bluuebunny/crossref_metadata_2025_split huggingface dataset:
Upregulation of Orexin in the Paraventricular Nucleus Contributes to Salt Sensitive Hypertension
Authors: Huber Michael , Zhu Fengli , Li Ningjun , Chen Qing‐Hui , Shan Zhiying 
Published: November 2023

Orexin and orexin receptors are extensively expressed in the hypothalamic paraventricular nucleus (PVN) and the hyperactivity of PVN orexin contributes to increased sympathetic nerve activity (SNA) and elevated blood pressure in several animal models. However, the role of PVN orexin in the development of salt sensitive hypertension (SSHTN) is unknown. In this study, we tested the hypothesis that PVN orexin expression is increased in SSHTN and contributes to the development of SSHTN via regulating vasopressin secretion. Eight‐week‐old Dahl salt sensitive (DS) rats were divided into two groups and were fed either a high salt (HS, 8% NaCl) or normal salt (NS, 0.4% NaCl) diet. Six weeks following diet treatment, rats were anesthetized and their mean arterial pressure (MAP) and sympathetic nerve activity (SNA) response to orexin receptor blockade were recorded. In a separate group of rats PVN orexin mRNA levels were measured. The results showed that HS intake induced significant increases in MAP (HS: 146±2 vs. NS: 112±5; n=5; P<0.05) and PVN orexin mRNA levels (HS: 3.8±0.37 vs. NS: 1.0±0.68; n=3; P<0.05). Bilateral PVN microinjection of orexin receptor 1 (OX1R) antagonist SB408124 (30 pmol/50nl) resulted in a greater reduction in arterial blood pressure in DS rats with a HS intake compared to their cohorts with a NS diet (HS: −16±5 vs. NS: −4±4 mmHg; n=5–6; P<0.05). OX1R blockade also increased splanchnic SNA (HS: 48.2±12.6%) vs. NS: 35.82±9%; P=0.2) and renal SNA (HS: 26.7±7.5% vs. NS: 17.4±9.5%; P=0.2) in DS rats with either HS or NS diet. Incubation of orexin A resulted in a dose‐dependent increase in vasopressin mRNA levels (100nM: 2.9‐fold; 1μM; 5.6 fold; 10μM: 18‐fold) in primary cultured neurons from the hypothalamus containing the PVN of neonatal Sprague Dawley rats. These orexin A‐induced increases of vasopressin mRNA were abolished by OX1R blockade. These results coupled with the evidence that plasma vasopressin is upregulated in DS rats under the condition of HS‐induced hypertension suggest that increased PVN orexin expression may be involved in the development of SSHTN through regulating vasopressin secretion.Support or Funding InformationThis study is supported by AHA 11SDG7420029 and NIH R15‐HL122952.
Improvement of Vagal Tone and Reduction in the Blood Pressure by Physical Training in Aging Spontaneously Hypertensive Rats
Authors: Dellacqua Laís Oliveira , Michelini Lisete Compagno , Hindmarch Charlie , Paton Julian Francis Richmond , Murphy David , Antunes Vagner 
Published: November 2023

The mechanisms by which physical exercise improve cardiovascular fitness with age are poorly understood. Here, we evaluate the hemodynamic effects of aerobic training and physical inactivity in aging (12‐months‐old) spontaneously hypertensive rats (SHR) compared to normotensive Wistar Kyoto (WKY) rats. Animals from each strain were divided into two groups: trained (T) and sedentary (S). The exercise training lasted 8 weeks (1h/day, 5 days/week), with adjustments of speed to 50–60% of the maximum test. Blood pressure (BP) and heart rate (HR) were recorded from the femoral artery and vein and activation of the baroreflex was performed with bolus injections of phenylephrine and nitroprussiate. BP, HR, spectral analysis and baroreflex analysis were performed at week zero (T0), just before the training protocol, in the second (T2) and eighth (T8) week of exercise training. The performance on the treadmill of trained WKY animals was higher both in the T2 (1.01±0.05 km/h, n=18) and in the T8 (1.04 ± 0,06km/h, n=18) when compared to their respective controls S (0.55 ± 0.05, n=27 and 0.35 ± 0,03km/h, n=27). For SHR the performance on the treadmill of T SHR, were also higher both in the T2 (1.52±0.1km/h, n=18) and in the T8 (1.27 ± 0,04km/h, n=18) when compared with their S controls (1.1 ± 0.14, n=27 and 0.87 ± 0,18km/h, n=27). Systolic blood pressure (SBP) of T8 SHR was lower (155±10 mmHg, n=5) than in control group S8 (198±10 mmHg, n=6). The baroreflex sensitivity in T8 SHR showed a trend of an improvement with no statistical difference when compared to the S8 group. The HF component of the pulse interval was higher in T8 SHR (22.4±5.9 A.U. n=5) than in the control S8 group (6.3±2.4 A.U. n=5). Collectively, our data show that exercise was able to reduce systolic blood pressure, without significantly changing in baroreflex function, and improve the control of cardiac function in the 8 week trained.Support or Funding InformationFinancial Support: FAPESP (# 2012/22368‐7, # 2011/51410‐9).
Pontine and Medullary Sources of Cardiac Vagal Tone
Authors: Farmer David George Stephen , Dutschmann Mathias , Paton Julian F , Pickering Anthony E , McAllen Robin Michael 
Published: November 2023

