Greater Increase In Mean Arterial Pressure Research Articles

The association between mean arterial pressure and acute kidney injury reversal among patients with decompensated cirrhosis.

This study informs how mean arterial pressure (MAP) impacts acute kidney injury (AKI) recovery among all patients hospitalized with cirrhosis, regardless of etiology. We identified incident AKI episodes among subjects in our cohort of patients with decompensated cirrhosis. AKI was defined as a ≥50% increase in creatinine from an outpatient baseline (≥7 days prior) that required hospitalization. Linear mixed effects models were completed to determine the impact between AKI recovery, MAP, and time. To determine the impact of MAP on AKI reversal, we completed time-dependent Cox regression models with time beginning at the time of peak creatinine and ending at death, discharge, or AKI reversal, among those hospitalized with AKI and those with persistent AKI (≥48h) We identified 702 hospitalized patients with cirrhosis with AKI. We found those with AKI reversal had, on average, higher MAP (2.1mmHg, p <0.05) and a greater increase in MAP over time (0.1mmHg per hour, p <0.001). Among all 702 hospitalized patients with AKI and adjusted for confounders, each 5mmHg increase in MAP was associated with 1.07× the hazard of AKI reversal ( p <0.01). Similarly, among those with persistent AKI after adjusting for confounders, each 5mmHg increase in MAP was associated with a 1.19× greater likelihood of AKI reversal ( p <0.001). Our data demonstrate that MAP significantly increases the likelihood of AKI recovery regardless of severity or injury or AKI phenotype. We believe these data highlight the importance of MAP as a clinical tool to promote kidney function recovery among patients with cirrhosis hospitalized with AKI.

Neuro-Cardiovascular Responses to Sympathetic Stimulation in Fighter Pilots.

INTRODUCTION: The chronic effects of regular exposure to high acceleration levels (G-force) on the neuro-cardiovascular system are unclear. We compared the mean arterial pressure (MAP) and cardiac autonomic modulation between nonpilots (NP) vs. military fighter (FP) and transport (TP) pilots. Additionally, we correlated the cardiac autonomic indices with the cardiorespiratory fitness and flight experience of FP.METHODS: A total of 21 FP, 8 TP, and 20 NP performed a tilt test (TT), during which beat-to-beat blood pressure and heart rate were recorded.RESULTS: No difference was detected between groups for changes in MAP and heart rate variability indices during the TT. However, the analysis of areas under the curves showed a greater increase in MAP in FP vs. TP and NP. Conversely, there was a greater decrease in indices reflecting vagal modulation in TP vs. FP and NP (rMSSD, pNN50, and SDNN), and a greater increase in heart rate and sympathovagal balance in TP vs. other groups (LF/HF). The maximal oxygen uptake was strongly correlated with the vagal reserve in FP (r = -0.74). Moreover, the total flying hours of FP were positively correlated with resting HFnu (r = 0.47) and inversely correlated with resting LFnu (r = -0.55) and LF/HF (r = -0.46).CONCLUSION: FP had a higher pressor response to TT than TP and NP. Vagal withdrawal and sympathovagal increase induced by TT in FP were similar vs. NP and attenuated vs. TP. Greater cardiorespiratory fitness and accumulated flying hours in FP seemed to favor lower sympathetic and greater vagal modulation at rest.dos Santos Rangel MV, de Sá GB, Farinatti P, Borges JP. Neuro-cardiovascular responses to sympathetic stimulation in fighter pilots. Aerosp Med Hum Perform. 2023; 94(10):761-769.

Utilization of Synthetic Human Angiotensin II for Catecholamine-Resistant Vasodilatory Shock in Critically Ill Children: A Single-Center Retrospective Case Series.

To describe our institutional experience utilizing adjunctive synthetic angiotensin II in critically ill children with catecholamine-resistant vasodilatory shock (CRVS). Single-center, retrospective case series. PICU and cardiac ICU (CICU) at a large, quaternary children's hospital in the United States. Twenty-three pediatric patients with CRVS who were prescribed synthetic angiotensin II at the discretion of bedside clinicians from January 2018 to April 2023. None. Twenty-three patients (20 in PICU, 3 in CICU) with a median age of 10.4 years (interquartile range [IQR] 1.5-18.5) received angiotensin II over the study period, 70% of whom died. At the time of angiotensin II initiation, 17 patients (74%) were receiving one or more forms of extracorporeal therapy, and median Pediatric Logistic Organ Dysfunction-2 Score-2 in the prior 24 hours was 9 (IQR 7-11). The median time between initiation of the first vasoactive agent and angiotensin II was 127 hours (IQR 13-289), and the median total norepinephrine equivalent (NED) at initiation was 0.65 μg/kg/min (IQR 0.36-0.78). The median duration of therapy was 27 hours (IQR 4-68), and at each timepoint assessed, patients had median improvement in NED and mean arterial pressure (MAP) with treatment. Survivors initiated angiotensin II nearly 3 days earlier in vasoactive course (91.5 hr vs 161 hr, p = 0.23), and had both greater reduction in NED (-75% [IQR -96 to -50] vs +2.1% [IQR -55 to 33], p = 0.008) and greater increase in MAP (+15 mm Hg [IQR 10-27] vs -1.5 mm Hg [IQR -27 to 18], p = 0.052) at angiotensin II discontinuation. We demonstrate reduction in NED and improved MAP following initiation of angiotensin II in critically ill children with CRVS. Further prospective work is needed to examine optimal timing of angiotensin II initiation, appropriate patient selection, and safety in this population.

