bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pinitol ameliorates impaired pressure‐natriuresis in experimental diabetes (1063.5)
Authors: Nascimento Nilberto , Cortez Lorrainy Umbelina , Sousa Luis Gustavo , Fonteles Manassés , Santos Claudia 
Published: June 2021

Pressure‐induced natriuresis is a physiological protective mechanism that counteracts increased blood pressure with increased diuresis and natriuresis. We evaluated whether diabetes would affect this mechanism and if pinitol, an antidiabetic compound , could prevent and/or reverse any alterations. We induced diabetes by a single injection of 70 mg/kg streptozotocin (i.p) and 2‐month and 4‐months diabetic rats (Diab) compared to time‐matched euglycemic rats (eugly). We employed the Roman‐Cowley model of pressure‐natriuresis (P‐N) in male Wistar rats. We measured fractional excretion of sodium (FENa) and glomerular filtration rate (GFR), filtration fraction (FF), renal blood flow (RBF) and renal vascular resistance (RVR). We have shown that STZ‐diabetes blunts pressure‐natriuresis, in animals submitted to similar increases in renal perfusion pressure, after 2‐months (eugly‐ FENa from 0.5± 0.4 to 3.8±1.5% during P‐N vs diab‐ 0.4 ±0.2% to 0.8±0.2%) and after 4 months pressure‐natriuresis is completely absent (FENa from 0.16±0.04% to 0.23±0.08%). In another set of experiments, two regimens of pinitol treatments were administered to different diabetic groups. One received 20 mg/kg/12h (p.o) during 2‐months beginning 2‐months after the initial diagnosis of diabetes. The other group received the same dosage after the first day of diagnosis and was kept on this regimen during two months. The firs regimen was able to ameliorate kidney function during the P‐N period (FENa from 0.2±0.08% to 0.48±0.2%). Remarkably, the second treatment regimen further improved renal function during the pressure‐natriuresis period (FENa from 0.8±0.03% to 2.34±0.9%). Diabetes profoundly decreases kidney ability to respond to increased perfusion pressure with increased sodium excretion and 2‐month pinitol treatment is able to both reverse and especially prevent this diabetic complication.Grant Funding Source: CNPq/Brazil; FUNCAP‐CE/Brazil
Mitochondrial superoxide generation in the rat pup kidney during sepsis (1063.7)
Authors: Sims Clark , Patil Naeem , MacMillian‐Crow Lee Ann , Mayeux Philip 
Published: June 2021

Sepsis is a leading cause of acute kidney injury (AKI) and mortality in children. In order to develop new therapies, it is critical to understand the development of pediatric sepsis and its effects. In this study, we used a clinically relevant cecal ligation and puncture (CLP) model of peritonitis in rat pups 17‐19 days old to characterize the development of sepsis‐induced AKI. CLP produced severe sepsis demonstrated by hypothermia and a time‐dependent renal microcirculatory failure. Analysis of the renal microcirculation using intravital video microscopy showed a decrease in the number of continuously flowing cortical capillaries and an increase in capillaries with no flow. Renal microcirculatory failure was associated with an increase in mitochondrial superoxide generation as measured using MitoSOX Red. These effects were observed as early as 6h after CLP and were sustained through 18h. To determine if mitochondria dysfunction leads to superoxide generation, high‐resolution respirometry (HRR) was used in fresh tissue biopsies to measure the activities of complexes I, II/III, and IV. HRR showed that CLP did not produce changes in any of the mitochondrial complexes at these early time points studied. Therefore, sepsis does not appear to cause severe mitochondrial dysfunction in rat pups despite an increase in mitochondrial superoxide generation.Grant Funding Source: Supported by NIH/NIDDK R01 DK075991
Pharmacokinetic and pharmacodynamic properties of β‐hydroxyphospho‐carnitine (1064.1)
Authors: Mendoza‐Rivera Brissa , Reyes‐Esparza Jorge , De La Cruz Cordero Ricardo , Rodriguez‐Fragoso Lourdes 
Published: June 2021

