Regulation Of Arterial Pressure Research Articles

Risk of Frailty According to the Values of the Ankle-Brachial Index in the Toledo Study for Healthy Aging.

Vascular function (VF) is a general term used to describe the regulation of blood flow, arterial pressure, capillary recruitment, filtration and central venous pressure, it´s well known that age has direct effects on the VF, and this may affect the frailty status. To analyse the association between Frailty Trait Scale 5 (FTS 5) with VF and its changes at values below and above a nadir. Prospective population-based cohort study. Data from 1.230 patients were taken from the first wave (2006-2009) of the Toledo Study for Healthy Aging. Frailty was evaluated using FTS 5, which evaluates 5 items: Body mass index, progressive Romberg, physical activity, usual gait speed and hand grip strength. VF was assessed using the ankle-brachial index (ABI) as an indirect measure of VF. Screening for cardiovascular and cerebrovascular disease was also performed by self-reporting and by searching medical records, and was used as exclusion criteria. The optimal ABI cut-off point that maximized the adjusted R2 was 1.071. We observed a statistically significant association for FTS 5 score above and below the ABI cut-off points. For every tenth that the ABI decreased below the cut-off point the patient had an increase in the FTS 5 score of 0.47 points and in every tenth that increased above the cut-off point the increase in the FTS 5 score was 0.41 points. Of all FTS 5 items, the gait speed was the only item that showed a significant association with an ABI changes 0.28 and 0.21 points for every tenth below and above the cut-off point, respectively. Frailty is highly associated with VF. In addition, FTS 5 and its gait speed criteria are useful to detect VF impairments, via changes in ABI.

Comprehensive medical rehabilitation using therapeutic physical factors including hydrokinesiotherapy in a pool with mineral water and its effect on circadian rhythms of arterial pressure and autonomic regulation in patients with arterial hypertension and with chronic psychoemotional stress

To study the effect of the course-based comprehensive rehabilitation using the therapeutic physical factors of the Belokurikha resort, including hydrokinesiotherapy in a pool with mineral water on the circadian rhythms of arterial pressure and its autonomous regulation in patients with arterial hypertension (AH) associated with chronic psychoemotional stress (CPES). The study involved 83 patients with stage I-II grade 1-2 of AH, whose professional activities were associated with CPES. Each participant had 24-hours Holter blood pressure monitored, and cardiointervalography (CIG) was performed before and after the medical rehabilitation course. The rehabilitation complex of the main group (II) included medication therapy for AH, diet, morning hygienic gymnastics, manual massage, total magnet therapy, and hydrokinesiotherapy in a pool with mineral water. Patients in the comparison group (I) were exposed to similar therapeutic physical factors with identical parameters of the procedures, except hydrokinesiotherapy, which was replaced by full baths with mineral water. Medical rehabilitation using the therapeutic physical factors of the Belokurikha resort with hydrokinesiotherapy in a pool promotes a decrease in the activity of a sympathetic nervous system and increase of vagal effects contribute to the regulation of vital functions of the AH patients, associated with CPES, thus minimizing the frequency of abnormal daily profiles night-peaker and over-dipper to 12.5% and 1.78% of cases, respectively, and increasing the percentage of subjects with its normal type (dipper) to 57.1% (p=0.039). The study results show the benefits of hydrokinesiotherapy in a pool with mineral water as a part of the course-based comprehensive rehabilitation in patients with hypertension and chronic psychoemotional stress in terms of normalizing circadian rhythms of arterial pressure and optimizing the activity of higher autonomous centers, which largely determine the cardiovascular system performance in this setting.

Changes in sympathetic nerve activity and arterial pressure regulation induced by exercise

Changes in sympathetic nerve activity and arterial pressure regulation induced by exercise

Arcuate Angiotensin II Increases Arterial Pressure via Coordinated Increases in Sympathetic Nerve Activity and Vasopressin Secretion.

