Interactions between NO and O2 in the microcirculation: a mathematical analysis

Lamkin-Kennard, Kathleen A.; Buerk, Donald G.; Jaron, Dov

doi:10.1016/j.mvr.2004.03.001

Cited by 61 publications

(70 citation statements)

References 31 publications

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“…Moreover, Kleinbongard et al [40] discovered the expression of functional NOS3 on the RBC membranes, which is also potentially a source of NO in the arteriole. Other NOS isoforms in the vasculature, such as NOS2 or the putative mitochondrial nitric oxide synthase (mtNOS) [7,41], could contribute to the perivascular NO concentration.…”

Section: Discussionmentioning

confidence: 99%

“…Previous mathematical models [6,7] have shown that NO derived from perivascular NOS1 has a significantly stronger effect on the NO distribution around an arteriole than NO derived from NOS3. Here we have calculated the relative influence of NOS1 and NOS3 on the NO profile using the NO release rates from the kinetic models without considering the mast cells as NO sources.…”

Section: The Relative Influence Of Nos1 and Nos3 On The No Profilementioning

confidence: 97%

“…We considered a small arteriole and its surrounding tissue containing both NOS1 and NOS3 and evaluated the NO concentration distribution. Previous models considering the contribution of different NOS isoforms to NO exposure in smooth muscle [6,7] have estimated the NO production rates: the NO production rate from the endothelium containing NOS3 was estimated with a mathematical model that fit the experimental data from perivascular NO measurements [8], while the NO production rate from the nerve fibers containing NOS1 was tested using similar values. In this study, we used the NO production rates obtained from our biochemical pathway analysis and conducted sensitivity analysis with respect to the substrate concentrations.…”

Section: No Transport Around An Arteriolementioning

confidence: 99%

“…Recently, microfluorographic and immunohistochemical analyses have indicated that there is strong expression of NOS1 around arterioles [3][4][5] while the expression of NOS3 is much lower [4]. Computational models [6,7] have demonstrated that the enzymatic activity of NOS1 has a significant effect on the levels of NO in the smooth muscle. In these previous models, the level of NO production catalyzed by NOS1 was assumed to be equal or similar to that of NOS3, which was estimated by fitting the data for the perivascular NO concentration to a mathematical model with the assumption that all the measured NO was derived from NOS3 [8].…”

Section: Introductionmentioning

confidence: 99%

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Vascular and perivascular nitric oxide release and transport: Biochemical pathways of neuronal nitric oxide synthase (NOS1) and endothelial nitric oxide synthase (NOS3)

Chen

Popel

2007

Free Radical Biology and Medicine

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Nitric oxide (NO) derived from nitric oxide synthase (NOS) is an important paracrine effector that maintains vascular tone. The release of NO mediated by NOS isozymes under various O 2 conditions critically determines the NO bioavailability in tissues. Because of experimental difficulties, there has been no direct information on how enzymatic NO production and distribution change around arterioles under various oxygen conditions. In this study, we used computational models based on the analysis of biochemical pathways of enzymatic NO synthesis and the availability of NOS isozymes to quantify the NO production by neuronal NOS (NOS1) and endothelial NOS (NOS3). We compared the catalytic activities of NOS1 and NOS3 and their sensitivities to the concentration of substrate O 2 . Based on the NO release rates predicted from kinetic models, the geometric distribution of NO sources and mass balance analysis, we predicted the NO concentration profiles around an arteriole under various O 2 conditions. The results indicated that NOS1-catalyzed NO production was significantly more sensitive to ambient O 2 concentration than that catalyzed by NOS3. Also, the high sensitivity of NOS1 catalytic activity to O 2 was associated with significantly reduced NO production and therefore NO concentrations, upon hypoxia. Moreover, the major source determining the distribution of NO was NOS1, which was abundantly expressed in the nerve fibers and mast cells close to arterioles, rather than NOS3, which was expressed in the endothelium. Finally, the perivascular NO concentration predicted by the models under conditions of normoxia was paradoxically at least an order of magnitude lower than a number of experimental measurements, suggesting a higher abundance of NOS1 or NOS3 and/or the existence of other enzymatic or nonenzymatic sources of NO in the microvasculature.

