bluuebunny/crossref_metadata_2025_split huggingface dataset:
BLOCKADE OF NMDA RECEPTORS IN THE INSULAR CORTEX OF SPONTANEOUSLY HYPERTENSIVE RATS RESULTS IN LARGE FALL IN ARTERIAL PRESSURE
Authors: Marins Fernanda Ribeiro , Iddings Jennifer A , Filosa Jessica A , Fontes Marco Antônio Peliky 
Published: November 2023

We have recently shown that the intermediate region of the posterior insular cortex (intermediate IC) of spontaneously hypertensive rats (SHR) presents marked alterations in the neurovascular unit. Immunofluorescence data also shows increased NMDA receptor (NMDAR) density within the intermediate IC of SHR. In addition, stimulation of NMDAR in the intermediate IC of SHR results in higher amplitude responses of renal sympathetic activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) when compared to normotensive controls (WKY). The aim of this study was to determine the sympathetic and cardiovascular changes evoked by blockade of endogenous NMDA in the intermediate IC of SHR. Under urethane anesthesia (1.4 g/Kg, i.p.), bilateral microinjection of the NMDA receptor antagonist, AP‐5 (5mM/100nL), was performed in the intermediate IC of SHR (n=4) or WKY (n=6) with simultaneous recording of RSNA, HR and MAP. When compared to WKY, SHR presented higher baseline levels (measured before AP‐5 injection) of sympathetic nerve activity discharge (SHR 182±6 vs. WKY 122±4 discharges/second, P<0.0001) and MAP (SHR 144±6 vs. WKY 91±3 mmHg, P<0.0001). No differences were observed in baseline HR (SHR 368±12 vs. WKY 383±5 bpm, P= 0.3761). Bilateral injection of AP‐5 into the intermediate IC of SHR evoked a marked decrease in MAP (Δ= −31.7±4.8 mmHg, P=0.0004) accompanied by substantial decreases in RSNA (Δ= −16 ± 3.6 %, P=0.0114) and HR (Δ= −18.1±9.5 bpm, P =0.0381). No significant changes were observed after AP‐5 injection into the intermediate IC of WKY (Δ RSNA= 1±4.1 %, P=0.3866, ΔMAP= −1.3±1.4 mmHg, P=0.5010 and ΔHR= 0.6±0.8 bpm, P =0.4411). Taken together with our previous findings, the results suggest that activation of NMDA receptors in the intermediate insular cortex contribute to an enhanced sympathetic vasomotor tone in spontaneously hypertensive rats. CNPq, FAPEMIG, CAPES, NHLBI.Support or Funding InformationSupported by Conselho Nacional de Desenvolvimento Científico e Tecnológico do Brazil (PQ CNPQ 306000/2013‐0), Fundação de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG), INCT Nanobiofar, and CAPES (99999.003909/2015‐08 Programa PDSE), National Heart, Lung, and Blood Institute (NHLBI) of the NIH (R01 HL089067‐02 to JAF).
Opposite Arterial Pressure Responses to Renal Afferent Nerve Stimulation in Unanesthetized Versus Anesthetized Rats: Implications for the Neural‐Renal Axis and Hypertension
Authors: Banek Christopher T , Osborn John W 
Published: November 2023