Concomitantly higher resting arterial blood pressure and transduction of sympathetic neural activity in human obesity without hypertension.

Central (abdominal) obesity is associated with elevated adrenergic activity and arterial blood pressure (BP). Therefore, we tested the hypothesis that transduction of spontaneous muscle sympathetic nerve activity (MSNA) to BP, that is, sympathetic transduction, is augmented in abdominal obesity (increased waist circumference) and positively related to prevailing BP. Young/middle-aged obese (32 ± 7 years; BMI: 36 ± 5 kg/m2, n = 14) and nonobese (29 ± 10 years; BMI: 23 ± 4 kg/m2, n = 14) without hypertension (24-h ambulatory average BP < 130/80 mmHg) were included. MSNA (microneurography) and beat-to-beat BP (finger cuff) were measured continuously and the increase in mean arterial pressure (MAP) during 15 cardiac cycles following MSNA bursts of different patterns (single, multiples) and amplitude (quartiles) was signal-averaged over a 10 min baseline period. MSNA burst frequency was not significantly higher in obese vs. nonobese (21 ± 3 vs. 17 ± 3 bursts/min, P = 0.34). However, resting supine BP was significantly higher in obese compared with nonobese (systolic: 127 ± 3 vs. 114 ± 3; diastolic: 76 ± 2 vs. 64 ± 1 mmHg, both P < 0.01). Importantly, obese showed greater increases in MAP following multiple MSNA bursts (P = 0.02) and MSNA bursts of higher amplitude (P = 0.02), but not single MSNA bursts (P = 0.24), compared with nonobese when adjusting for MSNA burst frequency. The increase in MAP following higher amplitude bursts among all participants was associated with higher resting supine systolic (R = 0.48; P = 0.01) and diastolic (R = 0.48; P = 0.01) BP when controlling for MSNA burst frequency, but not when also controlling for waist circumference (P > 0.05). In contrast, sympathetic transduction was not correlated with 24-h ambulatory average BP. Sympathetic transduction to BP is augmented in abdominal obesity and positively related to higher resting supine BP but not 24-h ambulatory average BP.

Abstract P062: Interaction Of Cytochrome P450 1B1 And 12/15 Lipoxygenase In Paraventricular Nucleus In The Regulation Of Angiotensin II-induced Hypertension In Female Mice

Recently, we showed that 17β-estradiol (E2)-cytochrome P450 (CYP) 1B1-generated metabolite 2-methoxyestradiol (2-ME) in the paraventricular nucleus (PVN) protects from angiotensin (Ang) II-induced hypertension. Moreover, we showed that 2-ME produces this action by inhibiting the cytosolic phospholipase (cPLA) 2 α/arachidonic acid (AA)-cyclooxygenase (COX)-generated metabolites prostaglandin (PG)E 2 and thromboxane (TX)A 2 exerting prohypertensive effects via prostanoid receptors EP1, EP3, and TP, respectively, in female mice. 12/15 lipoxygenase (ALOX15), which also metabolizes AA, is present in the brain in neural tissue, endothelial cells, microglia, and astrocytes. This study was conducted to determine the contribution of central 12/15 lipoxygenase (ALOX15) and its relationship to CYP1B1 in Ang II-induced hypertension in the female mice. ALOX15 knockdown in the PVN by transduction with adenovirus (Ad)-ALOX15-short hairpin (sh)RNA (200 nL, bilaterally 7.04х10 11 pfu/mL) but not its control Ad-scrambled (Scr)-shRNA (6.4х10 11 pfu/mL) produced a greater reduction in systolic blood pressure (SBP, mmHg) measured by tail-cuff in response to Ang II (700 ng/kg/min, subcutaneous, osmotic pump, two weeks) in intact Cyp1b1 knockout (KO, E2 present but lacking 2-ME) than wild-type (WT, endogenous E2 and 2-ME present) female mice (Day 12: 177±4 vs 143±1 and 133±3 vs 124±1, respectively, P&lt;0.05, n=4/group). Moreover, administration of ALOX15-generated AA metabolite 12(S)-hydroxyeicosatetraenoic acid (HETE) in a dose (50 ng/ 2 μL/ every 3rd day, intracerebroventricularly) that did not alter the mean arterial pressure (MAP) alone produced a greater increase in MAP in response to Ang II in ovariectomized (both E2 and 2-ME are lacking) than intact Alox15 KO female mice (Day 0 vs Day 12: 103±4 vs 167±2 and 103±2 vs 128±1, respectively, P&lt;0.05, n=4/group). These results suggest that E2, via its CYP1B1-derived metabolite 2-ME, inhibits the generation of ALOX15/AA metabolite 12(S)-HETE in the brain to protect against Ang II-induced hypertension in female mice. Thus, 2-ME and/or ALOX15/12(S)-HETE inhibitors could be useful for treating hypertension and its pathogenesis in females.

