Nitric Oxide-dependent Vasodilation Research Articles

Effect of home-based heat therapy on 24-h blood pressure and cutaneous microvascular function in post-menopausal women with hypertension

Hypertension is a leading risk factor for cardiovascular morbidity and mortality and is often accompanied by microvascular dysfunction. Despite a clear effcacy in men, standard antihypertensive medications are less effective in post-menopausal women. Consequently, adjuvant therapies are needed to improve blood pressure control and microvascular function in post-menopausal women. Heat therapy may fill this therapeutic gap as it has been shown to reduce blood pressure and improve microvascular function in healthy and certain clinical populations. Therefore, the purpose of this study was to test the hypothesis that 8 weeks of home-based heat therapy would improve 24-h blood pressure and cutaneous nitric oxide-dependent vasodilation in post-menopausal women with hypertension. Post-menopausal women (69 ± 5 y) with hypertension were randomized to 8 weeks of sham ( N = 15) or heat therapy ( N = 13). Participants immersed their lower legs ~33 cm into a circulated and temperature-controlled (sham: 35 °C; heat therapy: 42 °C) water bath 4 days per week, and 45 min per session. Blood pressure and cutaneous microvascular function and were assessed before (pre) and after (post) the 8-week intervention. Mean arterial blood pressure was measured across 24-h using an ambulatory monitor. To assess microvascular function, an intradermal microdialysis probe was inserted in the anterior aspect of the lower leg at a site directly exposed to water (immersed) and at another site not directly exposed (non-immersed). Red blood cell flux was measured (laser doppler flowmetry) during cutaneous hyperemia induced by 39 °C local heating. N(G)-nitro-L-arginine methyl ester (L-NAME; 20mM) was then infused in each probe until a nadir in red blood cell flux was achieved. Cutaneous vascular conductance was calculated as red blood cell flux divided by mean arterial pressure and normalized to maximal vasodilation (42 °C heating + 56 mM sodium nitroprusside; CVC%max). Nitric oxide-dependent dilation was calculated as the difference between CVC%max measured during the 39 °C plateau and the L-NAME nadir. Mean arterial blood pressure did not differ across time or between groups (sham: pre, 96 ± 5 mmHg vs. post, 96 ± 6 mmHg; heat therapy: pre, 97 ± 4 mmHg vs. 99 ± 7 mmHg; P = 0.5 for interaction). Cutaneous vasodilation induced by local heating did not differ across time for either group (sham: pre, 60 ± 19 CVC%max vs. post, 64 ± 12 CVC%max; heat therapy: pre, 68 ± 15 CVC%max vs. post, 63 ± 13 CVC%max) or between immersed and non-immersed sites ( P = 0.9 for interaction). Similarly, nitric oxide-dependent vasodilation did not differ across time or between sites for either group ( P = 1.0 for interaction). Taken together, 8 weeks of home-based heat therapy does not improve blood pressure or cutaneous microvascular function in post-menopausal women with hypertension. This work was supported by grants from the National Institutes of Health (T32 AG020494; R01AG059314; F32HL167556) and the American Heart Association (TPA958179). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Inhibition of superoxide and iNOS augment cutaneous nitric oxide-dependent vasodilation in non-Hispanic black young adults.

We assessed the combined effect of superoxide and iNOS inhibition on microvascular function in non-Hispanic Black and non-Hispanic White participants (n = 15 per group). Participants were instrumented with four microdialysis fibers: (1) lactated Ringer's (control), (2) 10 μM tempol (superoxide inhibition), (3) 0.1 mM 1400 W (iNOS inhibition), (4) tempol + 1400 W. Cutaneous vasodilation was induced via local heating and NO-dependent vasodilation was quantified. At control sites, NO-dependent vasodilation was lower in non-Hispanic Black (45 ± 9% NO) relative to non-Hispanic White (79 ± 9% NO; p < 0.01; effect size, d = 3.78) participants. Tempol (62 ± 16% NO), 1400 W (78 ± 12% NO) and tempol +1400 W (80 ± 13% NO) increased NO-dependent vasodilation in non-Hispanic Black participants relative to control sites (all p < 0.01; d = 1.22, 3.05, 3.03, respectively). The effect of 1400 W (p = 0.04, d = 1.11) and tempol +1400 W (p = 0.03, d = 1.22) was greater than tempol in non-Hispanic Black participants. There was no difference between non-Hispanic Black and non-Hispanic White participants at 1400 W or tempol + 1400 W sites. These data suggest iNOS has a greater effect on NO-dependent vasodilation than superoxide in non-Hispanic Black participants.

