Nitric oxide-mediated cutaneous microvascular function is not altered in middle-aged-to-older adults following mild SARS-CoV-2 infection: A pilot study.

We tested the hypothesis that post-COVID-19 adults (PC) would have impaired cutaneous nitric oxide (NO)-mediated vasodilation compared to controls (CON). We performed a cross-sectional study including 10 (10 F/0 M, 69 ± 7 years) CON and 7 (2 F/5 M, 66 ± 8 years) PC (223 ± 154 days post-diagnosis). COVID-19 symptoms severity (survey) was assessed (0-100 scale for 18 common symptoms). NO-dependent cutaneous vasodilation was induced by a standardized 42°C local heating protocol and quantified via perfusion of 15 mM NG-nitro-L-arginine methyl ester during the plateau of the heating response (intradermal microdialysis). Red blood cell flux was measured with laser-Doppler flowmetry. Cutaneous vascular conductance (CVC = flux/mm Hg) was presented as a percentage of maximum (28 mM sodium nitroprusside +43°C). All data are means ± SD. The local heating plateau (CON: 71 ± 23% CVCmax vs. PC: 81 ± 16% CVCmax , p = 0.77) and NO-dependent vasodilation (CON: 56 ± 23% vs. PC: 60 ± 22%, p = 0.77) were not different between groups. In the PC group neither time since diagnosis nor peak symptom severity (46 ± 18 AU) correlated with NO-dependent vasodilation (r < 0.01, p = 0.99 and r = 0.42, p = 0.35, respectively). In conclusion, middle-aged and older adults who have had COVID-19 did not have impaired NO-dependent cutaneous vasodilation. Additionally, in this cohort of PC, neither time since diagnosis nor symptomology were related to microvascular function.

Seven days of statin treatment improves nitric-oxide mediated endothelial-dependent cutaneous microvascular function in women with endometriosis.

INTRODUCTION: Endometriosis is associated with systemic inflammation and increased risk of cardiovascular disease (CVD). Endothelial dysfunction is one of the first manifestations of CVD but is unexplored in women with endometriosis. HMG-CoA-reductase inhibitors (statins) exert potent anti-inflammatory effects, and have been proposed as an adjunctive therapy in women with endometriosis. We hypothesized that microvascular endothelial function would be impaired in otherwise healthy women with endometriosis mediated by reduced nitric oxide (NO)-dependent dilation and that short term statin administration would improve endothelial function. METHODS: In 8 healthy control (HC: 33 ± 9 yr) and 8 women with endometriosis (EN: 34 ± 9 yr), laser-Doppler flux (LDF) was measured continuously during graded intradermal microdialysis perfusion of the endothelium-dependent agonist acetylcholine (Ach: 10-10-10-1 M) alone and in combination with the NO synthase inhibitor (L-NAME: 0.015 M). 6 EN repeated the microdialysis experiment following 7 days of oral atorvastatin treatment (10 mg). Cutaneous vascular conductance was calculated (CVC = LDF*mmHg-1) and normalized to site-specific maximum (28 mM sodium nitroprusside, 43 °C). The NO-dependent dilation was calculated as the difference between the areas under the dose response curves. RESULTS: Ach-induced vasodilation was blunted in women with endometriosis (main effect p < 0.01), indicating impaired endothelial function. NO-dependent vasodilation was also reduced in women with endometriosis (HC: 217 ± 120.3 AUC vs. EN: 88 ± 97 AUC, p = 0.03). Oral atorvastatin improved Ach-induced (main effect p < 0.01) and NO-dependent (295 ± 153 AUC; p = 0.05) vasodilation in women with endometriosis. CONCLUSION: Microcirculatory endothelium-dependent vasodilation is impaired in women with endometriosis, mediated in part by reductions in NO. Short-term oral atorvastatin improved endothelium-dependent vasodilation, suggesting that statin therapy may be a viable intervention strategy to mitigate accelerated CVD risk in women with endometriosis.

Skin pigmentation is negatively associated with circulating vitamin D concentration and cutaneous microvascular endothelial function.

