The neurocirculatory responses to exercise are exaggerated in hypertension, increasing cardiovascular risk, yet the mechanisms remain incompletely understood. The aim of this study was to examine the in vitro effectiveness of pyridoxal-5-phosphate as a purinergic (P2) receptor antagonist in isolated murine dorsal root ganglia (DRG) neurons and the in vivo contribution of P2 receptors to the neurocirculatory responses to exercise in older adults with moderately elevated systolic blood pressure (BP). In vitro, pyridoxal-5-phosphate attenuated the ATP-induced increases in [Ca 2ϩ ]i (73 Ϯ 15 vs. 11 Ϯ 3 nM; P Ͻ 0.05). In vivo, muscle sympathetic nerve activity (MSNA; peroneal microneurography) and arterial BP (Finometer) were assessed during exercise pressor reflex activation (static handgrip followed by postexercise ischemia; PEI) during a control trial (normal saline) and localized P2 receptor blockade (pyridoxal-5-phosphate). Compared with normotensive adults (63 Ϯ 2 yr, 117 Ϯ 2/70 Ϯ 2 mmHg), adults with moderately elevated systolic BP (65 Ϯ 1 yr, 138 Ϯ 5/79 Ϯ 3 mmHg) demonstrated greater increases in MSNA and BP during handgrip and PEI. Compared with the control trial, local antagonism of P2 receptors during PEI partially attenuated MSNA (39 Ϯ 4 vs. 34 Ϯ 5 bursts/min; P Ͻ 0.05) in adults with moderately elevated systolic BP. In conclusion, these data demonstrate pyridoxal-5-phosphate is an effective P2 receptor antagonist in isolated DRG neurons, which are of particular relevance to the exercise pressor reflex. Furthermore, these findings indicate that exercise pressor reflex function is exaggerated in older adults with moderately elevated systolic BP and further suggest a modest role of purinergic receptors in evoking the abnormally large reflex-mediated increases in sympathetic activity during exercise in this clinical population.hypertension; metaboreflex; muscle sympathetic nerve activity; calcium imaging; dorsal root ganglia AUGMENTED PRESSOR RESPONSES to exercise are associated with adverse cardiovascular and cerebrovascular events during and after physical activity (22,34,45). Additionally, nonhypertensive individuals with an exaggerated blood pressure (BP) response to exercise are more likely to develop clinical hypertension (12, 53) and are at higher risk of cardiovascular death compared with those with a normal BP response (57, 61). This risk is further modified by baseline hypertension status (61), making exaggerated BP responses to acute exercise especially problematic in adults with chronically elevated resting BP. Resting systolic BP increases with advancing age, such that ϳ65% of older adults have a resting systolic BP in the high-normal or stage I hypertensive range (i.e., 130 -159 mmHg) (5, 16, 40). Therefore, examining neurocirculatory regulation during exercise in this population is clinically relevant.Muscle contraction causes intensity-dependent increases in arterial BP, heart rate (HR), and sympathetic nerve activity (SNA). Afferent feedback from the exercising skeletal muscle is an import...

