Greater Increase In Blood Pressure Research Articles

Both sexes develop DKD in the CD1 uninephrectomized streptozotocin mouse model

Diabetic kidney disease (DKD) is characterized by a progressive increase in albuminuria and typical pathologic features. Recent studies have shown that sex is an important factor to consider in the pathogenesis of DKD. Presently, the hallmarks of this disease have primarily been studied in male rodent models. Here we explored the influence of sex in a murine model of DKD. CD1 mice underwent a right nephrectomy followed by intraperitoneal injection with 200 mg/kg streptozotocin to induce type 1 diabetes. Due to a high mortality rate, females required a reduction in streptozotocin to 150 mg/kg. Mice were followed for 12 weeks. Both sexes developed comparable hyperglycemia, while albuminuria and glomerular volume were increased to a greater degree in females and kidney hypertrophy was only seen in females. Males had a greater increase in blood pressure and glomerular basement membrane thickening, and a greater decrease in endpoint weight. Serum TGFβ1 levels were increased only in females. However, both sexes showed a similar increase in induction of kidney fibrosis. T cell and macrophage infiltration were also increased in both sexes. While some differences were observed, overall, both sexes developed clinical and pathologic characteristics of early DKD. Future studies evaluating therapeutic interventions can thus be assessed in both sexes of this DKD model.

The Effect of Sitting Duration on Peripheral Blood Pressure Responses to Prolonged Sitting, With and Without Interruption: A Systematic Review and Meta-Analysis.

A previous meta-analysis reported that: (i) an acute bout of prolonged uninterrupted sitting induces a significant increase in peripheral blood pressure (BP) and (ii) the increase in BP can be offset by interrupting the sitting bout with light aerobic activities such as walking. However, the temporal association between prolonged uninterrupted sitting and BP was not determined. A better understanding of temporality, for example, how long it takes BP to increase, will assist in prescribing sitting interruption strategies. We aimed to determine: (1) the temporal association between the duration of uninterrupted sitting and BP and (2) whether regular sitting interruptions moderate the association between uninterrupted sitting and BP. Electronic databases (PubMed, Web of Science, SPORTDiscus) were searched from inception to July 2022. Reference lists of eligible studies and relevant reviews were also screened. Inclusion criteria for objective (1) were: (i) participants aged ≥ 18years; (ii) a prolonged sitting bout ≥ 1h; and (iii) peripheral BP measurements (systolic BP, diastolic BP, and/or mean arterial pressure) at more than two timepoints during the sitting bout. Additional criteria for objective (2) were: (i) the sitting interruption strategy was implemented during the sitting bout (i.e., not prior to engaging in sitting) and (ii) the study included a control (uninterrupted sitting) condition or group. There were 1555 articles identified, of which 33 met inclusion criteria for objective (1). Of those articles, 20 met inclusion criteria for objective (2). To investigate the effect of sitting duration on the BP response, unstandardized b coefficients (mmHg/h) and 95% confidence intervals (CIs) were calculated using a three-level mixed-effect meta-regression. Increased sitting duration was positively associated with systolic BP (b = 0.42mmHg/h, 95% CI 0.18-0.60), diastolic BP (b = 0.24mmHg/h, 95% CI 0.06-0.42), and mean arterial pressure (b = 0.66mmHg/h, 95% CI 0.36-0.90). In trials where sitting was interrupted, there was a significant decrease in systolic BP (b = - 0.24mmHg/h, 95% CI - 0.42 to - 0.06) and diastolic BP (b = - 0.24mmHg/h, 95% CI - 0.42 to - 0.12), and a non-significant change in mean arterial pressure (p = 0.69). Increased uninterrupted sitting duration results in greater increases in BP; however, regularly interrupting sitting may offset negative effects.

Acute nitric oxide synthase inhibition induces greater increases in blood pressure in female versus male Wistar Kyoto rats.