Darkly pigmented individuals are at the greatest risk of hypovitaminosis D, which may result in microvascular endothelial dysfunction via reduced nitric oxide (NO) bioavailability and/or increased oxidative stress and inflammation. We investigated the associations among skin pigmentation (M-index; skin reflectance spectrophotometry), serum vitamin D concentration [25(OH)D], circulating inflammatory cytokine (TNF-α, IL-6, and IL-10) concentrations, and the NO contribution to local heating-induced cutaneous vasodilation (%NO-mediated vasodilation) in a diversely pigmented cohort of young adults. An intradermal microdialysis fiber was placed in the forearms of 33 healthy adults (14 men/19 women; 18-27 yr; M-index, 30-81 AU) for local delivery of pharmacological agents. Lactated Ringer's solution was perfused through the fiber during local heating-induced (39°C) cutaneous vasodilation. After attaining stable elevated blood flow, 15 mM NG-nitro-l-arginine methyl ester (l-NAME; NO synthase inhibiter) was infused to quantify %NO-mediated vasodilation. Red cell flux was measured (laser-Doppler flowmetry; LDF) and cutaneous vascular conductance (CVC = LDF/MAP) was normalized to maximal (%CVCmax; 28 mM sodium nitroprusside + 43°C). Serum [25(OH)D] and circulating cytokines were analyzed by ELISA and multiplex assay, respectively. M-index was negatively associated with [25(OH)D] (r = -0.57, P < 0.0001) and %NO-mediated vasodilation (r = -0.42, P = 0.02). Serum[25(OH)D] was positively related to %NO (r = 0.41, P = 0.02). Controlling for [25(OH)D] weakened the association between M-index and %NO-mediated dilation (P = 0.16, r = -0.26). There was a negative curvilinear relation between [25(OH)D] and circulating IL-6 (r = -0.56, P < 0.001), but not TNF-α or IL-10 (P ≥ 0.14). IL-6 was not associated with %NO-mediated vasodilation (P = 0.44). These data suggest that vitamin D insufficiency/deficiency may contribute to reduced microvascular endothelial function in healthy, darkly pigmented young adults.NEW & NOTEWORTHY Endothelial dysfunction, an antecedent to hypertension and overt CVD, is commonly observed in otherwise healthy Black adults, although the underlying causes remain unclear. We show that reduced vitamin D availability with increasing degrees of skin pigmentation is associated with reduced microvascular endothelial function, independent of race or ethnicity, in healthy young adults. Greater prevalence of vitamin D deficiency in more darkly pigmented individuals may predispose them to increased risk of endothelial dysfunction.

Nitric oxide-mediated cutaneous microvascular function is not altered in young adults following mild-to-moderate SARS CoV-2 infection.

Vascular dysfunction has been reported in adults who have recovered from COVID-19. To date, no studies have investigated the underlying mechanisms of persistent COVID-19-associated vascular dysfunction. Our purpose was to quantify nitric oxide (NO)-mediated vasodilation in healthy adults who have recovered from SARS-CoV-2 infection. We hypothesized that COVID-19-recovered adults would have impaired NO-mediated vasodilation compared with adults who have not had COVID-19. In methods, we performed a cross-sectional study including 10 (5 men/5 women, 24 ± 4 yr) healthy control (HC) adults who were unvaccinated for COVID-19, 11 (4 men/7 women, 25 ± 6 yr) healthy vaccinated (HV) adults, and 12 (5 men/7 women, 22 ± 3 yr) post-COVID-19 (PC, 19 ± 14 wk) adults. COVID-19 symptoms severity (survey) was assessed. A standardized 39°C local heating protocol was used to assess NO-dependent vasodilation via perfusion (intradermal microdialysis) of 15 mM NG-nitro-l-arginine methyl ester during the plateau of the heating response. Red blood cell flux was measured (laser-Doppler flowmetry) and cutaneous vascular conductance (CVC = flux/mmHg) was expressed as a percentage of maximum (28 mM sodium nitroprusside + 43°C). In results, the local heating plateau (HC: 61 ± 20%, HV: 60 ± 19%, PC: 67 ± 19%, P = 0.80) and NO-dependent vasodilation (HC: 77 ± 9%, HV: 71 ± 7%, PC: 70 ± 10%, P = 0.36) were not different among groups. Neither symptom severity (25 ± 12 AU) nor time since diagnosis correlated with the NO-dependent vasodilation (r = 0.46, P = 0.13; r = 0.41, P = 0.19, respectively). In conclusion, healthy adults who have had mild-to-moderate COVID-19 do not have altered NO-mediated cutaneous microvascular function.NEW & NOTEWORTHY Healthy young adults who have had mild-to-moderate COVID-19 do not display alterations in nitric oxide-mediated cutaneous microvascular function. In addition, healthy young adults who have COVID-19 antibodies from the COVID-19 vaccinations do not display alterations in nitric oxide-mediated cutaneous microvascular function.

