bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of age and chronic alcohol self‐administration on plasma mineralocorticoid and glucocorticoid concentrations in male rhesus monkeys
Authors: Helms Christa M , Grant Kathleen A
Published: June 2021

To investigate the mechanisms mediating blunted hypothalamic‐pituitary‐adrenal (HPA) axis in alcoholics, we measured plasma mineralocorticoids (deoxycorticosterone, DOC; aldosterone, ALD) and glucocorticoids (cortisol) in male rhesus monkeys during controlled induction of alcohol drinking then 12 months of daily “open access” to alcohol and water for 22 h/d. Heavy alcohol drinking was defined >; 3.0 g/kg/d alcohol (~12 drinks). Morning hormones were measured for ~20 months at ~6–8‐week intervals in four cohorts of differing ages, basal testosterone and alcohol intake: adolescents, 3/8 heavy drinkers; young adults, two cohorts; older adults, 0/11 heavy drinkers. Four adolescent monkeys were isocaloric controls. Perhaps related to environmental history, one of the young adult cohorts had greater testosterone at baseline (5/8 heavy drinkers) compared to the other (0/8 heavy drinkers). ALD and DOC were constant except amongst adolescent monkeys, for whom DOC decreased during open access. Cortisol decreased during open access compared to induction, significantly for the heaviest drinkers. Glucocorticoids were more sensitive than mineralocorticoids to chronic alcohol self‐administration. Early age of onset may increase mineralocorticoid regulation by alcohol that could contribute to later heavy drinking, e.g., via neuroactive steroid metabolites like allotetrahydrodeoxycorticosterone.
Abuse‐related behavioral effects of ketamine in adult and adolescent rats
Authors: Greenwood Maria A. , Nicholson Katherine L.
Published: June 2021

The dissociative anesthetic ketamine has been subject to growing rates of abuse worldwide, particularly in adolescent populations. This project compared the behavioral effects of ketamine in place conditioning and intravenous self‐administration procedures in adolescent (PND 28–50) and adult (>;PND72) male Sprague Dawley rats. Cocaine served as a positive control. In the place conditioning study, 4 conditioning sessions following administration of 1, 3 or 10 mg/kg ketamine were counterbalanced with 4 sessions following saline administration. Preference was determined based on change in time spent in the drug‐paired environment. In the self‐administration assay, 0.03, 0.1 or 0.3 mg/kg/infusion of ketamine was evaluated for acquisition of self‐administration behavior and level of drug taking under a progressive ratio schedule. In the place‐conditioning assay, the 3 and 10 mg/kg ketamine produced aversion in the adults whereas adolescents demonstrated place preference for the 1 and 3 mg/kg doses. Conversely both age groups acquired self‐administration behavior at all doses of ketamine and cocaine. These divergent results for ketamine in the adults may reflect inherent differences in the two procedures. However, because cocaine produced evidence of hedonic effects in both age groups, it also suggests unique behavioral characteristics of ketamine and important differences in its effects based on age.
Effects of propofol and midazolam on picrotoxin ( PTX)‐ induced convulsions in the rat.
Authors: Hasan Zuheir A
Published: June 2021

Propofol , a short‐acting , intravenous anesthetic, has been used in the treatment of status epilepticus. However, reports of seizure‐like movements during either induction or recovery from propofol anesthesia promoted concerns that propofol may have proconvulsant effects in some patients.

Our prior studies showed that propofol displays anticonvulsant effects in several seizures models at peak anesthetic effect. This study examines the time course of the effects of intravenous (i.v) administration of various doses of propofol and midazolam on seizures induced by intraperitoneal (i.p) injection of the convulsant PTX.

Male Sprague‐Dawley rats (250–300 gm) were treated with PTX (4 mg/kg). Five min following PTX treatment, and before the onset of seizures, groups of rats (N=10), were given propofol (5, 10 , 20 mg /kg) or midazolam (2.5, 5, 10 mg/kg) via a tail vein. Control rats had saline. Individual rats were placed in plexiglass cages and observed for two hours The latency to clonic seizures was recorded. Incidence of clonic and generalized tonic‐clonic seizures were recorded Mortality over 24 hours was also observed.

The higher two doses of propofol and all doses of midazolam significantly increased the latency of clonic seizures. However, propofol did not significantly affect the incidence of generalized tonic‐clonic seizures. In contrast, the higher two doses of midazolam significantly reduced the incidence of generalized tonic‐clonic seizures and greatly reduced mortality. These findings suggest that midazolam was more effective than propofol in aborting PTX‐induced generalized tonic‐clonic seizure. Supported by a research grant from Arabian Gulf University.
In vitro and In vivo effects of Manganese (MnCl2) and Lead (Pb acetate)
Authors: Phattanarudee Siripan , Towiwat Pasarapa , Maher Timothy J
Published: June 2021

The effects of MnCl2 (1, 10, 100 nM, 1, 10, 100 μM, 1mM) and Pb acetate (1, 10, 100 nM, 1, 10, 100 μM, 1mM) on PC12 cell viability after exposure for 24 and 48 hours were examined using the MTT assay. Exposure to MnCl2 (Mn) and Pb acetate (Pb) produced dose‐dependent decreases in cell viability. Percent viability from exposure for 48 hours was less than that from 24 hours. In the in vivo study, pregnant Sprague Dawley rats were exposed during perinatal period to MnCl2 (1.25, 5 and 10 mg/mL) and Pb acetate (2.5–25, 100–250 and 2500–4000 μg/mL), and the effects on neurobehavioral and neurochemical outcomes were determined in the offspring. Exposures to Mn and Pb led to dose‐dependent impairment of learning and memory, evaluated at PND 35 with the Morris water maze. Impulsivity and locomotor activity were also adversely affected when evaluated with the elevated plus maze (EPM) at PND 56. Mn exposure also attenuated high K+‐ evoked increases in extracellular dopamine (DA) and glutamate (Glu), as determined by in vivo microdialysis. Pb similarly attenuated GLU neurotransmission, but had no effect on DA. Impairments in neurotransmission might underlie some of the neurocognitive/neurobehavioral deficits found in this study.
Tissue specific regulation of kappa opioid receptors and Nr4a2 expression by acrylamide
Authors: El‐Alfy Abir T , Dunker Abby , Brown Jaime , Cooper Brandy , Dudek Michelle , Ostil Rainier
Published: June 2021

