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The purpose of this investigation was to study the effect of the presence of red blood cells (RBCs) in the plasma layer near the arteriole wall on nitric oxide (NO) and oxygen (O2) transport. To this end, we extended a coupled NO and O2 diffusion-reaction model in the arteriole, developed by our group, to include the effect of the presence of RBCs in the plasma layer and the effect of convection. Two blood flow velocity profiles (plug and parabolic) were tested. The average hematocrit in the bloodstream was assumed to be constant in the central core and decreasing to zero in the boundary layer next to the endothelial surface layer. The effect of the presence or absence of RBCs near the endothelium was studied while varying the endothelial surface layer and boundary layer thickness. With RBCs present in the boundary layer, the model predicts that 1) NO decreases significantly in the endothelium and vascular wall; 2) there is a very small increase in endothelial and vascular wall Po2; 3) scavenging of NO by hemoglobin decreases with increasing thickness of the boundary layer; 4) the shape of the velocity profile influences both NO and Po2 gradients in the bloodstream; and 5) the presence of RBCs in the boundary layer near the endothelium has a much larger effect on NO than on O2 transport. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) and oxygen (02) transport in the microcirculation are coupled in a complex manner, since enzymatic production of NO depends on O2 availability, NO modulates vascular tone and O2 delivery, and tissue O2 consumption is reversibly inhibited by NO. The authors investigated whether NO bioavailability is influenced by the well-known Fåhraeus effect, which has been observed for over 70 years. This phenomenon occurs in small-diameter blood vessels, where the tube hematocrit is reduced below systemic hematocrit as a plasma boundary layer forms near the vascular wall when flowing red blood cells (rbcs) migrate toward the center of the bloodstream. Since hemoglobin iii the bloodstream is thought to be the primary scavenger of NO in vivo, this might have a significant impact on NO transport. To investigate this possibility, the authors developed a multilayered mathematical model for mass transport in arterioles using finite element numerical methods to simulate coupled NO and O2 transport in the blood vessel lumen, plasma layer, endothelium, vascular wall, and surrounding tissue. The Fahraeus effect was modeled by varying plasma layer thickness while increasing core hematocrit based on conservation of mass. Key findings from this study are that (1) despite an increase in the NO scavenging rate in the core with higher hematocrit, the model predicts enhanced vascular wall arid tissue NO bioavailability due to the relatively greater resistance for NO diffusion through the plasma layer; (2) increasing the plasma layer thickness also increases the resistance for O2 diffusion, causing a larger PO2 gradient near the vascular wall and decreasing tissue O2 availability, although this can be partially offset with inhibition of O2 consumption by higher tissue NO levels; (3) the Fåhraeus effect can become very significant in smaller blood vessels (diameters <30 µm); and (4) models that ignore the Fãhraeus effect may underestimate NO concentrations in blood and tissue. Objective: To examine whether prostaglandins are involved in endotheliurn-dependent vasodilatory responses of the skin microcirculation. Methods: Twenty-three young male volunteers were studied on 2 different days 1-3 weeks apart. On each experimental day the forearm skin blood flow response to iontophoretically applied acetylcholirie (Ach, an endothelium-dependent vasodilator) was determined with laser Doppler imaging following the intravenous administration of either the cyclo-oxygenase inhibitor lysine acetylsalicylate (L-AS), 900 mg, or the oral intake of indornethacin, 75 mg. Acetylcholine was iontophoresed both in presence and in absence of surface anesthesia. In some subjects, the effects of L-AS on skin reactive hyperemia were also assessed. Results: Acute cyclo-oxygenase inhibition with either drug influenced neither the skin blood flow response to 4 different doses of Ach (0.28, 1.4, 7, and 14 mC/cm²) nor reactive hyperemia. The peak vasodilatory response to Ach was significantly increased by skin anesthesia, regardless of whether the subjects received the cyclo-oxygenase inhibitor or not. For example, the mean response (+SD) to the largest dose of Ach (tested in 6 subjects, expressed in perfusion units) were as follows: in absence of anesthesia: L-AS 339 ± 105, placebo 344 ± 68; with anesthesia: L-AS 453 + 76, placebo 452 + 65 (p < .01 for effect of anesthesia). Conclusions: These data give no support for a contribution of prostaglandins to acetylcholine-induced vasodilation or to reactive hyperemia in the skin microcirculation. In this vascular bed, local anesthesia seems to amplify acetylcholine-induced vasodilation via a prostaglandin-independent mechanism. [ABSTRACT FROM AUTHOR]

Increased neuronal activity induced by diffuse flickering illumination of the ocular fundus generates increases in blood flow and decreases in tissue pO[sub 2] in the optic nerve head (ONH). This suggests that in the ONH, as in the brain, a coupling exists between function, perfusion, and metabolism, in accordance with the hypothesis of Roy and Sherrington. Following a review of the characteristics of the activity-induced blood flow response in the cat ONH, the relationship between blood flow and metabolism is discussed. We then examine possible mediators of the neurovascular coupling, some of the factors which may interfere with it, and point out various problems which remain to be addressed in order to better understand this coupling. [ABSTRACT FROM AUTHOR]