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Section: Discussionmentioning

confidence: 99%

Section: The Relative Influence Of Nos1 and Nos3 On The No Profilementioning

confidence: 97%

Section: No Transport Around An Arteriolementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Vascular and perivascular nitric oxide release and transport: Biochemical pathways of neuronal nitric oxide synthase (NOS1) and endothelial nitric oxide synthase (NOS3)

Chen

Popel

2007

Free Radical Biology and Medicine

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“…Combining reaction kinetics and diffusion, the-oretical models of NO transport in the microcirculation primarily have considered a single arteriolar vessel (9,23,27,44,45). These models have provided useful predictions including 1) the factors affecting NO levels in vessel wall (9,42,45), 2) the role of myoglobin (22,24), 3) the contribution of different isoforms of NOS (22,26), and 4) the interactions of NO and oxygen in the microcirculation (25,26).…”

mentioning

confidence: 99%

Venular endothelium-derived NO can affect paired arteriole: a computational model

Kavdia¹,

Popel²

2006

American Journal of Physiology-Heart and Circulatory Physiology

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Kavdia, Mahendra, and Aleksander S. Popel. Venular endothelium-derived NO can affect paired arteriole: a computational model. Am J Physiol Heart Circ Physiol 290: H716 -H723, 2006. First published September 9, 2005 doi:10.1152/ajpheart.00776.2005.-Venular endothelial cells can release nitric oxide (NO) in response to intraluminal flow both in isolated venules and in vivo. Experimental studies suggest that venular endothelium-released NO causes dilation of the adjacent paired arteriole. In the vascular wall, NO stimulates its target hemoprotein, soluble guanylate cyclase (sGC), which relaxes smooth muscle cells. In this study, a computational model of NO transport for an arteriole and venule pair was developed to determine the importance of the venular endothelium-released NO and its transport to the adjacent arteriole in the tissue. The model predicts that the tissue NO levels are affected within a wide range of parameters, including NO-red blood cell reaction rate and NO production rate in the arteriole and venule. The results predict that changes in the venular NO production affected not only venular endothelial and smooth muscle NO concentration but also endothelial and smooth muscle NO concentration in the adjacent arteriole. This suggests that the anatomy of microvascular tissue can permit the transport of NO from arteriolar to venular side, and vice versa, and may provide a mechanism for dilation of proximal arterioles by venules. These results will have significant implications for our understanding of tissue NO levels in both physiological and pathophysiological conditions. vasodilation; shear stress; microcirculation; nitric oxide; mathematical model VASCULAR ENDOTHELIAL CELLS release nitric oxide (NO) through enzymatic conversion of L-arginine by endothelial NO synthase (eNOS). The major target of NO is in the smooth muscle cells, where it activates the enzyme soluble guanylate cyclase (sGC), which catalyzes the conversion of GTP to cGMP and causes vasodilation (19).Endothelial cells line both arteriolar and venular vessels. The rate at which endothelial cells release NO increases upon exposure to the shear stress caused by flowing blood or to other agonists. Many studies have shown close pairings of larger arterioles and venules in the microcirculation, and a few studies have demonstrated physiological significance of such an arrangement (12,16,31,48). Some of these studies have demonstrated that substances including soluble gases can be transported between paired arteriole and venule. This transport of vasoactive mediators from venule could control arteriolar tone. The hypothesized mediators involved in venular control of arteriolar tone include prostaglandins, arachidonic acid, and NO (12,16,17).A number of studies have examined the role of venular control of arteriolar tone in a closely paired arrangement. Using segments of first-order arterioles and venules isolated from skeletal muscle and connected in series, Falcone and Meininger (12) reported that the venular endothelium-derived NO can caus...

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Nitric Oxide and the Cardiovascular System

Bohlen

2015

Comprehensive Physiology

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Nitric oxide (NO) generated by endothelial cells to relax vascular smooth muscle is one of the most intensely studied molecules in the past 25 years. Much of what is known about NO regulation of NO is based on blockade of its generation and analysis of changes in vascular regulation. This approach has been useful to demonstrate the importance of NO in large scale forms of regulation but provides less information on the nuances of NO regulation. However, there is a growing body of studies on multiple types of in vivo measurement of NO in normal and pathological conditions. This discussion will focus on in vivo studies and how they are reshaping the understanding of NO's role in vascular resistance regulation and the pathologies of hypertension and diabetes mellitus. The role of microelectrode measurements in the measurement of [NO] will be considered because much of the controversy about what NO does and at what concentration depends upon the measurement methodology. For those studies where the technology has been tested and found to be well founded, the concept evolving is that the stresses imposed on the vasculature in the form of flow-mediated stimulation, chemicals within the tissue, and oxygen tension can cause rapid and large changes in the NO concentration to affect vascular regulation. All these functions are compromised in both animal and human forms of hypertension and diabetes mellitus due to altered regulation of endothelial cells and formation of oxidants that both damage endothelial cells and change the regulation of endothelial nitric oxide synthase.

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Interactions between NO and O2 in the microcirculation: a mathematical analysis

Cited by 61 publications

References 31 publications

Vascular and perivascular nitric oxide release and transport: Biochemical pathways of neuronal nitric oxide synthase (NOS1) and endothelial nitric oxide synthase (NOS3)

Vascular and perivascular nitric oxide release and transport: Biochemical pathways of neuronal nitric oxide synthase (NOS1) and endothelial nitric oxide synthase (NOS3)

Venular endothelium-derived NO can affect paired arteriole: a computational model

Nitric Oxide and the Cardiovascular System

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