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Impedance aggregometry is an alternative to light transmission aggregometry that allows analysis of platelet function in whole blood samples. We hypothesized (1) impedance aggregometry would produce repeatable results, (2) inhibition of cyclooxygenase with aspirin would attenuate aggregation responses to collagen and abolish the aggregation response to arachidonic acid (AA), and (3) thromboxane receptor antagonism (terutroban) would attenuate the aggregation response to AA. Venous blood was obtained from 11 participants three times separated by at least 2 weeks. One sample followed 7-day-aspirin intervention (81 mg once daily; ASA), the others no intervention (control). Aggregation was induced using 1 µg/mL collagen ([col 1]), 5 µg/mL collagen ([col 5]), and 50 mM AA via impedance aggregometry to determine total aggregation (AUC) analyzed for intra-test repeatability, inter-test repeatability, intervention (ASA or control), and incubation (saline or terutroban). [col 1] showed high intra-test (p ≤ 0.03 visit 1 and 2) and inter-test repeatability (p < 0.01). [col 5] and AA showed intra- ([col 5] p < 0.01 visit 1 and 2; AA p < 0.001 visit 1 and 2) but not inter-test repeatability ([col 5] p = 0.48; AA p = 0.06). ASA attenuated AUC responses to [col 1] (p < 0.01), [col 5] (p = 0.03), and AA (p < 0.01). Terutroban attenuated AUC in response to AA (p < 0.01). [col 1] shows sufficient repeatability for longitudinal investigations of platelet function. [col 5] and AA may be used to investigate mechanisms of platelet function and metabolism at a single time point.
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Aspirina , Inhibidores de la Ciclooxigenasa , Impedancia Eléctrica , Agregación Plaquetaria , Pruebas de Función Plaquetaria , Propionatos , Receptores de Tromboxanos , Humanos , Agregación Plaquetaria/efectos de los fármacos , Masculino , Proyectos Piloto , Femenino , Inhibidores de la Ciclooxigenasa/farmacología , Aspirina/farmacología , Receptores de Tromboxanos/antagonistas & inhibidores , Receptores de Tromboxanos/metabolismo , Adulto , Pruebas de Función Plaquetaria/métodos , Propionatos/farmacología , Naftalenos/farmacología , Ácido Araquidónico/farmacología , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/farmacología , Colágeno/farmacologíaRESUMEN
The transcriptional regulator nuclear factor-κB (NF-κB) is a mediator of endothelial dysfunction. Inhibiting NF-κB with salsalate is used to investigate inflammatory mechanisms contributing to accelerated cardiovascular disease risk. However, in the absence of disease, inhibition of NF-κB can impact redox mechanisms, resulting in paradoxically decreased endothelial function. This study aimed to measure microvascular endothelial function during inhibition of the transcriptional regulator NF-κB in reproductive-aged healthy women. In a randomized, single-blind, crossover, placebo-controlled design, nine healthy women were randomly assigned oral salsalate (1,500 mg, twice daily) or placebo treatments for 5 days. Subjects underwent graded perfusion with the endothelium-dependent agonist acetylcholine (ACh, 10-10 to 10-1 M, 33°C) alone and in combination with 15 mM NG-nitro-l-arginine methyl ester [l-NAME; nonselective nitric oxide (NO) synthase inhibitor] through intradermal microdialysis. Laser-Doppler flux was measured over each microdialysis site, and cutaneous vascular conductance (CVC) was calculated as flux divided by mean arterial pressure and normalized to site-specific maximum (CVC%max; 28 mM sodium nitroprusside + 43°C). The l-NAME sensitive component was calculated as the difference between the areas under the dose-response curves. During the placebo and salsalate treatments, the l-NAME sites were reduced compared with the control sites (both P < 0.0001). Across treatments, there was a significant difference between the control and l-NAME sites, where both sites shifted upward following salsalate treatment (both P < 0.0001), whereas the l-NAME-sensitive component was not different (P = 0.94). These data demonstrate that inhibition of the transcriptional regulator NF-κB improves cutaneous microvascular function in reproductive-aged healthy women through non-NO-dependent mechanisms.NEW & NOTEWORTHY The transcription factor nuclear factor-κB (NF-κB) regulates multiple aspects of innate and adaptive immunity by encoding for genes that participate in inflammation and impact endothelial function following NF-κB inhibition with salsalate treatment. Our results show that cutaneous microvascular function is increased through non-nitric oxide (NO)-dependent mechanisms following salsalate treatment in reproductive-aged healthy women.