The arcuate nucleus (ArcN) is an integrative hub for the regulation of energy balance, reproduction, and arterial pressure (AP), all of which are influenced by Angiotensin II (AngII); however, the cellular mechanisms and downstream neurocircuitry are unclear. Here, we show that ArcN AngII increases AP in female rats via two phases, both of which are mediated via activation of AngII type 1 receptors (AT1aRs): initial vasopressin-induced vasoconstriction, followed by slowly developing increases in sympathetic nerve activity (SNA) and heart rate (HR). In male rats, ArcN AngII evoked a similarly slow increase in SNA, but the initial pressor response was variable. In females, the effects of ArcN AngII varied during the estrous cycle, with significant increases in SNA, HR, and AP occurring during diestrus and estrus, but only increased AP during proestrus. Pregnancy markedly increased the expression of AT1aR in the ArcN with parallel substantial AngII-induced increases in SNA and MAP. In both sexes, the sympathoexcitation relied on suppression of tonic ArcN sympathoinhibitory neuropeptide Y (NPY) inputs, and activation of proopiomelanocortin (POMC) projections, to the paraventricular nucleus (PVN). Few or no NPY or POMC neurons expressed the AT1aR, suggesting that AngII increases AP and SNA at least in part indirectly via local interneurons, which express tyrosine hydroxylase (TH) and VGat (i.e., GABAergic). ArcN TH neurons release GABA locally, and central AT1aR and TH neurons mediate stress responses; therefore, we propose that TH AT1aR neurons are well situated to locally coordinate the regulation of multiple modalities within the ArcN in response to stress.

Reliance on vascular responses for the maintenance of blood pressure in healthy older adults - Insights from the Valsalva maneuver.

Effective baroreflex-mediated cardiac and vascular resistance responses are crucial for homeostatic blood pressure control. We investigated the impacts of age and sex on arterial blood pressure regulation during a standard supine Valsalva maneuver (40mmHg, 20s) in 46 healthy young and 25 healthy older adults. Noninvasive, continuous cardiovascular parameters were recorded. In older adults, cardiac output (older: -58.4±2.4%; young: -40.8±1.4%; p<0.001) and stroke volume (older: -63.6±2.6%; young: -48.7±1.9%; p<0.001) fell more than in young adults and was compensated by augmented vascular resistance responses (older: +189.8±17.6%; young: +105.8±6.7; p<0.001); heart rate responses were attenuated in older adults. Male and female responses were comparable in their respective age groups.

Low-dose fentanyl does not alter muscle sympathetic nerve activity, blood pressure, or tolerance during progressive central hypovolemia.

Hemorrhage is a leading cause of battlefield and civilian trauma deaths. Several pain medications, including fentanyl, are recommended for use in the prehospital (i.e., field setting) for a hemorrhaging solider. However, it is unknown whether fentanyl impairs arterial blood pressure (BP) regulation, which would compromise hemorrhagic tolerance. Thus, the purpose of this study was to test the hypothesis that an analgesic dose of fentanyl impairs hemorrhagic tolerance in conscious humans. Twenty-eight volunteers (13 females) participated in this double-blinded, randomized, placebo-controlled trial. We conducted a presyncopal limited progressive lower body negative pressure test (LBNP; a validated model to simulate hemorrhage) following intravenous administration of fentanyl (75 µg) or placebo (saline). We quantified tolerance as a cumulative stress index (mmHg·min), which was compared between trials using a paired, two-tailed t test. We also compared muscle sympathetic nerve activity (MSNA; microneurography) and beat-to-beat BP (photoplethysmography) during the LBNP test using a mixed effects model [time (LBNP stage) × trial]. LBNP tolerance was not different between trials (fentanyl: 647 ± 386 vs. placebo: 676 ± 295 mmHg·min, P = 0.61, Cohen's d = 0.08). Increases in MSNA burst frequency (time: P < 0.01, trial: P = 0.29, interaction: P = 0.94) and reductions in mean BP (time: P < 0.01, trial: P = 0.50, interaction: P = 0.16) during LBNP were not different between trials. These data, the first to be obtained in conscious humans, demonstrate that administration of an analgesic dose of fentanyl does not alter MSNA or BP during profound central hypovolemia, nor does it impair tolerance to this simulated hemorrhagic insult.

Unveiling the Nanotechnology-Based Drug Delivery Systems and Patent Literature for Diabetic Retinopathy

Diabetes mellitus is a principal reason for globally developing chronic microvascular disorders defined as diabetic retinopathy (DR). Proliferative retinopathy and non-proliferative retinopathy are the two types of DR. Long-term diabetes, and poor blood sugar and arterial blood pressure regulation are the key risk factors for the onset and advancement of DR. A variety of biochemical pathways are involved in the pathogenesis of DR, which includes increased polyol pathway fluxes, advanced glycation end product growth, protein kinase C isoform activation, and increased hexosamine pathway flux. The varieties of cells are involved in diabetic retinopathy, including glial cells, retinal ganglion cells, endothelial cells, and pericytes. Surgical treatment of DR includes laser treatment, panretinal photocoagulation, focal laser photocoagulation, and vitrectomy surgery. The systemic treatment of DR includes glycemic management and control of blood pressure and hyperlipidemia. Nanotechnology-based formulations like nanoparticles, polymeric nanomicelles, and nanocarrier composite, and various patented formulations have been investigated for the treatment of DR.

