC 50 was initially reported to be as high as 250 nM in vitro [40]. Recent studies have pointed to the amount of NO required to activate sGC to half-maximal activity as being on the nanomolar level [41,42] or even sub-nanomolar [43]. Our predicted NO values obtained for the protected transport form were close to the sub-nanomolar EC 50 .…”

Section: Is Erythrocyte-produced No Sufficient To Induce Vasodilation?supporting

confidence: 60%

Nitric oxide from nitrite reduction by hemoglobin in the plasma and erythrocytes

et al. 2008

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Experimental evidence has shown that nitrite anion plays a key role in one of the proposed mechanisms for hypoxic vasodilation, in which the erythrocyte acts as a NO generator and deoxygenated hemoglobin in pre-capillary arterioles reduces nitrite to NO, which contributes to vascular smooth muscle relaxation. However, because of the complex reactions among nitrite, hemoglobin, and the NO that is formed, the amount of NO delivered by this mechanism under various conditions has not been quantified experimentally. Furthermore, paracrine NO is scavenged by cellfree hemoglobin, as shown by studies of diseases characterized by extensive hemolysis (e.g., sickle cell disease) and the administration of hemoglobin-based oxygen carriers. Taking into consideration the free access of cell-free hemoglobin to the vascular wall and its ability to act as a nitrite reductase, we have now examined the hypothesis that in hypoxia this cell-free hemoglobin could serve as an additional endocrine source of NO. In this study, we constructed a multicellular model to characterize the amount of NO delivered by the reaction of nitrite with both intraerythrocytic and cell-free hemoglobin, while intentionally neglecting all other possible sources of NO in the vasculature. We also examined the roles of hemoglobin molecules in each compartment as nitrite reductases and NO scavengers using the model. Our calculations show that: (1) ~0.04 pM NO from erythrocytes could reach the smooth muscle if free diffusion were the sole export mechanism; however, this value could rise to ~43 pM with a membrane-associated mechanism that facilitated NO release from erythrocytes; the results also strongly depend on the erythrocyte membrane permeability to NO; (2) despite the closer proximity of cell-free hemoglobin to the smooth muscle, cell-free hemoglobin reaction with nitrite generates approximately 0.02 pM of free NO that can reach the vascular wall, because of a strong self-capture effect. However, it is worth noting that this value is in the same range as erythrocytic hemoglobin-generated NO that is able to diffuse freely out of the cell, despite the tremendous difference in hemoglobin concentration in both cases (μM hemoglobin in plasma vs. mM in erythrocyte); (3) intraerythrocytic hemoglobin encapsulated by a NO-resistant membrane is the major source of NO from nitrite reduction, and cell-free hemoglobin is a significant scavenger of both paracrine and endocrine NO.* Corresponding

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Section: Is Erythrocyte-produced No Sufficient To Induce Vasodilation?supporting

confidence: 60%

Nitric oxide from nitrite reduction by hemoglobin in the plasma and erythrocytes

et al. 2008

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“…We have discussed the perivascular NO concentration measurements (see Table 1) that are in the range of 200-1,000 nM, or even higher. These studies have left us with an apparent paradox: On the one hand, the perivascular values for the concentration of NO as measured in vivo by NO microelectrodes have been generally reported as several hundred nanomolar under control conditions, and, in the interpretation of the results, most of the NO available to the smooth muscle has been attributed solely to endothelial sources; on the other hand, although variations are found in the EC 50 values reported in the literature (see Table 2), studies in the cellular environment and using endogenous NO as the source usually point to levels Ͻ10 nM (81,112). Furthermore, as suggested by Kollau et al (53), concentrations Ͻ1 nM could trigger maximal vascular relaxation through a mechanism that does not require the full potential of 3Ј,5Ј-cyclic guanosine monophosphate (cGMP) accumulation achievable with full cyclase activation.…”

Section: No Concentration and Ec 50mentioning

confidence: 92%

Nitric Oxide in the Vasculature: Where Does It Come From and Where Does It Go? A Quantitative Perspective

Chen

Pittman

Popel³

2008

Antioxidants & Redox Signaling

220

168

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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.

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“…NO gas was scrubbed of higher nitrogen oxides by passage first through a U-tube containing NaOH pellets and then through a 1 M deaerated (bubbled with 100% argon) KOH solution, in a custom-designed apparatus constructed of only glass or stainless steel tubing and fittings [10, 17]. The purified NO was collected by saturating a deaerated phosphate buffer solution (0.2 M potassium phosphate, pH 7.4), contained in a glass sampling flask with a septum purchased from Kimble/Kontes (Vineland, NJ).…”

Section: Experimental Methodsmentioning

confidence: 99%

Oxygen regulates the effective diffusion distance of nitric oxide in the aortic wall

Liu¹,

Collard²,

Grajdeanu

et al. 2010

Free Radical Biology and Medicine

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Endothelium-derived nitric oxide (NO) is critical in maintaining vascular tone. Accumulating evidence shows that NO bioavailability is regulated by oxygen concentration. However, it is unclear to what extent the oxygen concentration regulates NO bioavailability in the vascular wall. In this study, a recently developed experimental setup was used to measure the NO diffusion fluxes across the aortic wall at different oxygen concentrations. It was observed that for a constant NO concentration at the endothelial surface, the measured NO diffusion flux out of the adventitial surface at [O2]=0 μM is around 5-fold greater than at [O2]=150 μM, indicating that NO is consumed in the aortic wall in an oxygen-dependent manner. Analysis of experimental data shows that the rate of NO consumption in the aortic wall is first order with respect to [NO] and first order with respect to [O2], and the rate constant k1 was determined as (4.0 ± 0.3)×103 M-1s-1. Computer simulations demonstrate that NO concentration distribution significantly changes with oxygen concentration and the effective NO diffusion distance at low oxygen level ([O2]≤25 μM) is significantly longer than that at high oxygen level ([O2]=200 μM). These results suggest that the oxygen-dependent NO consumption may play an important role in dilating blood vessels during hypoxia by increasing the effective NO diffusion distance.

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Potency of authentic nitric oxide in inducing aortic relaxation

Cited by 14 publications

References 18 publications

Nitric oxide from nitrite reduction by hemoglobin in the plasma and erythrocytes

Nitric oxide from nitrite reduction by hemoglobin in the plasma and erythrocytes

Nitric Oxide in the Vasculature: Where Does It Come From and Where Does It Go? A Quantitative Perspective

Oxygen regulates the effective diffusion distance of nitric oxide in the aortic wall

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