The aim of this investigation was to study the pharmacokinetics properties in two species and the pharmacodynamics effects of β‐HPC in obese Zucker fa/fa rats administered during a period of time. Lean and obese Zucker fa/fa rats were treated for 14 weeks with β‐HPC (100 mg/kg) to assess its impact on glucose, triglycerides and cholesterol in liver and blood samples, and on hepatic steatosis. Besides of that, we described the first study about the pharmacokinetic properties of β‐HPC after single oral administration in rats and rabbits. β‐HPC reduced the levels of glucose, triglycerides and cholesterol in the liver, the levels of triglycerides and cholesterol in serum, and improved the architecture and reduced steatosis in the liver in obese rats. After a single oral dose of β‐HPC (100 mg/kg) the elimination half‐life (t1/2), clearance and the area under the concentration vs time (AUC) in rats and rabbits were 23.7 vs 8.87 h, 13.9 vs 151.1 mL/h, and 2174.4 vs 3128 µg.h/mL, respectively. The values of Tmax, Cmax, and Ka in rats and rabbits were 0.58 vs 1.5 h, 62.4 vs 221.4 µg/mL, and 0.02 vs 2.40 h‐1, respectively. This study demonstrated that, although there exist differences between species, the β‐HPC administered orally is rapidly absorbed, highly distributed and efficiently cleared. According with the pharmacodynamics properties β‐HPC could be useful for treating some metabolic alterations present in metabolic syndrome.Grant Funding Source: CONACYT
Gender comparison of recovery from intravenous and inhalational anaesthetics among adult patients in South‐West Nigeria (1064.3)
Authors: Okunoren‐Oyekenu Yewande , Sanusi Arinola , Gbotosho Grace 
Published: June 2021

Gender is a known factor in recovery from general anaesthetics. This study reports such a difference in South‐West Nigerian patients, and proposes gender‐based differences in pharmacokinetic profiles as explanation. Two main strata (20 males and 20 females) were considered, and written informed consents were obtained for both strata. Intravenous general anaesthesia was induced with propofol or thiopental and maintained with inhalational agent halothane or isoflurane. Patient plasma samples were analyzed with high performance liquid chromatography (HPLC), for anaesthetic agents before induction; at 10, 30 60, 180 mins after induction of anaesthesia, and at recovery. The Elimination Half Life, Mean Resident Time, and Clearance measured in propofol patients maintained on halothane or isoflurane were 310.7 ± 138.4 min, 459.2 ± 199.4 min and 431.1 ± 154.1 ml/min, respectively for females versus 503.0 ± 312.2 min, 732.8 ± 448.3 min and 290.0 ± 157.8 ml/min for males. The corresponding values with thiopental induction were 148.0 ± 112.7 min, 220.9 ± 180.3 min and 544.6 ± 500.1 ml/min for females versus 76.8 ± 28.7 min, 115.4 ± 35.4 min and 533.7 ± 502.5 ml/min for males. Data was significantly different (p<0.05) across gender. Gender differences in recovery from anaesthetic agents in Southwest Nigerian patients is due to differences in pharmacokinetic profiles.Anaesthesia, Recovery time, HPLC, Pharmacokinetics.Grant Funding Source: Self‐Funded Research Student supported by Supervisors
Stromal interaction molecule 1 deletion in smooth muscle cells protects hypertension‐induced vascular dysfunction by endoplasmic reticulum stress‐dependent mechanism (1065.13)
Authors: Kassan Modar , Belmadani Souad , Trebak Mohamed , Matrougui Khalid 
Published: June 2021