Chronic intermittent hypobaric hypoxia induces cardiovascular dysfunction in a high-altitude working shift model

AimsChronic intermittent hypobaric hypoxia (CIHH) exposure due to shift work occurs mainly in 4 × 4 or 7 × 7 days shifts in mining, astronomy, and customs activities, among other institutions. However, the long-lasting effects of CIHH on cardiovascular structure and function are not well characterized. We aimed to investigate the effects of CIHH on the cardiac and vascular response of adult rats simulating high-altitude (4600 m) x low-altitude (760 m) working shifts. Main methodsWe analyzed in vivo cardiac function through echocardiography, ex vivo vascular reactivity by wire myography, and in vitro cardiac morphology by histology and protein expression and immunolocalization by molecular biology and immunohistochemistry techniques in 12 rats, 6 exposed to CIHH in the hypoxic chamber, and respective normobaric normoxic controls (n = 6). Key findingsCIHH induced cardiac dysfunction with left and right ventricle remodeling, associated with an increased collagen content in the right ventricle. In addition, CIHH increased HIF-1α levels in both ventricles. These changes are associated with decreased antioxidant capacity in cardiac tissue. Conversely, CIHH decreased contractile capacity with a marked decreased in nitric oxide-dependent vasodilation in both, carotid and femoral arteries. SignificanceThese data suggest that CIHH induces cardiac and vascular dysfunction by ventricular remodeling and impaired vascular vasodilator function. Our findings highlight the impact of CIHH in cardiovascular function and the importance of a periodic cardiovascular evaluation in high-altitude workers.

Pravastatin Prevents Increases in Activity of Metalloproteinase-2 and Oxidative Stress, and Enhances Endothelium-Derived Nitric Oxide-Dependent Vasodilation in Gestational Hypertension.

Pre-eclampsia (PE) is a hypertensive disorder of pregnancy and has been associated with placental growth restriction. The pre-eclamptic placenta releases free radicals to maternal circulation, thus increasing oxidative stress. An impaired redox state leads to reduction in circulating nitric oxide (NO) levels and activation of extracellular matrix metalloproteinases (MMPs). However, activation of MMPs induced by oxidative stress is still unclear in PE. Antioxidant effects have been demonstrated with the use of pravastatin. Therefore, we hypothesized that pravastatin protects against oxidative stress-induced activation of MMPs in a rat model of PE. The animals were divided into four groups: normotensive pregnant rats (Norm-Preg); pregnant rats treated with pravastatin (Norm-Preg + Prava); hypertensive pregnant rats (HTN-Preg); and hypertensive pregnant rats treated with pravastatin (HTN-Preg + Prava). The deoxycorticosterone acetate (DOCA) and sodium chloride (DOCA-salt) model was used to induce hypertension in pregnancy. Blood pressure, and fetal and placental parameters were recorded. The gelatinolytic activity of MMPs, NO metabolites and lipid peroxide levels were also determined. Endothelium function was also examined. Pravastatin attenuated maternal hypertension, prevented placental weight loss, increased NO metabolites, inhibited increases in lipid peroxide levels, and reduced the activity of MMP-2, and these effects were observed along with enhanced endothelium-derived NO-dependent vasodilation. The present results provide evidence that pravastatin protects against activation of MMP-2 induced by oxidative stress in pre-eclamptic rats. These findings may also involve improvement in endothelial function related to NO and antihypertensive effects of pravastatin, thus suggesting pravastatin as a therapeutic intervention for PE.

Endothelin A receptor inhibition increases nitric oxide-dependent vasodilation independent of superoxide in non-Hispanic Black young adults.

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 means ± 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 contributes 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.NEW & NOTEWORTHY Endothelin-1 A receptors (ETARs) have been shown to reduce endothelial function independently and through increased production of superoxide. We show that independent ETAR inhibition increases microvascular endothelial function in non-Hispanic Black young adults. However, administration of a superoxide dismutase mimetic alone and in combination with ETAR inhibition had no effect on microvascular endothelial function suggesting that, in the cutaneous microvasculature, the negative effects of ETAR in non-Hispanic Black young adults are independent of superoxide production.