Acute systemic inhibition of inflammation augments endothelium-dependent dilation in women with a history of preeclamptic pregnancy.

Women who have had preeclampsia demonstrate microvascular endothelial-dysfunction, mediated in part by reduced nitric oxide (NO)-dependent dilation. Preeclamptic pregnancies are associated with elevated inflammation, and inhibition of inflammation attenuates endothelial damage in animal models of preeclampsia. However, it is unclear if inhibition of vascular inflammation improves endothelial function in women after a preeclamptic pregnancy. Using the cutaneous microcirculation as a model, we hypothesized that acute systemic inhibition of vascular inflammation (oral salsalate; 1500 mg/twice daily, 4 days) would improve endothelium- and NO-dependent vasodilation in women with a history of preeclampsia (PE) but not in women with a history of uncomplicated pregnancy (HC). Twelve HC (30 ± 1yrs, 10 ± 2 months postpartum) and 10 PE (30 ± 2yrs, 8 ± 2 months postpartum) participated in a double-blind placebo-controlled study. Following each treatment, 2 intradermal microdialysis fibers were placed in the skin of the ventral forearm for graded infusion of acetylcholine (Ach, 10-7-102mM) or Ach + 15 mM L-NAME (NO synthase antagonist). Red blood cell flux was measured over each site by laser-Doppler flowmetry (LDF). Cutaneous vascular conductance was calculated (CVC = LDF/mean arterial pressure) and normalized to maximum (%CVCmax; 28 mM SNP + local heat 43 °C). ACh-induced (77 ± 3 vs. 92 ± 3%CVCmax; p = 0.01) and NO-dependent (20 ± 6 vs. 33 ± 4%; p = 0.02) vasodilation were attenuated in PE compared to HC. Salsalate augmented ACh-induced (95 ± 2%CVCmax; p = 0.002) and NO-dependent (39 ± 3%; p = 0.009) dilation in PE compared to placebo but had no effect in HC (all p > 0.05). Salsalate treatment augmented endothelium-dependent vasodilation via NO-mediated pathways in women who have had preeclampsia, suggesting that inflammatory signaling mediates persistent endothelial dysfunction following preeclampsia.

Menthol-induced activation of TRPM8 receptors increases cutaneous blood flow across the dermatome.

Topical menthol-based analgesics increase skin blood flow (SkBF) through transient receptor potential melastatin 8 (TRPM8) receptor-dependent activation of sensory nerves and endothelium-derived hyperpolarization factors. It is unclear if menthol-induced TRPM8 activation mediates a reflex change in SkBF across the dermatome in an area not directly treated with menthol. The purpose of this study was to determine the effects of localized topical menthol application on SkBF across a common dermatome. We hypothesized that SkBF would be increased with menthol at the site of application and across the dermatome (contralateral limb) through a spinal reflex mechanism. In a double blind, placebo controlled, cross-over design, 15 healthy participants (7 men; age = 22 ± 1 yrs) were treated with direct application (3 ml over 8 × 13 cm) of 5% menthol gel (Biofreeze™) or placebo gel on the L4 dermatome, separated by 48 h. Red blood cell flux was measured using laser Doppler flowmetry over the area of application, on the contralateral leg of the same dermatome, and in a separate dermatome (L5/S1) to serve as control. Cutaneous vascular conductance was calculated for each measurement site (CVC = flux/MAP). At baseline there were no differences in CVC between menthol and placebo gels, or among sites (all p > 0.05). After 30 ± 6 min, CVC increased at the treated site with menthol (0.12 ± 0.02 vs. 1.36 ± 0.19 flux/mm Hg, p < 0.01) but not the placebo (0.10 ± 0.01 vs. 0.18 ± 0.04 flux/mm Hg, p = 0.91). There was a modest increase in CVC at the contralateral L4 dermatome with menthol gel (0.16 ± 0.04 vs. 0.29 ± 0.06 flux/mm Hg, p < 0.01), but not placebo (0.11 ± 0.02 vs. 0.15 ± 0.03 flux/mm Hg, p = 0.41). There was no effect on SkBF from either treatments at the L5/S1 control dermatome (both, p > 0.05), suggesting the lack of a systemic response. In conclusion, menthol containing topical analgesic gels increased SkBF at the treated site, and modestly throughout the dermatome. These data suggest menthol-induced activation of the TRPM8 receptors induces an increase in SkBF across the area of common innervation through a localized spinal reflex mechanism.