Acrylamide is a monomer with established human neurotoxic actions. Public concern was lately heightened by the finding that acrylamide is formed in starch‐based foods cooked at high temperatures. However, the extent of neurotoxicity particularly in children is not understood. The primary objective of this project was to assess gene expression and translational changes induced by acrylamide in juvenile rats. Animals were administered acrylamide daily (p.o., 30 mg/kg doses, n=6) for 21 days. Neurobehavioral effects were assessed and gene expression changes were evaluated in different brain regions, spinal cord, and sciatic nerve. Quantitative RT‐PCR followed by western blot analyses were conducted. Acrylamide treatment induced significant behavioral symptoms. Gene expression changes identified differentially expressed genes that play a role in neuronal development, pain pathways, and control of motor function. Western blot analyses revealed a significant decrease (p<0.05) in expression of kappa opioid receptors (KOR) in motor cortex and cerebellar tissues, while the expression was significantly increased in the sciatic nerve (p<0.01). The current study revealed that acrylamide‐caused down regulation of KOR expression in motor cortex and cerebellum. Such an effect might be responsible for the enhanced pain sensation observed in animal studies as well as in workers who have high acrylamide exposure.
Cytotoxicity of Zinc Oxide Nanparticles in Human Neurotumor Cells
Authors: Singh Maibam Ratan Mani , Lai Maria , Mukka Krishnaveni , Idikuda Vinaykumar , Tadinada Satya Murthy , Pfau Jean , Bhushan Alok , Leung Solomon , Lai james
Published: June 2021

Increasing applications of metal oxide nanoparticles has made the environmental safety and health impact assessment of such particles very important. Our previous studies have demonstrated the cytotoxicity of several metallic and non‐metallic oxide nanoparticles in several cell types. This study extends our previous work as part of a systematic investigation of elucidating the putative cytotoxicity of zinc oxide nanoparticles in neural cells employing human neuroblastoma SK‐N‐SH and astrocytoma U87 cells. We hypothesized that apoptosis is one mechanism underlying the putative toxicity of ZnO nanoparticles in these neural cells. Our results demonstrate that treatment of these cell types with the nanoparticles induced dose‐related decreases in the cell survival. Flow cytometric findings reveal that at higher concentrations of 20–50 μg/mL of ZnO nanoparticles, significant proportions (>;60%) of both SK‐N‐SH and U87 cells were undergoing apoptosis. Our results strongly suggest that apoptosis is one cell death mechanism underlying the cytotoxicity of ZnO nanoparticles in the two types of neural cells and as such may have pathophysiological implications in the biocompatibility and health hazard of the nanoparticles.
Educating the Next Generation of Pharmacologists & Toxicologists: The ASPET SURF Program at the University of Arizona
Authors: Bender Carol
Published: June 2021

The American Society for Pharmacology and Experimental Therapeutics (ASPET) created the ASPET Summer Undergraduate Research Fellow (SURF) Awards in 1991 to support undergraduate researchers working with ASPET members. Both Institutional SURF fellowships and Individual SURF fellowships are available. The University of Arizona (UA) has been home to an Institutional ASPET SURF Program continuously since 1991. To date, 90 students have been part of this program. This poster details what is offered through the UA ASPET SURF Program and provides outcome data on program alumni. ASPET SURF funding insures that undergraduate students have exposure to the fields of pharmacology and toxicology and the requisite training to pursue careers in these disciplines.
Pharmacogenetics of warfarin safety and effectiveness in children
Authors: Shaw Kaitlyn , Amstutz Ursula , Hildebrand Claudette , Rassekh S. Rod , Dubé Marie‐Pierre , Hayden Michael R , Ross Colin J , Carleton Bruce C
Published: June 2021

Objectives

To assess the contribution of CYP2C9/VKORC1 genotypes and variation in other genes involved in warfarin biotransformation and coagulation pathways to warfarin‐related outcomes in children. Furthermore, to validate the performance of a previously published pediatric pharmacogenetics‐dosing model when predicting the required dose in an independent cohort of children.

Methods

Clinical and genetic data was collected from 93 patients ≤18 years of age who received warfarin therapy. Genotyping was performed using a custom 96 SNP genotyping assay.

Results

Together, VKORC1–1639G/A and CYP2C9 *2/*3 accounted for 21.1% of dose variability. There was a strong correlation (R2=0.64; P<0.001) between actual and predicted warfarin dose using a pediatric pharmacogenetics‐dosing model. VKORC1 genotype also had a significant impact on time to therapeutic INR (P=0.047), time to INR>;4 (P=0.028), and risk of over‐anticoagulation (INR>;4) during the initiation of therapy (odds ratio, 3.3; P=0.014). An additional variant in CYP2C9 (rs7089580) was significantly associated with warfarin dose in a multivariate model.

Conclusions

This study confirms the importance of VKORC1/CYP2C9 genotype for warfarin outcomes in children and validates a pediatric‐specific genotype‐based dosing algorithm. Research funding provided by CIHR‐DSEN and CFI.
Mechanisms of endothelial dysfunction in penetrating cerebral arterioles of DOCA‐salt hypertensive rats
Authors: Pires Paulo Wagner , Matin Nusrat , Garver Hannah , Jackson William F , Dorrance Anne McLaren
Published: June 2021

Impaired endothelium‐dependent dilation is a hallmark of hypertension. Dilation of penetrating cerebral arterioles (PenA) is necessary to guarantee proper perfusion to regions of increased metabolism. Dysfunction of this system can lead to vascular dementia and Alzheimer's disease. The aim of this study was to understand the mechanisms of impaired dilation in PenA from deoxycorticosterone acetate (DOCA)‐salt hypertensive rats. Isolated PenA from DOCA and sham rats were mounted in a pressure myograph and endothelium‐dependent dilation was assessed with acetylcholine (Ach, 100μM, data shown as change in diameter from baseline). Data are means±SEM, n=5. PenA from DOCA‐salt rats dilated less to Ach. Nitric oxide synthase (NOS) inhibition with 10μM L‐NAME reduced Ach dilation in Sham but not in DOCA. Cyclooxygenase (COX) inhibition with 10μM indomethacin blunted Ach dilation in Sham but not in DOCA. These data suggest that hypertensive both uncoupling of NOS and increased COX activity play a role in endothelial dysfunction in DOCA‐salt hypertension.