Cerebral Microcirculation and Oxygenation Modulation by Transcranial Alternating Current Stimulation in Awake and Anesthetized Mice.

Transcranial alternating current stimulation (tACS) is a novel non-invasive electrical stimulation technique where a sinusoidal oscillating low-voltage electric current is applied to the brain. TACS is being actively investigated in practice for cognition and behavior modulation and for treating brain disorders. However, the physiological mechanisms of tACS are underinvestigated and poorly understood. Previously, we have shown that transcranial direct current stimulation (tDCS) facilitates cerebral microcirculation and oxygen supply in a mouse brain through nitric oxide-dependent vasodilatation of arterioles. Considering that the effects of tACS and tDCS might be both similar and dissimilar, we tested the effects of tACS on regional cerebral blood flow and oxygen saturation in anesthetized and awake mice using laser speckle contrast imaging and multispectral intrinsic optical signal imaging. The anesthetized mice were imaged under isoflurane anesthesia ∼1.0% in 30% O2 and 70% N2O. The awake mice were pre-trained on the rotating ball for awake imaging. Baseline imaging with further tACS was followed by post-stimulation imaging for ~3h. Differences between groups were determined using a two-way ANOVA analysis for multiple comparisons and post hoc testing using the Mann-Whitney U test. TACS increased cerebral blood flow and oxygen saturation. In awake mice, rCBF and oxygen saturation responses were more robust and prolonged as opposed to anesthetized, where the response was weaker and shorter with overshoot. The significant difference between anesthetized and awake mice emphasizes the importance of the experiments on the latter as anesthesia is not typical for human stimulation and significantly alters the results.

In Vivo Characterization of a Red Light-Activated Vasodilation: A Photobiomodulation Study.

Nitric oxide dependent vasodilation is an effective mechanism for restoring blood flow to ischemic tissues. Previously, we established an ex vivo murine model whereby red light (670 nm) facilitates vasodilation via an endothelium derived vasoactive species which contains a functional group that can be reduced to nitric oxide. In the present study we investigated this vasodilator in vivo by measuring blood flow with Laser Doppler Perfusion imaging in mice. The vasodilatory nitric oxide precursor was analyzed in plasma and muscle with triiodide-dependent chemiluminescence. First, a 5–10 min irradiation of a 3 cm2 area in the hind limb at 670 nm (50 mW/cm2) produced optimal vasodilation. The nitric oxide precursor in the irradiated quadriceps tissue decreased significantly from 123 ± 18 pmol/g tissue by both intensity and duration of light treatment to an average of 90 ± 17 pmol/g tissue, while stayed steady (137 ± 21 pmol/g tissue) in unexposed control hindlimb. Second, the blood flow remained elevated 30 min after termination of the light exposure. The nitric oxide precursor content significantly increased by 50% by irradiation then depleted in plasma, while remained stable in the hindlimb muscle. Third, to mimic human peripheral artery disease, an ameroid constrictor was inserted on the proximal femoral artery of mice and caused a significant reduction of flow. Repeated light treatment for 14 days achieved steady and significant increase of perfusion in the constricted limb. Our results strongly support 670 nm light can regulate dilation of conduit vessel by releasing a vasoactive nitric oxide precursor species and may offer a simple home-based therapy in the future to individuals with impaired blood flow in the leg.

Systemic administration of choline acetyltransferase decreases blood pressure in murine hypertension

Acetylcholine (ACh) decreases blood pressure by stimulating endothelium nitric oxide-dependent vasodilation in resistance arterioles. Normal plasma contains choline acetyltransferase (ChAT) and its biosynthetic product ACh at appreciable concentrations to potentially act upon the endothelium to affect blood pressure. Recently we discovered a T-cell subset expressing ChAT (TChAT), whereby genetic ablation of ChAT in these cells produces hypertension, indicating that production of ACh by TChAT regulates blood pressure. Accordingly, we reasoned that increasing systemic ChAT concentrations might induce vasodilation and reduce blood pressure. To evaluate this possibility, recombinant ChAT was administered intraperitoneally to mice having angiotensin II-induced hypertension. This intervention significantly and dose-dependently decreased mean arterial pressure. ChAT-mediated attenuation of blood pressure was reversed by administration of the nitric oxide synthesis blocker l-nitro arginine methyl ester, indicating ChAT administration decreases blood pressure by stimulating nitic oxide dependent vasodilation, consistent with an effect of ACh on the endothelium. To prolong the half life of circulating ChAT, the molecule was modified by covalently attaching repeating units of polyethylene glycol (PEG), resulting in enzymatically active PEG-ChAT. Administration of PEG-ChAT to hypertensive mice decreased mean arterial pressure with a longer response duration when compared to ChAT. Together these findings suggest further studies are warranted on the role of ChAT in hypertension.

