bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effects of radiation on schedule‐controlled responding and quinpirole‐induced yawning (839.6)
Authors: Davis Catherine , Hienz Robert 
Published: June 2021

A previous report noted that rats receiving head‐only radiation exposure displayed neurobehavioral deficits on the rodent psychomotor vigilance task (rPVT), including changes in accuracy and premature responding. These changes were only apparent in a subset of irradiated rats, such that radiation‐sensitive and radiation‐insensitive groups emerged. Group specific changes in levels of the dopamine D2 receptor and dopamine transporter (DAT) protein were also evident, in addition to differential sensitivity to the rate‐decreasing effects of quinpirole on schedule‐controlled responding.To better understand DA system differences in radiation sensitivity, a cohort of rats was trained to perform the rPVT and then trained on a fixed‐ratio 30 fixed‐interval 2‐min schedule of reinforcement; dopaminergic compounds were administered prior to the FR‐FI session to determine the rate‐altering effects of these drugs in individual subjects. A second cohort of rats was trained to perform the rPVT and was then observed for quinpirole‐induced yawning. Pre‐irradiation rPVT, FR/FI, and yawning data was compared to post‐irradiation data in the same animals, in order to determine how radiation might impact the dopamine system as measured by these behaviors induced by administration of dopaminergic compounds.Grant Funding Source: This work was funded by NSBRI through NASA NCC 9‐58‐PF02602 and 9‐58‐NBPF02802.
Comparison of antioxidative and antifibrotic effects of Allium sativum in rat model of chronic pancreatitis (840.4)
Authors: Sharma Surendra , Rana Satya , Bhasin Deepak , Rana Surinder , Nada Ritambhra , Malhotra Samir 
Published: June 2021

OBJECTIVE: Allium sativum (Garlic) is considered effective antioxidant. This study aimed to compare the antioxidative and antifibrotic effects of Allium sativum in L‐Arginine induced chronic pancreatitis in rats METHODS: Oral administration of freshly homogenized Allium sativum (0.25g/kg per day) started two day before induction of chronic pancreatitis. L‐arginine hydrochloride (250mg/100g bw/day) was administered intraperitoneally (IP) in 2 repeated doses of 1 hour interval on day 1, repeated with 250mg/100 g bw/day, on day 4, 7, 10, 13, 16 &amp; 19 was used to induce CP. Histological examination by masson’s trichrome staining and measurement of reduced glutathione (GSH) and lipid peroxidation (LPO) of pancreatic tissue were performed to evaluate pancreatic damage and fibrosis. IHC staining of α‐SMA was done to evaluate the activated pancreatic stellate cells and mRNA levels (densitometry analysis) of transforming growth factor‐β1 (TGF‐β1), fibronectin 1 and collagen‐α1(I) were performed by reverse transcription polymerase chain reaction.RESULTS: Allium sativum, supplementation increased the level of GSH and decreased the level of LPO which indicates reduction in oxidative stress. It also reduces inflammation and fibrosis. It also down‐regulates the mRNA expression of TGF‐β1, fibronectin 1 and collagen‐α1(I) in L‐arginine induced CP.CONCLUSION: Oral administration of Allium sativum improves pancreatic inflammation and fibrosis in L‐arginine induced CP rats. Therefore, Allium sativum can be a novel option for alleviating inflammation and fibrotic process in CP.
M4 muscarinic acetylcholine receptor modulation of associative learning and behavioral flexibility in a novel touchscreen cognitive assessment (845.8)
Authors: Dencker Ditte , Gould Robert , Bubser Michael , Bridges Thomas , Wood Michael , Duggan Mark , Wood Michael , Fink‐Jensen Anders , Wess Jürgen , Conn P , Jones Carrie 
Published: June 2021