Abstract 10528: Exaggerated Inspiratory Muscle Metaboreflex in Heart Failure with Preserved Ejection Fraction

Introduction: Heart failure patients with preserved ejection fraction (HFpEF) may exhibit inspiratory muscle dysfunction potentially contributing to exercise intolerance. Activation of neural afferents in response to inspiratory muscle contraction (metaboreflex) elicits increases in mean arterial pressure (MAP) and leg vascular resistance (LVR) through enhanced sympathetic outflow leading to decreases in leg blood flow (LBF) in healthy humans. It is unknown if HFpEF patients exhibit exaggerated cardiovascular responses to inspiratory muscle metaboreflex activation. Hypothesis: We hypothesize that patients with HFpEF will exhibit a greater increase in MAP and LVR with a decrease in LBF during inspiratory muscle metaboreflex activation than controls. Methods: HFpEF patients (n=15, 10M/5W, 69±10 yrs; 33±4 kg/m2) and controls (n=14; 10M/4W; 70±8 yrs; 28±4 kg/m2) performed inspiratory resistive breathing tasks (IRBT) at 2% and 60% of their maximal inspiratory pressure. During the IRBTs, the breathing frequency was 20 breaths/min with a 50% duty cycle. At rest and during the IRBTs, MAP was measured by photoplethysmography, venous norepinephrine was measured, LBF was measured by near-infrared spectroscopy and indocyanine green dye injections, and LVR was calculated. Results: During the 2% IRBT, there were no differences between groups in the changes from rest in MAP (HFpEF: 2±4 vs. CTL: 3±4 mmHg) or LBF (HFpEF: 1±14 vs. CTL: 1±12%) (both, p&gt;0.05). During the 60% IRBT, venous norepinephrine increased from rest in HFpEF and controls (p&lt;0.05), while no differences existed between groups (p&gt;0.05). During the 60% IRBT, HFpEF patients, compared to controls, exhibited a greater increase from rest in MAP (HFpEF: 16±7 vs. CTL: 10±6 mmHg) and LVR (HFpEF: 76±45 vs. CTL: 32±19%) coupled with a greater decrease in LBF (HFpEF: -32±14 vs. CTL: -17±9%) (all, p&lt;0.05). Conclusions: These data indicate that patients with HFpEF exhibit exaggerated cardiovascular responses with inspiratory muscle metaboreflex activation compared to healthy individuals. These findings have important implications for the integrative physiology of exercise in HFpEF patients.

Abstract P363: Annexin-A1 Deficiency Exaggerates Cardiac Remodeling In Angiotensin II-induced Hypertension

Introduction: We have previously demonstrated that the naturally-occurring anti-inflammatory and pro-resolving protein Annexin-A1 (Anx-A1) limits the acute inflammatory response post myocardial infarction, but its impact on chronic inflammation, such as hypertension, has not been explored. This study aims to investigate the role of Anx-A1 in a preclinical model of hypertension, induced by angiotensin-II (Ang-II). Methods: 15-week-old male C57BL/6 or ANXA1 -/- were anesthetized (isoflurane, 2-4% v/v) and implanted with an osmotic minipump randomly assigned to receive Ang-II (0.7mg/kg/day) or vehicle (saline). Radiotelemetry recordings of blood pressure were taken at 10 intermittent timepoints from baseline to the end of the 29-day infusion period. Animals were euthanized with pentobarbitone (100mg/kg; i.p.) at endpoint and organ weights recorded and normalized to bodyweight. Left ventricle (LV) samples were stained with picrosirius red to assess total LV collagen deposition. Results: Ang II-induced mice at the end of the study had elevated mean arterial pressure (MAP), cardiac hypertrophy and fibrosis compared to normotensive mice (Table). Anx-A1 deficient mice given Ang II had an even greater increase in MAP and cardiac remodeling compared to WT. Interestingly, MAP of Anx-A1 deficient mice at baseline is significantly higher compare to C57BL/6 counterparts (Table). Conclusion: This is the first study to demonstrate that deficiency of Anx-A1 exaggerates cardiac remodeling in AngII-induced hypertension, suggesting that endogenous Anx-A1 might play previously unappreciated physiological role in regulating blood pressure. This supports the development of Anx-A1 based pharmacotherapy against hypertension-induced cardiac damage.

Increased sympathetic and haemodynamic responses to exercise and muscle metaboreflex activation in post-menopausal women with rheumatoid arthritis.