Diabetes and COVID-19: Role of insulin resistance as a risk factor for COVID-19 severity.

Patients with diabetes are more susceptible to coronavirus disease 2019 (COVID-19), and as a consequence, develop more severe form of disease. This is partly due to a systemic inflammatory state and pro thrombotic milieu seen in metabolic syndrome. In this review, we attempt to explore the pathogenetic links between insulin resistance and COVID-19 disease severity. Insulin resistance is an underlying condition for metabolic syndromes, including type 2 diabetes, which impairs insulin signaling pathways affecting metabolic and cardiovascular homeostasis. A high concentration of circulating insulin shifts the balance to mitogen activated protein kinase (MAPK)-dependent signaling and causes endothelial cell damage. The phosphatidylinositol 3 kinase and MAPK dependent signaling pathways maintain a balance between nitric oxide-dependent vasodilator and endothelin-1 dependent vasoconstriction actions of insulin. Vascular smooth muscle cell dysfunction is responsible for inflammation and blood coagulation leading to microvascular and macrovascular complications in diabetes. Hyperactivity in renin-angiotensin system is implicated in development of islet oxidative stress and subsequent β-cell dysfunction, as it alters the islet blood flow. These deleterious effects of insulin resistance involving altered blood pressure, vascular dysfunction, and inflammation could be associated with increased severity in COVID-19 patients. We conclude that clinical and/or biochemical markers of insulin resistance should be included as prognostic markers in assessment of acute COVID-19 disease.

Localized Delivery of Caveolin-1 Peptide Assisted by Ultrasound-Mediated Microbubble Destruction Potentiates the Inhibition of Nitric Oxide-Dependent Vasodilation Response

In the endothelium, nitric oxide synthase (eNOS) is the enzyme that generates nitric oxide, a key molecule involved in a variety of biological functions and cancer-related events. Therefore, selective inhibition of eNOS represents an attractive therapeutic approach for NO-related diseases and anticancer therapy. Ultrasound-mediated microbubble destruction (UMMD) conjugated with cell-permeable peptides has been investigated as a drug delivery system for effective delivery of anticancer molecules. We investigated the feasibility of loading antennapedia-caveolin-1 peptide (AP-Cav), a specific eNOS inhibitor, onto microbubbles to be delivered by UMMD in rat aortic endothelium. AP-Cav-loaded microbubbles (AP-Cav-MBs) and US parameters were characterized. Aortas were treated with UMMD for 30 s with 1.3 × 108 MBs/mL AP-Cav (8 μM)-MBs at 100-Hz pulse repetition frequency, 0.5-MPa acoustic pressure, 0.5 mechanical index and 10% duty cycle. NO-dependent vascular responses were assessed using an isolated organ system, 21 h post-treatment. Maximal relaxation response was inhibited 61.8% ± 1.6% in aortas treated with UMMD-AP-Cav-MBs, while in aortas treated with previously disrupted AP-Cav-MBs and then US, the inhibition was 31.6% ± 1.6%. The vascular contractile response was not affected. The impact of UMMD was evaluated in aortas treated with free AP-Cav; 30 μM of free AP-Cav was necessary to reach an inhibition response similar to that obtained with UMMD-AP-Cav-MBs. In conclusion, UMMD enhances the delivery and potentiates the effect of AP-Cav in the endothelial layer of rat aorta segments.

Nitric oxide-dependent vasodilation induced by minoxidil in isolated rat aorta.