Background: stromal interacting molecule‐1 (STIM1) and endoplasmic reticulum (ER) regulate intracellular calcium for vascular function. Hypertension is associated with vascular dysfunction raising the question of whether STIM1 has any role in vascular dysfunction through ER stress and oxidative stress in hypertension.Methods &amp; results: We used male C57/BL6, homozygous/heterozygous STIM1 knockout specifically in smooth muscle cells (STIM1SMC‐/‐, STIM1SMC‐/+), and homozygous CHOP knockout (CHOP‐/‐) mice infused with and without angiotensin II (Ang II, 400 ng/Kg/min) for 4 weeks. Hypertension development was significantly delayed in STIM1SMC‐/‐ and CHOP‐/‐ mice infused with Ang II compared to control and STIM1SMC‐/+ with Ang II. The vasoconstriction of mesenteric resistance artery and thoracic aorta in response to phenylephrine was significantly reduced only in STIM1SMC‐/‐ mice infused with and without Ang II. However, vasoconstriction to thromboxane was identical in all groups and was augmented in hypertension with low effect in STIM1SMC‐/‐ and CHOP‐/‐. The endothelium‐dependent relaxation was similar in all groups but it was impaired in the control and STIMSMC‐/+ infused with Ang II, protected in STIM1SMC‐/‐ + Ang II and rescued in CHOP‐/‐ + Ang II. The NADPH oxidase activity was elevated, while eNOS phosphorylation, cGMP and nitrite levels were reduced in control with Ang II, compared to STIM1SMC‐/‐ and CHOP‐/‐ with and without Ang II. ER stress markers were only enhanced in control infused with Ang II. The expression of STIM1 was augmented in all groups of mice infused with Ang II.Conclusions: We conclude that in hypertension, the aberrant increase in STIM1 expression causes vascular dysfunction through ER stress and increases oxidative stress‐dependent mechanisms.
A novel anti‐inflammatory signaling role for the deubiquitinase USP20 in vivo (1065.5)
Authors: Jean‐Charles Pierre‐Yves , Zhang Lisheng , Han Sang‐oh , Kommaddi Reddy , Wu Jiao‐Hui , Freedman Neil , Shenoy Sudha 
Published: June 2021

The pro‐inflammatory Toll‐like receptor‐4 (TLR4) signals via Lys63‐linked autoubiquitination of TRAF family E3 ligases, which effect ubiquitin‐dependent activation of NFκB. In vascular smooth muscle cells (SMCs), we found TLR4 activation by LPS induced Lys63 polyubiquitination of the endocytic/signaling adaptor β‐arrestin2 (βarr2), which regulates NFκB. In co‐IP from intact cells, endogenous ubiquitin‐specific protease‐20 (USP20) associated with βarr2 and TRAF6. To determine if USP20 regulates these proteins in vivo, we created mice with SMC‐specific expression of WT‐USP20 or dominant‐negative (DN)‐USP20. In SMCs from these mice, LPS induced activation of NFκB (assessed by Ser536‐phosphorylation of p65) was 4‐fold greater in DN‐USP20‐Tg than in WT‐USP20‐Tg and non‐Tg control SMCs. Furthermore, Lys63 ubiquitination of both βarr2 and TRAF6 was augmented in DN‐USP20‐Tg SMCs. Congruently, 4 wk after endothelial denudation injury, carotid arteries of SMC‐DN‐USP20‐Tg mice showed 1.8‐fold greater NFκB activation (phospho‐p65Ser536) and 2.6‐fold greater neointimal hyperplasia (comprising proliferating SMCs) than non‐Tg or SMC‐WT‐USP20 mice (p<0.01)_even though all groups had equivalent carotids at baseline. Thus, USP20 seems to function as an anti‐inflammatory deubiquitinase by inhibiting ubiquitin‐dependent activation of β‐arrestin2, TRAF6 and NFκB in SMCs.Grant Funding Source: Supported by T32 HL007101 (PJYC), HL77185 (NJF) and HL080525 (SKS)
Suramin sensitive P2 receptor is involved in α1‐adrenergic receptor mediated mesenteric arterial constriction in normotensive and DOCA‐salt hypertensive rats (1065.9)
Authors: Lian Mary , Xu Hui , Galligan James 
Published: June 2021