Vascular Health Triad in Humans With Hypertension-Not the Usual Suspects.

Hypertension (HTN) affects more than one-third of the US population and remains the top risk factor for the development of cardiovascular disease (CVD). Identifying the underlying mechanisms for developing HTN are of critical importance because the risk of developing CVD doubles with ∼20 mmHg increase in systolic blood pressure (BP). Endothelial dysfunction, especially in the resistance arteries, is the primary site for initiation of sub-clinical HTN. Furthermore, inflammation and reactive oxygen and nitrogen species (ROS/RNS) not only influence the endothelium independently, but also have a synergistic influence on each other. Together, the interplay between inflammation, ROS and vascular dysfunction is referred to as the vascular health triad, and affects BP regulation in humans. While the interplay of the vascular health triad is well established, new underlying mechanistic targets are under investigation, including: Inducible nitric oxide synthase, hydrogen peroxide, hydrogen sulfide, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and nuclear factor activated T cells. This review outlines the role of these unusual suspects in vascular health and function in humans. This review connects the dots using these unusual suspects underlying inflammation, ROS and vascular dysfunction especially in individuals at risk of or with diagnosed HTN based on novel studies performed in humans.

Hydrogen sulfide-dependent microvascular vasodilation is improved following chronic sulfhydryl-donating antihypertensive pharmacotherapy in adults with hypertension.

Hypertension is characterized by systemic microvascular endothelial dysfunction, in part due to a functional absence of hydrogen sulfide (H2S)-mediated endothelium-dependent dilation. Treatment with a sulfhydryl-donating ACE inhibitor (SH-ACE inhibitor) improves endothelial function in preclinical models of hypertension. To date, no studies have directly assessed the effects of SH-ACE-inhibitor treatment on H2S-dependent vasodilation in humans with hypertension. We hypothesized that SH-ACE-inhibitor treatment would improve H2S-mediated endothelium-dependent vasodilation. Ten adults with hypertension [1 woman and 9 men; 56 ± 9 yr; systolic blood pressure (SBP): 141 ± 8.5 mmHg; diastolic blood pressure (DBP): 90.3 ± 6 mmHg] were treated (16 wk) with the SH-ACE-inhibitor captopril. Red blood cell flux (laser-Doppler flowmetry) was measured continuously during graded intradermal microdialysis perfusion of the endothelium-dependent agonist acetylcholine (ACh; 10-10 to 10-1 M) alone (control) and in combination with an inhibitor of enzymatic H2S production [10-3 M aminooxyacetate (AOAA)] preintervention and postintervention. Cutaneous vascular conductance (CVC; flux/mmHg) was calculated and normalized to the site-specific maximal CVC (0.028 M sodium nitroprusside and local heat to 43°C). Area under the curve was calculated using the trapezoid method. The 16-wk SH-ACE-inhibitor treatment resulted in a reduction of blood pressure (systolic BP: 129 ± 10 mmHg; diastolic BP: 81 ± 9 mmHg, both P < 0.05). Preintervention, inhibition of H2S production had no effect on ACh-induced vasodilation (316 ± 40 control vs. 322 ± 35 AU AOAA; P = 0.82). Captopril treatment improved ACh-induced vasodilation (316 ± 40 pre vs. 399 ± 55 AU post; P = 0.04) and increased the H2S-dependent component of ACh-induced vasodilation (pre: -6.6 ± 65.1 vs. post: 90.2 ± 148.3 AU, P = 0.04). These data suggest that SH-ACE-inhibitor antihypertensive treatment improves cutaneous microvascular endothelium-dependent vasodilation in adults with hypertension, in part via H2S-dependent mechanisms.NEW & NOTEWORTHY This is the first study to prospectively assess the effects of sulfhydryl antihypertensive treatment on microvascular endothelial function in adults with hypertension. Our data suggest that 16 wk of SH-ACE-inhibitor antihypertensive treatment improves cutaneous microvascular endothelium-dependent vasodilation in middle-aged adults with hypertension, in part via H2S-dependent mechanisms.