Sham
DOCA
p value

Myogenic Tone (%)
28±4
31±3
>;0.05

Ach
9.8±2.8μm
3.2±2.1μm
<0.05

Ach+L‐NAME 10μM
6±1.7μm
8.8±1.3μm
>;0.05

Ach+Indomethacin 10μM
5.4±1.5μm
10±2.4μm
0.09
VEGF‐C induces lymphangiogenesis in the rat mesentery culture model
Authors: Sweat Richard Shelton , Lee Murfee Walter
Published: June 2021

Recently, the rat mesentery culture model was established as a tool for investigating multi‐cellular dynamics involved in angiogenesis. Cultured tissues displayed intact blood and lymphatic microvascular networks. The objective of this study was to determine whether VEGF‐C induces lymphangiogenesis in this model. Mesenteric tissue windows were harvested from adult male Wistar rats and cultured for 5 days in either serum‐free minimum essential media (MEM) or MEM supplemented with VEGF‐C (100 ng/ml). Tissues were then labeled for PECAM and LYVE‐1. VEGF‐C treatment caused a significant increase in the number of lymphatic sprouts per lymphatic network area compared to MEM controls (p < 0.01). Lymphatic sprouts were observed along the hierarchy of intact lymphatic networks and were PECAM and LYVE‐1 positive. These results suggest the rat mesentery culture model can be used to investigate the interrelationships between lymphangiogenesis and angiogenesis in a controlled environment.
High Dietary Fat Intake Does Not Influence Endothelial Fibrinolytic Function in Older Adults
Authors: Greiner Jared , Stauffer Brian , DeSouza Christopher
Published: June 2021

High dietary fat intake is linked to an increased risk of cardiovascular disease. Diminished fibrinolytic capacity underlies thrombogenic risk. The capacity of the endothelium to release tissue‐type plasminogen activator (t‐PA) is critical to endogenous thrombolysis. We have previously demonstrated that endothelial t‐PA release is impaired with aging. It is currently unknown if a high fat diet further worsens t‐PA release in older adults. The aim of this study was to determine the influence of dietary fat intake on t‐PA release in older adults. 26 older healthy adults were studied: 14 consumed a lower fat diet (age: 61±1 yr; % of calories from fat: 30±1; LFD) and 12 consumed a higher fat diet (59±1 yr; % of calories from fat: 42±2; HFD). Dietary fat content was assessed by 4‐day dietary recall. Net endothelial release of t‐PA was determined, in vivo, in response to intrabrachial infusions of bradykinin (BK: 125–500 ng/min) and sodium nitroprusside (SNP: 2.0–8.0 μg/min). Total caloric intake was similar between the groups (LFD: 2111±153; HFD: 2514±172 kcals). Net t‐PA release and total t‐PA release to BK were not significantly different between the LFD (from −0.2±0.5 to 44.7±5.3 ng/100 mL tissue/min; 239.9±27.6 ng/100 mL tissue) and HFD (from −0.6±0.6 to 42.8±5.9; 234.8±29.0) groups. High dietary fat intake does not worsen the capacity of the endothelium to release t‐PA in older adults.
Acute Ischemia Activates Distinct Ion Currents in Endothelial Cells and Pericytes of Capillaries in Guinea Pig Cochlear Lateral Wall
Authors: Yang Yuqin , Nuttall Alfred L , Jiang Zhi‐Gen
Published: June 2021

Capillary blood flow in spiral ligament (SL) and strial vascularis (SV) of the cochlear lateral wall are critical for cochlear health and to meet the high energy‐demand of auditory transduction, but the physio‐pathology of the local capillary cells remains poorly understood. Using acutely isolated capillary segments and whole‐cell recording techniques, we characterized the main membrane currents and the responses to acute ischemic treatment (AIT, hypercapnic pH 6.2, pO2=0 mmHg) of the endothelial cells (EC) and pericytes (PC) in the SL and SV. We found: 1) In physiological solutions, the PCs, but not ECs, showed a [K+]o‐regulated and Ba2+‐sensitive inward rectifier current (Kir). 2) ECs, but PCs rarely, showed a significant outward rectifier current, which was inhibited by 1 mM 4‐AP, 100 μM niflumic acid (NFA) but not TEA. 3) When recorded in situ of a vessel segment, both types of cells showed variable electrical coupling that was blocked by 30 μM 18β‐glycyrrhetinic acid or 100 μM 2‐APB. 4) AIT (3 – 24 min) caused a reversible and partially repeatable outward current at holding potential −20 mV in isolated ECs and PCs. The AIT‐activated net current had I‐V curves and kinetics which mostly resemble to those of Ca2+−activated Cl−channels: strong outward rectification with quick or slow time course to reach steady‐state within 0.5 – 2 s voltage steps. This AIT‐induced current was inhibited by niflumic acid and 1 mM TEA but not 4‐AP. 5) AIT (>;3 min) also inhibited gap junction coupling current. We conclude that the capillary EC and PC in the SV and SL express different K+‐channels, suggesting a role of PCs as the K+‐sensor for blood flow regulation, and the acute ischemia activates chloride channels and BK channels likely via elevation of cytosolic Ca2+ in both ECs and PCs. Supported by NIH grants DC004716 (ZGJ) and DC005983, DC 00105 (ALN).
Pharmacological intervention to the endotoxemia‐induced arterial hyporeactivity to vasoconstrictors
Authors: Zhang Shuang , Cui Ningren , Li Shanshan , Wu Yang , Jiang Chun
Published: June 2021