Young adults with a family history of hypertension (+FH) have increased risk of developing hypertension. Furthermore, the blood pressure (BP) response to sympathoexcitatory stimuli in young adults can predict the future development of hypertension. Therefore, we hypothesized young women with a +FH would have exaggerated cardiovascular and sympathetic reactivity compared with young women without a family history of hypertension (-FH). Beat-by-beat mean arterial pressure (MAP) and muscle sympathetic nerve activity (MSNA) were measured in 14 women +FH (22 ± 1 yr, 21 ± 1 kg/m(2), MAP 80 ± 2 mmHg) and 15 women -FH (22 ± 1 yr, 22 ± 1 kg/m(2), MAP 78 ± 2 mmHg) during acute sympathoexcitatory maneuvers: cold pressor test, 2 min of isometric handgrip (HG) exercise at 30% of maximal voluntary contraction, and 3 min of postexercise ischemia (PEI; isolated activation of the skeletal muscle metaboreflex). During cold pressor test, the increase in BP was greater in women +FH (ΔMAP: +FH 16 ± 2 vs. -FH 11 ± 1 mmHg, P < 0.05), which was accompanied by an exaggerated increase in MSNA (ΔMSNA: +FH 17 ± 2 vs. -FH 8 ± 2 burst/min, P < 0.05). The increase in BP was greater in +FH during the last minute of HG (ΔMAP: +FH 23 ± 3 vs. -FH 12 ± 1 mmHg, P < 0.05) and during PEI (ΔMAP: +FH 17 ± 3 vs. -FH 9 ± 2 mmHg, P < 0.05). Similarly, the increase in MSNA was greater in +FH during both HG (ΔMSNA: +FH 12 ± 2 vs. -FH 6 ± 2 burst/min, P < 0.05) and PEI (ΔMSNA: +FH 16 ± 2 vs. -FH 4 ± 2 burst/min, P < 0.05). These data demonstrate that +FH women have greater BP and sympathetic reactivity compared with -FH women.

Recent studies demonstrate that high dietary sodium (HS) impairs endothelial function in those with salt-resistant (SR) blood pressure (BP). The effect of HS on endothelial function in those with salt-sensitive (SS) BP is not currently known. We hypothesized that HS would impair brachial artery flow-mediated dilation (FMD) to a greater extent in SS compared with SR adults. Ten SR (age 42 ± 5 yr, 5 men, 5 women) and 10 SS (age 39 ± 5 yr, 5 men, 5 women) healthy, normotensive participants were enrolled in a controlled feeding study consisting of a run-in diet followed by a 7-day low dietary sodium (LS) (20 mmol/day) and a 7-day HS (300 mmol/day) diet in random order. Brachial artery FMD and 24-h BP were assessed on the last day of each diet. SS BP was individually assessed and defined as a change in 24-h mean arterial pressure (MAP) of >5 mmHg between the LS and HS diets (ΔMAP: SR -0.6 ± 1.2, SS 7.7 ± 0.4 mmHg). Brachial artery FMD was lower in both SS and SR individuals during the HS diet (P < 0.001), and did not differ between groups (P > 0.05) (FMD: SR LS 10.6 ± 1.3%, SR HS 7.2 ± 1.5%, SS LS 12.5 ± 1.7%, SS HS 7.8 ± 1.4%). These data indicate that an HS diet impairs brachial artery FMD to a similar extent in adults with SS BP and SR BP.

Background and Aims Dietary sodium loading has been shown to adversely impact endothelial function independently of blood pressure (BP). However, it is unknown whether dietary sodium loading impacts endothelial function differently in men as compared to women. The aim of this study was to test the hypothesis that endothelial-dependent dilation (EDD) would be lower in men as compared to women in response to a high sodium diet. Methods and Results Thirty subjects (14F, 31±2y; 16M, 29±2y) underwent a randomized, crossover, controlled diet study consisting of 7 days of low sodium (LS; 20 mmol/day) and 7 days of high sodium (HS; 300–350 mmol/day). Salt-resistance was determined by a change in 24-hr mean arterial pressure (MAP)≤ 5 mmHg between HS and LS as assessed on day 7 of each diet. Blood and 24-hr urine were also collected and EDD was assessed by brachial artery flow-mediated dilation(FMD). By design, MAP was not different between LS and HS conditions and urinary sodium excretion increased on HS diet (p<0.01). FMD did not differ between men and women on the LS diet (10.2±0.65 vs. 10.7±0.83; p>0.05) and declined in both men and women on HS (p<0.001). However, FMD was lower in men as compared to women on HS (5.7±0.5 vs. 8.6±0.86; p<0.01). Conclusions HS reduced FMD in both men and women. In response to a HS diet, FMD was lower in men compared to women suggesting a greater sensitivity of the vasculature to high sodium in men.