Nitric oxide (NO) contributes to blood pressure (BP) regulation via its vasodilatory and anti-inflammatory properties. We and others previously reported sex differences in BP in normotensive and hypertensive rat models where females have lower BP than age-matched males. As females are known to have greater NO bioavailability than age-matched males, the current study was designed to test the hypothesis that anesthetized female normotensive Wistar Kyoto rats (WKY) are more responsive to acute NOS inhibition-induced increases in BP compared to male WKY. Twelve-week-old male and female WKY were randomized to infusion of the nonspecific NOS inhibitor NG -nitro-L-arginine methyl ester (L-NAME, 1 mg/kg/min) or selective NOS1 inhibition with vinyl-L-NIO (VNIO, 0.5 mg/kg/min) for 60 min. Mean arterial BP, glomerular filtration rate (GFR), urine volume, and electrolyte excretion were assessed before, and during L-NAME or VNIO infusion. L-NAME and VNIO significantly increased BP in both sexes; however, the increase in BP with L-NAME infusion was greater in females versus males compared to baseline BP values. Acute infusion of neither L-NAME nor VNIO for 60 min altered GFR in either sex. However, urine volume, sodium, chloride and potassium excretion levels increased comparably in male and female WKY with L-NAME and VNIO infusion. Our findings suggest sex differences in BP responses to acute non-isoform-specific NOS inhibition in WKY, with females being more responsive to L-NAME-induced elevations in BP relative to male WKY. However, sex differences in the BP response did not coincide with sex differences in renal hemodynamic responses to acute NOS inhibition.

SARS-CoV-2 Spike Protein S1 Exposure Increases Susceptibility to Angiotensin II-Induced Hypertension in Rats by Promoting Central Neuroinflammation and Oxidative Stress.

The SARS-CoV-2 spike S1 subunit (S1) can cross the blood-brain barrier and elicit neuroinflammatory response independent of viral infection. Here we examined whether S1 influences blood pressure (BP) and sensitizes the hypertensive response to angiotensin (ANG) II by enhancing neuroinflammation and oxidative stress in hypothalamic paraventricular nucleus (PVN), a key brain cardiovascular regulatory center. Rats received central S1 or vehicle (VEH) injection for 5days. One week after injection, ANG II or saline (control) was subcutaneously delivered for 2weeks. S1 injection induced greater increases in BP, PVN neuronal excitation and sympathetic drive in ANG II rats but had no effects in control rats. One week after S1 injection, mRNA for proinflammatory cytokines and oxidative stress marker were higher but mRNA of Nrf2, the master regulator of inducible antioxidant and anti-inflammatory responses, was lower in the PVN in S1-injected rats than in VEH-injected rats. Three weeks after S1 injection, mRNA for proinflammatory cytokines and oxidative stress marker, microglia activation and reactive oxygen species in the PVN were comparable between S1 and VEH treated control rats but were elevated in two groups of ANG II rats. Notably, ANG II-induced elevations in these parameters were exaggerated by S1. Interestingly, ANG II increased PVN Nrf2 mRNA in VEH-treated rats but not in S1-treated rats. These data suggest that S1 exposure has no effect on BP, but post-S1 exposure increases susceptibility to ANG II-induced hypertension by downregulating PVN Nrf2 to promote neuroinflammation and oxidative stress and augment sympathetic excitation.

Arterial stiffness and blood pressure increase in pediatric kidney transplant recipients

BackgroundPulse wave velocity (PWV) is a measure of arterial stiffness. We investigated PWV and blood pressure (BP) to determine to what extent BP changes contribute to arterial stiffness, and secondly, to identify influencing factors on BP in children after kidney transplantation.MethodsSeventy children ≥ 2.5 years post-transplantation with at least two PWV measurements were included. Changes of systolic (Δ SBP) and diastolic BP (Δ DBP) were classified into “stable/decreasing,” “1–10 mmHg increase,” and “ > 10 mmHg increase.” Linear mixed modeling for PWV z-score (PWVz) adjusted either for Δ SBP or Δ DBP was performed. An extended dataset with monthly entries of BP, immunosuppression, and creatinine was obtained in 35 participants over a median of 74 months to perform linear mixed modeling for SBP and DBP.ResultsPWVz increased with a rate of 0.11/year (95% CI 0.054 to 0.16). Compared to participants with stable BP, those with 1–10-mmHg SBP and DBP increase showed a higher PWVz of 0.59 (95% CI 0.046 to 1.13) and 0.86 (95% CI 0.43 to 1.30), respectively. A > 10-mmHg BP increase was associated with an even higher PWVz (SBP β = 0.78, 95% CI 0.22 to 1.34; DBP β = 1.37, 95% CI 0.80 to 1.94). Female sex and participants with lower eGFR showed higher PWVz.In the extended analysis, DBP was positively associated with cyclosporin A and everolimus trough levels.ConclusionsA higher increase of PWV is seen in patients with greater BP increase, with higher cyclosporin A and everolimus trough levels associated with higher BP. This emphasizes the role of BP as a modifiable risk factor for the improvement of cardiovascular outcome after transplantation.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information

Is Exercise Blood Pressure Putting the Brake on Exercise Rehabilitation after Acute Type A Aortic Dissection Surgery?