People with septic shock develop uncontrolled hypotension leading to hypoperfusion, tissue hypoxia, multiple organ failure and death. It is unclear what causes the excessive vasodilation and vascular hyporeactivity to circulating vasoconstrictors in sepsis. The vascular responses may result from a loss of contractility of vascular smooth muscle (VSM) cells, enhanced VSM response to vasodilators, or depressed VSM response to vasoconstrictors. To test these possibilities, we performed these studies on isolated and perfused mesenteric arterial rings. A 20‐h exposure of the rings to bacterial endotoxins (LPS, 1μg/ml) led to marked hyporeactivity of the rings to phenylephrine (PE). However, the responses of the LPS‐treated rings to high concentrations of KCl remained comparable to the control rings, suggesting that the VSM contractility is retained. The hyporeactivity was barely affected by atropine, indomethacin and nitric oxide synthase inhibitor L‐NAME, suggesting that the endothelium‐dependent vasorelaxation does not appear to play a major role. Several vasoconstrictors were tested. With LPS treatment rings were hyporeactive to certain vasoconstrictors but constricted well in response to others. Although rings were hyporeactive to some of the vasoconstrictors, their vasoconstriction effects were significantly potentiated by a joint application with PE. These results suggest that a loss of sensitivities to certain vasoconstrictors appears crucial for the endotoxemic vasodilation and vascular hyporeactivity. (supported by NIH R01‐NS073875 and the MBD program of GSU)
Temporal Evaluation of Baroreflex Dysfunction: Role in Target Organ Damage
Authors: Aguiar Janaina Paulini , Jorge Luciana , Pires Romulo , Krieger Eduardo Moacir , Irigoyen Maria Claudia
Published: June 2021

Wistar rats were divided into 5 groups: control, D1(24h), D2(28 days), D3 (90 days) and D4 (6 months). Sinoaortic denervation (D) was used as a model of arterial baroreflex deficit. BP, HR were analysed using a data acquisition system. Cardiac output (CO) and tissues blood flow were evaluated using microspheres. BP and the HR was incresed in D after 24h (C:106 ± 0.6 vs. D1: 142 ± 2 mmHg; C: 355 ± 7 vs. D1: 453 ± 10 bpm), but it were normalizaed in chronic D. Moreover, it was observed a gradual reduction over time in CO (C: 111 ± 7, D1:81±5, D2:85 ± 6, D3:69±5 D4:35±2 mL/min) accompanied by an increase in total peripheral resistance (C:0.97±0.07, D1:1.74±0.05, D2:1.23±0.07, D3:1.60±0.09, D4:3.00±0.05 mL/min/mmHg) in D groups. Those alterations resulted in a decreased renal blood flow (C:3.47±0.21, D1:1.37±0.19, D2:1.49±0.18, D3:1.12±0.13, D4:0.42±0.16 mL/min/g), coronary flow (C:2.91±0.71, D1:2.07±0.19, D2:1.58±0.28, D3:0.92±0.13, D4:0.34±0.16 mL/min/g) and muscle flow (C:0.24±0.02, D1:0.08±0.005, D2:0.10±0.02, D3:0.05±0.01, D4:0.05±0.007 mL/min/g) in D groups. The acute total baroreflex dysfuntion incresed BP and HR and reduced blood flow and cardiac output, these changes are associated with the body's attempt to maintain homeostasis. However, was observed a progressive reduction in CO and regional flow associated with an increase in RPT. These adjustements may play an important role in target organ‐damage.
Heart rate variability is altered by dietary sodium: a randomized cross‐over study in healthy young adults
Authors: Allen Alexander Ross , Gullixson Leah R. , Wolhart Sarah C. , Kost Susan L. , Schroeder Darrell R. , Eisenach John H.
Published: June 2021

Dietary sodium influences intermediate physiological traits in healthy young adults independent of changes in blood pressure. The purpose of this study was to test the hypothesis that dietary sodium affects cardiac autonomic function. In prospective, randomized cross‐over design separated by 1 month or more between diets, 69 normotensive healthy young adults (M/F: 26/43, ages 18–38 yr) consumed a 5‐day low (10 mmol/day), normal (150 mmol), and high sodium (400mmol) diet prior to a protocol examining cardiovascular traits including heart rate variability (HRV) by time domain and frequency domain analysis (Nevrokard). All women were studied in the low hormone phase of the menstrual cycle. Diet did not affect blood pressure, but HR (mean ± SE) was 68±1, 65±1, and 64±1 in low, normal, and high sodium conditions, resp. (RM ANOVA p < 0.01). For HRV there was a main effect of sodium on SDNN, RMSSD, HF, LFnu, HFnu, and LF/HF ratio (p < 0.01 for all). The response to low sodium was most marked and consistent with sympathetic activation, with increased LFnu and LF/HF ratio, and decreased SDNN, RMSSD, and HFnu compared to both normal and high sodium conditions (p ≤ 0.05 for all). These findings suggest that autonomic control of HRV is altered through changes in dietary sodium without changes in blood pressure. Support: UL1 TR000135, HL‐89331
Central Angiotensin II ‐ induced hypertension downregulates AT2R and the mir‐29 family in rats
Authors: GAO LIE , YU LI , SHAO CHUNHONG
Published: June 2021

Ang II plays a critical role in the pathogenesis of hypertension by enhancing sympathetic outflow via the AT1R. However, the role of AT2R in this process is not clear. The data from our lab revealed an inhibitory influence of AT2R on sympathetic tone. Mir‐29 is predicted to regulate AT2R expression. We hypothesized that the decreased AT2R expression may contribute to hypertension induced by central infusion of Ang II by a mechanism dependent on mir‐29. Male rats received icv infusion of Ang II (50 ng/min) for 7 days. Blood pressure (BP) and heart rate (HR) were measured by telemetry. On day 7, the brain was removed to evaluate protein and mir‐29. As expected, the rats receiving Ang II exhibited an increased BP (38.1 ± 5.2 mmHg) and HR (86.3 ± 11.5 bpm) and an up‐regulated AT1R. In addition, (1) icv Ang II significantly downregulated AT2R protein in PVN and RVLM by 39.2 ± 3.7% and 64.1 ± 4.4%; (2) Gαi2 and nNOS, two downstream signal molecules activated by the AT2R, were significantly down regulated; (3) The expression of mir‐29a and mir‐29b, two potential regulators of AT2R protein, were decreased by 37.5 ± 4.1% and 32.8 ± 2.8%. (4) All of the above alterations were abolished by Losartan. These results suggest that, in the brain, the down regulated AT2R and its downstream signaling pathways contribute to Ang II induced hypertension. The decreased AT2R may be attributable to the inhibition of mir‐29 family by Ang II. Supported by HL093028.
Afferent renal nerve stimulation excites RVLM projecting PVN neurons in rats
Authors: Xu Bo , Zheng Hong , Patel Kaushik P
Published: June 2021