Neural control of the kidney remains a primary focus of treatment of cardiovascular and renal disease, including hypertension (HTN). Moreover, recent studies support a role of renal afferent nerves in the modulation of sympathetic nerve activity (SNA), and in turn, arterial pressure (AP). We recently reported resting afferent nerve activity (ARNA) is elevated in the DOCA‐salt hypertensive rat, and that targeted afferent renal nerve ablation attenuates this model of hypertension (Banek et al. Hypertension 2016). These findings suggest that increased ARNA contributes to the pathogenesis of HTN. Previous investigations of the responses of AP and SNA to renal afferent nerve stimulation have been conducted in anesthetized animals have reported a sympatho‐inhibitory response. The present study was designed to measure the acute AP response to increased ARNA in anesthetized and unanesthetized preparations. Male Sprague Dawley rats (300–400g) underwent acute renal afferent stimulation while under 2% isoflurane anesthesia (ISO; n=12) or in the absence of anesthesia following a cortical decerebration (DEC; n=12). Animals were instrumented to measure AP, heart rate (HR), and ARNA. To activate renal afferent nerves, a ureteral catheterization was performed to perfuse the renal pelvis with vehicle 0.9% saline [VEH] or with the TRPV1‐agonist 50μM capsaicin (CAP). Following instrumentation and a 30‐minute stabilization period, ARNA and cardiovascular responses to VEH or CAP stimulation were recorded. Peak responses in ARNA, AP, and HR were quantified and compared between ISO vs. DEC preparations by a Student's t‐test (α=.05). ARNA responses were calculated as percent change from baseline (%ARNA). Data presented as mean±SEM. There was no difference in resting ∫ARNA, AP, or HR prior to afferent stimulation between ISO and DEC groups. VEH perfusion of the renal pelvis elicited no response in both ISO and DEC groups. In contrast, CAP administration resulted in marked increase in %ARNA that was similar in magnitude in both groups (ISO 214±31% vs. DEC 239±40%). More importantly, whereas the CAP‐induced increase in ARNA elicited a depressor response in ISO rats (−17±6mmHg), CAP evoked an opposing pressor response in DEC rats (+54±9mmHg). These findings suggest the existence of a renal afferent nerve‐dependent sympatho‐excitatory reflex in the rat, and anesthesia may directly interfere in this signaling pathway. It is important to note it is unknown whether this acute reflex translates to long‐term regulation of SNA and AP. While the anatomical and biological mechanisms of this reflex remain rudimentary, further studies are underway to chronically monitor afferent nerve activity and blood pressure in conscious freely moving rats to elucidate this important neural‐renal axis.Support or Funding InformationNIH 5R01HL116476; NIH 2T32HL7741
High fat diet increases salt sensitivity and promotes metabolic disorder‐independent hypertension in Dahl salt sensitive rats
Authors: Fernandes Roxanne , Bonilla Patricia A Perez , Garver Hannah , Galligan James J , Fink Gregory D , Xu Hui 
Published: November 2023

Salt sensitivity of blood pressure is common in obesity associated hypertension and may have a neurogenic basis. We and others have previously reported that high fat (HF) diet promotes hypertension in Dahl salt sensitive (SS) male rats ingesting a “normal” salt diet (0.33% NaCl). It is unclear if a low salt intake would reduce blood pressure in this model of obesity‐associated hypertension. Therefore in the current study Dahl SS rats were fed a normal fat (NF, 10% kcal from fat) and HF (60% kcal from fat) diet with different salt contents for 24–26 weeks after weaning (3 weeks of age). In rats fed a diet containing 0.24–0.33% NaCl (the normal salt content (NS) in rodent diets), HFNS (n=9) rats had a much higher MAP than NFNS rats (n=10) at the end of the study (158±1 mmHg versus 130±1 mmHg, P<0.05), confirming our previous findings. However, in low salt fed rats (LS, 0.1% NaCl), MAP at the end of the study was only slightly higher in HFLS (n=4) than NFLS (n=5) rats (131±1 mmHg vs 121±3 mmHg, P<0.05). Body weight was not significantly greater, but visceral adipose accumulation was higher, in HFNS and HFLS rats compared to NFNS and NFLS fed rats, respectively. HF fed rats did not show significant alterations in plasma levels of fasting glucose, insulin, leptin, aldosterone and serum creatinine compared to NF rats. Only HFNS rats showed hyperlipidemia and only NFLS rats showed lower plasma urea BUN levels than the other groups of rats. HFNS rats had a larger depressor response to ganglion blockade than did NFNS rats, but this was not observed in HFLS rats compared to NFLS animals. HF diet did not affect the mesenteric arterial (MA) contractile responses to neurotransmitters (norepinephrine and ATP), but MA from HFNS rats exhibited significantly increased wall‐thickness (and cardiac hypertrophy) compared to NFNS rats. Morphological studies did not reveal greater fibrosis in adventitia of mesenteric, intrarenal or coronary arteries in HF rats, suggesting arterial hyperplasia accounted for arterial remodeling in HFNS rats. Our studies suggested that obesity‐associated hypertension in Dahl SS rats is salt‐sensitive and neurogenic, but not associated with obvious metabolic disorders.Support or Funding InformationSupported by NIH2P01HL070687‐11A1
Chronic Renal Medullary Infusion of Interleukin‐1 Receptor Antagonist Delays the Onset of Salt Sensitive Hypertension in Uninephrectomized Dahl SS Rats
Authors: Dasinger John Henry , Abais‐Battad Justine M , Lund Hayley , Fehrenbach Daniel J , Mattson David L 
Published: November 2023

