Attenuated Blood Pressure Responses Research Articles

Reflex sympathetic activation to inspiratory muscle loading is attenuated in females relative to males.

Intense inspiratory muscle work can evoke a metabolite stimulated pressor reflex, commonly referred to as the respiratory muscle metaboreflex. When completing similar relative and absolute levels of inspiratory work, females have an attenuated blood pressure response. We sought to test the hypothesis that the lower blood pressure response to the respiratory muscle metaboreflex in females is associated with a reduced sympathetic response. Healthy young (26±4 y) males (n=9) and females (n=7) completed two experimental days. On day one participants completed pulmonary function testing and became familiarized with an inspiratory pressure-threshold loading (PTL) task. On the second day, balloon-tipped catheters were placed in the esophagus and stomach to measure pleural and gastric pressures and transdiaphragmatic pressure was calculated. A microelectrode was inserted into the fibular nerve to quantify muscle sympathetic nerve activity (MSNA) and participants then completed isocapnic PTL to task failure. There was a significant sex and time interaction in the mean arterial pressure (MAP, p=0.015) and burst frequency (p=0.039) response to PTL. Males had a greater rise in MAP (∆ 21±9 mmHg) relative to females (∆ 13±5 mmHg, p=0.026). Males also demonstrated a greater rise in MSNA burst frequency (∆ 18±7 bursts/min) relative to females (∆ 10±5 bursts/min, p=0.015). The effect of sex was observed despite females and males completing the same magnitude of diaphragm work throughout the task (p=0.755). Our findings provide novel evidence that the lower blood pressure response to similar relative and absolute inspiratory muscle work in females is associated with lower sympathetic activation.

Association between Daytime Sleepiness, Fatigue and Autonomic Responses during Head-Up Tilt Test in Multiple Sclerosis Patients.

We aimed to assess dynamic changes in hemodynamic and autonomic function in response to the head-up tilt test (HUTT) in patients with multiple sclerosis (MS) compared to healthy controls (HCs) and evaluate its relationship with the patients' reported daytime sleepiness and fatigue symptoms. A total of 58 MS patients and 30 HCs were included in the analysis. Fatigue and sleepiness were evaluated using the Chalder Fatigue Scale (CFQ) and the Epworth Sleepiness Scale (ESS), respectively. Hemodynamic response, baroreflex sensitivity, heart rate variability, and systolic and diastolic blood pressure (BP) variability (SBPV, DBPV) parameters were calculated at rest, and in response to the HUTT. The MS patients displayed attenuated BP responses coupled with a more pronounced decrease in cardiac index as well as a reduced increase in the low frequency (LFnu) of DBPV (p = 0.021) and the sympathovagal ratio (p = 0.031) in the latter-phase orthostatic challenge compared to HCs. In MS patients, the ESS score showed no correlation with CFQ or clinical disease outcomes, but exhibited a moderate correlation with LFnu of BPVrest. Fatigue and disease variants predicted blood pressure response to HUTT. These findings underscore the importance of subjective daytime sleepiness and fatigue symptoms and their role in blood pressure regulation in MS patients.

ACE2 Ubiquitination in the Paraventricular Nucleus of the Hypothalamus Contributes to Angiotensin‐II‐Induced Hypertension in Mice

Ubiquitination is a post‐translational modification of proteins where the ubiquitin moiety is covalently attached at the C‐terminus to specific lysine residues on the target protein, leading to degradation in proteasome or lysosomes. Angiotensin converting enzyme 2 (ACE2) is a transmembrane protein with a primary role in converting Angiotensin (Ang)‐II into Ang‐(1‐7) and thereby reducing blood pressure (BP). We previously reported that ACE2 undergoes internalization and degradation via ubiquitination in response to Ang‐II. Here we investigated whether ACE2 ubiquitination in the paraventricular nucleus of the hypothalamus (PVN), contributes to Ang‐II mediated hypertension in mice. Wildtype C57BL/6J (WT, n=6) and ACE2 KO (n=6) male mice were bilaterally injected into the PVN with an adeno‐associated virus vector expressing a ubiquitin resistant ACE2 mutant in which 5 lysine residues from the C‐terminus of the human ACE2 protein were replaced with arginine (hACE2‐5R). Six‐weeks later, anesthetized mice were connected to a stereotaxic setup and BP was recorded from the common carotid artery. Focal microinjections of Ang‐II (100 ng in 100 nL) were administered into PVN, and BP responses were analyzed. In another group, mice were chronically implanted subcutaneously with BP telemetry and administered Ang‐II via osmotic minipump (600 ng/kg/day) for 2‐weeks. In comparison to WT mice (n=6), acute microinjections of Ang‐II into PVN resulted in a significantly attenuated BP response in hACE2‐5R transfected WT mice (9±1 vs. 14±2 mmHg; n=6, p<0.05). A similarly attenuated response was observed in ACE2 KO mice (n=8) expressing hACE2‐5R when compared to ACE2 KO mice (7±2 vs. 16±3, n=5, p<0.05). Furthermore, chronic Ang‐II‐infused WT and ACE2 KO mice expressing hACE2‐5R exhibited a similar reduction of hypertension (125±2 and 121±1 mmHg, respectively) in comparison to their naïve WT and ACE2 KO controls (137±1 and 148±2 mmHg, respectively, p<0.05). Protein analysis revealed a significant attenuation of AT1receptor expression and increased ACE2 activity in the hypothalamus of mice transfected with hACE2‐5R in the PVN. Our results demonstrate that ACE2 is ubiquitinated by circulating Ang‐II and overexpression of ubiquitination resistant ACE2 enhances the enzyme’s activity and decreases BP in hypertensive mice.

