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We tested the hypothesis that inducible NO synthase (iNOS) contributes to reduced NO-dependent vasodilation in non-Hispanic Blacks and prehypertensive non-Hispanic Whites. Twenty Black and 20 White participants (10 normotensive, 10 prehypertensive per group; n=40 total) participated in this study. Participants were instrumented with two microdialysis fibers and each site was randomized as control (lactated Ringer's) or iNOS inhibition (0.1 mM 1400W). Laser-Doppler flow probes and local heaters were used to measure skin blood flow and heat the skin to induce vasodilation, respectively. Each site was heated from 33°C to 39°C (rate: 0.1°C/sec). Once a plateau was established, 20 mM L-NAME, a non-specific NOS inhibitor, was infused at each site to quantify NO-dependent vasodilation. At control sites, %NO-dependent vasodilation was reduced in prehypertensive Whites (47 ± 10 %NO) and in both normotensive and prehypertensive Blacks (39 ± 9 and 28 ± 5 %NO, respectively) relative to normotensive Whites (73 ± 8 %NO; p < 0.0001 all comparisons). Compared to respective control sites, iNOS inhibition increased NO-dependent vasodilation in prehypertensive Whites (68 ± 8 %NO) and in both normotensive and prehypertensive Blacks (78 ± 8 and 55 ± 6 %NO, respectively; p < 0.0001 all comparisons). We failed to find an effect for normotensive Whites (77 ± 7 %NO). Following iNOS inhibition, %NO-dependent vasodilation was similar between normotensive Whites, prehypertensive Whites, and normotensive Blacks. Inhibition of iNOS increased NO-dependent vasodilation to a lesser extent in prehypertensive Blacks. These data suggest iNOS contributes to reduced NO-dependent vasodilation in prehypertension and in Black participants.

Overt hypertension is known to reduce cutaneous sensory nerve-mediated and nitric oxide (NO)-dependent vasodilation, but the effect of subclinical increases in blood pressure (i.e., prehypertension) is unknown. The combined effect of race and prehypertension is also unknown. In this study, we found that prehypertension reduces cutaneous sensory nerve-mediated and NO-dependent vasodilation in both non-Hispanic white and black populations, with the greatest reductions observed in prehypertensive non-Hispanic blacks.

Substantial barriers exist to the engraftment of hematopoietic cells in mice after in utero transplantation. Although high levels of donor-derived hematopoiesis have been reported in SCID mice, the majority of chimeric recipients exhibit decreasing levels of donor cells over time. To directly test whether the natural killer cell and macrophage activity of the recipients represents a barrier to sustained engraftment, fetal NOD/SCID mice were injected on day 13.5 of gestation with an enriched congenic hematopoietic progenitor cell population. Forty-four percent of pups showed the presence of Ly5.1+ donor cells 4 weeks after transplantation. The mean number of donor-derived nucleated cells in the peripheral blood (PB) was 30%. Although the majority of circulating donor cells were lymphocytes, up to 15% expressed myelomonocytic markers. Serial PB samples from individual mice indicated that the percentage of circulating donor cells increased from 17% to 55% between 4 and 24 weeks. At 6 months posttransplantation, an increased frequency of multilineage, donor-derived cells was also observed in the bone marrow (BM) and the spleen of chimeric recipients. The engraftment of pluripotent hematopoietic stem cells was evaluated by transplanting BM from chimeric mice into irradiated congenic recipients. Irradiated secondary recipients also exhibited multilineage donor-derived hematopoiesis in the PB, BM, and spleen for up to 6 months. These results show that the in utero transplantation of lineage-depleted BM cells into NOD/SCID recipients produces a high frequency of sustained engraftment of allogeneic hematopoietic stem cells.

Interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha) protect normal human hematopoietic progenitors from the toxicity of 4-hydroperoxycyclophosphamide (4-HC). Aldehyde dehydrogenase Class 1 (ALDH-1) is the enzyme that inactivates 4-HC. Diethylaminobenzaldehyde (DEAB), a competitive inhibitor of ALDH-1, was shown to prevent the protective effects of IL-1 and TNF alpha. In this study, we examined the effect of IL-1 and TNF alpha on the expression of ALDH-1 in normal bone marrow as well as malignant cells. ALDH-1 mRNA and protein were quantified using Northern and Western blotting, respectively. In addition, the ALDH-1 enzyme activity in untreated as well as IL-1 and TNF alpha treated bone marrow cells was determined spectrophotometrically. The role of glutathione (GSH) in the protection against 4-HC toxicity was also studied. The results show that pretreatment with IL-1 and TNF alpha for 6 h or 20 h increase the expression of ALDH-1 mRNA and protein, respectively, in human bone marrow cells. In contrast, IL-1 and TNF alpha treatment did not affect the ALDH-1 expression in several leukemic and solid tumor cell lines, regardless of whether or not ALDH-1 is expressed constitutively. Furthermore, the ALDH-1 enzyme activity was significantly induced in bone marrow cells after 20 h pre-treatment with IL-1 and TNF alpha. Finally, the depletion of or inactivation of GSH did not affect the protection against 4-HC toxicity. In conclusion, inhibition of the protection from 4-HC toxicity by DEAB, together with the increase in ALDH-1 expression and activity, provide strong evidence that IL-1 and TNF alpha mediate their protective action, at least partially, through ALDH-1.