Recently renal denervation in hypertensive patients has proven to be very successful, however the underlying mechanism is not entirely clear. To determine if pre‐autonomic neurons in the paraventricular nucleus of the hypothalamus (PVN) are responsive to afferent renal nerve stimulation (ARN‐Sti), extracellular recording was used to investigate the contribution of the rostral ventrolateral medulla (RVLM) projecting PVN (PVN‐RVLM) neurons to ARN‐Sti. We also examined if these same neurons were responsive to baroreflex (BR) (i.v. injection of phenylephrine), or cardiac sympathetic afferent reflex (CSAR) (epicardial bradykinin). In 109 spontaneously active neurons recorded in the PVN of anesthetized rats, 25 units were antidromically activated from the RVLM. Among units classified as RVLM projecting PVN neurons, 84% (21/25) were activated by ARN‐Sti and the baseline discharge rate was significantly higher in them compared to those that were not activated by ARN‐Sti (16%, 4/25). In addition, almost all of neurons sensitive to ARN‐Sti were sensitive to BR (95%) and CSAR (100%). Among the non‐evoked neurons (not responding to stimulated from the RVLM) in the PVN, 23% respond to ARN‐Sti while 77% did not; most of the ARN sensitive neurons (83%) were responsive to baroreflex stimulation. Non of the non‐evoked neurons respond to CSAR. These results demonstrate that sensory information originating in kidney is integrated at the level pre‐autonomic neurons within the PVN, providing a novel mechanistic insight for use of renal denervation in modulation of sympathetic outflow in disease states such as hypertension and heart failure. Supported by NIH 62222.
Estrogen modulation of the voltage‐gated potassium channel in rat presympathetic PVN neurons
Authors: Lee Seul Ki , Ryu Pan Dong , Lee So Yeong
Published: June 2021

The hypothalamic paraventricular neurons projecting to the rostral ventrolateral medulla (PVN‐RVLM) play a regulatory role in sympathetic outflow. Their neuronal activities are influenced by Atype potassium currents (IA). Based on the reports on estrogen receptor β subunit expression in PVN‐RVLM neurons, we investigated the effects of estrogen on IA and its functional components, Kv4.2 and Kv4.3. Whole cell patch clamp recording and single cell real‐time RT‐PCR were performed with PVN‐RVLM neurons in the oil‐ and the 17β‐estradiol (E2)‐treated group of ovariectomized female rats. The results revealed a significant reduction in IA, in Kv4.2 mRNA expression, and in a delay in the onset of the first action potential by E2. In addition, these modulations were different depending on subdivisions of PVN‐RVLM neurons. In conclusion, Kv4.2 is involved in estrogen modulation of the PVN‐RVLM neuron's activity with a subdivision‐dependent sensitivity to estrogen. This study received support from the National Research Foundation of Korea (2010–0017216).
Oscillatory pulse pressure changes endothelial sensitivity to shear stress and myogenic tone in isolated mouse cerebral arteries
Authors: Bolduc Virginie , Colinas Olaia , Lesage Frédéric , Cole William C , Thorin Eric
Published: June 2021

Circulating blood travels in an oscillating waveform where the peak‐to‐peak amplitude is called the pulse pressure (PP) and the frequency is dictated by the heart rate. We investigated in vitro the impact of PP (amplitude: 30 mm Hg; rate: 550 beat per min) compared to static pressure (SP) on cerebral myogenic tone (MT) and endothelium‐dependent flow‐mediated dilation (FMD). Cerebral arteries (~160 μm diameter, n=5–9 per group) isolated and pressurized (80 mm Hg) from C57Bl6 (3‐mo) mice were used with or without a functional endothelium (eNOS inhibition by L‐NNA and endothelium removal). MT was magnified by PP compared to SP (20±3 vs. 6±2% reduction in diameter, p<0.05). L‐NNA (10 μM) and endothelium denudation increased MT under SP (25±3 and 14±3%, respectively, p<0.05) but not PP (25±3 and 13±4%, respectively). Under SP, arteries fully dilated at low shear stress (SS) to gradually re‐constrict at high SS (33±11% and 2±9% dilation at 4 and 20 dyn/cm2, respectively; p<0.05). In contrast, under PP, cerebral arteries gradually dilated at low to then lose tone and fully dilated at high SS (10±4 and 75±19% at 4 and 20 dyn/cm2, respectively; p<0.05). In conclusion, compared to static conditions, PP 1) increases MT that is insensitive to the endothelium and 2) suppresses flow‐mediated constriction at high SS. Supported by CIHR MOP89733.
Cerebral ischemia and reperfusion increases the heterogeneity of local oxygen supply/consumption balance
Authors: Weiss Harvey R , Grayson Jeremy , Shah Harsh , Barsoum Sylviana , Liu Xia , Chi Oak Z
Published: June 2021