Vasopressin and Breathing: Review of Evidence for Respiratory Effects of the Antidiuretic Hormone.

Vasopressin (AVP) is a key neurohormone involved in the regulation of body functions. Due to its urine-concentrating effect in the kidneys, it is often referred to as antidiuretic hormone. Besides its antidiuretic renal effects, AVP is a potent neurohormone involved in the regulation of arterial blood pressure, sympathetic activity, baroreflex sensitivity, glucose homeostasis, release of glucocorticoids and catecholamines, stress response, anxiety, memory, and behavior. Vasopressin is synthesized in the paraventricular (PVN) and supraoptic nuclei (SON) of the hypothalamus and released into the circulation from the posterior lobe of the pituitary gland together with a C-terminal fragment of pro-vasopressin, known as copeptin. Additionally, vasopressinergic neurons project from the hypothalamus to the brainstem nuclei. Increased release of AVP into the circulation and elevated levels of its surrogate marker copeptin are found in pulmonary diseases, arterial hypertension, heart failure, obstructive sleep apnoea, severe infections, COVID-19 due to SARS-CoV-2 infection, and brain injuries. All these conditions are usually accompanied by respiratory disturbances. The main stimuli that trigger AVP release include hyperosmolality, hypovolemia, hypotension, hypoxia, hypoglycemia, strenuous exercise, and angiotensin II (Ang II) and the same stimuli are known to affect pulmonary ventilation. In this light, we hypothesize that increased AVP release and changes in ventilation are not coincidental, but that the neurohormone contributes to the regulation of the respiratory system by fine-tuning of breathing in order to restore homeostasis. We discuss evidence in support of this presumption. Specifically, vasopressinergic neurons innervate the brainstem nuclei involved in the control of respiration. Moreover, vasopressin V1a receptors (V1aRs) are expressed on neurons in the respiratory centers of the brainstem, in the circumventricular organs (CVOs) that lack a blood-brain barrier, and on the chemosensitive type I cells in the carotid bodies. Finally, peripheral and central administrations of AVP or antagonists of V1aRs increase/decrease phrenic nerve activity and pulmonary ventilation in a site-specific manner. Altogether, the findings discussed in this review strongly argue for the hypothesis that vasopressin affects ventilation both as a blood-borne neurohormone and as a neurotransmitter within the central nervous system.

Does COVID‐19 influence the sympathetic regulation of blood pressure?

Does COVID‐19 influence the sympathetic regulation of blood pressure?

Особливості інтраопераційної регуляції артеріального тиску у пацієнтів з артеріальною гіпертензією

Робота присвячена визначенню впливу артеріальної гіпертензії (АГ) на розвиток післяопераційних ускладнень у пацієнтів старшої вікової групи, які перенесли операцію аортокоронарного шунтування в умовах штучного кровообігу, і вивченню ефективності різних методик інтраопераційної регуляції артеріального тиску. У дослідження увійшло 96 пацієнтів з АГ І–ІІІ ст., яким була виконана операція аортокоронарного шунтування з накладенням 2–3 коронарно-венозних анастомозів. В результаті роботи було визначено, що у пацієнтів із супутньою АГ на етапі увідного наркозу спостерігаються гемодинамічні порушення двох типів: зниження артеріального тиску в результаті вазодилатації і зниженої компенсаторної здатності міокарда; пресорні гемодинамічні реакції у вигляді підвищення артеріального тиску на етапі інтубації, пов’язані з симпатичною імпульсацією, подразненням глибоких сенсорних рецепторів гортані і різким підвищенням рівня ендогенних катехоламінів. Серед обстежених пацієнтів супутній цукровий діабет 2-го типу визначався у 22,9 %. Наявність даної патології визначало зниження ударного індексу на 21,30 ± 1,21 %, серцевого індексу — на 12,5 ± 1,3 %, індексу скоротливості — на 14,6 ± 1,3 %. У ранньому післяопераційному періоді у пацієнтів з АГ у 7,3 % випадків спостерігався розвиток енцефалопатії та цілого ряду післяопераційних когнітивних дисфункцій, що пов’язано з перекалібровкою церебральних судин на тлі АГ.

Sleep Duration and Hypertension: Epidemiological Evidence and Underlying Mechanisms.