(1) Background: Exercise is recommended to improve physical fitness in patients recovering from acute type A aortic dissection (ATAAD). However, surgery corrects the diseased blood vessels and reduces the risk of ATAAD, but it does not redefine a safe exercise blood pressure (BP) threshold. This review aimed to discuss whether the safe threshold of exercise BP can be upregulated after ATAAD surgery to increase exercise intensity with additional benefits. (2) Data sources: The PubMed databases were searched with the keywords “type A acute aortic dissection surgery”, “exercise”, “BP”, “stress”, and variations of these terms. (3) Study selection: Data from clinical trials, guidelines, and recent reviews were selected for review. (4) Results: Regular exercise can be considered a cardioprotective intervention for aortic dissection patients by attenuating hemodynamic responses at rest and during exercise. Previous studies have mainly focused on moderate-intensity aerobic exercise. In practice, the exercise systolic BP of some patients was higher than 160 mm Hg without adverse events, which indicates that the training intensity may be underestimated for patients after ATAAD surgery. Limited studies suggest a light-to-moderate resistance training for selected patients because it may cause a greater increase in BP. (5) Conclusions: Moderate-intensity continuous aerobic exercise supplemented by low-intensity resistance training is appropriate for cardiac rehabilitation after ATAAD surgery. The BP increase based on the normal exercise BP response, corresponding to the moderate-intensity is relatively safe. For high-risk post-ATAAD patients, considering the overall volume of training, personalizing the exercise regimen to remain within “safe” BP limits, and avoiding excessive fluctuations in BP should be the primary considerations for exercise training.

Anxiety Disorder Associated with the COVID-19 Pandemic Causes Deterioration of Blood Pressure Control in Primary Hypertensive Patients.

ObjectiveThe new coronavirus disease (COVID-19) has spread rapidly all over the world and caused anxiety disorders. Recent studies have also shown that the prevalence of depression and anxiety increased during the COVID-19 outbreak. We aimed to evaluate the anxiety and depression levels during the pandemic and identify the effect of pandemic-related stress on blood pressure (BP) control in primary hypertensive patients.MethodA total of 142 patients with primary hypertension (HT) who continued to use the same antihypertensive drugs before and during the pandemic were included in the study. Twenty-four -hour Ambulatory Blood Pressure Monitoring (ABPM) and the Hospital Anxiety and Depression Scale (HADS) questionnaire were applied to patients. We retrospectively reviewed 24-h ABPM records of the same patients for the year before the pandemic.ResultsDaytime, nighttime and 24 -hour-systolic blood pressure (SBP) levels as well as daytime, nighttime, and 24- hour-diastolic blood pressure (DBP) levels , were significantly elevated during the COVID-19 outbreak compared to the pre-pandemic period (p<0.001). Higher HADS-A scores (HADS-A ≥7) were significantly associated with much greater increase in BP compared to the patients with lower HADS-A scores.ConclusionPsychological stress due to the COVID-19 outbreak led to worsening of the regulation of BP in controlled hypertensive patients whose antihypertensive treatments did not change.

HIF-1α inhibition alleviates the exaggerated exercise pressor reflex in rats with peripheral artery disease induced by femoral artery occlusion.

Hypoxia‐inducible factor 1α (HIF‐1α) is a transcription factor mediating adaptive responses to hypoxia and ischemia. Our previous work showed that HIF‐1α is increased in muscle sensory nerves of rats with peripheral artery disease (PAD) induced by femoral artery occlusion. The present study was further to examine the role played by HIF‐1α in regulating the response of arterial blood pressure (BP) to the activation of muscle afferent nerve during static muscle contraction in rats with femoral artery occlusion. A rat model of femoral artery ligation was used to study PAD in this study. Western blot analysis was employed to examine the protein levels of HIF‐1α in the dorsal root ganglion (DRG) tissues. BAY87, a synthesized compound with the characteristics of highly potent and specific suppressive effects on expression and activity of HIF‐1α, was given into the arterial blood supply of the ischemic hindlimb muscles before the exercise pressor reflex was evoked by static muscle contraction. First, HIF‐1α was increased in the DRG of occluded limbs (optical density: 0.89 ± 0.13 in control versus 1.5 ± 0.05 in occlusion; p < 0.05, n = 6 in each group). Arterial injection of BAY87 (0.2 mg/kg) then inhibited expression of HIF‐1α in the DRG of occluded limbs 3 hr following its injection (optical density: 1.02 ± 0.09 in occluded limbs with BAY87 versus 1.06 ± 0.1 in control limbs; p > 0.05, n = 5 in each group). In addition, muscle contraction evoked a greater increase in BP in occluded rats. BAY87 attenuated the enhanced BP response in occluded rats to a greater degree than in control rats. Our data suggest that the inhibition of HIF‐1α alleviates the exaggeration of the exercise pressor reflex in rats under ischemic circumstances of the hindlimbs in PAD induced by femoral artery occlusion.