The Dahl SS rat is a well‐established model of salt‐sensitive hypertension and renal disease with the immune system contributing in the pathology of the disease. Recent work from our laboratory demonstrated that in response to a high salt challenge, in addition to increases in blood pressure and urinary albumin excretion, there is an upregulation of the Nod‐like receptor protein‐3 (NLRP3) inflammasome in the renal medulla. This upregulation of the NLRP3 inflammasome leads to a subsequent increase in interleukin 1 beta (IL‐1β) production. This proinflammatory cytokine has been shown to be elevated in hypertension in humans making it a potential therapeutic target for salt sensitive hypertension. Therefore, we tested the hypothesis that chronic renal medullary infusion of IL‐1 receptor antagonist (IL‐1RA) would attenuate the development of salt sensitive hypertension in the Dahl SS rat. Animals underwent a right uninephrectomy at 7 weeks of age to avoid compensatory changes in blood pressure from the contralateral kidney. After a week of recovery, the left femoral artery was cannulated to measure mean arterial pressure (MAP) while a chronically implanted medullary interstitial catheter was placed in the left kidney for continuous infusion IL‐1RA (600μg/day, n=5) or vehicle (0.9% NaCl saline, n=6). MAP was measured during a 4‐day period while animals were maintained on 0.4% NaCl chow then switched to a high salt (4.0% NaCl) challenge for a 10‐day. MAP did not differ between saline and IL‐1RA treated animals during the 0.4% diet period (127±3 mmHg vs 121±4 mmHg, P>0.05). However, following a 10‐day challenge of 4.0% NaCl diet, MAP was significantly reduced in the IL‐1RA treated rats compared to the saline‐treated rats (157±9 mmHg vs 176±5 mmHg, P<0.05). Despite seeing a reduction in MAP, urinary albumin (118±18 vs 126±10 mg/day) and protein (284±28 vs 277±19 mg/day) excretion in IL‐1RA treated did not differ from saline‐treated rats. Furthermore, when medullary IL‐1β levels were measured by ELISA, there was no difference between the IL‐1RA treated rats compared to the saline‐treated rats (76±25 pg/mL vs. 83±11 pg/mL). In contrast to the effects of intarenal infusion, systemic administration of the same dose of IL‐1RA did not alter salt‐sensitive hypertension compared to vehicle‐treated control SS (132±8mmHg vs 141±mmHg, n=5–6/group), demonstrating that the effects observed with medullary interstitial infusion are due to intrarenal effects. These data indicate that blockade of the IL‐1 receptor in the renal medulla attenuates salt‐sensitive hypertension in the Dahl SS rat. Further studies are required to understand the mechanism by which renal medullary inhibition of IL‐1β results in reduction in blood pressure in response to a high salt diet.Support or Funding InformationSupported by DK96859, HL116264, and 15SFRN2391002.
Sex‐Dependent Regulation of Blood Pressure by the Circadian Clock Protein Per1
Authors: Solocinski Kristen , Cheng Kit‐Yan , Lynch I. Jeanette , Cain Brian D. , Wingo Charles S. , Gumz Michelle L. 
Published: November 2023