While the contribution of several physiological systems to arterial blood pressure regulation has been studied extensively, the role of normal and disrupted sleep as a modifiable determinant of blood pressure control, and in the pathophysiology of hypertension, has only recently emerged. Several sleep disorders, including sleep apnea and insomnia, are thought to contribute to the development of hypertension, although less attention is paid to the relationship between sleep duration and blood pressure independent of sleep disorders per se. Accordingly, this review focuses principally on the physiology of sleep and the consequences of abnormal sleep duration both experimentally and at the population level. Clinical implications for patients with insomnia who may or may not have abbreviated sleep duration are explored. As a corollary, we further review studies of the effects of sleep extension on blood pressure regulation. We also discuss epidemiological evidence suggesting that long sleep may also be associated with hypertension and describe the parabolic relationship between total sleep time and blood pressure. We conclude by highlighting gaps in the literature regarding the potential role of gut microbial health in the cross-communication of lifestyle patterns (exercise, diet, and sleep) with blood pressure regulation. Additionally, we discuss populations at increased risk of short sleep, and specifically the need to understand mechanisms and therapeutic opportunities in women, pregnancy, the elderly, and in African Americans.

Cyclic GMP-Dependent Regulation of Vascular Tone and Blood Pressure Involves Cysteine-Rich LIM-Only Protein 4 (CRP4).

The cysteine-rich LIM-only protein 4 (CRP4), a LIM-domain and zinc finger containing adapter protein, has been implicated as a downstream effector of the second messenger 3′,5′-cyclic guanosine monophosphate (cGMP) pathway in multiple cell types, including vascular smooth muscle cells (VSMCs). VSMCs and nitric oxide (NO)-induced cGMP signaling through cGMP-dependent protein kinase type I (cGKI) play fundamental roles in the physiological regulation of vascular tone and arterial blood pressure (BP). However, it remains unclear whether the vasorelaxant actions attributed to the NO/cGMP axis require CRP4. This study uses mice with a targeted deletion of the CRP4 gene (CRP4 KO) to elucidate whether cGMP-elevating agents, which are well known for their vasorelaxant properties, affect vessel tone, and thus, BP through CRP4. Cinaciguat, a NO- and heme-independent activator of the NO-sensitive (soluble) guanylyl cyclase (NO-GC) and NO-releasing agents, relaxed both CRP4-proficient and -deficient aortic ring segments pre-contracted with prostaglandin F2α. However, the magnitude of relaxation was slightly, but significantly, increased in vessels lacking CRP4. Accordingly, CRP4 KO mice presented with hypotonia at baseline, as well as a greater drop in systolic BP in response to the acute administration of cinaciguat, sodium nitroprusside, and carbachol. Mechanistically, loss of CRP4 in VSMCs reduced the Ca2+-sensitivity of the contractile apparatus, possibly involving regulatory proteins, such as myosin phosphatase targeting subunit 1 (MYPT1) and the regulatory light chain of myosin (RLC). In conclusion, the present findings confirm that the adapter protein CRP4 interacts with the NO-GC/cGMP/cGKI pathway in the vasculature. CRP4 seems to be part of a negative feedback loop that eventually fine-tunes the NO-GC/cGMP axis in VSMCs to increase myofilament Ca2+ desensitization and thereby the maximal vasorelaxant effects attained by (selected) cGMP-elevating agents.

An Improved Integral Inequality for Delay-Dependent Gain-Scheduled LPV Control

The present work examines the delay-dependent gain-scheduling feedback control with guaranteed closed-loop stability and induced L2 norm performance for continuous-time linear parameter-varying (LPV) systems with arbitrary time-varying delay. An extension of Lyapunov stability utilizing Krasovskii functionals is considered to derive stability analysis and synthesis conditions for delay-dependent dynamic output feedback LPV control design. The main challenges associated with this approach are selecting appropriate Lyapunov-Krasovskii functionals (LKFs) and finding efficient integral inequalities to bound the derivative of the LKF. Accordingly, a novel modified parameter-dependent LKF candidate along with an affine version of Jensen’s inequality bounding technique are employed leading to the derivation of less conservative sufficient conditions expressed in terms of convex linear matrix inequalities (LMIs). The proposed methodology is compared with past work in the literature in terms of conservatism reduction and performance improvement through a numerical example. Finally, the application of the proposed output-feedback LPV control design is evaluated on the automated mean arterial blood pressure (MAP) regulation in critical patient resuscitation via vasoactive drug infusion. Closed-loop simulation results are presented to illustrate the potential of the introduced LPV gain-scheduling design to provide MAP set-point tracking in the presence of disturbances and varying input delays.

Baroreflex responses to activity at different temperatures in the South American rattlesnake, Crotalus durissus.