Cardiac vagal tone is a major determinant of health. Here, we investigate the origins of cardiac vagal tone in the working heart‐brainstem preparation (WHBP). The WHBP shows ongoing activity in the cardiac vagal branch (CVB) and a normal pattern of respiratory sinus arrhythmia (RSA). Ongoing activity in the CVB peaks in late inspiration/postinspiration, correlating with the nadir of heart rate. Bilateral inhibition of the pontine Kölliker‐Fuse nucleus (KF) with isoguvacine (GABAA receptor agonist; 10 mM, 50–70nl) abolished RSA at the same time as removing postinspiratory phrenic activity. Mean heart rate rose modestly (baseline: 245.0 ± 9.2 bpm; KF isoguvacine: 270.6 ± 10.0 bpm; p=0.0370; n=8). Cardiac vagal nerve activity continued, however, adopting a tonic discharge pattern with minor early‐inspiratory dips. In sympathetically disabled rats, transection of the brainstem at caudal pontine level had an effect on heart rate that varied between animals (bradycardia or tachycardia) (baseline: 205.6 ± 10.2, pontine transection: 233.9 ± 8.2, p = 0.1024; n=6). Subsequent bilateral inhibition of the nucleus tractus solitarii (NTS) in these animals produced tachycardia (261.5 ± 8.0 bpm, p=0.0020 vs. pontine transection). Atropine (0.1μg/ml) after either KF inhibition or pontine transection followed by NTS inhibition produced tachycardia, confirming that substantial cardiac vagal tone survived those procedures. We conclude that (a) postinspiration is integral to shaping of CVB discharge and to the generation of RSA; (b) a large component of cardiac vagal tone does not require connections to the pons and is independent of central respiratory drive; (c) part of that medullary component depends on neurons in the NTS.Support or Funding InformationSupported by ARC
Dynamic Gene Regulation Across Physiological Systems Coordinates the Pathogenesis of Hypertension
Authors: Anderson Warren , DeCicco Danielle , Brureau Anthony , Schwaber James , Vadigepalli Rajanikanth 
Published: November 2023

The characteristics of hypertension pathophysiology have been extensively studied at levels of analysis ranging from organ physiology to cellular function and molecular expression. However, the dynamics of functional disregulation underlying the pathogenesis of hypertension, both within and across organs, have not been elucidated. We addressed this issue by profiling molecular expression across organs in hypertensive (spontaneously hypertensive rat, SHR) and non‐hypertensive (Wistar Kyoto, WKY) rat strains. We sampled tissue from the brainstem, kidney, adrenal gland, left ventricle, and spleen at ages 4, 6, 8, 12, and 16 weeks. We analyzed expression of 22 genes from three functional classes: inflammation (e.g., cytokines and chemokines), renin‐angiotensin signaling (e.g., angiotensin metabolism, angiotensin receptor), and autonomic regulation (e.g., catecholamine metabolism, adrenergic receptors). Analysis of variance revealed a significant three‐way interaction involving rat strain, organ, and age for Il1b (p‐adjusted = 2.2 × 10−6). Post‐hoc analysis revealed a number of significant differences, including downregulation of Il1b in the SHR kidney compared to that of WKY at 16 wk (p = 0.002). To assess whether there were strain‐dependent differences in the temporal profiles of gene expression in individual organs, we performed a time‐series analysis using the Optimal Discovery Procedure (Storey et al., PNAS, 2005). Our analyses revealed that all genes assayed in the brainstem showed differential dynamics in SHR compared to WKY, and the following genes showed strain‐dependent temporal profiles in the kidney: Il1b, Ccl5, Agtr1a, Ren, Ace, Adrb1, and Adra1a (p‐adjusted < 0.05). Twenty genes showed strain‐dependent temporal profiles in the adrenal gland (p‐adjusted < 0.05). To enhance our understanding of the regulatory mechanisms underlying hypertension development, we integrated an empirical dynamic modeling approach with our data analysis. We estimated kinetic parameters governing gene‐gene interactions within and across organs, and we simulated the corresponding models described by ordinary differential equations. Model simulations supported our time‐series data analysis by showing transient expression variations in the 4–8 wk range for many genes in SHR compared to relatively flat temporal profiles for WKY. This analysis revealed a coordinated wave of expression variations both within and across organs in SHR. Our experimental and modeling results elaborate a multi‐organ coordinated gene expression program underlying the pathogenesis of hypertension.Support or Funding InformationFunding: NIH/NHLBI R01 HL111621
Microglia modulate Ang II induced neuronal activity and neuroinflammation
Authors: Santisteban Monica M , Zubcevic Jasenka , Febo Marcelo , Raizada Mohan K 
Published: November 2023