The circadian clock is integral to the maintenance of daily rhythms of many physiological outputs including blood pressure. Our lab has demonstrated the importance of the clock protein Per1 to blood pressure regulation. Previously, we determined the effects of a high salt diet plus mineralocorticoid on Per1‐mediated blood pressure regulation in male C57BL/6 mice (Solocinski et al. Acta Physiol 2016). As expected, mean arterial pressure (MAP) in wild type mice was not affected by a high salt diet (4%)(HS) plus injection with the long‐acting mineralocorticoid deoxycorticosterone pivalate (DOCP). However, Per1 knockout mice exhibited non‐dipping hypertension in response to this treatment. The goal of the present study was to determine the role of Per1 in the regulation of MAP in female mice. For the first time, we demonstrate that loss of a circadian clock protein in female mice results in increased MAP relative to littermate wild type control mice on a C57BL/6 background. These mice were subjected to HS/DOCP treatment as well. In contrast to what we previously observed in male wild type mice, female wild type mice did experience a significant increase in MAP in response to HS/DOCP (7.35 ± 1.00 mmHg p < 0.0001). The Per1 knockout female mice also experienced an increase (8.29 ± 1.17 mmHg, p < 0.0001). Neither genotype experienced changes in the day/night MAP ratio in response to HS/DOCP. Together these data demonstrate that Per1 is important for MAP regulation in female animals and that this regulation appears to be salt‐ and mineralocorticoid‐independent. This effect is distinct from the non‐dipping hypertension seen in male Per1 knockout mice, demonstrating that female sex appears to be protective against Per1‐ mediated non‐dipping hypertension in response to HS/DOCP. Together these data support an important role for the circadian clock protein Per1 in the modulation of blood pressure and suggest that Per1 acts in a sex‐dependent manner in the regulation of cardiovascular rhythms.Support or Funding InformationNIH NIDDKUF Department of Medicine, Division of NephrologyAmerican Society of NephrologyUF Hypertension CenterT32 Grant # 2T32HL083810American Heart Association
PVN inflammation ‐ the driver of sympathetic outflow and sodium retention in salt sensitive hypertension?
Authors: Wainford Richard 
Published: November 2023

BackgroundWe have reported central Gαi2 protein down regulation evokes sympathetically mediated salt sensitive hypertension in multiple salt‐resistant rat phenotypes. Interestingly, several laboratories report that PVN inflammation is a mechanism that contributes to increased sympathetic nervous system (SNS) activity and HTN.AimWe hypothesize PVN inflammation contributes to increased SNS activity and salt sensitive HTN following central Gαi2 protein down regulation in the Sprague‐Dawley rat.MethodsMale Sprague‐Dawley (SD) rats receiving a continuous i.c.v. control scrambled (SCR) or targeted Gαi2 oligodeoxynucleotide (ODN) infusion (25μg/5μl/day) were fed a 0.6% (NS) or 4% NaCl (HS) diet for 7 days (N=4/group). On day 7 24h sodium balance, basal MAP, plasma NE content (via ELISA) and PVN specific mRNA levels of IL1β, IL6, IL10 and TNFα (via RT‐PCR) were assessed. Additional groups of rats received a SCR or Gαi2 ODN and minocycline (120 μg/day) co‐infusion and a 7‐day HS diet.ResultsIn Male SD rats CNS Gαi2 down regulation, but not control SCR ODN treatment, results in HS evoked HTN, sympathoexcitation, sodium retention, increased PVN mRNA levels of the pro‐inflammatory cytokines (PIC) IL1β, IL6 and TNFα and a decrease in PVN anti‐inflammatory 1L10 mRNA expression. ICV minocycline (anti‐inflammatory antibiotic) co‐infusion did not alter the physiological responses to HS intake in SCR ODN infused rats but abolished the increase in HS evoked PVN PIC mRNA levels and attenuated HTN, sympathoexcitation and sodium retention following CNS Gαi2 down regulation.ConclusionOur data suggests that PVN inflammatory mechanisms contribute to the pathophysiology of CNS Gαi2 dependent salt sensitive HTN through influences on central sympathetic outflow and sodium homeostasis. These data broaden the settings in which PVN inflammation influences blood pressure to include salt sensitive HTN.Support or Funding InformationThis work was supported by NIH grants R01HL107330 and K02HL112718 and AHA 16MM32090001 to RDW.