In humans, physical exercise imposes narrower limits for the heart rate (fH) response of the baroreflex, and vascular modulation becomes largely responsible for arterial pressure regulation. In undisturbed reptiles, the baroreflex-related fH alterations at the operating point (Gop) decreases at elevated body temperatures (Tb) and the vascular regulation changes accordingly. We investigated how the baroreflex of rattlesnakes, Crotalus durissus, is regulated during an activity at different Tb, expecting that activity would reduce the capacity of the cardiac baroreflex neural pathway to buffer arterial pressure fluctuations while being compensated by the vascular neural pathway regulation. Snakes were catheterized for blood pressure assessment at three different Tb: 15, 20 and 30°C. Data were collected before and after activity at each Tb. Baroreflex gain (Gop) was assessed with the sequence method; the vascular limb, with the time constant of pressure decay (τ), using the two-element Windkessel equation. Both Gop and τ reduced when Tb increased. Activity also reduced Gop and τ in all Tb. The relationship between τ and pulse interval (τ/PI) was unaffected by the temperature at resting snakes, albeit it reduced after activity at 20°C and 30°C. The unchanged τ/PI and normalized Gop at different Tb indicated those variables are actively adjusted to work at different fH and pressure conditions at rest. Our data suggest that during activity, the baroreflex-related fH response is attenuated and hypertension is buffered by a disproportional increase in the rate which pressure decays during diastole. This compensation seems especially important at higher Tb where Gop is already low.

The Effect of Bilateral Nephrectomy on Renalase and Catecholamines in Hemodialysis Patients.

Background/Aims: Renalase is an enzyme with monoamine oxidase activity that metabolizes catecholamines; therefore, it has a significant influence on arterial blood pressure regulation and the development of cardiovascular diseases. Renalase is mainly produced in the kidneys. Nephrectomy and hemodialysis (HD) may alter the production and metabolism of renalase. The aim of this study was to examine the effect of bilateral nephrectomy on renalase levels in the serum and erythrocytes of hemodialysis patients. Methods: This study included 27 hemodialysis patients post-bilateral nephrectomy, 46 hemodialysis patients without nephrectomy but with chronic kidney disease and anuria and 30 healthy subjects with normal kidney function. Renalase levels in the serum and erythrocytes were measured using an ELISA kit. Results: Serum concentrations of renalase were significantly higher in post-bilateral nephrectomy patients when compared with those of control subjects (101.1 ± 65.5 vs. 19.6 ± 5.0; p < 0.01). Additionally, renalase concentrations, calculated per gram of hemoglobin, were significantly higher in patients after bilateral nephrectomy in comparison with those of healthy subjects (994.9 ± 345.5 vs. 697.6 ± 273.4, p = 0.015). There were no statistically significant differences in plasma concentrations of noradrenaline or adrenaline. In contrast, the concentration of dopamine was significantly lower in post-nephrectomy patients when compared with those of healthy subjects (116.8 ± 147.7 vs. 440.9 ± 343.2, p < 0.01). Conclusions: Increased serum levels of renalase in post-bilateral nephrectomy hemodialysis patients are likely related to production in extra-renal organs as a result of changes in the cardiovascular system and hypertension.

Noncanonical Thyroid Hormone Receptor α Action Mediates Arterial Vasodilation.

Hypothyroidism impairs cardiovascular health and contributes to endothelial dysfunction with reduced vasodilation. How 3,5,3'-triiodothyronine (T3) and its receptors are involved in the regulation of vasomotion is not yet fully understood. In general, thyroid hormone receptors (TRs) either influence gene expression (canonical action) or rapidly activate intracellular signaling pathways (noncanonical action). Here we aimed to characterize the T3 action underlying the mechanism of arterial vasodilation and blood pressure (BP) regulation. Mesenteric arteries were isolated from male rats, wild-type (WT) mice, TRα knockout (TRα 0) mice, and from knockin mice with a mutation in the DNA-binding domain (TRα GS). In this mutant, DNA binding and thus canonical action is abrogated while noncanonical signaling is preserved. In a wire myograph system, the isolated vessels were preconstricted with norepinephrine. The response to T3 was measured, and the resulting vasodilation (Δ force [mN]) was normalized to maximum contraction with norepinephrine and expressed as percentage vasodilation after maximal preconstriction with norepinephrine (%NE). Isolated vessels were treated with T3 (1 × 10-15 to 1 × 10-5 mol/L) alone and in combination with the endothelial nitric oxide-synthase (eNOS) inhibitor L-NG-nitroarginine methyl ester (L-NAME) or the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin. The endothelium was removed to determine the contribution of T3 to endothelium-dependent vasodilation. The physiological relevance of T3-induced vasodilation was determined by in vivo arterial BP measurements in male and female mice. T3 treatment induced vasodilation of mesenteric arteries from WT mice within 2 minutes (by 21.5 ± 1.7%NE). This effect was absent in arteries from TRα 0 mice (by 5.3 ± 0.6%NE, P < .001 vs WT) but preserved in TRα GS arteries (by 17.2 ± 1.1%NE, not significant vs WT). Inhibition of either eNOS or PI3K reduced T3-mediated vasodilation from 52.7 ± 4.5%NE to 28.5 ± 4.1%NE and 22.7 ± 2.9%NE, respectively. Removal of the endothelium abolished the T3-mediated vasodilation in rat mesenteric arteries (by 36.7 ± 5.4%NE vs 3.5 ± 6.2%NE). In vivo, T3 injection led to a rapid decrease of arterial BP in WT (by 13.9 ± 1.9 mm Hg) and TRα GS mice (by 12.4 ± 1.9 mm Hg), but not in TRα 0 mice (by 4.1 ± 1.9 mm Hg). These results demonstrate that T3 acting through noncanonical TRα action affects cardiovascular physiology by inducing endothelium-dependent vasodilation within minutes via PI3K and eNOS activation.