It has previously been shown that high dietary salt impairs vascular function independent of changes in blood pressure. Rodent studies suggest that NADPH-derived reactive oxygen species mediate the deleterious effect of high salt on the vasculature, and here we translate these findings to humans. Twenty-nine healthy adults (34 ± 2 yr) participated in a controlled feeding study. Participants completed 7 days of a low-sodium diet (LS; 20 mmol sodium/day) and 7 days of a high-sodium diet (HS; 300 mmol sodium/day) in random order. All participants were salt resistant, defined as a ≤5-mmHg change in 24-h mean BP determined while on the LS and HS diets. Laser Doppler flowmetry was used to assess cutaneous vasodilation in response to local heating (42°C) during local delivery of Ringer’s ( n = 29), 20 mM ascorbic acid (AA; n = 29), 10 µM Tempol ( n = 22), and 100 µM apocynin ( n = 22). Additionally, endothelial cells were obtained in a subset of participants from an antecubital vein and stained for nitrotyrosine ( n = 14). Cutaneous vasodilation was attenuated by the HS diet compared with LS [LS 93.0 ± 2.2 vs. HS 86.8 ± 2.0 percentage of maximal cutaneous vascular conductance (%CVCmax); P < 0.05] and was restored by AA during the HS diet (AA 90.7 ± 1.2 %CVCmax; P < 0.05 vs. HS). Cutaneous vasodilation was also restored with the local infusion of both apocynin ( P < 0.01) and Tempol ( P < 0.05) on the HS diet. Nitrotyrosine expression was increased on the HS diet compared with LS ( P < 0.05). These findings provide direct evidence of dietary sodium-induced endothelial cell oxidative stress and suggest that NADPH-derived reactive oxygen species contribute to sodium-induced declines in microvascular function. NEW & NOTEWORTHY High-sodium diets have deleterious effects on vascular function, likely mediating, in part, the increased cardiovascular risk associated with a high sodium intake. Local infusion of apocynin and Tempol improved microvascular function in salt-resistant adults on a high-salt diet, providing evidence that reactive oxygen species contribute to impairments in microvascular function from high salt. This study provides insight into the blood pressure-independent mechanisms by which dietary sodium impairs vascular function. Listen to this article’s corresponding podcast at https://ajpheart.podbean.com/e/dietary-sodium-oxidative-stress-and-microvascular-function/ .

Introduction: Postmenopausal women (PMW) display exaggerated increases in blood pressure (BP) during exercise, yet the mechanism(s) involved remain unclear. Moreover, research on the impact of menopausal changes in estradiol on cardiovascular control during exercise are limited. Herein, we tested the hypothesis that sympathetic responses during exercise are augmented in PMWcompared with young women (YW), and estradiol administration attenuates these responses. Methods: Muscle sympathetic nerve activity (MSNA) and mean arterial pressure (MAP) were measured in 13 PMW (58 ± 1 yr) and 17 YW (22 ± 1 yr) during 2 min of isometric handgrip. Separately, MSNA and BP responses were measured during isometric handgrip in six PMW (53 ± 1 yr) before and after 1 month of transdermal estradiol (100 μg•d −1 ). A period of postexercise ischemia (PEI) to isolate muscle metaboreflex activation followed all handgrip bouts. Results: Resting MAP was similar between PMW and YW, whereas MSNA was greater in PMW (23 ± 3 vs 8 ± 1 bursts per minute; P < 0.05). During handgrip, the increases in MSNA (PMW Δ16 ± 2 vs YW Δ6 ± 1 bursts per minute; P < 0.05) and MAP (PMW Δ18 ± 2 vs YW Δ12 ± 2 mm Hg; P < 0.05) were greater in PMW and remained augmented during PEI. Estradiol administration decreased resting MAP but not MSNA in PMW. Moreover, MSNA (PMW (−E2) Δ27 ± 8 bursts per minute versus PMW (+E2) Δ12 ± 5 bursts per minute; P < 0.05) and MAP (Δ31 ± 8 mm Hg vs Δ20 ± 6 mm Hg; P < 0.05) responses during handgrip were attenuated in PMW after estradiol administration. Likewise, MAP responses during PEI were lower after estradiol. Conclusions: These data suggest that PMW exhibit an exaggerated MSNA and BP response to isometric exercise, due in part to heightened metaboreflex activation. Furthermore, estradiol administration attenuated BP and MSNA responses to exercise in PMW.