Acute L-citrulline Attenuates Blood Pressure Responses To Exercise And Cold Stress In Hypertensive Postmenopausal Women

Acute L-citrulline Attenuates Blood Pressure Responses To Exercise And Cold Stress In Hypertensive Postmenopausal Women

Attenuated aortic blood pressure responses to metaboreflex activation in older adults with dynapenia.

Low muscle strength (dynapenia) is a primary characteristic of sarcopenia, the age-related loss of muscle mass and strength or low walking speed. New evidence suggests that muscle strength positively affects blood pressure (BP) responses to exercise. As older adults with lowest handgrip strength also have lowest BP at rest, those with dynapenia may experience attenuated BP responses during physical activity. The purpose of this study was to test the hypothesis that dynapenic older adults would exhibit lower BP response to post-exercise muscle ischemia (PEMI). Brachial and aortic systolic BP (SBP), diastolic BP (DBP), and mean arterial pressure (MAP) were measured in older adults (age, 80±5 y) with dynapenia (n=16) and non-dynapenia (n=9) at rest and during PEMI following 2min of isometric handgrip exercise at 30% maximal voluntary contraction. Walking speed was assessed by an 8-foot (2.44m) walk course. Increases in aortic SBP (11±2 vs. 23±6mmHg, p=.03), DBP (6±2 vs.14±4mmHg, p=.04), and MAP (8±1 vs. 17±5mmHg, p=.02) were lower in dynapenic compared to non-dynapenic adults. Aortic MAP (r=0.52, p<.05) response to PEMI was correlated with MVC in dynapenic adults. Gait speed was correlated with aortic DBP response to PEMI (r=0.698, p=.05) in non-dynapenic adults. Our findings indicate that aortic DBP response to muscle metaboreflex activation is attenuated in older adults with dynapenia. Normal aortic DBP response during metaboreflex activation may positively affect walking performance in non-dynapenic older adults.

Angiotensin II receptor blocker attenuates stress pressor response in young adult African Americans.

African Americans (AAs) are susceptible to hypertension (HTN) and its associated organ damage leading to adverse cardiovascular (CV) outcomes. Psychological stress is proposed to contribute to the development of HTN; however, the potential role of the renin-angiotensin system (RAS) in stress-related HTN in AAs is largely unknown. In this study, we tested the hypothesis that activation of RAS is a potential contributing factor for altered CV responses to stress, and suppression of angiotensin II (Ang II) activity will improve hemodynamic responses to a prolonged mental stressor in healthy young AAs. Utilizing a double-blind, randomized, crossover study design, 132 normotensive AAs (25±7years) were treated with either a placebo (PLC) or 150mg/d irbesartan (an Ang II type 1 receptor blocker; ARB) for 1week. On the final day of each treatment, hemodynamic measures and urinary sodium excretion (UNaV) were collected before, during and after a 45minute-mental stress. The magnitude of stress-induced increase in blood pressure with ARB was blunted and delayed compared to PLC. Systolic blood pressure at the end of recovery on ARB was significantly lower compared to either PLC (110±13 vs 117±12mmHg respectively; P<0.001) or the prestress level on ARB (P=0.02). ARB treatment reduced overall vasoconstriction and improved poststress UNaV. ARB attenuated blood pressure responses to mental stress and improved the poststress BP recovery process which were partly linked to reduced overall vasoconstriction and improved stress-induced UNaV in young adult AAs prior to the development of disease conditions. These results suggest that treatment approaches that inhibit RAS action could have significant relevance to potentially lower susceptibility to stress responses and eventually the premature development of HTN in AAs.