Sequential Afferent‐Targeted and Total Renal Denervation and Impact on Regulation of Arterial Pressure, Glomerular Filtration, and Sodium Handling in Sprague Dawley Male Rats

Renal denervation (RDNx) is often reported to chronically decrease mean arterial pressure (MAP) in conscious, unchallenged Sprague Dawley (SD) rats, but has no effect of salt-sensitivity of MAP. Although these findings indicate an important role of renal nerves in long-term regulation of MAP under unchallenged conditions, the individual contributions of sympathetic and afferent renal nerves in MAP and renal homeostasis remain unclear. The present study was conducted to test the hypothesis that efferent (sympathetic) renal nerves are the primary contributors both MAP and renal function responses to RDNx in normotensive Sprague Dawley rats. To test this hypothesis, 12 adult male Sprague Dawley rats (300-325g) were subjected to sequential denervation procedures to ablate afferent and efferent nerves separately by subjecting rats to the following surgical sequence: Sham, then afferent-targeted RDNx (A-RDNx), then complete (T)-RDNx. A-RDNx was achieved by periaxonal application of 33mM capsaicin, and T-RDNx was achieved by surgical dissection followed by perivascular application of 10%(v/v) phenol in ethanol. One week was permitted for recovery from surgery before cardiovascular and renal measurements were collected. 24-hour mean arterial pressure (MAP) was recorded by implanted telemetry. Glomerular filtration rate (GFR) was assessed in unrestrained, conscious rats by acute FITC-sinistrin clearance. Renal excretory function was assessed by measuring the urinary sodium excretion response to an acute saline challenge (150mM PBS, 10% bodyweight, i.p.) over four hours. Data was analyzed by one-way repeated-measures ANOVA with Bonferroni post-hoc test (α=0.05). Data presented as mean±SEM. Sham surgery had no significant effect on MAP, GFR or Na Clearance. Following A-RDN treatment, MAP increased ∆5.4±0.9mmHg; (p<0.01); however, no significant changes in GFR or the excretory response to acute sodium load were detected. In contrast, following T-RDN, MAP was decreased 4.9±0.9mmHg (p<.01) following T-RDN vs. compared to A-RDN. Regarding renal function, GFR increased (1.20±0.05 vs. 1.06±0.04 mL/min/100gBWT; p<.01) as did the sodium excretory response to a saline load (28.2±2.3 vs. 18.6±1.0% Na load excreted per 4 hours; p<.01). Together, these data partly support our hypothesis and solidify the role for renal efferent (sympathetic) nerves contribute to long-term regulation of MAP, GFR, and sodium handling in the conscious SD rat. Contrary to our hypothesis, A-RDNx resulted in a small, yet significant, increase in MAP; however, no impact on renal function was observed. We speculate that the increased GFR and decrease in MAP are likely due to a decrease in renal vascular resistance and dilation of the renal afferent arterioles. Moreover, renal afferent nerves appear to contribute to maintenance of MAP in Sprague Dawley rats, which we speculate is through a tonic sympatho-inhibition due to the increase MAP following A-RDNx. These data highlight the important, yet differential roles of efferent and afferent renal nerves, and further studies are underway to further test this hypothesis.