After cerebral vessel blockage, local blood flow and O2 consumption are lower and oxygen extraction increases. With reperfusion, flow is partially restored. We examined the effects of ischemia‐reperfusion on the heterogeneity of local venous oxygen saturation in isoflurane anesthetized rats. The middle cerebral artery was blocked for 1 hr using the internal carotid approach in one group and was reperfused for 2 hr in another group. Regional cerebral blood flow was determined using a C14‐iodoantipyrine autoradiographic technique. Regional small vessel arterial and venous oxygen saturations were determined microspectrophotometrically. After 1 hr of ischemia, local cerebral blood flow (96±10 vs. 54±10 ml/min/100g) and O2 consumption (4.3±0.5 vs. 2.4±0.3 ml O2/min/100g) decreased compared to the contralateral cortex. Oxygen extraction increased (4.8±0.3 vs. 5.6±0.3 ml O2/100ml) and the variation in small vein (20–70 μm) O2 saturation as determined by its coefficient of variation (CV=100*SD/mean) increased (10.4 vs. 5.2). With 2 hr of reperfusion, the blood flow decrement decreased and O2 consumption returned toward the value in the contralateral cortex. Oxygen extraction remained elevated and the CV of small vein O2 saturation increased further (15.6). This indicated many small regions of low oxygenation within the reperfused cortical region.
INCREASED PRODUCTION OF THE ARACHIDONIC ACID METABOLITE 20‐HETE CONTRIBUTES TO HYPERTENSION‐INDUCED CEREBROVASCULAR ALTERATIONS
Authors: Toth Peter , Csiszar Anna , Sosnowska Danuta , Tucsek Zsuzsanna , Cseplo Peter , Springo Zsolt , Tarantini Stefano , Sonntag William E , Ungvari Zoltan , Koller Akos
Published: June 2021

Hypertension increases oxidative stress and inflammation in cerebral arteries and impairs vasomotor function. We tested the hypothesis that increased production of the arachidonic acid metabolite 20‐hydroxy‐5,8,11,14‐eicosatetraenoic acid (20‐HETE) contributes to hypertension‐induced cerebrovascular alterations.

Male spontaneously hypertensive rats (SHR) were treated with HET0016, an inhibitor of 20‐HETE synthesis. In middle cerebral arteries (MCAs) of SHRs vasomotor responses were obtained and cellular production of reactive oxygen species (ROS), inflammatory cytokine expression and NF‐κB activation were assessed.

Treated SHRs remained hypertensive, although their blood pressure was decreased compared to control SHRs. In MCAs of SHRs flow‐induced constriction was augmented and acetylcholine‐and ATP‐induced dilations were impaired. These alterations were reversed by HET0016. In MCAs of SHRs HET0016 decreased ROS level and inhibited inflammation and NF‐κB activation. Also, 20‐HETE significantly increased vascular production of ROS and promoted NF‐κB activation in cultured cerebromicrovascular endothelial cells.

Inhibition of 20‐HETE synthesis in hypertension elicits reduction in blood pressure, anti‐oxidative, anti‐inflammatory effects and improve vasomotor function of cerebral arteries potentiating cerebrovascular protection.
Combined Effects of Streptozotocin and Doxorubicin on Cardiac Function in Rats
Authors: Greufe Stephanie Erin , Gibson Noah M , Hydock David S , Schneider Carole M , Hayward Reid
Published: June 2021

Diabetes is a metabolic disorder that affects over 25 million Americans. Large epidemiological studies have shown that individuals with diabetes are at increased risk of many types of cancer; including those often treated with the cardiotoxic anticancer drug doxorubicin (DOX).

PURPOSE

To examine the combined effects of streptozotocin (STZ) ‐induced diabetes and DOX on cardiac function.

METHODS

Twenty four rats were given an injection of STZ in order to induce diabetes. Three days following STZ injection, diabetes was confirmed in 21 rats. Blood glucose (BG) was measured each week for 10 weeks at which time 7 rats received a DOX (10 mg/kg) injection and the remaining received a saline (SAL) injection. Cardiac function was assessed both in vivo and ex vivo 5 days post injections. Controls of identical age were used in the statistical analysis.

RESULTS

Fractional shortening, left ventricular developed pressure and end systolic pressure all decreased significantly (p<.05) in STZ animals. STZ + DOX animals showed additional declines (p<.05) compared to STZ alone and DOX alone.

CONCLUSION

Both STZ and DOX independently induced cardiac dysfunction and this dysfunction was exacerbated when these two were combined. This suggests that diabetes may be a complicating factor when considering DOX‐induced cardiac dysfunction in cancer patients undergoing treatment with this chemotherapeutic agent.
Meprin deficient mice have a more severe form of diabetic nephropathy
Authors: Conley Sabena , Han Jian , Hurley Steven , Ongeri Elimelda Moige
Published: June 2021

Diabetic nephropathy (DN) is the leading cause of end stage renal disease, and is associated with high morbidity and mortality rates. Key morphological changes observed in DN include accumulation of extracellular matrix (ECM) proteins and tubulointerstitial fibrosis. Meprins are metalloproteinases that are abundantly expressed in the brush border membranes of proximal kidney tubules. Meprins are also expressed in leukocytes (monocytes and macrophages) and podocytes. Meprins cleave ECM proteins such as collagen IV, collagen VI, fibronectin, laminin, and nidogen‐1 in vitro. Meprins could thus reverse or prevent the buildup of ECM which causes fibrosis in DN. Meprin β single nucleotide polymorphisms are also associated with DN in the Pima Indians, a Native American tribe with an extremely high rate of type 2 diabetes and DN. The objective of this study was to characterize DN in meprin deficient mice. Low dose streptozotocin was used to induce type 1 diabetes in wild‐type and meprin knockout mice on a C57BL/6 background. Additional comparisons were made in mice on a C3H/He background, which are deficient in meprin α. Mortality rates were significantly higher in diabetic meprin deficient mice. Eight week blood urea nitrogen (BUN) and the urine creatinine/albumin ratio were significantly higher in the meprin deficient mice, indicating a more severe form of DN. The results suggest that meprins protect against DN in mice.
Chronic high fructose intake impairs renal calcitriol metabolism
Authors: Douard Veronique , Patel Chirag , Sabbagh Yves , Lee Jacklyn , Ferraris Ronaldo P.
Published: June 2021