Aerobic Exercise Training Attenuates Blood Pressure Response During Maximal Aerobic Exercise and Improves Endothelial Function in Chronic Kidney Disease

IntroductionChronic Kidney Disease (CKD) patients experience an exaggerated increase in blood pressure during exercise that is associated with an increased risk of cardiovascular mortality. Recent work from our group suggests that this exaggerated blood pressure response is associated with endothelial dysfunction. We hypothesized that 12 weeks of structured, aerobic exercise training would attenuate blood pressure increases during maximal exercise and improve endothelial function compared to stretching (an active control intervention) in CKD.Methods12 participants (age =65±2y) with CKD stages III or IV were randomized to 12 weeks of supervised aerobic cycling exercise (N=6) or stretching (N=6) for 45 minutes, 3 times per week. A maximum treadmill exercise test was performed via the modified Balke Protocol to assess blood pressure response and maximal aerobic capacity (VO2peak) before and after the 12‐week intervention. Blood pressure was measured manually by a single investigator (J Park) during the final 30s of each stage of the maximal exercise test. Reactive hyperemia index (RHI), an index of endothelial function assessed via peripheral artery tonometry was also measured at the beginning and end of the intervention. A linear mixed model was used to compare the rate of increase in heart rate, systolic and diastolic blood pressure during the maximal exercise tests, and VO2peak and RHI were compared via a 2‐way repeated measures ANOVA.ResultsVO2peak increased in the exercise group (Pre, 24.6±2.5 vs. Post, 28.2±2.3 ml/kg/min, P=0.046) but not in the stretching group (Pre, 26.8±2.2 vs. Post, 26.04±2.1 ml/kg/min, P=0.641). Similarly, RHI tended to increase with exercise training (Pre, 1.68 ±0.1 vs. Post, 2.21±0.31, P=0.081) but not stretching (Pre, 1.59±0.06 vs. Post, 1.83±0.24, P=0.403). While there was a trend for an attenuation in the rate of increase in systolic blood pressure from pre‐ to post‐intervention in the exercise group (Pre, 11.3±1.1 vs. Post, 8.1±1.0 mmHg/stage, P=0.07), this difference was not observed in the stretching group (Pre, 12.8±1.7 vs Post, 13.0±1.3 mmHg/stage, P=0.876). There were no differences in heart rate or diastolic blood pressure responses during exercise in either group.DiscussionIn support of our hypothesis, 12 weeks of structured aerobic exercise training attenuates blood pressure responses during maximal exercise and improves endothelial function in CKD. These findings suggest that exercise training may attenuate the exaggerated blood pressure responses during exercise and improve endothelial dysfunction that characterize this population. Future work should seek to explore the mechanistic link between endothelial function and blood pressure responses in CKD and determine the optimum dose (frequency, intensity, and duration) of exercise training.Support or Funding InformationThis work was supported by National Institutes of Health R01 HL135183 (to J. Park); National Institutes of Health training grants T32 DK‐00756 (to J. Sands).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Contrasting effects of low versus high ascorbate doses on blood pressure responses to oral nitrite in L-NAME-induced hypertension

Nitrite reduces blood pressure (BP) in both clinical and experimental hypertension. This effect is attributable to the formation of nitric oxide (NO) and other NO-related species, which may be improved by ascorbate or other antioxidants. However, the BP responses to oral nitrite result, at least in part, of increased gastric S-nitrosothiol formation. This study tested the hypothesis that ascorbate may destroy S-nitrosothiols and therefore not all doses of ascorbate enhance the BP responses to oral nitrite. We assessed the BP responses to oral sodim nitrite (0.2 mmol/kg) in L-NAME hypertensive rats pretreated with ascorbate (0, 0.02, 0.2, or 2 mmol/kg). Plasma and gastric wall concentrations of nitrite and nitroso compounds concentrations were determined using an ozone-based reductive chemiluminescence assay. Nitrate concentrations were determined using the Griess reaction. Free thiol concentrations were determined by a colorimetric assay. The BP responses to nitrite exhibited a bell-shape profile as they were not modified by ascorbate 0.02 mmol/l, whereas the 0.2 mmol/kg dose enhanced and the 2 mmol/kg dose attenuated BP responses. In parallel with BP responses, nitrite-induced increases in plasma nitrite and RSNO species were not modified by ascorbate 0.02 mmol/l, whereas the 0.2 mmol/kg dose enhanced and the 2 mmol/kg dose attenuated them. Similar experiments were carried out with an equimolar dose of S-nitrosogluthathione. Ascorbate dose-dependently impaired the BP responses to S-nitrosogluthathione, and the corresponding increases in plasma RSNO, but not in plasma nitrite concentrations. This is the first study to show that while ascorbate dose-dependently impairs the BP responses to oral S-nitrosogluthathione, there are contrasting effects when low versus high ascorbate doses are compared with respect to its effects on the blood pressure responses to oral nitrite administration. Our findings may have special implications to patients taking ascorbate, as high doses of this vitamin may impair protective mechanisms associated with nitrite or nitrate from dietary sources.