ObjectiveOur studies have previously established that neurogenic hypertension is associated with microglial activation in cardioregulatory brain centers, such as the paraventricular nucleus of the hypothalamus (PVN). Treatment with minocycline, an inhibitor of microglial activation, attenuates the persistent increase in blood pressure, peripheral and central inflammation, as well as autonomic dysfunction in vivo. In the present study, we tested the hypothesis that microglia play an important role in modulating Ang II induced neuronal activity and neuroinflammation.MethodsAdult Sprague Dawley (SD) rats were infused with SQ saline or Ang II (200ng/kg/min) and treated with oral vehicle or minocycline (50mg/kg). Manganese‐enhanced magnetic resonance imaging (MEMRI) was performed at 4 weeks of infusion to indirectly visualize neuronal activity across cardioregulatory brain networks. After imaging, brains were isolated for microglia Iba1 immunostaining to establish potential mechanisms underlying altered brain activity. Primary neuronal and mixed neuroglia cultures were prepared from SD pups on day E20–21. Cultures were treated with 20μM minocycline for 1 hour followed by 1μM Ang II for 6 hours on day 5 for mixed cultures or day 10 for primary neuronal cultures.ResultsUnder control conditions, MEMRI detected basal activation of the PVN. In rats infused with Ang II, there was a marked increase in manganese accumulation in the PVN, which is likely indicative of increased PVN neural activity; this effect was markedly reduced by the minocycline treatment, an effect associated with decreased microglial activation in the PVN. In vitro, Ang II induced a 40% upregulation of c‐fos in mixed culture (p<0.01), indicative of neural activation, which was effectively blocked by minocycline pretreatment. Additionally, Ang II increased pro‐inflammatory genes mRNA in vitro, including Il1b (1.5‐fold, p<0.001), Tnf (1.4‐fold, p<0.05), Ccl2 (1.2‐fold, p<0.01), and Nos2 (1.8‐fold, p<0.01), indicative of M1 microglial polarization. Minocycline pretreatment was able to reverse these effects in mixed neuroglia cultures. However, in primary neuronal cultures, minocycline only decreased Nos2 (p<0.05), and did not affect c‐fos or pro‐inflammatory gene expression.ConclusionThese data indicate microglia activation plays an important role in modulating Ang II induced neuronal activity and neuroinflammation in PVN. Furthermore, minocycline indirectly modulates neuronal activity in vivo and in vitro by inhibiting microglial activation.Support or Funding InformationHL 33610 (MKR)
Renal Pelvic Afferent Nerves Are Responsible for Greater Resting and Evoked Vasoconstrictor Tone in Individual Rats
Authors: Knuepfer Mark M , Hoffman‐Schepers Nicole B , Perry Jeffrey L 
Published: November 2023