Rheumatoid arthritis (RA) patients present exacerbated blood pressure responses to exercise, but little is known regarding the underlying mechanisms involved. This study assessed autonomic and haemodynamic responses to exercise and to the isolated activation of muscle metaboreflex in post-menopausal women with RA. Participants with RA showed augmented pressor and sympathetic responses to exercise and to the activation of muscle metaboreflex. These responses were associated with multiple pro- and anti-inflammatory cytokines and with pain. The results of the present study support the suggestion that an abnormal reflex control of circulation is an important mechanism underlying the exacerbated cardiovascular response to exercise and increased cardiovascular risk in RA. Studies have reported abnormal cardiovascular responses to exercise in rheumatoid arthritis (RA) patients, but little is known regarding the underlying mechanisms involved. This study assessed haemodynamic and sympathetic responses to exercise and to the isolated activation of muscle metaboreflex in women diagnosed with RA. Thirty-three post-menopausal women diagnosed with RA and 10 matched controls (CON) participated in this study. Mean arterial pressure (MAP), heart rate (HR) and muscle sympathetic nerve activity (MSNA frequency and incidence) were measured during a protocol of isometric knee extension exercise (3min, 30% of maximal voluntary contraction), followed by post-exercise ischaemia (PEI). Participants with RA showed greater increases in MAP and MSNA during exercise and PEI than CON (ΔMAPexercise =16±11 vs. 9±6mmHg, P=0.03; ΔMAPPEI =15±10 vs. 5±5mmHg, P=0.001; ΔMSNAexercise =17±14 vs. 7±9burstsmin-1 , P=0.04; ΔMSNAPEI =14±10 vs. 6±4burstsmin-1 , P=0.04). Autonomic responses to exercise showed significant (P<0.05) association with pro- (i.e. IFN-γ, IL-8, MCP-1 and TNFα) and anti-inflammatory (i.e. IL-1ra and IL-10) cytokines and with pain. In conclusion, post-menopausal women with RA showed augmented pressor and sympathetic responses to exercise and to the activation of muscle metaboreflex. These findings provide mechanistic insights that may explain the abnormal cardiovascular responses to exercise in RA.

Abstract P101: Sympathetic Transduction In Young Adults With A Family History Of Hypertension

Exaggerated sympathetic transduction (i.e., the vascular response to a burst of muscle sympathetic nerve activity; MSNA) has recently been demonstrated in certain populations of young adults at risk for future hypertension. However, it remains unknown the degree to which a family history of hypertension (FH), a risk factor for future hypertension, may influence sympathetic transduction. Purpose: The purpose of this study was to test the hypothesis that a +FH augments the pressor response following spontaneous bursts of MSNA at rest in young adults. A secondary purpose was to compare the influence of a +FH on sympathetic transduction between young men and women. Methods: We retrospectively examined beat-by-beat blood pressure (finger photoplethysmography) and MSNA (peroneal microneurography) in 21 +FH young adults (9 +FH men: 26 ± 2 yr, 25 ± 4 kg/m 2 , 12 +FH women: 22 ± 2 yr, 22 ± 3 kg/m 2 ) and 15 -FH young adults (8 -FH men: 24 ± 5 yr, 25 ± 2 kg/m 2 , 7 -FH women: 22 ± 3 yr, 23 ± 3 kg/m 2 ) during 10 minutes of supine rest. Signal averaging was used to characterize changes in BP for the 10 cardiac cycles following a spontaneous MSNA burst. Resting baseline variables were compared using 2-way ANOVAs. Mean arterial pressure (MAP) changes over 10 cardiac cycles following a burst of MSNA were compared using a 2-way repeated measures ANOVA (Time, FH status) and a 3-way repeated measures ANOVA (Time, FH status, Sex). Data are presented as mean ± SD. Results: Resting MAP (+FH: 86 ± 9 vs. -FH: 82 ± 7 mmHg; P = 0.14) and resting MSNA (+FH: 10 ± 6 vs. -FH: 9 ± 6 mmHg; P = 0.65) did not differ by FH status. The increase in MAP over the 10 cardiac cycles following a spontaneous burst of MSNA did not differ by FH status (Time, P &lt; 0.0001; FH status, P = 0.17; Time * FH status, P = 0.70) and this influence did not differ between the sexes (Time * FH status, P = 0.58; Time * Sex, P = 0.06; Time * FH status * Sex, P = 0.99). Conclusions: These preliminary data suggest that spontaneous MSNA bursts do not elicit greater increases in MAP in +FH young adults, regardless of sex. Additional data are needed to determine the interactions between FH status, sex, and sympathetic transduction. Supported by NIH Grant P20 GM 113125, P20 GM 103446, U54 GM 104941, K99/R00 HL133414, and The University of Delaware Research Foundation.

Angiotensin II Infusion for Shock: A Multicenter Study of Postmarketing Use

Vasodilatory shock refractory to catecholamine vasopressors and arginine vasopressin is highly morbid and responsible for significant mortality. Synthetic angiotensin II is a potent vasoconstrictor that may be suitable for use in these patients. What is the safety and effectiveness of angiotensin II and what variables are associated with a favorable hemodynamic response? We performed a multicenter, retrospective study at five tertiary medical centers in the United States. The primary end point of hemodynamic responsiveness to angiotensin II was defined as attainment of mean arterial pressure (MAP) of≥ 65mmHg with a stable or reduced total vasopressor dosage 3h after drug initiation. Of 270 included patients, 181 (67%) demonstrated hemodynamic responsiveness to angiotensin II. Responders showed a greater increase in MAP (+10.3mmHg vs+1.6mmHg, P< .001) and reduction in vasopressor dosage (-0.20 μg/kg/min vs+0.04 μg/kg/min; P< .001) compared with nonresponders at 3 h. Variables associated with favorable hemodynamic response included lower lactate concentration (OR 1.11; 95%CI, 1.05-1.17, P< .001) and receipt of vasopressin (OR, 6.05; 95%CI, 1.98-18.6; P= .002). In severity-adjusted multivariate analysis, hemodynamic responsiveness to angiotensin II was associated with reduced likelihood of 30-day mortality (hazard ratio, 0.50; 95%CI, 0.35-0.71; P< .001). Arrhythmias occurred in 28 patients (10%) and VTE was identified in 4 patients. In postmarketing use for vasopressor-refractory shock, 67%of angiotensin II recipients demonstrated a favorable hemodynamic response. Patients with lower lactate concentrations and those receiving vasopressin were more likely to respond to angiotensin II. Patients who responded to angiotensin II experienced reduced mortality.