Evidence of the Importance of Nox4 in Production of Hypertension in Dahl Salt-Sensitive Rats.

This study reports the consequences of knocking out NADPH (nicotinamide adenine dinucleotide phosphate) oxidase 4 (Nox4) on the development of hypertension and kidney injury in the Dahl salt-sensitive (SS) rat. Zinc finger nuclease injection of single-cell SS embryos was used to create an 8 base-pair frame-shift deletion of Nox4, resulting in a loss of the ≈68 kDa band in Western blot analysis of renal cortical tissue of the knock out of Nox4 in the SS rat (SS(Nox4-/-)) rats. SS(Nox4-/-) rats exhibited a significant reduction of salt-induced hypertension compared with SS rats after 21 days of 4.0% NaCl diet (134±5 versus 151±3 mm Hg in SS) and a significant reduction of albuminuria, tubular casts, and glomerular injury. Optical fluorescence 3-dimensional cryoimaging revealed significantly higher redox ratios (NADH/FAD [reduced nicotinamide adenine dinucleotide/flavin adenine dinucleotide]) in the kidneys of SS(Nox4-/-) rats even when fed the 0.4% NaCl diet, indicating greater levels of mitochondrial electron transport chain metabolic activity and reduced oxidative stress compared with SS rats. Before the development of hypertension, RNA expression levels of Nox subunits Nox2, p67(phox), and p22(phox) were found to be significantly lower (P<0.05) in SS(Nox4-/-) compared with SS rats in the renal cortex. Thus, the mutation of Nox4 seems to modify transcription of several genes in ways that contribute to the protective effects observed in the SS(Nox4-/-) rats. We conclude that the reduced renal injury and attenuated blood pressure response to high salt in the SS(Nox4-/-) rat could be the result of multiple pathways, including gene transcription, mitochondrial energetics, oxidative stress, and protein matrix production impacted by the knock out of Nox4.

Arterial α2-Na+ pump expression influences blood pressure: lessons from novel, genetically engineered smooth muscle-specific α2 mice.

Arterial myocytes express α1-catalytic subunit isoform Na(+) pumps (75-80% of total), which are ouabain resistant in rodents, and high ouabain affinity α2-Na(+) pumps. Mice with globally reduced α2-pumps (but not α1-pumps), mice with mutant ouabain-resistant α2-pumps, and mice with a smooth muscle (SM)-specific α2-transgene (α2 (SM-Tg)) that induces overexpression all have altered blood pressure (BP) phenotypes. We generated α2 (SM-DN) mice with SM-specific α2 (not α1) reduction (>50%) using nonfunctional dominant negative (DN) α2. We compared α2 (SM-DN) and α2 (SM-Tg) mice to controls to determine how arterial SM α2-pumps affect vasoconstriction and BP. α2 (SM-DN) mice had elevated basal mean BP (mean BP by telemetry: 117 ± 4 vs. 106 ± 1 mmHg, n = 7/7, P < 0.01) and enhanced BP responses to chronic ANG II infusion (240 ng·kg(-1)·min(-1)) and high (6%) NaCl. Several arterial Ca(2+) transporters, including Na(+)/Ca(2+) exchanger 1 (NCX1) and sarcoplasmic reticulum and plasma membrane Ca(2+) pumps [sarco(endo)plasmic reticulum Ca(2+)-ATPase 2 (SERCA2) and plasma membrane Ca(2+)-ATPase 1 (PMCA1)], were also reduced (>50%). α2 (SM-DN) mouse isolated small arteries had reduced myogenic reactivity, perhaps because of reduced Ca(2+) transporter expression. In contrast, α2 (SM-Tg) mouse aortas overexpressed α2 (>2-fold), NCX1, SERCA2, and PMCA1 (43). α2 (SM-Tg) mice had reduced basal mean BP (104 ± 1 vs. 109 ± 2 mmHg, n = 15/9, P < 0.02) and attenuated BP responses to chronic ANG II (300-400 ng·kg(-1)·min(-1)) with or without 2% NaCl but normal myogenic reactivity. NCX1 expression was inversely related to basal BP in SM-α2 engineered mice but was directly related in SM-NCX1 engineered mice. NCX1, which usually mediates arterial Ca(2+) entry, and α2-Na(+) pumps colocalize at plasma membrane-sarcoplasmic reticulum junctions and functionally couple via the local Na(+) gradient to help regulate cell Ca(2+). Altered Ca(2+) transporter expression in SM-α2 engineered mice apparently compensates to minimize Ca(2+) overload (α2 (SM-DN)) or depletion (α2 (SM-Tg)) and attenuate BP changes. In contrast, Ca(2+) transporter upregulation, observed in many rodent hypertension models, should enhance Ca(2+) entry and signaling and contribute significantly to BP elevation.