This study investigates the role of tumor nitric oxide (NO) and vascular regulation in tumor ulceration following high-dose tumor necrosis factor-alpha (TNF) treatment. Using TNF-responsive (MethA) and nonresponsive (LL2) mouse tumors, tumor NO concentration was measured with an electrochemical sensor and tumor blood flow by Doppler ultrasound. Mice were also pretreated with a selective inducible nitric oxide synthase (iNOS) inhibitor, 1400 W. Tumors harvested from TNF-treated mice were cryosectioned and immunostained for murine macrophages, or/and iNOS. MethA tumor-bearing mice were depleted of macrophages. Pre- and post-TNF tumor NO levels were measured continuously, and mice were followed for gross tumor response. In MethA tumors, TNF caused a 96% response rate, and tumor NO concentration doubled. Tumor blood flow decreased to 3% of baseline by 4 hr and was sustained at 24 hr and 10 days post-TNF. Selective NO inhibition with 1400 W blocked NO rise and decreased response rate to 38%. MethA tumors showed tumor infiltration by macrophages post-TNF and the pattern of macrophage immunostaining overlapped with iNOS immunostaining. Depletion of macrophages inhibited tumor NO increase and response to TNF. LL2 tumors had a 0% response rate to TNF and exhibited no change in NO concentration. Blood flow decreased to 2% of baseline by 4 hr, recovered to 56% by 24 hr and increased to 232% by 10 days. LL2 tumors showed no infiltration by macrophages post-TNF. We conclude that TNF causes tumor infiltrating, macrophage-derived iNOS-mediated tumor NO rise and sustained tumor blood flow shutdown, resulting in tumor ulceration in the responsive tumor., ((c) 2008 Wiley-Liss, Inc.)

Tumor oxygen status is a reliable prognostic marker that impacts malignant progression and outcome of tumor therapy. However, tumor oxygenation is heterogeneous and cannot be sufficiently described by a single parameter. It is influenced by several factors including microvessel density (MVD), blood flow (BF), blood volume (BV), blood oxygen saturation, tissue pO(2), oxygen consumption rate, and hypoxic fraction. The goal of this investigation was to integrate these measurements to obtain a comprehensive profile of tumor oxygenation. Platelet/endothelial cell adhesion molecule immunohistochemistry, the recessed oxygen microelectrode, color and power Doppler ultrasound (DUS), and diffuse light spectroscopy (DLS) were used to measure tumor oxygen status using vascular endothelial growth factor (VEGF)-transfected hypervascular human melanoma xenografts and their nontransfected counterparts as a model. NIH1286 human melanoma cells were transfected with a retroviral vector +/- a 720-bp fragment of human VEGF(121). High VEGF-producing clones were selected by ELISA. Oxygen consumption rate was measured in NIH1286/VEGF+ [VEGF-transfected cells (VEGF+ cells)] and NIH1286/Vec cells [cells transfected with vector alone (Vec cells)] using a standard Clark oxygen electrode. Athymic nude 6-8-week-old mice received s.c. injection in the right flank with 5 x 10(6) VEGF+ or Vec cells. When tumors were 10-14 mm in maximum dimension, serum was analyzed for VEGF by ELISA. Cryopreserved tumor tissue sections were immunostained for platelet/endothelial cell adhesion molecule, and MVD measurements were made. Tumor-bearing mice were anesthetized, and pO(2) measurements were made using Eppendorf pO(2) histograph or the recessed oxygen microelectrode. Tumor BF and BV were measured by quantitative analysis of DUS images. DLS was used to measure tumor BF and blood oxygen saturation variation. VEGF+ cell supernatants had 15,500 pg/ml VEGF, and Vec cells had 10 pg/ml. VEGF+ and Vec cells had equivalent oxygen consumption rates. VEGF+ tumors had a faster growth rate than Vec tumors. Serum from VEGF+ tumor-bearing mice showed 4,211 pg/ml VEGF, whereas VEGF was undetectable in the serum of control mice. MVD values were 74 +/- 11 in VEGF+ tumors and 39 +/- 4 in control tumors at x200 magnification/0.95-mm(2) area. The median pO(2) values were 3.5-fold higher in VEGF+ tumors than in Vec tumors by the recessed oxygen microelectrode and 18-fold higher by Eppendorf pO(2) histograph. DUS showed a 3.3-fold higher mean BF and a 5.5-fold higher BV in VEGF+ tumors than in Vec tumors. DLS showed a 3.2-fold higher mean BF and 1.7-fold higher oxygen saturation in the hypervascular tumors as compared with the control tumor type, consistent with increased BF and BV data by DUS. An integrated approach that yields a comprehensive and consistent profile of oxygen status in tumors could potentially provide critical information for prognosis and treatment.