The Relationship Between Urine Uromodulin and Blood Pressure Changes: The DASH-Sodium Trial.

Uromodulin modulates the sodium-potassium-two-chloride transporter in the thick ascending limb of the loop of Henle, and its overexpression in murine models leads to salt-induced hypertension. We hypothesized that individuals with higher baseline levels of urine uromodulin would have a greater increase in systolic blood pressure (SBP) for the same increase in sodium compared with those with lower uromodulin levels. We used data from 157 subjects randomized to the control diet of the Dietary Approaches to Stop Hypertension (DASH)-Sodium trial who were assigned to 30 days of low (1,500 mg/d), medium (2,400 mg/d), and high salt (3,300 mg/d) diets in random order. Blood pressure was measured prerandomization and then weekly during each feeding period. We evaluated the association of prerandomization urine uromodulin with change in SBP between diets, as measured at the end of each feeding period, using multivariable linear regression. Baseline urine uromodulin stratified by tertiles was ≤17.64, 17.65-31.97, and ≥31.98 µg/ml. Across the tertiles, there were no significant differences in SBP at baseline, nor was there a differential effect of sodium diet on SBP across tertiles (low to high, P = 0.81). After adjusting for age, sex, body mass index, and race, uromodulin levels were not significantly associated with SBP change from low to high sodium diet (P = 0.42). In a randomized trial of different levels of salt intake, higher urine uromodulin levels were not associated with a greater increase in blood pressure in response to high salt intake.

Blood pressure, T cells, and mortality in people with HIV in Tanzania during the first 2years of antiretroviral therapy.

Cardiovascular disease is now a leading cause of mortality in people with HIV (PWH). High blood pressure is the major driver of cardiovascular disease. Despite this, little is known about blood pressure in PWH during the early years of antiretroviral therapy (ART). In this prospective cohort study in Tanzania, the authors conducted unobserved blood pressure measurements at enrollment, 3, 6, 12, 18, and 24months in 500 PWH initiating ART and 504 HIV-uninfected adults. The authors excluded measurements taken on antihypertensive medications. Although PWH had a significantly lower blood pressure before ART initiation, they had a significantly greater increase in blood pressure during the first 2years of ART compared to HIV-uninfected controls. Blood pressure correlates in PWH differed from HIV-uninfected controls. In PWH, lower baseline CD4+ T-cell counts were associated with lower blood pressure, and greater increases in CD4+ T-cell counts on ART were associated with greater increases in blood pressure, both on average and within individuals. In addition, PWH with a systolic blood pressure (SBP) <90mmHg at the time of ART initiation had ~30% mortality in the following 3months due to occult infections. These patients require careful investigation for occult infections, and those with tuberculosis may benefit from corticosteroids.

Greater T Regulatory Cells in Females Attenuate DOCA-Salt-Induced Increases in Blood Pressure Versus Males.

Hypertension is the most common risk factor for cardiovascular disease, causing over 18 million deaths a year. Although the mechanisms controlling blood pressure (BP) in either sex remain largely unknown, T cells play a critical role in the development of hypertension. Further evidence supports a role for the immune system in contributing to sex differences in hypertension. The goal of the current study was to first, determine the impact of sex on the renal T-cell profiles in DOCA-salt hypertensive males and females and second, test the hypothesis that greater numbers of T regulatory cells (Tregs) in females protect against DOCA-salt-induced increases in BP and kidney injury. Male rats displayed greater increases in BP than females following 3 weeks of DOCA-salt treatment, although increases in renal injury were comparable between the sexes. DOCA-salt treatment resulted in an increase in proinflammatory T cells in both sexes; however, females had more anti-inflammatory Tregs than males. Additional male and female DOCA-salt rats were treated with anti-CD25 to decrease Tregs. Decreasing Tregs significantly increased BP only in females, thereby abolishing the sex difference in the BP response to DOCA-salt. This data supports the hypothesis that Tregs protect against the development of hypertension and are particularly important for the control of BP in females.

Combined influence of inspiratory loading and locomotor subsystolic cuff inflation on cardiovascular responses during submaximal exercise.