Pannexin‐1 is an ATP permeable hemichannel that mediates ATP released from smooth muscle cells (SMCs) in response to stimulation of α1‐adrenergic receptors (AR) by norepinephrine. ATP is released and acts back on vascular SMCs to further enhance adrenergic constriction. It is unclear if the channel function is altered in hypertension. Our earlier studies have indicated that pannexin‐1 activation contributes to α1‐AR mediated mesenteric arterial (MA) constriction in normotensive (sham) and DOCA‐salt hypertensive rats, since the concentration‐response curves (CRCs) of phenylephrine (PE) were significantly right‐shifted by mefloquine (a pannexin‐1 blocker) in all MA. In this study, we determined the role of P2 receptors in α1‐AR mediated MA constriction in both rats. PE and ATP‐induced MA constrictions were recorded using a pressure myograph and video microscopy before and after adding P2 receptor (P2R) antagonists. The PE‐CRCs were similar in MA from sham and DOCA‐salt hypertensive rats with or without PPADs, a P2X/P2Y1 receptor antagonist. PPADs shifted ATP‐CRCs to the right in all MA. PE‐CRCs in all MA were significantly right‐shifted in a concentration‐dependent manner by suramin, a P2X/P2Y2 receptor antagonist. Our studies indicate that α1‐AR mediated constrictions of rat MA are not caused by ATP released from SMCs to acting on PPADs sensitive P2X or P2Y1 receptors. A suramin‐sensitive P2R may mediate the ATP‐induced MA constriction caused by α1‐AR activation of pannexin‐1 ATP permeable channels on SMCs.Grant Funding Source: Supported by NIH 5‐R25‐HL108864‐01 and HL P01 HL070687
Fingerprinting of GPCR activity across multiple G protein substrates unveils complex profiles of functional selectivity (1066.12)
Authors: Masuho Ikuo , Jones Christopher , Martemyanov Kirill 
Published: June 2021

Despite the tractability of G protein‐coupled receptors (GPCRs) as drug targets, there are substantial challenges in understanding the mechanisms of drug action at these receptors. Since more than 800 GPCRs and 16 Gα subunits are identified in human genome and are capable to generate enormous array of GPCR‐G protein combinations, G protein‐coupling profiles of GPCRs are a critical missing piece of the GPCR‐signaling puzzle. Here, we have undertaken an attempt to comprehensively characterize G protein‐coupling selectivity and its modulation by agonists and intracellular regulatory proteins. We employed a single‐platform BRET assay to evaluate GPCR responses via 14 different Gα subunits using dynamic association/dissociation of Venus‐tagged Gβγ with NanoLuc‐tagged GRK3‐derived sensor in living cells. Distinct G protein‐coupling profiles for different receptors in both maximal amplitudes and kinetics of responses were observed and used as a basis for modeling “fingerprints” for each of the examined receptors. These fingerprints in many cases differed between physiological agonists and synthetic ligands. We further found that members of Regulators of G protein Signaling (RGS) family shape GPCR fingerprints. These results reveal underappreciated complexity of GPCR coupling to different G protein substrates and suggest a new avenue for designing signaling pathway‐specific therapeutics.Grant Funding Source: Supported by the NIH grants HL105550 and NS081282.
Inhibition of microRNA‐429 in the renal medulla increased salt sensitivity of arterial blood pressure in Sprague Dawley rats (1067.1)
Authors: Zhu Qing , Hu Junping , Wang Zhengchao , Li Pin‐Lan , Han Weiqing , Li Ningjun 
Published: June 2021