Young non-Hispanic Black adults have reduced microvascular endothelial function compared with non-Hispanic White counterparts, but the mechanisms are not fully elucidated. The purpose of this study was to investigate the effect of endothelin-1 A receptor (ETAR) and superoxide on cutaneous microvascular function in young non-Hispanic Black (n=10) and White (n=10) adults. Participants were instrumented with four intradermal microdialysis fibers: 1) lactated Ringer's (control), 2) 500 nM BQ-123 (ETAR antagonist), 3) 10 μM tempol (superoxide dismutase mimetic), and 4) BQ-123 + tempol. Skin blood flow was assessed via laser-Doppler flowmetry (LDF), and each site underwent rapid local heating from 33°C to 39°C. At the plateau of local heating, 20 mM L-NAME [nitric oxide (NO) synthase inhibitor] was infused to quantify NO-dependent vasodilation. Data are mean ± standard deviation. NO-dependent vasodilation was decreased in non-Hispanic Black compared with non-Hispanic White young adults (p < 0.01). NO-dependent vasodilation was increased at BQ-123 sites (73 ± 10% NO) and at BQ-123 + tempol sites (71 ± 10 %NO) in non-Hispanic Black young adults compared with control (53 ± 13 %NO, p = 0.01). Tempol alone had no effect on NO-dependent vasodilation in non-Hispanic Black young adults (63 ± 14 %NO, p = 0.18). NO-dependent vasodilation at BQ-123 sites was not statistically different between non-Hispanic Black and White (80 ± 7 %NO) young adults (p = 0.15). ETAR contribute to reduced NO-dependent vasodilation in non-Hispanic Black young adults independent of superoxide, suggesting a greater effect on NO synthesis rather than NO scavenging via superoxide.

Relative to non-Hispanic Whites, non-Hispanic Blacks are disproportionately affected by elevated blood pressure (BP). It is unknown whether race or subclinical increases in BP affect the ability of cutaneous sensory nerves to induce cutaneous microvascular vasodilation. Sixteen participants who self-identified as non-Hispanic Black (n = 8) or non-Hispanic White (n = 8) were subgrouped as normotensive or prehypertensive. Participants were instrumented with three intradermal microdialysis fibers: (a) control, (b) 1 μM sodium nitroprusside (SNP), an exogenous nitric oxide (NO) donor, and (c) 20 mM N G -nitro-l-arginine methyl ester (L-NAME), a non-selective NO synthase inhibitor. A slow local heating protocol (33-40°C, 0.1°C/ min) was used to assess the onset of cutaneous sensory nerve-mediated vasodilation (temperature threshold) and skin blood flow was measured using laser-Doppler flowmetry. At control sites, the temperature threshold occurred at a higher temperature in non-Hispanic Blacks (normotensive: 37.2 ± 0.6°C, prehypertensive: 38.9 ± 0.5°C) compared to non-Hispanic Whites (normotensive: 35.2 ± 0.8°C, prehypertensive:35.2 ± 0.9°C). L-NAME shifted the temperature threshold higher in non-Hispanic Whites (normotensive: 37.8 ± 0.7°C, prehypertensive: 38.2 ± 0.8°C), but there was no observed effect in non-Hispanic Blacks. SNP did not affect temperature threshold in non-Hispanic Whites, but shifted the temperature threshold lower in non-Hispanic Blacks (normotensive: 34.6 ± 1.2°C, prehypertensive: 34.8 ± 1.1°C). SNP mitigated differences in temperature threshold across all groups. There was no effect found for BP status in either the non-Hispanic Black or non-Hispanic White groups. These data suggest that reduced NO bioavailability affects the ability of cutaneous sensory nerves to induce microvascular vasodilation in young, otherwise healthy non-Hispanic Blacks. K E Y W O R D S human, nitric oxide, skin How to cite this article: Turner CG, Miller JT, Otis JS, Hayat MJ, Quyyumi AA, Wong BJ. Cutaneous sensory nerve-mediated microvascular vasodilation in normotensive and prehypertensive non-Hispanic Blacks and Whites. Physiol Rep. 2020;8:e14437.

The purpose of this study was to evaluate in vivo endothelial function and nitric oxide (NO)-dependent vasodilation between women in either menstrual or placebo pill phases of their respective hormonal exposure [either naturally cycling (NC) or using oral contraceptive pills (OCP)] and men. A planned subgroup analysis was then completed to assess endothelial function and NO-dependent vasodilation between NC women, women using OCP, and men. Endothelium-dependent and NO-dependent vasodilation were assessed in the cutaneous microvasculature using laser-Doppler flowmetry, a rapid local heating protocol (39°C, 0.1°C/s), and pharmacological perfusion through intradermal microdialysis fibers. Data are mean ± standard deviation. Men displayed greater endothelium-dependent vasodilation (plateau, men: 71 ± 16 vs. women 52 ± 20 %CVCmax, p< 0.01), but lower NO-dependent vasodilation (men: 52 ± 11 vs. women 63 ± 17 %NO, p = 0.05), compared with all women. Subgroup analysis revealed NC women had lower endothelium-dependent vasodilation (plateau, NC women: 48 ± 21 %CVCmax, p = 0.01), but similar NO-dependent vasodilation (NC women: 52 ± 14 %NO, p > 0.99), compared with men. Endothelium-dependent vasodilation did not differ between women using OCP and men (p = 0.12) or NC women (p = 0.64), but NO-dependent vasodilation was significantly greater in women using OCP (74 ± 11 %NO) than both NC women and men (p < 0.01 for both). This study highlights the importance of directly quantifying NO-dependent vasodilation in cutaneous microvascular studies. This study also provides important implications for experimental design and data interpretation.