It is unknown if simultaneous stimulation of the respiratory and locomotor muscle afferents via inspiratory loading (IL) and locomotor subsystolic cuff inflation (CUFF) influences the cardiovascular responses during exercise. We hypothesized that combined IL and CUFF (IL + CUFF) will result in greater increases in blood pressure (MAP) and systemic vascular resistance (SVR) than IL and CUFF alone during exercise. Eight adults (6 males/2 females) were enrolled and performed four 10-min bouts of constant-load cycling eliciting 40% maximal oxygen uptake on a single day. For each exercise bout, the first 5 min consisted of spontaneous breathing. The second 5 min consisted of voluntary hyperventilation (i.e., breathing frequency of 40 breaths/min) with IL (30% maximum inspiratory pressure), CUFF (80 mmHg), IL + CUFF, or no intervention (CTL) in randomized order. During exercise, cardiac output and MAP were determined via open-circuit acetylene wash-in and manual sphygmomanometry, respectively, and SVR was calculated. Across CTL, IL, CUFF, and IL + CUFF, MAP was greater with each condition (CTL: 97 ± 14; IL: 106 ± 13; CUFF: 114 ± 14; IL + CUFF: 119 ± 15 mmHg, all P < 0.02). Furthermore, SVR was greater with IL + CUFF compared with IL, CUFF, and CTL (CTL: 6.6 ± 1.1; IL: 7.5 ± 1.4; CUFF: 7.5 ± 1.3; IL + CUFF: 8.2 ± 1.4 mmHg·L-1·min-1, all P < 0.02). Cardiac output was not different across conditions (CTL: 15.2 ± 3.8; IL: 14.8 ± 3.7; CUFF: 15.6 ± 3.5; IL + CUFF: 14.7 ± 4.3 L/min, all P > 0.05). These data demonstrate that simultaneous stimulation of respiratory and locomotor muscle afferent feedback results in additive MAP and SVR responses than IL and CUFF alone during submaximal exercise. These findings have important clinical implications for populations with exaggerated locomotor and respiratory muscle reflex feedbacks.NEW & NOTEWORTHY Reflexes arising from the respiratory and locomotor muscles influence cardiovascular regulation during exercise. However, it is unclear how the respiratory and locomotor muscle reflexes interact when simultaneously stimulated. Herein, we demonstrate that stimulation of the respiratory and locomotor muscle reflexes yielded additive cardiovascular responses during submaximal exercise.

Increases in renal segmental artery vascular resistance acutely provoked by soft drink consumption are likely caused by high fructose corn syrup

Regular excessive sugar‐sweetened soft drink consumption is associated with a higher risk of chronic kidney disease. Despite this association, relatively little is known about the acute physiological effects of soft drink consumption. High fructose corn syrup (HFCS) sweetened soft drinks elicit greater increases in blood pressure compared to soft drinks sweetened with sucrose. We have identified that, compared to drinking water, consuming a HFCS sweetened soft drink increases vascular resistance in the segmental arteries in the kidneys. It is unknown if this observation is unique to the HFCS in the soft drink or whether other beverage characteristics contributed to this response.PurposeTest the hypothesis that consuming a HFCS sweetened soft drink increases renal segmental artery vascular resistance compared to sucrose and artificially sweetened soft drinks, and water.MethodsTwelve healthy adults (24 ± 4 y, 2 females) participated in a randomized, double‐blind, quasi‐taste matched, crossover study. In four experimental trials, subjects drank 500 mL of a commercially available HFCS sweetened soft drink (HFCS, Mountain Dew®, osmolality: 846± 2 mOsm/kg), sucrose sweetened soft drink (SUCROSE, Mountain Dew Throwback®, osmolality: 730 ± 2 mOsm/kg), artificially sweetened soft drink (DIET, Diet Mountain Dew®, osmolality: 59 ± 2 mOsm/kg) and water (WATER, osmolality: 0 mOsm/kg) within a 5 min period. All soft drinks had a caffeine content of 77 mg. Data were collected following 20 min supine rest and 30 min post‐drinking. Blood pressure was measured in duplicate (sphygmomanometry). Renal and segmental artery blood velocities (BV) were obtained via Doppler ultrasound. Plasma osmolality was measured in venous blood samples. Vascular resistance (VR) in the renal and segmental arteries was calculated as mean arterial pressure (MAP) divided by BV. Data are presented as mean ± SD.ResultsThere were no differences between trials in MAP (P=0.90), renal artery BV (P=0.93) or VR (P=0.95), or segmental artery BV (P=0.32) or VR (P=0.28) pre‐drinking. Plasma osmolality increased post‐drinking of HFCS (by 2 ± 2 mOsm/kg, P=0.04) and SUCROSE (by 2 ± 2 mOsm/kg, P=0.04) but did not change with DIET (P=0.44) or WATER (P=0.98). MAP increased post‐drinking of SUCROSE (by 4 ± 4 mmHg, P=0.01) and DIET (by 4 ± 3 mmHg, P&lt;0.01) but not with HFSC (P=0.17) or WATER (P&gt;0.99). Renal artery BV increased post‐drinking of SUCROSE (by 2.6 ± 3.7 cm/s, P=0.04) but did not change with HFCS (P=0.43), DIET (P=0.99) or WATER (P=0.22). Renal artery VR did not change post‐drinking of HFCS (P=0.28), SUCROSE (P=0.31), DIET (P=0.77) or WATER (P=0.27). Drinking HFCS reduced segmental artery BV (by 1.6 ± 2.3 cm/s, P=0.01) but did not change with SUCROSE (P&gt;0.99), DIET (P=0.99) or WATER (P=0.95). Segmental artery VR increased post‐drinking of HFCS (by 0.34 ± 0.55 mmHg/cm/s, P=0.02) but did not change with SUCROSE (P=0.96), DIET (P=0.67) or WATER (P=0.72).ConclusionAcute increases in renal segmental artery vascular resistance following soft drink consumption were likely caused by HFCS in these drinks, and not beverage osmolality or caffeine content.