Clinical Differentiation Between Physiological Remodeling and Arrhythmogenic Right Ventricular Cardiomyopathy in Athletes With Marked Electrocardiographic Repolarization Anomalies

BackgroundPhysiological cardiac adaptation to regular exercise, including biventricular dilation and T-wave inversion (TWI), may create diagnostic overlap with arrhythmogenic right ventricular cardiomyopathy (ARVC). ObjectivesThe goal of this study was to assess the accuracy of diagnostic criteria for ARVC when applied to athletes exhibiting electrocardiographic TWI and to identify discriminators between physiology and disease. MethodsThe study population consisted of athletes with TWI (n = 45), athletes without TWI (n = 35), and ARVC patients (n = 35). Subjects underwent electrocardiography (ECG), signal-averaged electrocardiography (SAECG), echocardiography, cardiac magnetic resonance imaging (CMRI), Holter monitoring, and exercise testing. ResultsThere were no electrical, structural, or functional cardiac differences between athletes exhibiting TWI and athletes without TWI. When athletes were compared with ARVC patients, markers of physiological remodeling included early repolarization, biphasic TWI, voltage criteria for right ventricular (RV) or left ventricular hypertrophy, and symmetrical cardiac enlargement. Indicators of RV pathology included the following: syncope; Q waves or precordial QRS amplitudes <1.8 mV; 3 abnormal SAECG parameters; delayed gadolinium enhancement, RV ejection fraction ≤45%, or wall motion abnormalities at CMRI; >1,000 ventricular extrasystoles (or >500 non-RV outflow tract) per 24 h; and symptoms, ventricular tachyarrhythmias, or attenuated blood pressure response during exercise. Nonspecific parameters included the following: prolonged QRS terminal activation; ≤2 abnormal SAECG parameters; RV dilation without wall motion abnormalities; RV outflow tract ectopy; and exercise-induced T-wave pseudonormalization. ConclusionsTWI and balanced biventricular dilation are likely to represent benign manifestations of training in asymptomatic athletes without relevant family history. Diagnostic criteria for ARVC are nonspecific in such individuals. Comprehensive testing using widely available techniques can effectively differentiate borderline cases.

Role of caveolin 1 in AT1a receptor-mediated uptake of angiotensin II in the proximal tubule of the kidney.

Caveolin 1 (CAV-1) functions not only as a constitutive scaffolding protein of caveolae but also as a vesicular transporter and signaling regulator. In the present study, we tested the hypothesis that CAV-1 knockout (CAV-1 KO) inhibits ANG II type 1 [AT1 (AT1a)] receptor-mediated uptake of ANG II in the proximal tubule and attenuates blood pressure responses in ANG II-induced hypertension. To determine the role of CAV-1 in mediating the uptake of FITC-labeled ANG II, wild-type (WT) mouse proximal convoluted tubule cells were transfected with CAV-1 small interfering (si)RNA for 48 h before AT1 receptor-mediated uptake of FITC-labeled ANG II was studied. CAV-1 siRNA knocked down CAV-1 expression by >90% (P < 0.01) and inhibited FITC-labeled ANG II uptake by >50% (P < 0.01). Moreover, CAV-1 siRNA attenuated ANG II-induced activation of MAPK ERK1/2 and Na(+)/H(+) exchanger 3 expression, respectively (P < 0.01). To determine whether CAV-1 regulates ANG II uptake in the proximal tubule, Alexa 488-labeled ANG II was infused into anesthetized WT and CAV-1 KO mice for 60 min (20 ng/min iv). Imaging analysis revealed that Alexa 488-labeled ANG II uptake was decreased by >50% in CAV-1 KO mice (P < 0.01). Furthermore, Val(5)-ANG II was infused into WT and CAV-1 KO mice for 2 wk (1.5 mg·kg(-1)·day(-1) ip). Basal systolic pressure was higher, whereas blood pressure and renal excretory and signaling responses to ANG II were attenuated, in CAV-1 KO mice (P < 0.01). We concluded that CAV-1 plays an important role in AT1 receptor-mediated uptake of ANG II in the proximal tubule and modulates blood pressure and renal responses to ANG II.