We recently showed that excessive fructose (F) consumption inhibits adaptive increases in intestinal Ca transport in lactating and weanling rats with enhanced Ca needs, by preventing the increase in blood levels of the biologically active vitamin D, calcitriol. Here we tested the hypothesis that chronic F intake decreases calcitriol levels independent of Ca status. In the control study, adult mice fed for 5 wk a 40% glucose (G)‐low Ca diet displayed expected adaptive increases in intestinal and renal Ca transporter expression and activity as well as in serum calcitriol levels, compared with mice fed G‐ or F‐normal Ca diets. However, dietary F clearly prevented increases in calcitriol and Ca transporter expression to Ca deficiency. When the 40% F‐normal Ca diet was fed to adult rats for 3 mo, calcitriol levels and expression of CYP27B1 that synthesizes calcitriol decreased markedly compared to those in G‐fed mice. Ca status and Ca transporter expression were normal and independent of dietary sugar. Expression of CYP27B1 also decreased and of CYP24A1 increased in adult mice fed for 3 mo a 60% F‐normal Ca diet. Thus, chronic F intakes stimulate renal catabolism and impair synthesis of calcitriol, regardless of Ca status. This finding is highly significant because F constitutes a substantial portion of the average diet of Americans now highly vulnerable to F‐induced deficiencies in calcitriol
C3H Mice are Resistant to Hypertensive Renovascular Remodeling Due to Decreased Mitochondrial Oxidative Stress
Authors: Pushpakumar Sathnur , Kundu Sourav , Givvimani Srikanth , Tyagi Suresh C , Sen Utpal
Published: June 2021

Increased reactive oxygen species (ROS) has been implicated as a causative factor in angiotensin‐II (Ang‐II) induced hypertension. Sirtuin‐3 (SIRT3) is a mitochondrial protein involved in the regulation of micothondrial ROS. In earlier studies, we found that C3H mice develop mild hypertension and show decreased renal remodeling to pressor dose of Ang‐II. In this study, we hypothesized that C3H mice show decreased susceptibility to hypertension due to SIRT3 modulation of mitochondrial ROS production and by decreasing inflammation. Wildtype (WT) and C3H/HeJ mice were implanted with osmotic pumps loaded without or with Angiotensin‐II (Ang‐II) for delivery at 250 ng/kg/min. Mitochondrial oxidative stress was measured as H2O2 production. Ang‐II administration increased H2O2 in WT mice more than in C3H. Higher levels of SIRT3 and decreased levels of TNF alpha and IL‐6 was found in C3H+Ang‐II mice compared to WT+Ang‐II. C3H+AngII mice also showed decreased levels of MMP‐9 and activity compared to WT+Ang‐II. Vascular staining for collagen revealed decreased type‐1 and −III collagen in C3H mice indicating decreased fibrosis. We conclude that in C3H mice, SIRT3 modulation maintains mitochondrial homeostasis, reduces inflammation and protects the kidney from adverse effects of hypertension.
Exercise enhances inotropic responsiveness of cardiac myocytes
Authors: Galvin Amy , Kohler Jacob , Foster‐Bey Lianna , Kim JinSun , Bailey Beth A.
Published: June 2021

Exercise‐induced cardiac structural and functional remodeling has recently been shown to vary between the sexes. In this study we sought to examine the sex‐based differences in the cardiac remodeling after swim training.

Methods

Male and female Swiss Webster mice swam for 70 minutes two times daily for 4 weeks. Myocytes were isolated from control male (CM) and control female (CF) and swim‐trained male (STM) and swim‐trained female (STF) mice, field stimulated, and Fluo‐3 transients and sarcomere shortening were measured.

Results

Swim training resulted in significant cardiac hypertrophy in both males and females (16% and 12%, respectively). STF myocytes exhibited lower basal contractile properties (2Hz, 1.5mM Ca) compared to CF (% resting sarcomere length 4.5±.29% STF vs 7.1±.31% CF; fluo‐3 fluorescence 1.66±.04 STF vs 2.18±.09CF) while there were no differences between CM and STM contractile properties. Contractile reserve responses of myocytes were studied by application of isoproterenol (ISO, 10−7M). ISO caused a significantly greater increase in the contractile properties of STF (333±37%) and STM (325±39%) myocytes than in CF (209±13%) or CM (230±29%) myocytes.

Conclusion

Swim training induces physiological cardiac hypertrophy and causes increased contractile responses to catecholamines in both males and females which should enhance cardiac pump function during exercise.
Influence of weight status on muscle quality in older adults
Authors: Straight Chad R , Brady Anne O , Evans Ellen M
Published: June 2021

The aim of this study was to investigate the impact of weight status on muscle quality in older adults. Community‐dwelling older adults (n=139) were assessed for body composition via dual‐energy X‐ray absorptiometry scanning and muscle power using the Nottingham Power Rig. MQ (watts/kg) was defined as leg muscle power (watts) normalized for mineral‐free lean mass of the lower body (kg). The sample was divided into four groups: normal weight males (n=12, 74.1±5.3 y, 23.6±1.3 kg/m2), normal weight females (n=36, 74.5±6.4 y, 22.7±1.5 kg/m2), overweight/obese males (n=29, 77.9±7.3 y, 28.8±3.3 kg/m2), and overweight/obese females (n=62, 73.7±5.3 y, 29.4±3.5 kg/m2). Analysis of covariance adjusted for age and number of medical conditions was conducted to examine the effect of weight status on MQ. Normal weight males (12.8 watts/kg) had significantly greater MQ relative to normal weight females (9.6 watts/kg) and overweight/obese females (8.4 watts/kg) (both p<.01). In addition, MQ was significantly greater in overweight/obese males compared to overweight/obese females (10.5 vs. 8.4 watts/kg, respectively, p<.01). These findings suggest that both weight status and sex influence MQ in older adults. Additional research is necessary to elucidate how weight‐related differences in MQ contribute to varying levels of functional performance in older men and women.
Hydration status and sodium balance of endurance runners consuming post‐exercise supplements with varying macronutrient contents
Authors: Johnson Evan Carl , Favero Jeffery Del , Monteleone Andrew , Pryor John Luke , Armstrong Lawrence E , Rodriguez Nancy R
Published: June 2021

Post‐exercise protein supplementation may aid in recovery, however beef snacks contain up to 1000 mg of sodium (Na+); this may alter hydration status and total‐body Na+ balance.