Are Blood Pressure and Cardiovascular Stress Greater in Isometric or in Dynamic Resistance Exercise?

Medical and sports medicine associations are reluctant to endorse isometric exercise to the same extent as dynamic resistance exercise (RE). The major concern is the fear of greater increases in blood pressure (BP) that might be associated with isometric exercise. This review comprehensively presents all human studies that directly compared the magnitude of hemodynamic responses between isometric and dynamic RE. We also discuss possible mechanisms controlling BP-response and cardiovascular adjustments during both types of RE. The most prominent finding was that isometric and dynamic RE using small-muscle mass evoke equal increases in BP; however, the circulatory adjustments contributing to this response are different in dynamic and isometric RE. In contrast, studies using large-muscle mass report inconsistent results for the magnitude of BP-response between the two types of RE. Thus, when the same muscles and workloads are used, the increase in BP during isometric and dynamic RE is more comparable to what is commonly believed. However, it should be noted that only a few studies equalized the workload in two types of RE, most used small sample sizes, and all studies employed healthy participants. More studies are needed to compare the cardiovascular risks associated with isometric and dynamic RE, especially in individuals with chronic disease.

Abstract P332: Urine Uromodulin Does Not Alter the Relationship Between Salt Intake and Blood Pressure: The DASH-Sodium Trial

Introduction: Genome-wide association studies have revealed susceptibility variants for hypertension in the UMOD gene. The encoded protein, uromodulin, modulates NKCC2 transporter in the thick ascending limb of the loop of Henle, and its overexpression in murine models leads to salt-induced hypertension. Hypothesis: Individuals with higher levels of urine uromodulin will have a greater increase in systolic blood pressure compared to those with lower uromodulin levels. Methods: We used data from 157 subjects in the control diet of the DASH-Sodium trial assigned to 30 days of low (1500 mg/d), medium (2400 mg/d), and high salt (3300 mg/d) diets in random order. Blood pressure was measured at baseline and at 5 visits during the last 9 days of each feeding period. We evaluated the association of urine uromodulin with change in systolic blood pressure between diets, as measured by the average at the end of each feeding period, using multivariable linear regression. Results: Baseline urine uromodulin stratified by tertiles was less than or equal to 17.64, 17.65 - 31.97, and greater than or equal to 31.98 μg/mL (overall mean 30.0 μg/mL, SEM 1.85 μg/mL). Across the tertiles, there were no significant differences in systolic blood pressure (SBP) at baseline, nor was there a differential effect of sodium diet on SBP across tertiles (low to high p = 0.81, Figure). After adjusting for age, sex, BMI, and race, uromodulin levels were not significantly associated with SBP change from low to high sodium diet (β = -0.68 per 10 μg/mL increase in urine uromodulin, p = 0.28). Conclusion: In a randomized trial of different levels of salt intake, higher urine uromodulin levels were not associated with a greater increase in blood pressure in response to high salt intake. Further human studies are needed to evaluate the findings seen in animal models, where the expression of higher levels of urine uromodulin has been associated with salt sensitive hypertension.