Regulation of Pulmonary Arterial Pressure by Endothelial Pannexin1–TRPV4 Channel Signaling

Endothelial cells (EC) dilate small pulmonary arteries (PAs) and lower the resting pulmonary arterial pressure (PAP). Moreover, the loss of endothelial function is a key contributor to elevated PAP in pulmonary hypertension. Therefore, an in-depth understanding of endothelial mechanisms controlling PAP is necessary for designing novel therapeutic strategies against pulmonary hypertension. Pannexin 1 (Panx1), an ATP efflux pathway on the EC membranes, has emerged as a crucial controller of endothelial function. However, the impact of endothelial Panx1 (Panx1EC) on PA contractility and PAP is not known. Recent studies support the idea that endothelial transient receptor potential vanilloid 4 (TRPV4EC) channels dilate small PAs, and are activated by extracellular ATP (eATP). Since Panx1EC is an ATP efflux pathway, we hypothesized that Panx1EC-TRPV4EC channel signaling dilates PAs and lowers resting PAP. Right ventricular systolic pressure (RVSP), an indirect indicator of PAP, was higher in inducible, EC-specific Panx1 (Panx1EC-/-) and TRPV4 channel knockout (TRPV4EC-/-) mice compared to the respective control mice. The activity of TRPV4EC channels was recorded as individual Ca2+ influx signals (TRPV4EC sparklets) in fluo 4-loaded en face PAs using spinning disk confocal imaging. The TRPV4EC sparklet activity was lower in PAs from Panx1EC-/- mice than the control mice, identifying Panx1EC as a novel promoter of TRPV4EC channel activity. Apyrase (10 U/mL), an ATP hydrolyzing enzyme, also reduced the activity of TRPV4EC sparklets in PAs from control mice but not Panx1EC-/- mice. Pressurized PAs (15 mm Hg) from Panx1EC-/- and TRPV4EC-/- mice showed higher constriction to thromboxane A2 receptor agonist U46619 (1-300 nM) compared to PAs from the respective control mice. These data indicated that Panx1EC-eATP-TRPV4EC signaling lowers PA contractility and PAP. Consistent with previous findings that eATP dilates PAs via purinergic P2Y2 receptor (P2Y2R) signaling, ATP activation of TRPV4EC channels was lost in PAs from inducible P2Y2EC-/- mice. Together, these data identify a novel Panx1EC-eATP-P2Y2REC signaling pathway that promotes TRPV4EC channel activity in PAs. Panx1, P2Y2R, and TRPV4 channels have been shown to localize with the scaffolding protein caveolin 1 (Cav-1), raising the possibility that Cav-1EC may provide a signaling scaffold for Panx1EC-P2Y2REC-TRPV4EC signaling in PAs. Accordingly, P2Y2REC-activation of TRPV4EC channels was lost in PAs from inducible Cav-1EC-/- mice, and these mice showed higher resting RVSPs compared to the control mice. Additionally, in situ proximity ligation assay confirmed the nanometer proximity of Cav-1EC with Panx1EC, P2Y2REC, and TRPV4EC channel in PAs. Overall, our findings identify Cav-1EC-dependent Panx1EC-P2Y2REC-TRPV4EC channel pathway that dilates PAs and lowers PAP. Targeting individual elements of this pathway may provide novel therapeutic options in pulmonary vascular disorders.

Regulation of Blood Pressure and Renal Fibrosis by Class I Specific HDAC Inhibitor, Mocetinostat, in Npr1 Gene‐targeted Male and Female Mice

Mice lacking Npr1 (encoding guanylyl cyclase/natriuretic peptide receptor-A; GC-A/NPRA) exhibit hypertension, kidney disease, and heart failure; however, the epigenetic determinants regulating Npr1 expression and renal function are not well understood. The objective of this study was to investigate the effect of class I-specific histone deacetylase (HDAC) inhibitor, mocetinostat (MGCD0103; MGCD) on NPRA expression and regulation of mean arterial pressure (MAP) and renal pathology. Adult male and female Npr1 haplotype (1-copy, Npr1+/-), wild-type (2-copy, Npr1+/+), and gene-duplicated (3-copy, Npr1++/+) mice were injected intraperitoneally with MGCD (2 mg/kg) at alternate days for 2-weeks. Treatment with MGCD significantly enhanced NPRA protein levels and GC activity in male and female mice in all three genotypes. MAP was monitored by telemetry recording. Sex-differences were observed in MAP as female mice had lower MAP (p < 0.01) than male mice, in all genotypes; whereas, 1-copy mice exhibited higher MAP than 2-copy mice. Treatments with MGCD distinctly reduced MAP in 1-copy and 2-copy male mice (untreated 1-copy, 125 ± 3 vs. treated 1-copy, 108 ± 3 mmHg; p < 0.001; untreated 2-copy, 98 ± 2 vs. treated 2-copy, 90 ± 2 mmHg; p < 0.01) and 1-copy and 2-copy female mice (untreated 1-copy, 117 ± 3 vs. treated 1-copy, 105 ± 2 mmHg; p < 0.001; untreated 2-copy, 90 ± 2 vs. treated 2-copy, 84 ± 2 mmHg; p < 0.01). Treatment with MGCD attenuated HDAC activity by 30% in male and 40% in female animals (p < 0.05). The Western blot analyses indicated that 1-copy male and female mice showed upregulation of alpha-smooth muscle actin (α-SMA; 39% and 29%, p < 0.05) and collagen 1 alpha 2 (COL1α2; 49% and 20%, p < 0.05) proteins, respectively, compared with 2-copy mice. Picrosirius red staining in renal sections showed significant collagen deposition in 1-copy mice compared with 2-copy animals of both sexes. MGCD reduced fibrosis by 30%-45% (p < 0.05) in treated 1-copy mice compared with untreated control mice in both sexes. The present results indicate that MGCD lowers MAP, and repairs renal fibrosis in male and female mice. These findings will have important implications for treatment of hypertension and renal injury in humans in both genders.