Roles of the subfornical organ and area postrema in arterial pressure increases induced by 48-h water deprivation in normal rats.

In rats, water deprivation (WD) increases arterial blood pressure (BP) in part due to actions of elevated osmolality in the brain to increase vasopressin levels and sympathetic activity. However, the osmoreceptors that mediate this response have not been identified. To test the hypothesis that osmoregulatory circumventricular organs are involved, BP and heart rate (HR) were continuously recorded telemetrically during 48 h of WD in normal rats with lesions (x) or sham lesions (sham) of the subfornical organ (SFO) or area postrema (AP). Although WD increased BP in SFOx and SFOsham rats, no significant difference in the hypertensive response was observed between groups. HR decreased transiently but similarly in SFOx and SFOsham rats during the first 24 h of WD. When water was reintroduced, BP and HR decreased rapidly and similarly in both groups. BP (during lights off) and HR were both lower in APx rats before WD compared to APsham. WD increased BP less in APx rats, and the transient bradycardia was eliminated. Upon reintroduction of drinking water, smaller falls in both BP and HR were observed in APx rats compared to APsham rats. WD increased plasma osmolality and vasopressin levels similarly in APx and APsham rats, and acute blockade of systemic V1 vasopressin receptors elicited similar depressor responses, suggesting that the attenuated BP response is not due to smaller increases in vasopressin or osmolality. In conclusion, the AP, but not the SFO, is required for the maximal hypertensive effect induced by WD in rats.

The Impact of Four Different Classes of Anesthetics on the Mechanisms of Blood Pressure Regulation in Normotensive and Spontaneously Hypertensive Rats

Most anesthetics induce characteristic hemodynamic changes leading to blood pressure (BP) reduction but the role of renin-angiotensin system (RAS), sympathetic nervous system (SNS) and nitric oxide (NO) synthesis in this BP reduction is unknown. We therefore studied the influence of four widely used anesthetics - pentobarbital (P), isoflurane (ISO), ketamine-xylazine (KX) and chloralose-urethane (CU) - on the participation of these vasoactive systems in BP maintenance. BP effects elicited by the acute sequential blockade of RAS (captopril), SNS (pentolinium) and NO synthase (L-NAME) were compared in conscious and anesthetized Wistar or spontaneously hypertensive rats (SHR). Except for pentobarbital all studied anesthetics evidenced by diminished BP responses to pentolinium. The absolute pentolinium-induced BP changes were always greater in SHR than Wistar rats. KX anesthesia eliminated BP response to pentolinium and considerably enhanced BP response to NO synthase inhibition in SHR. In both rat strains the anesthesia with ISO or CU augmented BP response to captopril, decreased BP response to pentolinium and attenuated BP response to NO synthase inhibition. In conclusion, pentobarbital anesthesia had a modest influence on BP level and its maintenance by the above vasoactive systems. Isoflurane and chloralose-urethane anesthesia may be used in cardiovascular experiments if substantial BP decrease due to altered contribution of RAS, SNS and NO to BP regulation does not interfere with the respective research aim. Major BP reduction (namely in SHR) due to a complete SNS absence is a major drawback of ketamine-xylazine anesthesia.

Role of Shp2 in forebrain neurons in regulating metabolic and cardiovascular functions and responses to leptin

ObjectiveWe examined whether deficiency of Shp2 signaling in forebrain neurons alters metabolic and cardiovascular regulation under various conditions and if it attenuates the anorexic and cardiovascular effects of leptin. We also tested whether forebrain Shp2 deficiency alters blood pressure (BP) and heart rate (HR) responses to acute stress.DesignForebrain Shp2-/- mice were generated by crossing Shp2flox/flox mice with CamKIIα-cre mice. At 22 to 24 weeks of age, mice were instrumented for telemetry for measurement of BP, HR and body temperature (BT). Oxygen consumption (VO2), energy expenditure and motor activity were monitored by indirect calorimetry.ResultsShp2/CamKIIα-cre mice were heavier (46±3 vs 32±1 g), hyperglycemic, hyperleptinemic, hyperinsulinemic, and hyperphagic compared to Shp2flox/flox control mice. Shp2/CamKIIα-cre mice exhibited reduced food intake responses to fasting/refeeding and impaired regulation of BT when exposed to 15°C and 30°C ambient temperatures. Despite being obese and having many features of metabolic syndrome, Shp2/CamKIIα-cre mice had similar daily average BP and HR compared to Shp2flox/flox mice (112±2 vs 113±1 mmHg and 595±34 vs 650±40 bpm), but exhibited increased BP and HR responses to cold exposure and acute air-jet stress test. Leptin's ability to reduce food intake and to raise BP were markedly attenuated in Shp2/CamKIIα-cre mice.ConclusionThese results suggest that forebrain Shp2 signaling regulates food intake, appetite responses to caloric deprivation, and thermogenic control of body temperature during variations in ambient temperature. Deficiency of Shp2 signaling in the forebrain is associated with augmented cardiovascular responses to cold and acute stress but attenuated BP responses to leptin.