Temperature regulation during exercise in the heat: Insights for the aging athlete.

OBJECTIVE: The purpose of this review is to evaluate the currently-available literature regarding the impact of both primary aging and age-related fitness on thermoregulatory function during exercise in the heat. In so doing, we aim to (1) characterize the influence of fitness in mitigating age-related declines in thermoregulation, (2) address the limitations of prior experimental approaches for investigating age-related thermoregulatory impairments, (3) examine to what extent aerobic fitness can be maintained in the aging athlete, and (4) begin to address the specific environmental conditions in which age-related impairments in thermoregulatory function may place highly active older adults at increased risk for heat-related illness and injury and/or limited performance. DESIGN: Mini-review. METHODS: Review and synthesis of available information. RESULTS: The earth's climate is warming, accompanied by a consequently greater frequency and severity of extreme heat events. At the same time, lifespan is increasing and people of all ages are staying increasingly active. Age-related impairments in thermoregulatory function are well-documented, leading to increased heat-related health risks and reduced exercise/athletic performance for older adults in hot environmental conditions. High aerobic fitness improves body temperature regulation during exercise via augmented sweating and improved cardiovascular function, including cardiac output and skin blood flow, in humans of all ages. CONCLUSIONS: The masters athlete is better suited for exercise/heat-stress compared to his or her less fit peers. However, while age and thermoregulation in general has been studied extensively, research on the most fit older adults, including highly competitive athletes, is generally lacking.

Reproducibility of the neurocardiovascular responses to common laboratory-based sympathoexcitatory stimuli in young adults.

The magnitude of blood pressure (BP) and muscle sympathetic nerve activity (MSNA) responses to laboratory stressors is commonly used to compare neurocardiovascular responsiveness between groups and conditions. However, no studies have rigorously examined the reproducibility of BP and MSNA responsiveness. Here, we assess the within-visit reproducibility of BP (finger photoplethysmography) and MSNA (microneurography) responses to isometric handgrip (HG) and postexercise ischemia (PEI) in young healthy adults (n = 30). In a subset (n = 21), we also examined the between-visit reproducibility of responsiveness to HG, PEI, and the cold pressor test (CPT). Intraclass correlation coefficients (ICCs) were used as a primary reproducibility measure (e.g., ICC >0.75 is considered very good). Within a visit, the increase in mean arterial pressure during HG [ICC = 0.85 (0.69-0.93); P < 0.001] and PEI [ICC = 0.85 (0.69-0.93); P < 0.001] demonstrated very good reproducibility. Furthermore, the between-visit reproducibility of the pressor response to HG [ICC = 0.85 (0.62-0.94); P < 0.001], PEI [ICC = 0.84 (CI = 0.58-0.94); P < 0.001], and the CPT [ICC = 0.89 (0.72-0.95) P < 0.001]) were also very good. However, there was greater variability in both the within- [HG: ICC = 0.58 (-0.22-0.85), P = 0.001; PEI: ICC = 0.33 (-0.24-0.69), P = 0.042] and between-visit reproducibility of MSNA responsiveness [HG: ICC = 0.87 (0.53-0.96), P = 0.001; PEI: ICC = 0.24 (-0.62-0.78), P = 0.27; CPT: ICC = 0.77 (0.29-0.93), P = 0.007]. The magnitude of the BP response to several standard laboratory stimuli was very good, whereas the variability of the MSNA response to these perturbations was generally less consistent, particularly during PEI. These data provide novel insight for both study design and data interpretation when comparing neurocardiovascular responsiveness between different conditions, groups, or studies, as well as before and after interventions/treatments.NEW & NOTEWORTHY The magnitude of the increases in blood pressure and muscle sympathetic nerve activity in response to sympathoexcitatory stimuli such as static handgrip, postexercise ischemia, and the cold pressor test are commonly used to assess neurocardiovascular responsiveness. However, limited studies have comprehensively examined the reproducibility of these responses. We demonstrate that the reproducibility of the pressor response to these perturbations was very good within an individual, whereas the reproducibility of the MSNA response was less consistent.