Arterial stiffness is not acutely modified by consumption of a caffeinated soft drink sweetened with high fructose corn syrup in young healthy adults

Purpose Excessive intake of fructose is associated with an increased risk of developing cardiovascular disease. A major source of dietary fructose is the ingestion of high fructose corn syrup (HFCS) in sugar sweetened beverages (e.g., soft drinks). High arterial stiffness is an independent risk factor for cardiovascular morbidity and mortality. Thus, it is possible that regular consumption of beverages containing HFCS acutely and/or chronically increase arterial stiffness. However, this has never been explored. This study tested the hypothesis that ingestion of a caffeinated soft drink containing HFCS acutely increases arterial stiffness. Methods Fourteen healthy adults (25 ± 3 y, 6 women) reported to the laboratory for two experimental visits and consumed either 500 mL of tap water (H2O) or 500 mL of Mountain Dew® (an HFCS containing caffeinated beverage, DEW) in their first visit and consumed the other beverage in their next experimental visit, employing a counterbalanced, crossover, randomized design. Data were collected pre-consumption, 30 min post-consumption and 120 min post-consumption. Arterial stiffness was measured as carotid-to-femoral pulse wave velocity (cfPWV) using applanation tonometry. Peripheral (brachial) blood pressure was measured via electrosphygmomanometry. Central (aortic) blood pressure was estimated from transfer function analysis of the radial artery pressure waveform. Indices of pulse wave reflection were calculated from the synthesized central pressure waveforms. Data are presented as mean ± SD. Results cfPWV did not differ pre-consumption (DEW: 5.5 ± 0.6 m/s, H2O: 5.3 ± 0.7 m/s, P=0.69). At 30 min post-consumption, cfPWV was higher in the DEW trial (5.7 ± 0.6 m/s) compared to the H2O trial (5.3 ± 0.6 m/s, P=0.01), but cfPWV was not different between DEW and H2O at 120 min post-consumption (DEW: 5.7 ± 0.6 m/s, H2O: 5.5 ±0.6 m/s, P=0.13). Notably however, changes in cfPWV from pre-consumption did not differ between DEW and H2O at 30 min post- (DEW: 0.2 ± 0.3 m/s, H2O 0.0 ± 0.3 m/s, P=0.34) or 120 min post-consumption (DEW: 0.3 ± 0.4 m/s, H2O: 0.2 ± 0.3 m/s, P=0.77). Peripheral and central systolic (P≥0.50) and diastolic (P≥0.25) pressures did not differ between the DEW and H2O trials at any time point. Thus, peripheral (at 120 min post-consumption – DEW: 94 ± 6 mmHg, H2O: 92 ± 6 mmHg, P=0.31) and central (at 120 min post-consumption – DEW: 89 ± 7 mmHg, H2O: 85 ± 7 mmHg, P=0.13) mean arterial pressure also did not differ between trials. Moreover, aortic augmentation pressure, augmentation index, augmentation index corrected to a heart rate of 75 bpm, and reflection magnitude did not differ between the DEW and H2O trials at pre- (P≥0.22), 30 min post- (P≥0.55) or 120 min post-consumption (P>0.18). Conclusion Compared to drinking an equivalent volume of water, consumption of 500 mL of a commercially available caffeinated soft drink containing HFCS has little acute effect on indices of arterial stiffness or central blood pressure. The effect of chronic consumption of soft drinks containing HFCS on arterial stiffness and blood pressure regulation remain largely unknown.