The Effect of Menopause Status on the Skeletal Muscle Metaboreflex.

IntroductionIt is well established that the exercise pressor reflex contributes to cardiovascular control (e.g. mean arterial pressure (MAP)) during exercise. One arm of the exercise pressor reflex includes the metabolically sensitive group IV afferents (i.e. metaboreflex). The metaboreflex‐induced cardiovascular responses to exercise are incompletely understood, especially in women across the aging spectrum. For example, post‐menopausal women have greater increases in MAP and systemic vascular resistance (SVR) during locomotor muscle exercise compared to pre‐menopausal women. However, it is unclear if an exaggerated metaboreflex arising from the locomotor muscles is contributing to these cardiovascular adjustments with exercise in post‐menopausal women. We hypothesized that 1) post‐menopausal women will have an augmented MAP response with isolated metaboreflex activation compared to pre‐menopausal women and 2) the exaggerated increase in MAP in the post‐menopausal women will be primarily due to greater increases in SVR.MethodsPre‐ (n= 10, 25±3yrs, 24±3 kg/m2) and post‐menopausal women (n=12, 58±4yrs, 24±3 kg/m2) performed 2 sessions of cycling exercise at 20 W for 5 min with bilateral upper thigh pressure tourniquets inflated to 90 mmHg. At end exercise, the recovery was randomized to post‐exercise circulatory occlusion (PECO) to isolate the metaboreflex (via bilateral upper thigh pressure tourniquets rapidly inflated to suprasystolic pressure for 2 min) or normal recovery (NR) without intervention. Systolic and diastolic blood pressure were measured via manual sphygmomanometry and MAP was calculated. Cardiac output was measured via open circuit acetylene wash‐in and systemic vascular resistance (SVR) was calculated. Data is reported as the absolute change from rest to recovery.ResultsMAP was elevated during PECO compared to NR in both groups (p&lt;0.05), while MAP during PECO was greater in post‐ compared to pre‐menopausal women (20±9 vs. 13±5 mmHg, respectively) (p&lt;0.05). Similarly, SVR was elevated during PECO compared to NR in both groups (p&lt;0.05), while SVR was greater during PECO in post‐ compared to pre‐menopausal women (5±3 vs. 3±1 mmHg/L/min, respectively) (p&lt;0.05). In contrast, cardiac output was not different between NR and PECO in either pre‐ (NR: 0.3±1 vs. PECO: −0.2±1 L/min) and post‐menopausal (NR: −0.1±1 vs. PECO: −0.7±0.9 L/min) (all, p&gt;0.05).ConclusionThese data demonstrate that isolated metaboreflex stimulation following whole‐body exercise results in exaggerated increases in MAP and SVR in post‐ compared to pre‐menopausal women. These data suggest that exercise pressor reflex‐mediated control of MAP during exercise is accentuated in post‐menopausal women with menopause status.

Augmented pressor and sympathoexcitatory responses to the onset of isometric handgrip in patients with type 2 diabetes.

Patients with type 2 diabetes (T2D) exhibit greater daytime blood pressure (BP) variability, increasing their cardiovascular risk. Given the number of daily activities that incorporate short-duration isometric muscle contractions (e.g., carrying groceries), herein we investigated BP and muscle sympathetic nerve activity (MSNA) responses at the onset of isometric handgrip (HG). We tested the hypothesis that, relative to control subjects, patients with T2D would exhibit exaggerated pressor and MSNA responses to the immediate onset of HG. Mean arterial pressure (MAP) and MSNA were quantified during the first 30 s of isometric HG at 30% and 40% of maximal voluntary contraction (MVC) and during a cold pressor test (CPT), a nonexercise sympathoexcitatory stimulus. The onset of 30% MVC HG evoked similar increases in MAP between groups (P = 0.17); however, the increase in MSNA was significantly greater in patients with T2D versus control subjects with the largest group difference at 20 s (P < 0.001). At the onset of 40% MVC HG, patients with T2D demonstrated greater increases in MAP (e.g., 10 s, T2D: 9 ± 1 mmHg, controls: 5 ± 2 mmHg; P = 0.04). MSNA was also greater in patients with T2D at 40% MVC onset but differences were only significant at the 20-30 s timepoint (T2D: 15 ± 3 bursts/min, controls: -2 ± 4 bursts/min; P < 0.001). Similarly, MAP and MSNA responses were augmented during the onset of CPT in T2D patients. These findings demonstrate exaggerated pressor and MSNA reactivity in patients with T2D, with rapid and robust responses to both isometric contractions and cold stress. This hyper-responsiveness may contribute to daily surges in BP in patients with T2D, increasing their short-term and long-term cardiovascular risk.

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.