We examined the effect of endothelium and lipid emulsion on vasodilation induced by minoxidil at a toxic dose and determined the underlying mechanism. The effects of endothelial denudation, NW-nitro-L-arginine methyl ester (L-NAME), methylene blue, 1H-[1,2,4]oxadiazolo[4,3-a] quinoxalin-1-one (ODQ), and glibenclamide, alone or in combination, on minoxidil-induced vasodilation in endothelium-intact rat aorta were examined. Additionally, the effects of lipid emulsion on minoxidil-induced membrane hyperpolarization and minoxidil concentration were examined. The vasodilatory effects of minoxidil at the toxic dose were higher in endothelium-intact aorta than in endothelium-denuded aorta. L-NAME, methylene blue, ODQ, and glibenclamide attenuated minoxidil-induced vasodilation of endothelium-intact rat aorta. Combined treatment with L-NAME and glibenclamide almost eliminated minoxidil-induced vasodilation. However, lipid emulsion pretreatment did not significantly alter minoxidil-induced vasodilation. Lipid emulsion did not significantly alter minoxidil-induced membrane hyperpolarization and minoxidil concentration. Overall, minoxidil-induced vasodilation is mediated by ATP-sensitive potassium channels and pathways involving nitric oxide and guanylate cyclase.

Disrupted eNOS activity and expression account for vasodilator dysfunction in different stage of sepsis

AimsSepsis is a severe endothelial dysfunction syndrome. The role of endothelial nitric oxide synthase (eNOS) in endothelial dysfunction induced by sepsis is controversial. To explore the role of eNOS in vascular dysfunction. Main methodsThe effect of sepsis on vasodilation and eNOS levels was examined in septic mouse arteries and in cell models. Key findingsIn early sepsis mouse arteries, endothelium-dependent relaxation decreased and phosphorylation of the inhibitory Thr495 site in endothelial nitric oxide synthase increased. Mechanically, the phosphorylation of endothelial nitric oxide synthase at Thr497 in bovine aortic endothelial cells occurred in a protein kinase C-α dependent manner. In late sepsis, both nitric oxide-dependent relaxation responses and endothelial nitric oxide synthase levels were decreased in septic mice arteries. Endothelial nitric oxide synthase levels expression levels decreased in tumor necrosis factor-α-treated human umbilical vein endothelial cells and this could be prevented by the ubiquitin proteasome inhibitor (MG-132). MG-132 could reverse the decrease in endothelial nitric oxide synthase expression and improve nitric oxide-dependent vasodilator dysfunction in septic mice arteries. SignificanceThese data indicate that vasodilator dysfunction is induced by the increased phosphorylation of endothelial nitric oxide synthase in early sepsis and its degradation in late sepsis.

Metabolism of asymmetric dimethylarginine in hypoxia: from bench to bedside.

Acute hypoxia and chronic hypoxia induce pulmonary vasoconstriction. While hypoxic pulmonary vasoconstriction is a physiological response if parts of the lung are affected, global exposure to hypoxic conditions may lead to clinical conditions like high-altitude pulmonary hypertension. Nitric oxide is the major vasodilator released from the vascular endothelium. Nitric oxide-dependent vasodilation is impaired in hypoxic conditions. Inhibition of nitric oxide synthesis is the most rapid and easily reversible molecular mechanism to regulate nitric oxide-dependent vascular function in response to physiological and pathophysiological stimuli. Asymmetric dimethylarginine is an endogenous, competitive inhibitor of nitric oxide synthase and a risk marker for major cardiovascular events and mortality. Elevated asymmetric dimethylarginine has been observed in animal models of hypoxia as well as in human cohorts under chronic and chronic intermittent hypoxia at high altitude. In lowlanders, asymmetric dimethylarginine is high in patients with pulmonary hypertension. We have recently shown that high asymmetric dimethylarginine at sea level is a predictor for high-altitude pulmonary hypertension. Asymmetric dimethylarginine is a highly regulated molecule, both by its biosynthesis and metabolism. Methylation of L-arginine by protein arginine methyltransferases was shown to be increased in hypoxia. Furthermore, the metabolism of asymmetric dimethylarginine by dimethylarginine dimethylaminohydrolases (DDAH1 and DDAH2) is decreased in animal models of hypoxia. Whether these changes are caused by transcriptional or posttranslational modifications remains to be elucidated. Current data suggest a major role of asymmetric dimethylarginine in regulating pulmonary arterial nitric oxide production in hypoxia. Further studies are needed to decipher the molecular mechanisms regulating asymmetric dimethylarginine in hypoxia and to understand their clinical significance.