We have reported that high salt intake (HS) inhibits HIF prolyl‐hydroxylase 2 (PHD2), an enzyme promoting the degradation of hypoxia inducible factor (HIF)‐1α, and upregulates HIF‐1α along with its target genes such as NOS2 and HO‐1 in the renal medulla, which is an important molecular adaptation to promote extra sodium excretion and maintain blood pressure. Our preliminary data showed that HS significantly increased the expression of miR429, a microRNA targeting PHD2 mRNA, in the renal medulla. The present study determined whether inhibition of miR429 would increase the levels of PHD2, decrease the levels of HIF‐1α target genes in the renal medulla and induce salt sensitive hypertension. Transfection of miR429 inhibitor into the renal medulla decreased miR429 level by 93%, increased PHD2 mRNA level by 2.5 fold, and reduced the expression of NOS2 and HO‐1 by 67% and 74%, respectively. Ten‐day high salt diet significantly increased mean arterial pressure (MAP) in miR429 inhibitor‐treated rats compared with controls (145±3.5 vs. 118±4.1 mmHg). MAP did not change in miR429 inhibitor‐treated rats that were fed a low salt diet. These results suggested that renal medullary miR429 is an important regulator in renal adaptation to HS and that deficiency in miR429‐mediated PHD2 inhibition in response to HS in the renal medulla may represent a pathogenic mechanism for salt‐sensitive hypertension.Grant Funding Source: Supported by NIH grants HL089563 and HL106042
Inhibition of angiotensin‐converting enzyme‐2 (ACE‐2) activity and radioligand binding of a putative ACE‐2 inhibitor (1067.5)
Authors: Linares Andrea , Carrera Eduardo , Speth Robert 
Published: June 2021

While closely related to angiotensin‐converting enzyme (ACE), ACE‐2 has very different effects on the renin‐angiotensin system. A potent inhibitor of ACE‐2 (MLN‐4760) was developed, but then abandoned when it became clear that ACE‐2 metabolizes angiotensin II (Ang II) to form Ang 1‐7. To develop a novel inhibitor of ACE‐2 to use as a tool to study ACE‐2, we developed an analog of MLN‐4760 (JFS101) in which a leucinyl side‐chain (designed to mimic the carboxy terminal amino acid of Ang I) was replaced with a tyrosyl side‐chain to more closely mimic the carboxy terminal amino acid of Ang II and allow for the inhibitor to be radioiodinated. Both the uniodinated and radioiodinated and the S,S versus the S,R analogs were tested for their ability to inhibit ACE‐2 metabolism of an artificial ACE‐2 substrate (MCA‐APK(Dnp) using recombinant human ACE‐2 (rhACE‐2) and for their ability to bind to ACE‐2 in rat lung and kidney membranes. The S,S isomer of JFS101 inhibited rhACE‐2 in the nanomolar range and was 5‐10% as potent as the S,S, isomer of MLN‐4760, which inhibited rhACE‐2 in the low nanomolar range. The S,R isomer of JFS101 inhibited rhACE‐2 activity in the low micromolar range. Radioligand binding assays using 125I‐JFS101 (S,S isomer) revealed a high level of binding to lung and kidney membranes 196 and 321 fmoles/mg wet weight at 50 nM 125I‐JFS101. However, less than 10 % of this binding was displaceable by 1 µM MLN‐4760. In contrast, 2 mM EDTA inhibited ~80 % of total binding at concentrations ranging from 3 ‐35 nM 125I‐JFS101. The EDTA displaceable 125I‐JFS101 binding was not saturable suggesting that the KD of 125I‐JFS101 for lung membranes is >> 35 nM. The inability of MLN4760 combined with the ability of EDTA to inhibit 125I‐JFS101 binding suggests that 125I‐JFS101 is not selective for ACE‐2, but that it does bind to another metallopeptidase.Grant Funding Source: NIH‐HL113905
Cerebral autoregulation in fulminant hepatic failure (1068.10)
Authors: Nogueira Ricardo , Mendes Fernando , Pacheco Marcelo , Lins Karla , Teixeira Manoel , Bor‐Seng‐Shu Edson 
Published: June 2021