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Estudios Cruzados , Microcirculación , FN-kappa B , Óxido Nítrico , Piel , Humanos , Femenino , Adulto , Piel/irrigación sanguínea , Piel/efectos de los fármacos , Piel/metabolismo , FN-kappa B/metabolismo , Método Simple Ciego , Microcirculación/efectos de los fármacos , Óxido Nítrico/metabolismo , NG-Nitroarginina Metil Éster/farmacología , Vasodilatación/efectos de los fármacos , Adulto Joven , Acetilcolina/farmacología , Voluntarios Sanos , Vasodilatadores/farmacología , Inhibidores Enzimáticos/farmacología , Salicilatos/farmacología , Microvasos/efectos de los fármacos , Microvasos/metabolismo , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Flujo Sanguíneo Regional/efectos de los fármacosRESUMEN
OBJECTIVES: This analysis examined if financial hardship was associated with age-related decrements in kidney function using a material-psychosocial-behavioral framework. We also tested if this association was mediated by comorbidity of cardiometabolic risk factors (obesity, elevated blood pressure, and insulin resistance). METHODS: Data from 1,361 Non-Hispanic (NH) Black and white adults (ages 26-94; NH Black = 258) were obtained from the Wave 3 and Refresher phases of the Midlife in the United States (MIDUS) project. Kidney function was based on serum creatinine-based estimated glomerular filtration rate (CKD-EPI formula without race adjustment). Financial hardship was evaluated in three domains: material (income to poverty line ratio, health insurance coverage, and public/government financial assistance), psychological (perceived financial status, control over financial status, and perceived financial strains), and behavioral responses (financial adjustment/coping such as sold possessions and cutting back on spending). RESULTS: More severe financial hardship (overall score and in each domain) was associated with age-related decrements in eGFR, even after adjusting for sociodemographic, education, and health-related covariates. The association between financial hardship and age-related decrements in eGFR was conditional on sex but not race. Finally, cardiometabolic risk factors mediated the association between financial hardship and age-related decrements in eGFR. CONCLUSIONS: These findings affirm the negative effects of financial hardship on age-related decrements in renal clearance. In addition to incorporating traditionally used indicators of SES, such as education and income, future research on social hallmarks of aging should also consider the role of financial hardship on the aging process and age-related diseases.
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The cutaneous vasculature is an accessible tissue that can be used to assess microvascular function in humans. Intradermal microdialysis is a minimally invasive technique used to investigate mechanisms of vascular smooth muscle and endothelial function in the cutaneous circulation. This technique allows for the pharmacological dissection of the pathophysiology of microvascular endothelial dysfunction as indexed by decreased nitric oxide-mediated vasodilation, an indicator of cardiovascular disease development risk. In this technique, a microdialysis probe is placed in the dermal layer of the skin, and a local heating unit with a laser Doppler flowmetry probe is placed over the probe to measure the red blood cell flux. The local skin temperature is clamped or stimulated with direct heat application, and pharmacological agents are perfused through the probe to stimulate or inhibit intracellular signaling pathways in order to induce vasodilation or vasoconstriction or to interrogate mechanisms of interest (co-factors, antioxidants, etc.). The cutaneous vascular conductance is quantified, and mechanisms of endothelial dysfunction in disease states can be delineated.
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Piel , Vasodilatación , Humanos , Microdiálisis , Piel/metabolismo , Administración Cutánea , Fenómenos Fisiológicos de la Piel , Óxido Nítrico/metabolismo , Flujo Sanguíneo Regional , Flujometría por Láser-DopplerRESUMEN
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.