Abstract 123: Effect of Immune Cell-Derived Reactive Oxygen Species on Dahl SS Hypertension

Previous studies utilizing the SS p67 phox–/– rat have demonstrated the importance of systemic NADPH oxidase NOX2-derived reactive oxygen species (ROS) production in the pathogenesis of Dahl Salt-Sensitive (SS) hypertension and renal damage. Our laboratory has established a key role for renal immune cell infiltration in the development of SS hypertension and observed an enrichment of NOX2 subunits in infiltrating T cells. The contribution of ROS specifically derived from immune cells in SS hypertension remains unknown. To assess the role of ROS in immune cells, SS p67 phox–/– rats underwent total body irradiation and received bone marrow transfer from either SS p67 phox–/– (p67/p67) or SS (p67/SS) donor rats. p67/SS rats would be capable of producing NOX2-derived ROS only in the transferred SS cells of hematopoietic origin while the p67/p67 control group would be unable to produce NOX2-derived ROS globally. Mean arterial pressure (MAP) was not different between the p67/SS and p67/p67 rats when fed a 0.4% NaCl diet (112.6±1.4 vs 110.7±2.4 mmHg, n=4-5). After 3 weeks of high salt, however, there was a significantly greater increase in MAP in the p67/SS rats (176.1±4.7 mmHg) compared to the p67/p67 control rats (147.9±8.4 mmHg), which was accompanied by a significant increase in albuminuria (230.3±13.9 vs 153.1±14.9 mg/day, p67/SS vs p67/p67, n=5-6). Interestingly, upon analysis of the immune cells in the kidney, no differences were detected in the number of CD45+ total leukocytes, CD11b/c+ monocytes/macrophages, CD3+ T cells, and CD45R+ B cells between the p67/SS and p67/p67 (n=4-5), indicating that the recruitment of immune cells into the kidney during hypertension and renal damage is independent of NOX2-derived ROS production from the renal parenchyma. The respiratory burst response to phorbol 12-myristate 13-acetate stimulus (135 μM) in peritoneal macrophages isolated from p67/SS was 4.0-fold greater compared to nonresponsive p67/p67 cells, and was completely inhibited by superoxide dismutase, demonstrating that the reconstituted bone marrow cells in the p67/SS are capable of producing superoxide. In summary, the production of NOX2-derived ROS from immune cells alone is sufficient for the development of Dahl SS hypertension and renal damage.

Abstract P337: Sodium-independent Elevations of Blood Pressure are Accompanied by Immune Cell Infiltration in the Kidney and Renal Damage in Dahl SS Rats

Infiltration of immune cells in the kidney is driven by elevated renal perfusion pressure and amplifies sodium-sensitive hypertension and renal injury in Dahl Salt Sensitive (SS) rats fed a high salt diet. The present studies were performed to determine the importance of immunity in the development of sodium-independent hypertension and renal damage in SS rats and SS lacking T- and B-lymphocytes due to a null mutation in the Rag1 gene (SS-Rag1 em1Mcwi ). The baseline level of mean arterial pressure (MAP) was not different between groups, and the continuous infusion of AngII (5 ng/kg/min, iv) to SS and SS-Rag1 em1Mcwi fed low salt (0.4% NaCl) led to a significantly greater increase in MAP in SS (190±3 mmHg) than in SS-Rag1 em1Mcwi (177±3 mmHg) after 12 days of infusion (n=9 rats/group). Renal damage, as assessed by albumin excretion rate, was significantly increased after 12 days of AnglI infusion in the SS (from 32±4 to 81±9 mg/day) and in the Rag1 mutants (from 12±2 to 51±8 mg/day). Compared to vehicle-infused rats, kidneys of AngII-treated SS (n=4-5/group) had increased CD45+ total leukocytes (1.8±0.2 vs 4.4±1.2 x 10 6 cells/kidney), including CD11b/c+ macrophages/monocytes and CD3+ T Cells. Upon cessation of the AngII infusion, MAP in the SS-Rag1 em1Mcwi significantly decreased to a level not different from control values (135±5 vs 128±3 mmHg). In contrast, though MAP decreased in the SS when AngII infusion was stopped, blood pressure remained at a level greater than control values throughout the 9-day recovery period (157±8 vs 129±2 mmHg). Albumin excretion rate also tended to decrease in both SS and SS-Rag1 em1Mcwi rats following the return to saline infusion, but the reversibility was not complete. Despite the maintenance of elevated pressure in the SS following AngII withdrawal, there was a significant and complete reversal in the number of CD45+, CD11b/c+, and CD3+ cells in the SS kidneys. The present data indicate that immune cells amplify sodium-independent hypertension and the development of renal damage in the SS rat, but also indicate that factors in addition to renal perfusion pressure may mediate immune cell infiltration into the kidney in hypertension.

