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

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. PURPOSE: 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 to adults who have not had COVID-19. METHODS: We performed a cross-sectional study including: 10 (5M/5W, 24 ± 4yrs) healthy control (HC) adults who were unvaccinated for COVID-19, 11 (4M/7W, 25 ± 6yrs) healthy vaccinated (HV) adults, and 12 (5M/7W, 22 ± 3yrs) post-COVID-19 (PC, 19 ± 14wks) adults. COVID-19 symptoms severity (survey) were 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 (28mM sodium nitroprusside + 43°C). 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). CONCLUSION: Healthy adults who have had mild-to-moderate COVID-19 do not have altered NO-mediated cutaneous microvascular function.

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.

The vasodilatory mechanism of Nntroglycerin (NTG) is similar to sodium nitroprusside (SNP) in regard to action on guanosine 3'5'-monophosphate (cyclic GMP) via nitric oxide. However, it is unknown whether NTG can achieve the same magnitude of vasodilation in the forearm as SNP. Therefore, the purpose of the study was to evaluate the differences in forearm blood flow (FBF) and forearm vascular conductance (FVC) during escalating infusions of NTG vs. SNP at similar concentration doses and rates. We measured FBF using venous occlusion plethysmography (VOP) and Doppler ultrasound in eight young, healthy participants (mean age = 28 ± 2 yr) during four forearm volume (FAV)-specific doses (0.25, 0.5, 1, and 2 µg·100 ml FAV·min) of SNP and NTG infused via a brachial artery catheter. There was a significant difference in FVC of SNP vs. NTG only at the higher doses, as measured by VOP (14.9 ± 1.4 and 18.3 ± 1.5 vs. 11.6 ± 1.2 and 12.5 ± 1.2 ml/dl FAV·min·100 mmHg). FVC as measured by Doppler ultrasound unadjusted for FAV was significantly different at the lowest and the higher two doses of SNP compared with NTG (202.1 ± 25.8, 329.4 ± 46.7, and 408 ± 63.5 vs. 142.9 ± 22.4, 217.2 ± 18.8, and 247.5 ± 18.2 ml·min·100 mmHg). SNP induces significantly higher vasodilatory actions compared with NTG. However, NTG is comparable in eliciting equivalent vasodilator effects to SNP during low concentration doses when measured by VOP. Importantly, for forearm pharmacology studies, NTG can elicit marked endothelium-independent forearm vasodilation. We compared the vasodilatory capacities of NTG vs. SNP at similar concentration doses and rates into the forearm. Based on the results of the study, it may be feasible to use intra-arterial NTG as a measure of endothelial-independent vasodilator in research studies. However, NTG dosing may need to be higher if used as an endothelial-independent vasodilator due to significant differences in the vasodilatory effects during higher doses of SNP compared with NTG.

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 post-exercise 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 (ICC) were used as a primary reproducibility measure (e.g., ICC >0.75 is considered very good). Within a visit, the increase in MAP 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. Further, 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.

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 agerelated 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.

Darkly-pigmented individuals are at greatest risk of vitamin D insufficiency/deficiency, which may result in microvascular endothelial dysfunction via reduced nitric oxide (NO) bioavailability and/or increased oxidative stress and inflammation. We investigated the associations between 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 healthy, young adults. An intradermal microdialysis fiber was placed in the forearms of 33 healthy adults (14M/19W; 18-27 yrs; M-index, 30-81 a.u.) 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, 15mM NG-nitro-L-arginine methyl ester (L-NAME; nitric oxide synthase inhibiter) was infused at all sites 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; 28mM 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). 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 otherwise healthy, darkly-pigmented young adults.

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 pre-clinical models of hypertension. To date, no studies have directly assessed the effects of SH-ACE-inhibitor treatment on H2S-dependent vasodilation in hypertensive humans. We hypothesized that SH-ACE-inhibitor treatment would improve H2S-mediated endothelium-dependent vasodilation. Ten hypertensive adults (1W; 56±9yrs, Systolic BP: 141±8.5 mmHg; Diastolic BP: 90.3±6 mmHg) were treated (16 weeks) 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; 10-10-10-1 M) alone (control) and in combination with an inhibitor of enzymatic H2S production (10-3 M aminooxyacetate; AOAA) pre- and post-intervention. Cutaneous vascular conductance (CVC; flux/mmHg) was calculated and normalized to the site-specific maximal CVC (0.028M sodium nitroprusside and local heat to 43°C). Area-under-the-curve was calculated using the trapezoid method. The 16-week 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). Pre-intervention, 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 hypertensive adults, in part via H2S-dependent mechanisms.