Loss of smooth muscle CYB5R3 amplifies angiotensin II-induced hypertension by increasing sGC heme oxidation.

Nitric oxide regulates BP by binding the reduced heme iron (Fe2+) in soluble guanylyl cyclase (sGC) and relaxing vascular smooth muscle cells (SMCs). We previously showed that sGC heme iron reduction (Fe3+ → Fe2+) is modulated by cytochrome b5 reductase 3 (CYB5R3). However, the in vivo role of SMC CYB5R3 in BP regulation remains elusive. Here, we generated conditional smooth muscle cell-specific Cyb5r3 KO mice (SMC CYB5R3-KO) to test if SMC CYB5R3 loss affects systemic BP in normotension and hypertension via regulation of the sGC redox state. SMC CYB5R3-KO mice exhibited a 5.84-mmHg increase in BP and impaired acetylcholine-induced vasodilation in mesenteric arteries compared with controls. To drive sGC oxidation and elevate BP, we infused mice with angiotensin II. We found that SMC CYB5R3-KO mice exhibited a 14.75-mmHg BP increase, and mesenteric arteries had diminished nitric oxide-dependent vasodilation but increased responsiveness to sGC heme-independent activator BAY 58-2667 over controls. Furthermore, acute injection of BAY 58-2667 in angiotensin II-treated SMC CYB5R3-KO mice showed greater BP reduction compared with controls. Together, these data provide the first in vivo evidence to our knowledge that SMC CYB5R3 is an sGC heme reductase in resistance arteries and provides resilience against systemic hypertension development.

Estimation of the Microcirculatory Response to the Effect of Cold Helium Plasma

Abstract—This study was aimed at estimating the microcirculatory response to local application of cold helium plasma. Experiments were performed with 20 healthy male Wistar rats, which were divided into two groups of 10 rats each. Rats of one (control) group (n = 10) were tested once for microcirculatory indices. Rats of the other (test) group (n = 10) were treated daily with cold helium plasma for 5 days. Plasma was applied to the surface of the skin on the back; the duration of the exposure was 1 min. Cold helium plasma was generated with a special device, which was designed and constructed at the Institute of Applied Physics (Nizhny Novgorod, Russia) and utilized microwave-induced ionization of gas flow. Microcirculation was tested by laser Doppler flowmetry, using an LAKK-M device (Moscow, Russia). A short course (five daily procedures) of cold helium plasma treatment moderately decreased the intensity of blood flow through small vessels. The effect was associated with nitric oxide-dependent vasodilation and optimization of the role that bypass mechanisms play in microcirculation. Cold helium plasma treatment was assumed to exert a proadaptive hemodynamic effect.

The effect of acute cocoa flavanol intake on the BOLD response and cognitive function in type 1 diabetes: a randomized, placebo-controlled, double-blinded cross-over pilot study

Type 1 diabetes (T1D), a chronic autoimmune disease, can result in cognitive dysfunction and is associated with vascular dysfunction. Cocoa flavanols (CFs) can stimulate nitric oxide-dependent vasodilation, resulting in enhanced hemodynamic responses and better cognitive function. To investigate whether acute CF supplementation can improve cognitive function and hemodynamic responses in T1D. In this randomized, double-blinded, cross-over pilot study, 11 patients with T1D and their healthy matched controls consumed CF (900mg CF) and placebo (15mg CF) 2h before a flanker test. fMRI was used to measure blood oxygen level-dependent (BOLD) response during the cognitive test. Repeated measure ANOVAs were used to test the effects of CF and T1D on BOLD response and cognitive performance. CF improved reaction time on the flanker test and increased the BOLD response in the supramarginal gyrus parietal lobe and inferior frontal gyrus, compared to placebo, in both groups. In patients with T1D, cognitive performance was not deteriorated while the BOLD response was smaller in T1D compared to healthy controls in the subgyral temporal lobe and the cerebellum. Acute CF intake improved reaction time on the flanker test and increased the BOLD response in the activated brain areas in patients with T1D and their matched controls.