ICV SCR ODN INFUSION (25μg/5μl/day)
ICV Gai2 ODN INFUSION (25μg/5μl/day)

Normal Salt (0.6% NaCl)
High Salt [HS] 4% NaCl
HS + ICV MINO (120μg/5μl/day)
Normal Salt (0.6% NaCl)
High Salt [HS] 4% NaCl
HS + ICV MINO (120μg/5μl/day)

MAP (mmHg)
123±4
121±3
119±3
118±4
144±3*
130±4*#

Plasma NE (nmol/l)
62±7
38±4*
42±5*
59±5
92±7*
62±6#

24h Na+ balance (mEq)
0.3±0.1
0.4±0.1
0.3±0.1
0.3±0.1
1.8±0.3*
0.9±0.2*#

IL‐1β (fold increase)
0.9±0.2
0.8±0.1
1.1±0.2
1.1±0.2
2.4±0.4*
1.3±0.3#

IL‐6 (fold increase)
1.0±.2
0.9±0.1
1.1±0.1
1.0±0.1
2.2±0.3*
1.2±0.2#

TNFα (fold increase)
1.1±0.1
1.0±0.2
1.0±0.1
1.3±0.2
2.3±0.5*
1.1±0.2#

IL‐10 (fold increase)
1.0±0.1
1.3±0.1
1.3±0.2
1.1±0.2
0.4±.0.1*
1.1±0.2#

p<0.05 vs. respective normal salt (0.6% NaCl) group;
p<0.05 vs. respective high salt (4% NaCl) group (N=4/group ± SEM).
MINO = minocycline.
Maternal Hyperandrogenemia Causes Increased MAP and Proteinuria in Male Rat Offspring
Authors: Dalmasso Carolina , Maranon Rodrigo O. , Patil Chetan N. , Reckelhoff Jane F. 
Published: November 2023

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting 6–10 % of women, and is associated with hyperandrogenemia, oligo/anovulation and polycystic ovaries. Many women with PCOS have difficulty getting pregnant, and thus this population often opts for in vitro fertilization. However, the offspring of PCOS women are predisposed to lower birth weight, metabolic disorders during childhood, and an increased risk for the daughters to develop PCOS. However, the mechanisms by which the offspring of women with PCOS develop negative health outcomes are unknown. Therefore, these studies tested the hypotheses that females of PCOS model in rats would develop symptoms of PCOS and the males would develop other cardiovascular symptoms such as elevated blood pressure. Female (F) and male (M) offspring of control (C) and PCOS (P) dams (SD; DHT 7.5mg/90d) were divided into groups: F‐C, F‐P, M‐C and M‐P. At postnatal day 2, 7, 15 and 21 there was a significant increase (p<0.05) in body weight in both F‐P and M‐P, compared to F‐C and M‐C, respectively. This trend reversed by week 17 with F‐P and M‐P have lower body weights (p<0.05) compared with F‐C and M‐C, respectively. Proteinuria, measured at week 24, was similar in F‐P vs. F‐C (p=NS), but was significantly higher in M‐P than M‐C (18.8±4.1 vs. 48.5±14.1 mg/d, p<0.05). Baseline mean arterial pressure (MAP, telemetry) was tended to be higher in F‐P vs. F‐C (F‐C= 109±5 mmHg vs. F‐P= 118±3 mmHg; p=NS). However, in males, MAP was significantly higher in M‐P than M‐C (M‐C= 113±2 mmHg vs. M‐P= 121±3 mmHg; p<0.05). To test whether exposure to hyperandrogenemia in utero would cause an exaggerated response to Angiotensin II (Ang II), male and female offspring were treated with enalapril (7d; drinking water; 250 mg/l) for 5 days, and then Ang II (150 mg/kg/d, sc minipump, 7 days). MAP decreased with enalapril similarly in F‐C and F‐P, and in M‐C and M‐P, and were similar among the groups (F‐C: −18÷4; F‐P: −22±5; M‐C: −16±1; M‐P: −18±1 mm Hg; p=NS for all groups), and maintained the difference in MAP in females, but not males. ANG II infusion increased MAP to similar levels in males and females: F‐C: 162±9; F‐P: 160±7 mm Hg (p=NS); M‐C: 162±6; M‐P: 171±1 mm Hg (p=NS). Thus male offspring of PCOS dams have an increase in MAP and more proteinuria, but similar responses to Ang II compared to controls. Female offspring do not develop a PCOS phenotype. Future studies will be necessary to determine exact mechanisms responsible for increase in blood pressure and renal injury.Support or Funding InformationSupported by NIH‐R01HL66072, PO1HL51971 (JFR), 14POST18640015 (ROM).
Expansion of Regulatory T cells using Low‐dose Interleukin‐2 Attenuates Hypertension in an Experimental Model of Autoimmune Disease
Authors: Taylor Erin B. , Ryan Michael J. 
Published: November 2023