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COVID-19 , Óxido Nítrico , Persona de Mediana Edad , Humanos , Anciano , Proyectos Piloto , Estudios Transversales , SARS-CoV-2 , Piel/irrigación sanguínea , Vasodilatación/fisiología , NG-Nitroarginina Metil Éster , Microdiálisis , Flujo Sanguíneo RegionalAsunto(s)
Anticonceptivos Orales , Endotelio Vascular , Femenino , Humanos , Informes de Casos como Asunto , MicrovasosRESUMEN
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.
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Deficiencia de Vitamina D , Vitamina D , Femenino , Humanos , Interleucina-10 , Masculino , Microdiálisis , Microvasos , NG-Nitroarginina Metil Éster , Óxido Nítrico , Flujo Sanguíneo Regional , Piel/irrigación sanguínea , Pigmentación de la Piel , Vasodilatación , Deficiencia de Vitamina D/diagnóstico , Adulto JovenRESUMEN
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.
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Enfermedades Cardiovasculares , Endometriosis , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Atorvastatina/farmacología , Endometriosis/tratamiento farmacológico , Endotelio Vascular , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Microcirculación , Óxido Nítrico , Flujo Sanguíneo Regional , Piel/irrigación sanguínea , VasodilataciónRESUMEN
Reactive oxygen species (ROS)-mediated reductions in nitric oxide (NO)-dependent dilation are evident in adults with major depressive disorder (MDD); however, the upstream mechanisms remain unclear. Here, we hypothesized that nuclear factor-κB (NF-κB) activation-induced ROS production contributes to microvascular endothelial dysfunction in MDD. Thirteen treatment-naive adults with MDD (6 women; 19-23 yr) and 10 healthy nondepressed adults (HAs; 5 women; 20-25 yr) were tested before and after (open-label design) systemic NF-κB knockdown (nonacetylated salicylate; 3,000-4,500 mg/day × 4 days). Red cell flux (laser Doppler flowmetry) was measured during graded intradermal microdialysis perfusion of the endothelium-dependent agonist acetylcholine (ACh), alone and in combination with NO synthase inhibition [NG-nitro-l-arginine methyl ester (l-NAME)] or ROS scavenging (apocynin). Serum salicylate concentrations following treatment were not different between groups (22.8 ± 7.4 HAs vs. 20.8 ± 4.3 mg/dL MDD; P = 0.46). When compared with HAs, the NO-dependent component of ACh-induced dilation was blunted in adults with MDD before (P = 0.023), but not after (P = 0.27), salsalate treatment. In adults with MDD, the magnitude of improvement in endothelium-dependent dilation following salsalate treatment was inversely related to the degree of functional impairment at baseline (R2 = 0.43; P = 0.025). Localized ROS scavenging improved NO-dependent dilation before (P < 0.01), but not after (P > 0.05), salsalate treatment. Salsalate did not alter systemic concentrations of pro- or anti-inflammatory cytokines (all P > 0.05). These data suggest that NF-κB activation, via increased vascular ROS production, contributes to blunted NO-dependent dilation in young adults with MDD but otherwise free of clinical disease. These data provide the first direct evidence for a mechanistic role of vascular inflammation-associated endothelial dysfunction in human depression.NEW & NOTEWORTHY Our data indicate that short-term treatment with therapeutic doses of the nuclear factor-κB (NF-κB) inhibitor salsalate improved nitric oxide (NO)-mediated endothelium-dependent dilation in adults with major depressive disorder (MDD). In adults with MDD, acute localized scavenging of reactive oxygen species (ROS) with apocynin improved NO-dependent dilation before, but not after, salsalate administration. These data suggest that activation of NF-κB, in part via stimulation of vascular ROS production, contributes to blunted NO-mediated endothelium-dependent dilation in young adults with MDD.
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Trastorno Depresivo Mayor , Acetilcolina/farmacología , Trastorno Depresivo Mayor/tratamiento farmacológico , Dilatación , Endotelio Vascular , Femenino , Humanos , Masculino , FN-kappa B , Óxido Nítrico , Especies Reactivas de Oxígeno , Salicilatos/farmacología , Salicilatos/uso terapéutico , Vasodilatación , Adulto JovenRESUMEN
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.