Inclusion of Dairy Cheese In An 8‐day Controlled Dietary Intervention Prevents Sodium‐Induced Endothelial Dysfunction in the Cutaneous Microcirculation of Healthy Older Adults

Excess dietary sodium is associated with impaired vascular function and increased cardiovascular mortality. In controlled feeding studies, the inclusion of 3 daily servings of any dairy product improves blood pressure and measures of vascular health. Few studies have examined the inclusion of individual dairy products that contain both the beneficial bioactive dairy proteins and sodium. We recently demonstrated that single‐meal cheese consumption ameliorates acute sodium‐induced impairments in nitric oxide‐dependent vasodilation. However, controlled feeding studies examining the vasoprotective role of dairy cheese on sodium‐induced microvascular dysfunction are lacking. We hypothesized that (1) endothelium‐dependent vasodilation would be impaired by a high‐sodium diet compared to a low sodium diet, and (2) that a high‐cheese diet would preserve endothelium‐dependent vasodilation that is otherwise impaired by a high‐sodium diet. In a randomized, crossover study design, seven healthy older adults (63 ± 3 years; salt‐resistant: &lt;10 mmHg increase in mean arterial pressure, 24 hour monitoring) with normal to elevated blood pressure completed 4 separate 8‐day controlled dietary interventions: 1) low‐sodium (LNa: 1500 mg sodium) diet devoid of dairy products, 2) low‐sodium high‐cheese diet (LNaC: 1500 mg sodium, 6 oz/d cheese), 3) high‐sodium (HNa: 5500 mg sodium) diet devoid of dairy products, and 4) high‐sodium high‐cheese diet (HNaC: 5500 mg sodium, 6 oz/d cheese). At the end of each dietary intervention, subjects participated in an intradermal microdialysis protocol in which one microdialysis fiber was inserted into the forearm skin for measurement of red cell flux (laser Doppler flowmetry) during local infusion of the endothelium‐dependent agonist acetylcholine (Ach; 10−12 to 10−1 M). Data were expressed as a percentage of maximum cutaneous vascular conductance (%CVCmax; 28 mM sodium nitroprusside, 43°C). Ach‐induced vasodilation was significantly attenuated during the HNa diet compared to the LNa diet (LNa: −5.06±0.20 M vs HNa: −3.22±0.63 M logEC50: p &lt; 0.05). Conversely, Ach‐induced dilation during either the LNaC or HNaC diet was not different from the LNa diet (p &gt; 0.05). These results demonstrate that increased dietary sodium intake impairs endothelium‐dependent dilation whereas the inclusion of cheese prevents sodium‐induced endothelial dysfunction in salt‐insensitive older adults.Support or Funding InformationSupported by National Dairy CouncilThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Five Nights of Sleep Restriction Attenuates Microvascular Endothelial Function

Adequate sleep is requisite for optimal physiological function, including microvascular endothelial function. Short‐term sleep restriction (5 hours/night) negatively alters glucose metabolism and may also impair microvascular endothelial function via increased sympathetic nervous system activity and inflammatory pathways. The cutaneous microvasculature represents an accessible, well‐described vascular bed to non‐invasively assess the effects of sleep restriction on microvascular function. Our objective was to evaluate cutaneous microvascular endothelial function during baseline sleep replete conditions (10 hours/night time in bed), after 5 nights of sleep restriction (5 hours/night), and again after 2 nights of recovery sleep repletion. This was part of the Sleep Restriction Study (PI: Chang), an 11‐day inpatient study that took place in the Penn State University Clinical Research Center, during which diet and physical activity were controlled. Eight young, healthy men (23.3 ± 3.4 years) participated in the study. Cutaneous microvascular function was measured utilizing a standardized local skin heating protocol to induce endothelial nitric oxide‐synthase‐dependent vasodilation during all three study phases (baseline, sleep restricted, recovery). Red cell flux (laser Doppler flowmetry) was continuously measured on the ventral forearm at thermoneutral temperature (33 °C) and throughout local heating 0.5°C·5 s−1 to 42 °C until a stable (20 min) plateau had been reached. Red cell flux was normalized to cutaneous vascular conductance (CVC: flux·MAP−1) and expressed as a percentage of maximum CVC (43°C: %CVCmax). Compared to the baseline sleep replete state, the response to local heating was attenuated by 10% after 5 nights of sleep restriction (baseline: 89.2 ± 2.0, restricted: 80.4 ± 3.0 %CVCmax; p=0.045) and fully recovered after 2 nights of recovery sleep (88.7 ± 1.8 %CVCmax; p=0.99 compared to baseline). Maximum CVC was not affected by sleep restriction (all p&gt;0.05). These results suggest that 5 nights of sleep restriction impairs microvascular endothelial function, likely through attenuated nitric oxide‐dependent vasodilation, but that 2 nights of recovery sleep restores microvascular endothelial function in young, healthy men.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Endothelial function is impaired in the cutaneous microcirculation of adults with psoriasis through reductions in nitric oxide-dependent vasodilation.