AHA/ACC-defined stage 1 hypertensive adults do not display cutaneous microvascular endothelial dysfunction.

In 2017, the American Heart Association (AHA) and American College of Cardiology (ACC) redefined stage 1 hypertension to systolic blood pressure (BP) 130-139 mmHg or diastolic BP 80-89 mmHg; however, the degree to which microvascular endothelial dysfunction is evident in adults with stage 1 hypertension remains equivocal. We tested the hypotheses that cutaneous microvascular endothelial dysfunction would be present in adults with stage 1 hypertension (HTN1) compared with normotensive adults (NTN; BP <120/<80 mmHg) but would be less severe compared with adults with stage 2 hypertension (HTN2; systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg) and that this graded impairment would be mediated by reductions in nitric oxide (NO)-dependent dilation. This retrospective analysis included 20 NTN (5 men; 45-64 yr; BP 94-114/60-70 mmHg), 22 HTN1 (11 men; 40-74 yr; BP 110-134/70-88 mmHg), and 44 HTN2 (27 men; 40-74 yr; BP 128-180/80-110 mmHg). BP and nocturnal dipping status were also assessed using 24-h ambulatory BP monitoring. Red cell flux (laser Doppler flowmetry) was measured during intradermal microdialysis perfusion of acetylcholine (ACh; 10-10 to 10-1M) alone and concurrently with the nonspecific nitric oxide (NO) synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME; 15 mM). ACh-induced dilation was impaired in HTN2 (P < 0.01), but not in HTN1 (P = 0.85), compared with NTN. Furthermore, reductions in NO-dependent dilation were evident in HTN2 (P < 0.01) but not in HTN1 (P = 0.76). Regardless of BP, endothelium-dependent dilation was impaired in nondippers (nighttime drop in systolic BP <10%) compared with dippers (nighttime drop in systolic BP ≥10%, P < 0.05). In conclusion, functional impairments in NO-mediated endothelium-dependent dilation were not evident in HTN1. However, regardless of BP classification, the lack of a nocturnal dip in BP was associated with blunted endothelium-dependent dilation.NEW & NOTEWORTHY This is the first study to pharmacologically assess the mechanistic regulation of endothelial function in adults with hypertension, classified according to the 2017 clinical guidelines set for by the American Heart Association (AHA) and American College of Cardiology (ACC). Compared with that in normotensive adults, nitric oxide-mediated endothelium-dependent dilation is impaired in adults with stage 2, but not stage 1, hypertension. Adults lacking a nighttime dip in blood pressure demonstrated reductions in endothelium-dependent dilation.

Peripheral microvascular serotoninergic signaling is dysregulated in young adults with major depressive disorder.

Dysfunction of the brain serotonergic system is implicated in the pathogenesis of major depressive disorder (MDD). Serotonin is also a vasoactive signaling molecule, the effects of which are modulated by both nitric oxide (NO) and the serotonin transporter [the primary target of selective serotonin reuptake inhibitors (SSRIs)]. Despite its role in the neurobiology of depression, serotoninergic signaling mechanisms in the microvasculature of adults with MDD are unknown. We hypothesized that 1) cutaneous microvascular responsiveness to serotonin would be attenuated in MDD and mediated by reductions in both 2) NO-dependent and 3) serotonin reuptake-dependent mechanisms. In 12 adults with MDD (nonmedicated) and 12 nondepressed adults, red cell flux (laser-Doppler flowmetry) was measured during graded intradermal microdialysis perfusion of 1) serotonin (10-10 to 10-1 mol/L) alone and in combination with a nonselective NO synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME; 15 mmol/L) and the SSRI paroxetine (10 µmol/L); and 2) paroxetine (n = 6; 10-9 to 10-2 M) alone and in combination with l-NAME. Serotonin-induced vasodilation was preserved in MDD. The NO-dependent component of serotonin-induced vasodilation was not different between groups. Paroxetine augmented vasodilatory responsiveness to serotonin via NO-dependent mechanisms in both groups; however, the magnitude was blunted in MDD. The NO contribution to direct paroxetine-induced vasodilation was also reduced in adults with MDD. Collectively, these preliminary data suggest that cutaneous microvascular serotoninergic signaling is dysregulated in adults with MDD and mediated by NO-dependent and serotonin reuptake-dependent mechanisms, providing initial mechanistic insight to the purported vasculoprotective effect of chronic SSRI treatment.NEW & NOTEWORTHY Cutaneous microvascular vasodilatory responsiveness to serotonin was preserved in adults with major depressive disorder (MDD). However, the contribution of serotonin reuptake-dependent mechanisms to serotonin-induced dilation was reduced in MDD. Direct perfusion of the selective serotonin reuptake inhibitor (SSRI) paroxetine elicited vasodilation that is partially mediated by nitric oxide (NO)-dependent mechanisms, but these responses were blunted in MDD, reflective of a diminished contribution of NO to the direct effects of a SSRI on the cutaneous microvasculature.