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Antiinflamatorios no Esteroideos/administración & dosificación , Endotelio Vascular/efectos de los fármacos , Preeclampsia/tratamiento farmacológico , Salicilatos/administración & dosificación , Administración Oral , Adulto , Antiinflamatorios no Esteroideos/farmacología , Método Doble Ciego , Femenino , Humanos , Microcirculación/efectos de los fármacos , Preeclampsia/fisiopatología , Embarazo , Salicilatos/farmacología , Piel/irrigación sanguíneaRESUMEN
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.
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COVID-19/fisiopatología , Microcirculación/fisiología , Piel/irrigación sanguínea , Vasodilatación/fisiología , Adulto , COVID-19/metabolismo , COVID-19/prevención & control , Vacunas contra la COVID-19/uso terapéutico , Estudios de Casos y Controles , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Flujometría por Láser-Doppler , Masculino , Microcirculación/efectos de los fármacos , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/metabolismo , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Vasodilatación/efectos de los fármacos , Adulto JovenRESUMEN
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.
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Analgésicos/administración & dosificación , Mentol/administración & dosificación , Células Receptoras Sensoriales/efectos de los fármacos , Piel/irrigación sanguínea , Piel/inervación , Canales Catiónicos TRPM/agonistas , Vasodilatación/efectos de los fármacos , Administración Cutánea , Velocidad del Flujo Sanguíneo , Estudios Cruzados , Método Doble Ciego , Femenino , Geles , Humanos , Flujometría por Láser-Doppler , Masculino , Flujo Sanguíneo Regional , Células Receptoras Sensoriales/metabolismo , Transducción de Señal , Canales Catiónicos TRPM/metabolismo , Sensación Térmica/efectos de los fármacos , Adulto JovenRESUMEN
NEW FINDINGS: What is the central question of this study? Are sensory nerve-mediated vasodilatation and the NO-dependent contribution to that response attenuated in the cutaneous microvasculature of women who have had preeclampsia? What is the main finding and its importance? Women who have had preeclampsia demonstrate attenuated microvascular endothelium-dependent dilatation compared to women with a history of uncomplicated pregnancy. However, there are no differences in sensory nerve-mediated vasodilatation between groups. This suggests that the neurogenic response is not altered following preeclampsia, and that the NO-dependent vasodilatation of the neurogenic response is not related to endothelium-dependent NO-mediated dilatation in these women. ABSTRACT: Women who have had preeclampsia (PE) demonstrate microvascular endothelial dysfunction, mediated in part by reduced nitric oxide (NO)-dependent mechanisms. Localized heating of the skin induces a biphasic vasodilatation response: a sensory nerve-mediated initial peak, followed by a sustained endothelium-dependent plateau. We have previously shown that the endothelium-dependent plateau is attenuated in PE. However, it is unknown if the sensory nerve-mediated initial peak is similarly attenuated. Therefore, the purpose of this study was to examine the effect of PE history on sensory nerve-mediated vasodilatation and the NO-dependent contribution to that response. We hypothesized that PE would have an attenuated initial peak and a reduced NO-dependent contribution to that response compared to women with a history of normotensive pregnancy (healthy controls, HC). Nine HC (31 ± 4 years) and nine PE (28 ± 6 years) underwent a standard local heating protocol (42°C; 0.1°C s-1 ). Two intradermal microdialysis fibres were placed in the skin of the ventral forearm for the continuous local delivery of lactated Ringer solution alone (control) or 15-mM NG -nitro-l-arginine methyl ester for nitric oxide synthase (NOS) inhibition. Red blood cell flux was measured at 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). There were no differences in the initial peak between groups (HC: 79 ± 8 vs. PE: 80 ± 10%CVCmax ; P = 0.936). NOS inhibition attenuated the initial peak in both HC (57 ± 18% CVCmax ; P = 0.003) and PE (54 ± 10%CVCmax ; P = 0.002). However, there were no differences in the NO-dependent portion of the initial peak (HC: 23 ± 16 vs. PE: 24 ± 9%; P = 0.777). The local heating plateau (HC: 99 ± 4 vs. PE: 88 ± 7%CVCmax ; P = 0.001) and NO contribution to the plateau (HC: 31 ± 9 vs. PE: 17 ± 14%; P = 0.02) were attenuated in PE. There was no relation between NO-dependent dilatation in the initial peak and NO-dependent dilatation in the plateau across groups (R2 = 0.005; P = 0.943). Women who have had PE demonstrate attenuated microvascular endothelium-dependent dilatation. However, there are no differences in sensory nerve-mediated vasodilatation following PE, suggesting that the NO-dependent vasodilatation of the neurogenic response is not related to endothelium-dependent NO-mediated dilatation in these women.