Psoriasis is an independent risk factor for cardiovascular disease; however, the underlying mechanisms are not fully understood. Deficits in conduit arterial function are evident in patients with psoriasis, but potential impairments in microcirculatory endothelial function remain unclear. We hypothesized that cutaneous microvascular dysfunction would be detectable in otherwise healthy individuals with psoriasis. Two intradermal microdialysis fibers were placed in (nonlesional) forearm skin of nine patients (3 men and 6 women, 39 ± 5 yr) with moderate (16 ± 2% of body surface area) plaque psoriasis and nine healthy (nonpsoriatic) control subjects (3 men and 6 women, 38 ± 5 yr) for local delivery of 1) lactated Ringer solution (control) and 2) 10 mM l-ascorbate (a nonspecific antioxidant). An index of skin blood flow was measured using laser-Doppler flowmetry during local heating (42°C). Nitric oxide (NO)-dependent vasodilation was directly quantified after perfusion of the nonspecific NO synthase inhibitor NG-nitro-l-arginine methyl ester (15 mM). A third fiber was perfused with increasing concentrations (10-10 - 10-2 M) of norepinephrine to elicit adrenoreceptor-mediated cutaneous vasoconstriction. NO-dependent vasodilation was attenuated in patients with psoriasis (57 ± 5% and 39 ± 7% maximum cutaneous vascular conductance in control subjects and adults with psoriasis, respectively, P < 0.01). l-Ascorbate did not improve NO-dependent vasodilation ( P > 0.05). There was no group difference in maximal vasoconstriction or microvascular sensitivity to norepinephrine ( P > 0.05). These data suggest that NO bioavailability is reduced in otherwise healthy individuals with psoriasis, which contributes to systemic microvascular dysfunction. NEW & NOTEWORTHY In adults with psoriasis, reduced nitric oxide bioavailability mediates impaired endothelium-dependent vasodilation, independent of increases in oxidative stress. Furthermore, the degree of psoriatic symptomology is directly related to greater reductions in nitric oxide-dependent vasodilation.

Renal and femoral venous blood flows are regulated by different mechanisms dependent on α-adrenergic receptor subtypes and nitric oxide in anesthetized rats

Venous and arterial walls are responsive to sympathetic system and circulating substances, nevertheless, very few is known about the venous blood flow regulation simultaneously to arterial vascular beds. In this study, we compared the venous and arterial blood flow regulation in visceral and muscular beds upon injection of different doses of vasoactive drugs which act in arterial vascular beds. Anesthetized adult male Wistar rats underwent to right femoral artery and vein cannulation for hemodynamic recordings and infusion of drugs. Doppler flow probes were placed around the left renal artery and vein, and left femoral artery and vein to evaluate the changes in flood flow. Phenylephrine (PHE) injection (α1-adrenergic receptor agonist) elicited vasoconstriction in all arteries and veins. Intravenous prazosin (PZS) (1mg/kg, α1-adrenergic receptor blocker) caused renal artery vasodilation, but not in the other beds. Vasoconstrictor effect of PHE was abolished by PZS in all vascular beds, except in femoral vein. Phentolamine (PTL) injection (1mg/kg, α1/α2-adrenergic receptor blocker) produced renal artery vasodilation with no change in other beds. After PTL, the vasoconstriction evoked by PHE was abolished in all vascular beds. Sodium Nitroprusside (SNP), a nitric oxide donor, elicited vasodilation in all beds, and after PTL but not post PZS injection, SNP enhanced the vasodilatory effect in femoral vein. Our findings suggest that the vasoconstriction in renal and femoral veins is mediated by different subtypes of α-adrenoceptors. The nitric oxide-dependent vasodilation in femoral vein enhances when α2-adrenoceptors are not under stimulation, but not in the other vascular beds investigated.