Greater acute pressor responsiveness to behavioral stress has been observed in those patients susceptible to the development of essential hypertension. Likewise, differences in resting sympathetic tone have been observed with greater tone reflected in higher systemic vascular resistance in many hypertensive patients or those prone to develop hypertension. Since renal denervation (RDN) has been reported to reduce arterial pressure in some patients with resistant hypertension, we sought to define the role of the renal nerves in determining resting and evoked vasoconstrictor tone. We hypothesized that RDN or selective renal pelvic deafferentation (RPDA) would prevent differences in resting vasoconstrictor tone, presumably sympathetic, and prevent greater vasoconstrictor responsiveness to startle in those rats that are hyperreactors to stress. Outbred male Sprague‐Dawley rats were instrumented for arterial pressure, heart rate and cardiac output determination. After recovery, rats were tested for their cardiovascular responsiveness to air jet (20 psi, 1–2 sec) and to cold water stress (1 cm deep for 1 min). Rats were separated into those with larger pressor responsiveness (LP) to startle with air jet or cold water and compared to those with smaller pressor responses (SP). Sympathetic tone was estimated by responses to administration of hexamethonium (20 mg/kg) and by pentolinium (10 mg/kg). LP had greater reductions in arterial pressure after ganglionic blockade due to greater falls in calculated systemic vascular resistance. Subsequently, rats underwent either RDN with extracorporeal radiofrequency ablation of the renal artery (100 KHz, <1 mW, 20 sec duration, 4–6 times/artery) or RPDA with capsaicin infusion in the renal pelvis. One week later, rats were retested for stress responsiveness and sympathetic tone. Either RDN or RPDA prevented the differences observed in pressor responsiveness to startle such that there was no difference between SP and LP. In addition, there were no longer differences between SP and LP in resting vasoconstrictor tone determined with ganglionic blockade. These data suggest that renal pelvic afferent nerves are responsible for greater stress‐induced vasoconstrictor responses and higher vasoconstrictor tone in a subset of rats (LP). We propose that RDN acts selectively in hyperreactors to acute stress (LP) and lowers their overall resting and evoked vasoconstrictor tone to reduce arterial pressure in hypertension due to pelvic afferents. These data suggest that RDN or selective RPDA may be more efficacious in treating this cohort of the population with essential hypertension.Support or Funding InformationSupported by St. Louis University
The Effect of Humor Associated Mirthful Laughter Combined with Quiescence on Modulating C Reactive Protein Blood Levels: A Pilot Study
Authors: Bains Gurinder Singh , Berk Lee , Lohman Everett , Daher Noha , Alahmadi Bara , Jadav Dhara , Alsultan Alanood , Alghamdi Ahmed 
Published: November 2023

IntroductionWith an increase in life expectancy, there exists a need for whole‐person care that enhances Quality of Life. Humor associated mirthful laughter has proven to yield numerous whole person health related benefits such as lowering the stress hormone cortisol and improving vascular function. High sensitivity C Reactive Protein (hs‐CRP) is an inflammatory biomarker. There are no known studies that have shown an association between humor associated mirthful laughter and changes in acute hs‐CRP blood levels.PurposeThe purpose of this study was to evaluate the effect of humor associated mirthful laughter on acute CRP modulation in a humor group vs. a non‐humor control group.MethodsThirty two healthy adults were recruited and enrolled (humor group n = 16; control group n = 16). The humor group consisted of 8 males and 8 females with a mean age of 26.4 ± 4.4 years. The control group consisted of 8 males and 8 females with a mean age of 26.6 ± 2.9 years. The hs‐CRP levels were obtained through a finger stick blood test. The hs‐CRP levels were collected at three time points; immediately after signing the informed consent, immediately after watching a 20 minute humor video or sitting quietly for 20 minutes, and after 20 minutes of quiescence after the second hs‐CRP test. Blood pressure and heart rate were taken immediately before the first hs‐CRP sample and then five minutes after the first, second, and third hs‐CRP measurement. The humor group self‐selected a humor video of either 20 minutes of Russell Peters standup comedy or a montage of America's Funniest Home Videos. The control group sat quietly for 20 minutes and were not allowed to read, talk, sleep, or use their cell phone.ResultsThere were significant differences in mean CRP levels, systolic blood pressure, and heart rate over time (p=0.04, p=0.01, and p< 0.001, respectively). For the humor group, 1) CRP levels decreased from 1.65 ± 0.3 mg/L at baseline to 1.42 ± 0.3 mg/L post humor (p=0.05), 2) systolic blood pressure decreased from baseline to humor + quiescence (p=0.02), and 3) heart rate decreased from baseline to post humor (p=0.01) and baseline to post humor + quiescence (p=0.001).ConclusionsThe overall, complimentary health benefits of combining enjoyable humor associated mirthful laughter with a quiescent period showed a decrease in inflammation (hs‐CRP), systolic blood pressure, and heart rate and thus, is more beneficial than being quiescent alone. Our pilot research shows potential clinical and rehabilitative benefits that can be applied to whole person wellness programs. Humor and laughter appear to be beneficial, thus providing components in enhancing Quality of Life. Further research will be done to expand these positive findings.
Cardiovascular and behavioral sequelae of witnessing social defeat stress in male and female rats
Authors: Lombard Calliandra M , Melson Michael N , Fadel Jim R , Wood Christopher S , Wood Susan K 
Published: November 2023