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Preeclampsia , Dilatación , Femenino , Humanos , Microdiálisis , Microvasos , Óxido Nítrico , Embarazo , Flujo Sanguíneo Regional/fisiología , Piel/irrigación sanguínea , Vasodilatación/fisiologíaRESUMEN
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 â¼20 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.
RESUMEN
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.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Captopril/uso terapéutico , Sulfuro de Hidrógeno/metabolismo , Hipertensión/tratamiento farmacológico , Microcirculación/efectos de los fármacos , Piel/irrigación sanguínea , Vasodilatación/efectos de los fármacos , Anciano , Inhibidores de la Enzima Convertidora de Angiotensina/metabolismo , Antihipertensivos/metabolismo , Captopril/metabolismo , Femenino , Humanos , Hipertensión/diagnóstico , Hipertensión/metabolismo , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Óxido Nítrico/metabolismo , Prueba de Estudio Conceptual , Estudios Prospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
Evidence links osteoporosis and cardiovascular disease but the cellular and molecular mechanisms are unclear. Here we identify skeleton-secreted platelet-derived growth factor-BB (PDGF-BB) as a key mediator of arterial stiffening in response to aging and metabolic stress. Aged mice and those fed high-fat diet (HFD), relative to young mice and those fed normal chow food diet, respectively, had higher serum PDGF-BB and developed bone loss and arterial stiffening. Bone/bone marrow preosteoclasts in aged mice and HFD mice secrete an excessive amount of PDGF-BB, contributing to the elevated PDGF-BB in blood circulation. Conditioned medium prepared from preosteoclasts stimulated proliferation and migration of the vascular smooth muscle cells. Conditional transgenic mice, in which PDGF-BB is overexpressed in preosteoclasts, had 3-fold higher serum PDGF-BB concentration and developed simultaneous bone loss and arterial stiffening spontaneously at a young age. Conversely, in conditional knockout mice, in which PDGF-BB is deleted selectively in preosteoclasts, HFD did not affect serum PDGF-BB concentration; as a result, HFD-induced bone loss and arterial stiffening were attenuated. These studies confirm that preosteoclasts are a main source of excessive PDGF-BB in blood circulation during aging and metabolic stress and establish the role of skeleton-derived PDGF-BB as an important mediator of vascular stiffening.
Asunto(s)
Becaplermina/fisiología , Osteoclastos/fisiología , Rigidez Vascular/fisiología , Envejecimiento , Animales , Becaplermina/sangre , Resorción Ósea/etiología , Dieta Alta en Grasa , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Músculo Liso Vascular/citología , Miocitos del Músculo Liso/fisiología , Ratas , Ratas Sprague-DawleyRESUMEN
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.
Asunto(s)
Envejecimiento/fisiología , Regulación de la Temperatura Corporal , Ejercicio Físico/fisiología , Calor , Deportes/fisiología , Adolescente , Adulto , Anciano , Gasto Cardíaco , Trastornos de Estrés por Calor/fisiopatología , Humanos , Persona de Mediana Edad , Acondicionamiento Físico Humano/fisiología , Aptitud Física , Flujo Sanguíneo Regional , Factores de Riesgo , Piel/irrigación sanguínea , Adulto JovenRESUMEN
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.