Objective

Determine effects of post‐exercise beef jerky consumption on hydration status and Na+ balance.

Methods

Eight trained males (age = 22±3y, V̇O2max = 66 ± 4 mL·kg−1·min−1) completed three identical weeks of run training (6±0.3 run·wk−1, 45±6min·run−1, 74±5% HRR). After exercise, subjects consumed a carbohydrate beverage (CHO), beef jerky (B), or carbohydrate beverage + beef jerky (CHO+B) in a counterbalanced design. Hydration status was assessed via urinary biomarkers and body mass. Na+ balance = Na+ intake (diet records) − Na+ loss (24h urine collection) − sweat Na+ loss (whole‐body rinse).

Results

No differences main effects of treatment were observed for 24h urine volume (CHO, 1.7±0.5; B, 1.8±0.6; CHO+B, 1.4±0.4 L/d), urine specific gravity (USG; 1.016±0.005, 1.018±0.006, 1.017±0.006) or body mass (68.4±8.2, 68.3±7.7, 68.2±8.0 kg). No main effect of treatment existed for Na+ intake‐loss (−713±1486; −973±1123; −980±1220 mg·d−1).

Conclusions

A high protein/Na+ post‐exercise supplement imparted no measurable change of hydration status or Na+ balance. Urinary Na+ excretion accounted for the daily Na+ intake due to B. Endogenous Na+ storage may explain negative Na+ balances of CHO, B and CHO+B.
Octopamine has a dual effect on heart rate of Crassostrea virginica
Authors: Hoque Ruma , Louis Addy Jean , Carroll Margaret A. , Catapane Edward J.
Published: June 2021

Octopamine (OA) is well studied in arthropods and gastropods being a neurotransmitter and hormone. Its functions have rarely been reported in bivalves. We identified OA in cerebral and visceral ganglia (VG), gill, palps and hemolymph of the oyster Crassostrea virginica. We found OA is cardio‐acceleratory when applied to animals and speculated it is a neuro or endocrine agent. We tested OA on heart rate of C. virginica by applying OA to VG of animals (in situ) or isolated hearts. Average heart rate of animal preparations was 5.5 beats/min. Superfusion of OA (10−6–10−3 M) to VG increased it to 9.3 in a dose dependent manner. Average rates of isolated heart preparations was 13.4. Bath applications of OA (10−6–10−3 M) decreased it to 0. Actions of OA were prevented by the OA antagonist phentolamine. The study shows OA affects heart rate in 2 different fashions depending on site of application. It decreases heart rate when applied to isolated heart, but increases it when applied to VG. A possible explanation for the divergent results is OA is activating different receptors in the different locations. Superfusing OA to VG causes it to stimulate different neurons at simultaneously. The end result is due to the nerves being stimulated, which is not what happens in an animal's normal physiological actions. Under normal conditions OA would be discretely released to stimulate discrete neuronal circuits at a particular time.
Metabolic fate of lactate after anoxia at 20°C in the Western painted turtle
Authors: Hill Craig A. , Puchowicz Michelle A. , Brunengraber Henri , Berger Richard , Yarasheski Kevin E. , Warren Daniel E.
Published: June 2021

Western painted turtles (Chrysemys picta bellii) can survive anoxia for 120 days at 3°C and tolerate plasma lactate concentrations approaching 200 mM. The metabolic fate of lactate accumulated over 6 hours of anoxia and 39 hours of recovery at 20°C was investigated with stable isotope tracer methodology. A bolus infusion of [U‐13C]‐lactate tracer was given via an intra‐arterial catheter 2 hours into anoxia. 13C enrichment of metabolites and CO2 from expired air, blood and bone were measured using gas chromatography and isotope ratio mass spectrometry. The tracer completely equilibrated with the lactate pool by the end of anoxia. M3‐glucose enrichment slowly increased throughout the recovery period, and liver glycogen accounted for 26–33% of the label at the end of recovery. CO2 was the fate for ~44% of the lactate carbon, and CO2 exchange with the bone accounted for ~18% of the label, indicating that the shell is an important sink for metabolically produced CO2. The plasma concentration and enrichment of beta‐hydroxybutyrate also increased. Our results demonstrate that painted turtles are more like mammals in that oxidation accounts for the largest fraction of the labeled carbon. Turtles primarily utilize some other substrate to replenish muscle glycogen stores, most likely glucose derived from liver. This research was funded by Saint Louis University and the National Institutes of Health.
Significance of Type IIb Muscle Fibers in Diving Mammals
Authors: Moore Colby Daniels , Moore Michael , Fahlman Andreas , Trumble Stephen
Published: June 2021

Elephant seals (Mirounga angustirostris) are elite divers thought to exceed oxygen stores and thus initiate conversion to anaerobic pathways during a dive. One physiological adjustment accompanying deep, long dives is peripheral vasoconstriction consistent with tissue hypoxia in muscles associated with locomotion. Few data exists pertaining to fiber type ratios of diving mammal locomotory muscles, however, reports indicate Type IIb fibers are absent in pinniped locomotory musculature. In this study, sub‐adult male elephant seals were biopsied in situ. Succinate dehydrogenase (SDH) based fiber typing revealed Type I and Type IIa fibers in the Longissimus dorsi (LD) muscle, with an absence of Type IIb fibers. Cetaceans sampled in this study were found to have all fiber types in LD musculature. Lack of Type IIb fibers has been attributed to aerobic‐based dives, whereas Type IIb fibers in cetaceans indicate potential for anaerobic activity. Relatively deep/long breath‐hold diving is thought to instigate reduced metabolic rate and behavioral adjustments (low energy locomotion). Specifically, Type IIb fibers are a major component of ischemia reperfusion (IR) injury in humans, as the associated myosin is exclusively susceptible to injury. We present an intriguing hypothesis, which correlates metabolic suppression with a lack of Type IIb fibers for avoidance of IR injury in vasoconstricted musculature.