Abstract P3035: Role of T Cells in Sex Differences in Blood Pressure Elevation and Adipose Tissue Expansion Following Chronic High Fat Diet Feeding in Dahl Rats

Diets high in saturated fats are increasingly linked to the development of hypertension, yet the mechanisms by which high saturated fat diet (HFD) increases blood pressure remain unclear. Although young women are typically protected from hypertension relative to age-matched men, recent studies suggest that the cardiovascular protection in young women is compromised by chronic consumption of a HFD. We hypothesize that chronic HFD treatment causes a greater increase in blood pressure in females via sex-specific activation and recruitment of T cells and adipocyte expansion. Male and female Dahl rats (n=4-5) were placed on HFD at 8 wks of age. After 4 wks of HFD, blood pressure (BP) significantly increased in male and female Dahl rats to a comparable degree. Although BP continued to increase over the course of 10 wks of HFD treatment, female rats have a greater increases in BP (~40 mmHg increase in BP) after 10 weeks of HFD vs. males (~20 mmHg increase in BP). Fat pad weight and adipose tissue expansion increased in WT rats of both sexes following 10 wks of HFD treatment, yet females exhibited greater increases in fat pad weight and adipose tissue expansion vs. males. To determine whether T cells contributes to sex differences in BP elevation in Dahl rats fed HFD, we utilized Dahl rats lacking CD247 which encodes the T cell receptor CD3 chain that is required for T cell signaling. 10 wks of HF feeding did not change BP in either sex of Dahl CD247 KO rats. There were attenuated increases in fat pad weight and adipocyte expansion in Dahl CD247 KO rats and females exhibited more pronounced attenuations than males. Flow cytometric analysis revealed that HFD decreased Tregs and increased Th17 cells in both sexes of Dahl WT rats and females on HFD had the most pro-inflammatory T cell profile indicted by the Th17 cells:Tregs ratio. Our data suggest that greater adipocyte expansion with a HFD feeding in female Dahl rats vs. male might result in greater recruitment and activation of pro-inflammatory T cells and larger increases in BP.

Splenectomy Increases Blood Pressure and Alters the Renal T Cell Profile in a Sex‐Specific Manner in Spontaneously Hypertensive Rats

Over the past decade there has been increasing evidence for the role of the immune system in the development of hypertension. Our lab has previously reported that female Spontaneously Hypertensive Rats (SHR) have a blood pressure (BP)‐dependent increase in anti‐inflammatory regulatory T cells (Tregs), corresponding to lower BP compared to males. Based on the central role for immune cells in the control of BP and the known sex differences in the immune cell profile, the current study was designed to test the hypothesis that removal of the spleen will have a sex‐specific impact on BP in SHR. To test this hypothesis, baseline systolic BP was measured by tail cuff plethysmyography in male and female SHR. Rats were randomized to receive sham surgery (CON) or splenectomy (SPLNX, n=3). After 2 weeks, BP was recorded again and kidneys were harvested for flow cytometric analysis of T cells. BP was significantly higher in males compared to females at baseline and at Week 2 (Table, Effect of sex, p=0.0002 and p=0.0001, respectively, 2‐Way ANOVA). Splenectomy increased BP in both sexes after 2 weeks (Effect of SPLNX, p=0.0008), with females having a greater increase in BP than males (Interaction effect, p=0.05). Splenectomy did not alter total CD4+ cells in the kidney, but did affect the subpopulations of CD4+ cells. Renal Tregs (CD3+ CD4+ FoxP3+ cells, expressed as % CD3+ CD4+) decreased in both sexes after splenectomy, abolishing the sex differences in renal Tregs (Table, Effect of SPLNX, p&lt;0.001, Interaction effect, p=0.0015). Renal pro‐inflammatory Th17 cells (CD3+ CD4+ RORγ+ cells, expressed as % CD3+ CD4+) increased in both sexes with splenectomy (Table, Effect of SPLNX, p&lt;0.001). In conclusion, removing the spleen in male and female SHR significantly increased BP, with females having a greater increase in BP compared to males. Interestingly, this greater increase in BP in the female was accompanied by a greater reduction in renal Tregs, supporting the idea that renal Tregs play a critical role in BP control in female SHR, contributing to the sex difference in BP. Ongoing studies in the laboratory are further exploring the mechanisms for the relative increase in renal Tregs in females.Support or Funding InformationThis work was funded by AHA18POST34030252 to EEG and 5R01HL127091 to JCS.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Combined Influence of Subsytolic Circulatory Occlusion and Pedal Frequency on Cardiovascular Responses during Exercise in Younger and Older Adults