Rapid-onset vasodilator responses to exercise in humans: Effect of increased baseline blood flow.

NEW FINDINGS: What is the central question of this study? What is the effect of an elevated baseline blood flow, induced by high-dose intra-arterial infusion of either adenosine or ATP, on the rapid-onset vasodilatory response to a single forearm muscle contraction? What is the main finding and its importance? The peak response to a single contraction is unaffected by augmented baseline blood flow, and thus, is likely to be attributable to a feedforward vasodilatory mechanism. ABSTRACT: The hyperaemic responses to single muscle contractions are proportional to exercise intensity, which, in turn, is proportional to tissue metabolic demand. Hence, we tested the hypothesis that the rapid-onset vasodilatory response after a single muscle contraction would be unaffected when baseline blood flow was increased via high-dose intra-arterial infusion of either adenosine (ADO) or ATP. Twenty-four healthy young participants (28 ± 1 years) performed a single forearm contraction (20% maximal voluntary contraction) 75 min after commencement of a continuous infusion of ADO (n = 6), ATP (n = 8) or saline (control; n = 10). Brachial artery diameter and blood velocity were measured using Doppler ultrasound. Resting forearm vascular conductance (FVC; in millilitres per minute per 100 mmHg per decilitre of forearm volume) was significantly higher during ADO (33 ± 17) and ATP infusion (33 ± 17) compared with the control infusion (8 ± 3; P < 0.05). The peak FVCs post-contraction during ADO and ATP infusions were significantly greater than during the control infusion (P < 0.05), but not different from one another. The peak change in FVC from baseline was similar in all three conditions (control, 14 ± 1; ADO, 24 ± 2; and ATP, 23 ± 6; P = 0.15). Total FVC (area under the curve) did not differ significantly between ADO and ATP (333 ± 69 and 440 ± 125); however, total FVC during ATP infusion was significantly greater compared with the control value (150 ± 19; P < 0.05). We conclude that the peak response to a single contraction is unaffected by augmented baseline blood flow and is therefore likely to be attributable to a feedforward vasodilatory mechanism.

Aging Alters the Relative Contributions of the Sympathetic and Parasympathetic Nervous System to Blood Pressure Control in Women.

Autonomic support of blood pressure increases with age in humans. Large differences exist in the dose of trimethaphan (TMP) required for ganglionic blockade in young and older women. We asked whether differences in the dose of TMP required to achieve ganglionic blockade are because of differences in the relative contributions of the sympathetic and parasympathetic nervous system in control of blood pressure with age. Muscle sympathetic nerve activity (microneurography, peroneal nerve), heart rate (HR), and blood pressure were recorded before and during incremental doses of TMP camsylate until ganglionic blockade was achieved (absence of muscle sympathetic nerve activity and <5-bpm increase in HR during a valsalva maneuver; final TMP dose, 1-7 mg/min). HR variability was analyzed from the ECG waveform (WinCPRS). The dose of TMP required to achieve ganglionic blockade is positively related to basal HR variability, where women with high HR variability require a higher dose of TMP to achieve ganglionic blockade. In contrast, baseline muscle sympathetic nerve activity is inversely related with the dose of TMP required to achieve ganglionic blockade, such that women with high basal muscle sympathetic nerve activity required a lower dose of TMP. As such, the change in HR with ganglionic blockade was positively related, and the change in mean arterial pressure was inversely related, with the dose of TMP required to achieve ganglionic blockade. These data suggest loss of parasympathetic tone and increased sympathetic tone with aging contribute to the increase in blood pressure with age in women and dictate the dose of TMP that is necessary to achieve ganglionic blockade.