Systemic lupus erythematosus (SLE) is a prototypic multisystem autoimmune disorder that is characterized by prevalent hypertension, renal injury, and cardiovascular disease. In addition to a breakdown of tolerance to nuclear antigens that results in the activation of self‐reactive B and T lymphocytes, numerous studies report a low prevalence and/or impaired function of regulatory T cells (TREG) in both patients with SLE and in murine models. TREG are important for the maintenance of tolerance to self antigens and also secrete the anti‐inflammatory cytokines TGF‐β and IL‐10. Evidence suggests that TREG dysfunction in SLE results from a deficiency in interleukin (IL)‐2, a cytokine critical for maintenance of TREG cell populations. Recent studies suggest that low dose IL‐2 therapy expands TREG in mouse models of SLE, but whether expanding TREG protects against hypertension and renal injury during SLE is unclear. To examine this question, 30 week old female SLE (NZBWF1) and control (NZW) mice were injected intraperitoneally with phosphate buffered saline (PBS, vehicle) or 2 μg recombinant mouse IL‐2 in PBS (rIL‐2) three times in 24 hours followed by maintenance doses every five days for four weeks. Treatment with rIL‐2 effectively expanded the CD4+FoxP3+ TREG cell populations in the spleen (5.2±0.4 vs. 8.3±0.5%, p<0.0001), peripheral blood (0.66±0.05 vs. 0.94±0.13%, p<0.05), and kidneys (6.8±0.6 vs. 8.9±0.8%, p<0.05) when compared to vehicle treated SLE mice. Circulating levels of anti‐dsDNA IgG autoantibodies, a marker of SLE disease activity, were higher in SLE mice compared to control mice (1.53±0.17 vs. 0.39±0.10 OD450, p<0.01), but were unaffected by rIL‐2 treatment (SLE‐rIL‐2: 1.69±0.16 OD450, p=0.87). Similarly, urinary albumin excretion, an indicator of glomerular injury, was increased in SLE mice as compared to controls (8.2±4.6 vs. 0.032±0.01 mg/day), but was not different in SLE mice treated with rIL‐2 (SLE‐rIL‐2: 11.6±5.9 mg/day). As previously reported by our laboratory, mean arterial pressure (MAP; mmHg), measured in conscious mice by carotid catheter, was higher in SLE mice than in controls (136±3 vs. 115±3, p<0.05). MAP was significantly lower in rIL‐2 treated SLE mice when compared to vehicle treated SLE mice (SLE‐ rIL‐2: 125±4; p<0.05 vs. SLE‐vehicle), suggesting that expanding TREG using low dose IL‐2 attenuates the development of hypertension in female SLE mice. While the mechanism for the protection against hypertension is unclear, it does not appear to be related to the delay of SLE disease progression. Further studies are required to test whether anti‐inflammatory cytokines produced by TREG are responsible for the anti‐hypertensive effects of low‐dose IL‐2 therapy.Support or Funding InformationResearch supported by: VA Merit Award BX002604‐01A2, NIH PO1HL051971, P20GM104357, and T32HL105324‐05