IntroductionPeripheral nervous system feedback arising from mechanically and metabolically sensitive afferents (Group III/IV, respectively) are central components of the exercise pressor reflex. Experimentally, locomotor venous distention can be simulated via subsytolic regional circulatory occlusion (SubRCO) thereby augmenting the exercise pressor reflex. Furthermore, high pedal frequency increases type II muscle fiber recruitment during exercise likely increasing non‐oxidative metabolism. To date, studies investigating the influence of aging on the exercise pressor reflex have presented conflicting data with most utilizing small muscle mass exercise (e.g. handgrip). Therefore, the purpose of this study was to determine the influence of SubRCO, pedal frequency, and the combination thereof on blood pressure (BP) during exercise in older and younger adults. We hypothesized that during exercise 1) independent of pedal frequencies and age, SubRCO will augment BP and 2) older adults will have greater increases in BP at high pedal frequencies with and without SubRCO compared younger adults.Methods10 younger (22±2 yrs; 4M/6W; 24±4 kg/m2) and 10 older (63±10yrs; 4M/6W; 24±4 kg/m2) adults participated in two study visits each consisting of two cycling exercise sessions at 20 W, with bilateral upper thigh pressure cuffs. Participants engaged in 3 minutes of exercise at 35 (LOW) or 100 (HIGH) rpm with 5 additional minutes of exercise at that rpm with no cuffing (CTL) or SubRCO in randomized order. Systolic and diastolic blood pressure (SBP and DBP, respectively) were measured via manual sphygmomanometry. Mean arterial pressure (MAP) was calculated as (SBP‐DBP)/3+DBP and the changes in MAP from rest are reported.ResultsDuring LOW, SubRCO resulted in greater MAP than CTL in younger (CTL: 4±7; SubRCO: 13±7 mmHg) and older adults (CTL: 4±6; SubRCO: 13±4 mmHg) (both p&lt;0.01). During HIGH, SubRCO resulted in greater MAP than CTL in younger (CTL: 7±4; SubRCO: 20±6 mmHg) and older adults (CTL: 20±9; SubRCO: 31±8 mmHg) (both p&lt;0.01). Younger and older adults had greater increases in MAP during HIGH CTL and SubRCO compared to LOW CTL and SubRCO, respectively (all, p&lt;0.01). Within LOW, there were no differences between younger and older adults during CTL or SubRCO (all, p&gt;0.05). Within HIGH, older adults had greater increases in MAP than younger adults during CTL and SubRCO (both p&lt;0.01).ConclusionThese data support the hypothesis that older compared to younger adults have a greater BP response at higher pedal frequencies during exercise. Our results suggest that aging contributes to a greater exercise pressor response to exercise, possibly due to greater feedback from group III/IV afferents.Support or Funding InformationNIH HL126638AHA 18POST3990251This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The Impact of APOL1 on Chronic Kidney Disease and Hypertension.

Essential hypertension is a clinical diagnosis based on the presence of an elevated systemic blood pressure on physical examination without a clear inciting cause. It has multiple etiologies and is not a homogeneous disorder. Hypertension contributes to the development and progression of atherosclerotic cardiovascular diseases, and antihypertensive treatment reduces the risk of fatal and nonfatal myocardial infarction, stroke, and congestive heart failure. Although hypertension is frequently present in nondiabetic individuals with low levels of proteinuria and chronic kidney disease, reducing blood pressures in this population does not reliably slow nephropathy progression. Many of these patients with recent African ancestry have the primary kidney disease "solidified glomerulosclerosis" that is strongly associated with renal-risk variants in the apolipoprotein L1 gene (APOL1). This kidney disease contributes to secondarily elevated blood pressures. The APOL1-associated spectrum of nondiabetic nephropathy also includes proteinuric kidney diseases, idiopathic focal segmental glomerulosclerosis, collapsing glomerulopathy, severe lupus nephritis, and sickle cell nephropathy. This article reviews relationships between mild to moderate essential hypertension and chronic kidney disease with a focus on the role of APOL1 in development of hypertension. Available evidence strongly supports that APOL1 renal-risk variants associate with glomerulosclerosis in African Americans, which then causes secondary hypertension, not with essential hypertension per se.

Sex Differences in Hypertension: Where We Have Been and Where We Are Going.

While it has been known since the 1940s that men have greater increases in blood pressure (BP) compared with women, there have been intense efforts more recently to increase awareness that women are also at risk for developing hypertension and that cardiovascular diseases (CVDs) are the leading causes of death among both men and women in the United States. With the release of the 2017 Hypertension Clinical Guidelines, 46% of adults in the United States are now classified as hypertensive, and hypertension is the primary modifiable risk factor for the development of CVD. This increase in the prevalence of hypertension is reflected in an increase in prevalence among both men and women across all demographics, although there were greater increases in the prevalence of hypertension among men compared with women. As a result, the well-established gender difference in the prevalence of hypertension is even more pronounced and now extends into the sixth decade of life. The goals of this review are to (i) review the historical clinical trial data and hypertension guidelines from the perspective of both genders and then (ii) review the role of the renin-angiotensin system and T-cell activation in contributing to sex differences in BP control.