Effect of Age on Sex Differences in the Inspiratory Muscle Metaboreflex

Sex differences exist in the cardiovascular consequences of the inspiratory muscle metaboreflex in young adults. However, it is unknown if these sex differences are present in older adults. PURPOSE: To determine the effect of age on sex differences in the cardiovascular consequences of the inspiratory muscle metaboreflex. We hypothesized that, compared to their younger counterparts, older men and women would exhibit greater 1) increases in mean arterial pressure (MAP) and limb vascular resistance (LVR) and 2) decreases in limb blood flow (QL). We also hypothesized that the inspiratory muscle metaboreflex-induced cardiovascular responses would not be different between older men and women. METHODS: Sixteen young (8 men, 8 women; 18-24 yr) and older (8 men, 8 women; 60-73 yr) adults were recruited for this study. Subjects performed inspiratory resistive breathing tasks (IRBTs) at 2% and 65% of their maximal inspiratory pressure. During the IRBTs, breathing frequency was 20 breaths min-1 with a 50% duty cycle. At rest and during the IRBTs, MAP was measured via automated oscillometry, QL was measured via Doppler ultrasound, and LVR was calculated. End tidal CO2 remained at baseline levels during the IRBTs. EMG was recorded on the leg to ensure no muscle contraction occurred. RESULTS: The 65% IRBT led to significantly greater increases in MAP from baseline in OW (15.9±8.1 mmHg) compared to YW (6.9±1.4 mmHg), but not (p>0.05) between OM (12.3±5.7 mmHg) and YM (10.8±5.7 mmHg). OW (-20.2±7.2 %) had greater (p<0.05) decreases in QL from baseline compared to YW (-9.4±10.2 %), but no differences (p>0.05) were present between OM (-22.8±9.7 %) and YM (-22.7±11.3 %) during the 65% IRBT. The 65% IRBT led to greater (p<0.05) increases in LVR in OW (48.2±25.5 %) compared to YW (19.7±15.0 %), but no differences (p>0.05) existed among OM (54.4±17.8 %) and YM (47.1±23.3 %). No differences (p>0.05) were present in MAP, QL, or LVR between OM and OW. The 2% IRBT resulted in no changes (p>0.05) in MAP, QL, or LVR across time or among groups. CONCLUSIONS: These data suggest older women compared to younger women exhibit greater inspiratory muscle metaboreflex-induced cardiovascular consequences, while there were no differences between older and younger men. Lastly, sex differences in the inspiratory muscle metaboreflex are not present in older adults.

Food restriction increases the cardiovascular response evoked by angiotensin‐[1–10] and angiotensin‐[1–7] in female Fischer rats

Anorexia is associated with cardiovascular dysfunction including hypotension and cardiac arrhythmias. In a rat model of food restriction (FR) we previously demonstrated that the activity of endothelial α1 adrenergic receptors and brain type 1 angiotensin receptors were increased. The aim of this study was to determine the role of the angiotensin (Ang)‐[1–7] and Ang‐[I‐10] in the brain. Female Fischer rats (220g, 4 mo) were maintained for 14 days on a FR diet, that was 40% of the control group (C) food intake. Cannulas were implanted in the lateral ventricle (LV) on day 7. On day 14, the animals were catheterized with a polyethylene tube in the femoral artery for recording of mean arterial pressure (MAP) and heart rate (HR). After 14 days, MAP (mmHg) [C: 105±1, n=35 vs. FR: 102±2, n=36; p&lt;0.05] and HR (bpm) [C: 386±5, n=35 vs. FR: 353±8, n=36, p&lt;0.001] were reduced in the FR. Injection of Ang‐[1–7] caused a greater increase in MAP (Δ mm Hg) in the FR compared to C group (25pmol) [C: Δ −2±1, n=8 vs. FR: Δ 7±1, n=10; p&lt;0.05]. Moreover, there was a greater increase in HR (Δ bpm) in the FR compared to the C group [C: Δ 9±3, n=8 vs FR: Δ 29±9, n=10; p&lt;0.05]. Injection of Ang‐[1–10] caused a greater increase in MAP (Δ mm Hg) in the FR compared to C group (25pmol) [C: 5±1, n=7 vs. FR: 13±2, n=7; p&lt;0.005]; however, there was no effect on HR. This Ang‐[1–10]‐induced increase in MAP was attenuated by administering captopril into the LV, in both the FR and C groups, suggesting this increase in MAP was mediated by angiotensin converting enzyme. These results suggest that increased Ang‐[1–7] and Ang‐[1–10] activity in the brain play a role in the increased sympathetic activity observed in anorexia.Support or Funding InformationNIH 1R01HL119380 (KS)UFOP (AS)CAPES (AS)

Cardiovascular consequences of the inspiratory muscle metaboreflex: effects of age and sex.

With inspiratory muscle metaboreflex activation, we hypothesized that, compared with their younger counterparts, older men and women would exhibit greater 1) increases in mean arterial pressure (MAP) and limb vascular resistance (LVR) and 2) decreases in limb blood flow (Q̇L) but 3) no sex differences would be present in older adults. Sixteen young adults [8 young men (YM) and 8 young women (YW), 18-24 yr] and 16 older adults [8 older men (OM) and 8 older women (OW), 60-73 yr] performed inspiratory resistive breathing tasks (IRBTs) at 2% and 65% of their maximal inspiratory pressure. During the IRBTs, breathing frequency was 20 breaths/min with a 50% duty cycle. At baseline and during the IRBTs, MAP was measured via automated oscillometry, Q̇L was determined via Doppler ultrasound, and LVR was calculated. The 65% IRBT led to significantly greater increases in MAP in OW (15.9 ± 8.1 mmHg) compared with YW (6.9 ± 1.4 mmHg) but not (P > 0.05) between OM (12.3 ± 5.7 mmHg) and YM (10.8 ± 5.7 mmHg). OW (-20.2 ± 7.2%) had greater (P < 0.05) decreases in Q̇L compared with YW (-9.4 ± 10.2%), but no significant differences were present between OM (-22.8 ± 9.7%) and YM (-22.7 ± 11.3%) during the 65% IRBT. The 65% IRBT led to greater (P < 0.05) increases in LVR in OW (48.2 ± 25.5%) compared with YW (19.7 ± 15.0%), but no differences (P > 0.05) existed among OM (54.4 ± 17.8%) and YM (47.1 ± 23.3%). No significant differences were present in MAP, Q̇L, or LVR between OM and OW. These data suggest that OW exhibit a greater inspiratory muscle metaboreflex compared with YW, whereas no differences between OM and YM existed. Finally, sex differences in the inspiratory muscle metaboreflex are not present in older adults.NEW & NOTEWORTHY Premenopausal women exhibit an attenuated inspiratory muscle metaboreflex compared with young men; however, it is unknown whether these sex differences are present in older adults. Older women exhibited a greater inspiratory muscle metaboreflex compared with premenopausal women, whereas no differences were present between older and younger men.