Hypertensive adults demonstrate atypical increases in blood pressure (BP) and muscle sympathetic nerve activity (MSNA) at the immediate onset of static muscle contraction. However, it is unknown whether these abnormal responses occur in young, otherwise healthy adults at risk for developing future disease, such as those with a family history of hypertension (+FH). We tested the hypothesis that +FH young women have exaggerated increases in BP and MSNA at the onset of static muscle contraction compared to those without a family history of hypertension (-FH). We retrospectively examined beat-by-beat BP and MSNA during the initial 30 seconds of isometric handgrip exercise (30% of maximum voluntary contraction) in 16 +FH (22±2yrs, 22±3kg•m-2) and 16 -FH (22±3yrs, 22±3kg•m-2) women. Resting mean arterial pressure (MAP; +FH 80±11 vs. -FH 84±13mmHg), MSNA burst frequency (+FH 7±3 vs. -FH 9±5bursts•min-1), and burst incidence (+FH 12±4 vs. -FH 12±8bursts•100 heartbeats -1) were similar between groups (all P>0.05). Within the first 10 seconds of exercise, changes in MAP (+FH Δ8±6 vs. -FH Δ3±2 mmHg, P<0.05) and HR (+FH Δ8±5 vs. -FH Δ4±4 mmHg, P<0.05) were greater in +FH women. Absolute MSNA burst frequency during the first 30 seconds of exercise was not different between groups (-FH: 7±5 vs. +FH: 9±3 bursts/min). Cardiovascular and sympathetic responses during cold pressor test were not different between groups. These data demonstrate that young women at risk for developing cardiovascular disease exhibit greater changes in BP at the onset of static muscle contraction.

Impaired nocturnal blood pressure (BP) dipping (i.e., <10% decline in nocturnal BP) is associated with an increased risk of cerebrovascular and cardiovascular diseases. Excess sodium has been shown to impair BP regulation and increase cardiovascular disease risk, yet few studies have assessed the influence of dietary sodium on nocturnal dipping in normotensive adults. The purpose of this study was to determine the effects of dietary sodium on BP dipping in normotensive men and women. Eighty healthy normotensive adults participated in a controlled feeding study (men: n=39, 34±2 yrs; women: n=41, 41±2 yrs). Participants consumed a standardized run-in 100 mmol sodium·day−1 diet for 7 days, followed by 7 days of low sodium (LS; 20 mmol·day−1) and high sodium (HS; 300 mmol·day−1) diets in random order. On the final day of each diet, subjects wore a 24h ambulatory BP monitor, collected a 24h urine sample, and provided a blood sample. During the run-in diet, 24h urinary sodium excretion was 79.4±5.1 mmol·24h−1 in men and 85.3±5.5 mmol·24h−1 in women (p>0.05). Systolic BP dipping was not different between men (11.4±1.0%) and women (11.2±0.9%) (p>0.05). During the HS diet, 24h urinary sodium excretion increased compared to the LS diet in men (LS=31.7±4.6 mmol·24h−1 vs. HS=235.0±13.9 mmol·24h−1, p<0.01) and women (LS=25.8±2.2 mmol·24h−1 vs. HS=234.7±13.8 mmol·24h−1, p<0.01). Despite this large increase in sodium intake and excretion, systolic BP dipping was not blunted in men (LS=8.9±1.0% vs. HS=9.4±1.2%, p>0.05) or women (LS=10.3±0.8% vs. HS=10.5±0.8%, p>0.05). Among normotensive men and women, HS does not blunt nocturnal BP dipping.