Mice lacking the gene for Toll Like receptor‐4 (TLR4) had an attenuated blood pressure response to Angiotensin II infusion

Hypertension (HTN) is considered as a low grade inflammatory disease. Previous studies from our lab indicate that brain inflammatory molecules contribute to the development of HTN. Since TLR4 is a major modulator of inflammation, in this study, we explored the role of TLR4 in angiotensin II (ANGII) induced HTN. TLR4 knock‐out (KO) and wild type (WT) mice were implanted with telemetry probes for mean arterial pressure (MAP) measurements. After collecting baseline MAP, osmotic minipump containing ANGII (200ng/kg/min) or saline was implanted for 14 days. Then the brains microdissected for the paraventricular nucleus (PVN), sub fornical organ (SFO), nucleus tractus solatorius (NTS) and ventrolateral medulla (VLM) and examined for the expression of prorenin receptor (PRR) and interleukin(IL)‐1β by RT‐PCR. In WT mice, ANG II infusion increased MAP by day 3 (122±4) and peaked on day 9 (145±2) and remained elevated. This was accompanied by an increase in IL‐1β and PRR in the SFO, PVN, VLM and NTS. In contrast, ANGII infusion in TLR4 KO did not increase MAP (96±2) and remained lower (97±2) when compared with WT+ANGII (144±3). In addition, there was decrease in the expression of PRR and IL‐1β in the brain regions of TLR4 KO after ANGII. These finding indicate that ANGII induced HTN is at least in part mediated by TLR4 expression in the pressor regions of the brain and is associated with increase in PRR and IL‐1β expression. Funding: LSU

Common Genetic Variants in the Endothelial System Predict Blood Pressure Response to Sodium Intake: The GenSalt Study

BACKGROUND We examined the association between 14 endothelial system genes and salt-sensitivity of blood pressure (BP). METHODS After a 3-day baseline examination, during which time the usual diet was consumed, 1,906 Chinese participants received a 7-day low-sodium diet (51.3 mmol of sodium/day) followed by a 7-day high-sodium diet (307.8 mmol of sodium/day). BP measurements were obtained at baseline and at the end of each intervention using a random-zero sphygmomanometer. RESULTS The DDAH1 rs11161637 variant was associated with reduced BP salt sensitivity, conferring attenuated systolic BP (SBP) and mean arterial pressure (MAP) decreases from baseline to the low-sodium intervention (both P = 2×10(-4)). Examination of genotype-sex interactions revealed that this relation was driven by the strong associations observed in men (P for interactions = 1.10×10(-4) and 0.008, respectively). When switching from the low- to high-sodium intervention, increases in diastolic BP (DBP) and MAP were attenuated by the COL18A1 rs2838944 minor A allele (P = 1.41×10(-4) and 1.55×10(-4), respectively). Conversely, the VWF rs2239153 C variant was associated with increased salt sensitivity, conferring larger DBP and MAP reductions during low-sodium intervention (P = 1.22×10(-4) and 4.44×10(-5), respectively). Ten variants from 3 independent SELE loci displayed significant genotype-sex interactions on DBP and MAP responses to low-sodium (P for interaction = 1.56×10(-3) to 1.00×10(-4)). Among men, minor alleles of 4 correlated markers attenuated BP responses to low-sodium intake, whereas minor alleles of another 4 correlated markers increased BP responses. No associations were observed in women for these variants. Further, qualitative interactions were shown for 2 correlated SELE markers. CONCLUSIONS These data support a role for the endothelial system genes in salt sensitivity.