Attenuation of angiotensin type 2 receptor function in the rostral ventrolateral medullary pressor area of the spontaneously hypertensive rat

We hypothesized that blockade of angiotensin II type 2 receptors (AT2Rs) in the rostral ventrolateral medullary pressor area (RVLM) may elicit sympathoexcitatory responses which are smaller in hypertensive rats compared to normotensive rats. This hypothesis was tested in urethane-anesthetized, artificially ventilated male 14-week-old spontaneously hypertensive rats (SHR). Age-matched male Wistar–Kyoto rats (WKY) and Wistar rats were used as controls. PD123319 (AT2R antagonist) was microinjected into the RVLM and mean arterial pressure (MAP), heart rate (HR) and greater splanchnic nerve activity (GSNA) were recorded. Increases in MAP, HR and GSNA elicited by unilateral microinjections of PD123319 into the RVLM were significantly smaller in SHR when compared with those in WKY and Wistar rats. Unilateral microinjections of l-glutamate (l-Glu) into the RVLM elicited greater increases in MAP and GSNA in SHR compared to those in WKY. AT2R immunoreactivity was demonstrated in the RVLM neurons which were retrogradely labeled from the intermediolateral cell column (IML) of the spinal cord. These results indicate that AT2Rs are present on the RVLM neurons projecting to the IML and their blockade results in sympathoexcitatory responses. Activation of AT2Rs has an inhibitory influence in the RVLM and these receptors are tonically active. Attenuation of the function of AT2Rs in the RVLM may play a role in genesis and/or maintenance of hypertension in SHR.

Abstract P204: Food Restriction Increases the Cardiovascular Response Evoked by Angiotensin-[1-10] and Angiotensin-[1-7] in Female Fischer Rats

Anorexia is associated with cardiovascular dysfunction including hypotension, bradycardia and cardiac arrhythmias. In a rat model of food restriction (FR)-induced hypotension and bradycardia, we previously demonstrated that the activity of endothelial α1 adrenergic receptors and brain type 1 angiotensin receptors (AT1R) were increased. The aim of this study was to determine the role of the vasodilator, angiotensin (Ang)-[1-7] and the precursor Ang-[I-10] in the periphery and brain. Methods: Female Fischer rats (220g, 4 mo) were maintained for 14 days on a FR diet, that was 40% of the control group (C) food intake. Cannulas were implanted in the lateral ventricle (LV) on day 7. On day 14, the animals were catheterized with a polyethylene tube in the femoral artery for recording of mean arterial pressure (MAP) and heart rate (HR). Results: After 14 days, body weight (g) [C: 202±2, n=13 vs. FR: 176±2, n=14; p&lt;0.05], MAP (mm Hg) [C: 105±1, n=35 vs. FR: 102±2, n=36; p&lt;0.05] and HR (bpm) [C: 386±5, n=35 vs. FR: 353±8, n=36, p&lt;0.001) were reduced in the FR compared to control rats. Injection of Ang-[1-7] caused a greater increase in MAP (Δ mm Hg) in the FR compared to C group when delivered either into the LV (25pmol) (C: Δ -2±1, n=8 vs. FR: Δ 7±1, n=10; p&lt;0.05) or the femoral vein (1910pmol) [C: Δ 1±1, n=9 vs. FR: Δ 3±1, n=6; p&lt;0.05]. Moreover, there was a greater increase in HR (Δ bpm) in the FR compared to the C group after LV injection (C: Δ 9±3, n=8 vs FR: Δ 29±9, n=10; p&lt;0.05). Injection of Ang-[I-10] caused a greater increase in MAP (Δ mm Hg) in the FR compared to C group when delivered into the LV (25pmol) (C: 5±1, n=7 vs. FR: 13±2, n=7; p&lt;0.005) or i.v (1910pmol) (C: Δ 1±1, n=7 vs. FR: Δ 15±2, n=8; p&lt;0.05); however, there was no effect on HR. This Ang-[l-10]-induced increase in MAP was attenuated by administering captopril into the LV, in both the FR and C groups, suggesting this increase in MAP was mediated by angiotensin converting enzyme. Conclusion: These results suggest that increased Ang-[1-7] and Ang-[I-10] activity both in the periphery and brain play a role in the increased sympathetic activity observed in anorexia.