It is well recognized that exposure to social stress can contribute to psychosocial disorders (ie., depression) and comorbid medical disorders such as cardiovascular disease. While animal models of social defeat stress traditionally utilize a physical confrontation, recent studies have indicated that the psychological stress of witnessing the stressful event has long lasting behavioral consequences. In the present study we used the resident‐intruder paradigm to contrast the depressive‐like and cardiovascular consequences of social defeat stress in male Sprague Dawley rats that were directly exposed to the aggressive resident (intruder) with either male or female rats that were present in the cage, but only observing the stressful event (witness). Rats were implanted with cardiovascular transmitters that allowed for simultaneous measurements of blood pressure and ECG in two rats within the same cage (Data Sciences Intl). Following surgical recovery, rats were assigned to one of three groups; control, 5 consecutive days of social defeat (intruder, male), or observation of social defeat (witness, male or female) for 15 mins/day. For all experimental groups, cardiovascular telemetry was collected 24 hrs/day and continuous recordings were collected on the 1st and 5th exposure to stress/control. Five days after the final stress exposure all experimental rats were also subjected to the sucrose preference test to assess stress‐induced anhedonia. In agreement with our previous findings, social defeat stress produced a robust tachycardic and pressor response. Interestingly, the magnitude of increased blood pressure (MAP) and heart rate (HR) over controls was comparable between intruder and male witness rats. However, 12 hr light/dark cycle measurements revealed significantly greater increases in resting HR and MAP in male witness rats compared with controls and intruders. Female witness rats, on the other hand, exhibited blunted cardiovascular responsivity to social stress exposure compared with males and showed no long‐lasting changes in resting HR and MAP that was displayed in male witnesses. Importantly, assessment of depressive‐like behaviors using the sucrose preference test revealed that male witness rats displayed exaggerated anhedonia compared with male intruder rats while females again appeared unaffected. Taken together, these findings reveal that although females were generally unaffected by witnessing social defeat stress, in males, witnessing this social stressor may have a greater impact on the cardiovascular system and resulting depressive‐like behavior compared with experiencing the direct physical contact of social defeat stress.Support or Funding InformationResearch supported by 15SDG22430017 and P20GM103641.
Effects of Essential Oil on Fear Memory and the Immune Response; A Potential Alternative Therapy for Post‐Traumatic Stress Disorder (PSTD)
Authors: Moshfegh Cassandra , Swiercz Adam P , Hopkins Lauren , Marvar Paul J 
Published: November 2023

Stress and anxiety‐related mental health disorders such as post‐traumatic stress disorder (PTSD) are on the rise. Stress is known to modify the immune system. Despite the growing literature on immune system changes associated with direct stressors, the relationship between fear memory and the immune system has not been well characterized. Moreover, there are only two FDA‐approved medications for PTSD. Orange essential plant oil (OEPO) has been previously found to have CNS depressant‐like effects in mice. Therefore we examined the effects of OEPO on fear memory and immune cell activation in a mouse model of PTSD (Pavlovian Fear Conditioning). The treatment group (n=8) was administered 25% OEPO via olfactory exposure prior to and after fear conditioning. Mice exposed to 25% OEPO showed no difference in percent freezing during fear acquisition compared to controls. However, when tested for extinction retention 48 hours later the treatment group experienced a 17.21 ± 1.58 % (p < 0.01) significant decrease in freezing behavior versus control (3.67 ± 2.13%), suggesting that OEPO affects extinction of fear memory in mice. This appears to be independent of a shift in immune cell activation as treatment and control mice showed similar levels of splenocyte derived naïve / effector lymphocytes and antigen presenting cells. Both groups however showed increased levels of naïve T cells CD62hiCD44lo 56.9(± 0.83)% relative to non‐fear conditioned mice 46.3 (± 3.16)% (p < 0.01). These data suggest that OEPO enhances extinction of fear memory while its affects on the immune system remain unclear.Support or Funding InformationNIH R00 HL107675‐03