Acute cardiovascular responses in preterm infants at 34–39 weeks of gestational age

BackgroundPremature infants demonstrate immature physiological control mechanisms; however their acute cardiovascular control has not yet been widely studied. AimThe aim of this study was to analyze heart rate (HR) and blood pressure (BP) control in preterm infants. SubjectsTwenty preterm infants with a mean gestational age of 31±2.4 (26–34) weeks at birth were evaluated at a gestational age of 36±1.5 (34–39) weeks. Results were compared to twenty, healthy, full-term, control infants studied at the age of 12±3weeks. Outcome measuresHR and BP responses to 45° head-up tilt and side motion tests during non-rapid eye movement sleep were analyzed. In addition, HR responses to spontaneous arousals from non-rapid eye movement sleep were evaluated. ResultsPreterm infants showed significantly smaller initial HR and BP responses compared with controls in head-up tilt (HR p=0.0005, systolic BP p=0.02, diastolic BP p=0.01) and side motion tests (HR p=0.002, systolic BP p<0.0001, diastolic BP p<0.0001). Furthermore, in tilt tests, preterm infants presented with greater intersubject variability in BP responses than controls (systolic BP p=0.009, diastolic BP p=0005). Preterm HR responses to spontaneous arousals were similar to controls. ConclusionsThis study indicates immature vestibulo-mediated cardiovascular control in preterm infants compared with term infants. This is seen as attenuated BP responses to side motion test and more labile acute BP control to postural challenge.

Hemodynamic mechanisms of the attenuated blood pressure response to mental stress after a single bout of maximal dynamic exercise in healthy subjects

To determine the hemodynamic mechanisms responsible for the attenuated blood pressure response to mental stress after exercise, 26 healthy sedentary individuals (age 29 ± 8 years) underwent the Stroop color-word test before and 60 min after a bout of maximal dynamic exercise on a treadmill. A subgroup (N = 11) underwent a time-control experiment without exercise. Blood pressure was continuously and noninvasively recorded by infrared finger photoplethysmography. Stroke volume was derived from pressure signals, and cardiac output and peripheral vascular resistance were calculated. Perceived mental stress scores were comparable between mental stress tests both in the exercise (P = 0.96) and control (P = 0.24) experiments. After exercise, the systolic blood pressure response to mental stress was attenuated (pre: 10 ± 13 vs post: 6 ± 7 mmHg; P < 0.01) along with lower values of systolic blood pressure (pre: 129 ± 3 vs post: 125 ± 3 mmHg; P < 0.05), stroke volume (pre: 89.4 ± 3.5 vs post: 76.8 ± 3.8 mL; P < 0.05), and cardiac output (pre: 7.00 ± 0.30 vs post: 6.51 ± 0.36 L/min; P < 0.05). Except for heart rate, the hemodynamic responses and the mean values during the two mental stress tests in the control experiment were similar (P > 0.05). In conclusion, a single bout of maximal dynamic exercise attenuates the blood pressure response to mental stress in healthy subjects, along with lower stroke volume and cardiac output, denoting an acute modulatory action of exercise on the central hemodynamic response to mental stress.

Activation of 5HT1A receptors in the nucleus tractus solitarius contributes to blood pressure compensation with blood loss and peripheral chemoreflex responses in the presence of acidosis

Caudal serotonin neurons and the 5‐HT1A receptor ( 1AR) agonist, 8‐OH‐DPAT, promote sympathetic‐mediated increases in cardiac output after blood loss. We hypothesize that the metabolic acidosis of hemorrhage activates serotonin neurons and 1AR in the nucleus tractus solitarius (NTS) to facilitate chemoreflex responses to carotid body hypoxia. Here, we tested ventilatory responses to hypoxic hypercapnia (10% O2, 5% CO2) and blood pressure responses to hemorrhage and subsequent 8‐OH‐DPAT administration in rats subjected to bilateral knockdown of the 1AR in the NTS. An adeno‐associated viral vector harboring a short hairpin RNA targeting the rat 1AR (1ARshRNA) or a scrambled shRNA (Scram) was injected into the caudal NTS of male Sprague Dawley rats. After 4 weeks, rats injected with the 1AshRNA (n=12) had lower cumulative minute ventilation during hypoxic hypercapnia vs. Scram‐injected rats (n=13, P&lt;0.01). Rats injected with 1AshRNA (n=8) had a more rapid fall in blood pressure with blood loss and an attenuated blood pressure response to 8‐OH‐DPAT injection (30 nmol/kg, iv, P&lt;0.01) vs. Scram‐injected rats (n=9). 1AshRNA injection decreased 1AR protein in the caudal NTS (−35%, P&lt;0.05). Thus, the beneficial hemodynamic effect of 8‐OH‐DPAT and endogenous serotonin in hemorrhage is related to activation of 1AR in the NTS and possibly to facilitation of chemoreflex responses to hypoxia. Funded by AHA 10PRE4000023.