Objective: The aim of this study is to evaluate hemodynamic and cerebrovascular autoregulation capacity in patients with fulminant hepatic failure (FHF) before and after liver transplantation.Material and Methods: Twenty five patients with FHF diagnosis were evaluated. Cerebral hemodynamic was evaluated by cerebral blood flow velocity in the middle cerebral arteries, using transcranial Doppler device equipped with 2 MHz probe. CA assessment was carried out through static autoregulation index (SARI) which studies the effects of increases in mean arterial blood pressure (MAP) on cerebral blood flow velocity. MAP was increased pharmacologically up to a maximum limit of 120 mmHg.Results: From 25 patients with FHF diagnoses, 17 were evaluated before and after liver transplantation. Twenty one patients (84%) had pre transplantation impaired CMA. Ten of 17 patients recovered CMA in 48 hours following LTx.Conclusion: Our findings showed impaired CMA in most patients with FHF. For the majority of patients who underwent LTx, CMA was restored 48 hours after transplantation.
Blunted cerebrovascular response to exogenous nitric oxide in POTS (1068.12)
Authors: Del Pozzi Andrew , Medow Marvin , Stewart Julian 
Published: June 2021

Cognitive deficits are characteristic of postural tachycardia syndrome (POTS). Intact nitrergic nitric oxide (NO) is important to cerebral blood flow (CBF) regulation, to neurovascular coupling, and to cognitive efficacy. POTS patients often experience defective (NO) mediated vasodilation caused by oxidative stress. We used combined transcranial Doppler ultrasound, to measure CBF velocity (CBFv), and near‐infrared spectroscopy (NIRS), to measure cerebral oximetry while supine. We previously showed dilation of the middle cerebral artery (MCA) in response to a bolus administration of the NO donor sodium nitroprusside (SNP) in healthy volunteers. We hypothesized a blunted MCA response to SNP in POTS. The SNP responses of 17 POTS patients were compared with 12 healthy controls (ages 14‐28). CBFv in POTS and control were not different at baseline (75 ± 3 vs. 71 ±2 cm • s‐1 P = 0.31) and decreased to a lesser degree with SNP in POTS (to 71 ± 3 vs 62 ± 2 cm • s‐1; P = 0.02). The changes in total and oxygenated hemoglobin (8.83 ± 0.45 and 8.13 ± 0.48 µmol/kg tissue) were markedly reduced in POTS compared to control (14.2 ± 1.4 and 13.6 ± 1.6 µmol/kg tissue), primarily due to increased venous efflux. The data indicate reduced cerebral oxygenation, blunting of cerebral arterial vasodilation and heightened cerebral venodilation in response to exogenous NO.Grant Funding Source: NHLBI
tPA‐S481A prevents impairment of cerebrovascular autoregulation by endogenous tPA after traumatic brain injury by upregulating p38 MAPK and inhibiting ET‐1 (1068.13)
Authors: Armstead William , Bohman Leif‐Erik , Riley John , Yarovoi Serge , Higazi Abd Al‐Roof , Cines Douglas 
Published: June 2021

Traumatic brain injury (TBI) causes loss of cerebrovascular autoregulation. Mitogen activated protein kinase (MAPK) isoforms ERK and JNK and ET‐1 are mediators of impaired cerebral hemodynamics after TBI. Excessive tPA released after TBI may impair autoregulation either by over‐activating NMDA receptors (NMDA‐Rs) or by predisposing to intracranial hemorrhage. Our work shows that a catalytically inactive tPA variant (tPA‐S481A) that competes with wild type (wt) tPA for binding to NMDA‐R through its receptor docking site but that cannot activate it, prevents activation of ERK by wt tPA and impairment of autoregulation when administered 30 min after FPI. We investigated the ability of variants that lack proteolytic activity but bind/block activation of NMDA‐Rs by wt tPA (tPA‐S481A), don’t bind/block activation of NMDA‐Rs but are proteolytic (tPA‐A296‐299), or neither bind/block NMDA‐Rs nor are proteolytic (tPA‐A296‐299S481A) to prevent impairment of autoregulation after TBI and the role of MAPK and ET‐1 in such effects. Fluid percussion brain injury was induced in anesthetized pigs equipped with a closed cranial window. Results show that tPA‐S481A given 3h post TBI, but not tPA‐A296‐299 or tPA‐A29‐299S481A prevents impaired autoregulation by upregulating p38 and inhibiting ET‐1. These data suggest that tPA‐S481A has a realistic therapeutic window and focuses intervention on NMDA‐Rs to improve outcome.Grant Funding Source: Supported by HD 57355