Recent findings indicate that selective activation of the M4 muscarinic acetylcholine receptor (M4 mAChR) may represent a novel treatment approach for the psychotic symptoms and cognitive disturbances observed in several neuropsychiatric disorders. In the present studies, cognitive performance of M4 mAChR knock‐out mice (M4‐KO mice) was examined across a series of computer touchscreen‐based pairwise discrimination tasks assessing susceptibility to interference from previously learned competing sets of information. While M4‐KO mice acquired the initial discrimination task in a similar number of sessions as wildtype mice, the M4‐KO mice showed impaired acquisition on all subsequent visual discriminations. In addition, the novel M4 positive allosteric modulator VU0467154 reversed disruptions in pairwise discrimination induced by MK‐801, an antagonist of the N‐methyl‐D‐aspartate subtype of glutamate receptors. These data reveal that selective M4 mAChR activation is critical for modulation of normal associative learning and behavioral flexibility in visual discrimination tasks. Moreover, our studies suggest that selective M4 PAMs may have therapeutic potential for the treatment of cognitive deficits observed in patients with schizophrenia.Grant Funding Source: This work was funded by grants# 2R01 MH73676‐06, 1R01 MH086601‐04, AstraZeneca.
Nicorandil increases Na/Ca exchange current in heart (850.2)
Authors: Watanabe Yasuhide , Kimura Junko 
Published: June 2021

Nicorandil is a K(ATP) channel opener, nitric oxide donor and antioxidant, and is used as a drug for the treatment of angina pectoris. This durg induces cardioprotection and vasodilatation after ischemia reperfusion. It was previously reported that nicorandil may exert antiarrhythmic actions by abolishing both spontaneous and triggered activity [early after‐depolarization (EADs), delayed after‐depolarization (DADs)] (Lathrop et al., Br J Pharmacol, 1990). The triggered activity induced by DADs is one of the mechanisms of ventricular arrhythmias associated with intracellular Ca2+ overload.In this study we examined the effect of nicorandil on Na+/Ca2+ exchange current (INCX) in isolated guinea pig ventricular myocytes using the whole‐cell patch clamp technique.Nicorandil enhanced INCX in a concentration‐dependent manner. The EC50 values of nicorandil were 15.0 μM and 8.7 μM for the outward and inward components of INCX, respectively. Eight‐Br‐cGMP, a membrane permeable analog of cGMP also enhanced the INCX in a concentration‐dependent manner. ODQ, a guanylate cyclase inhibitor (10 µM) almost completely abolished the effects of both nicorandil and Eight ‐Br‐cGMP on INCX. DADs induced by electrical stimulation with ouabain disappeared in the presence of 100 µM nicorandil. We conclude that nicorandil enhances the function of Na+/Ca2+ exchanger (NCX) via guanylate cyclase, and this may partially contribute to the cardioprotection of nicorandil by acceleratiing Ca2+ exit via NCX.
In vitro responses of insulin resistant and nonresistant digital vessels of healthy and laminitic horses (851.11)
Authors: Venugopal Changaram , Holmes Earnestine , Beadle Ralph , Kearney Michael , Eades Susan 
Published: June 2021

Hyperinsulinemia leads to insulin resistance of blood vessels and interferes with circulation of lamina of the equine foot. The objective of the study was to compare the digital vessel responses of clinically healthy and laminitic horses with and without experimental induction of insulin resistance. Vessel segments (artery and vein) collected after euthanasia, were cut into 3 mm wide rings and were prepared in tissue baths containing Tyrode’s solution for response studies. Two rings from each horse were used as non‐resistant and two were made insulin‐resistant. All rings were contracted with phenylephrine (10‐6.5M). When the contraction reached a plateau, insulin (10‐5M) was added and the response monitored. The response to insulin was calculated as a percentage of the phenylephrine response. The results showed that the responses of the non‐resistant rings differed significantly between the groups. However, when all rings were made insulin‐resistant, the significance between the groups disappeared. In the laminitic group, responses of resistant and non‐resistant rings did not differ, whereas in the healthy group, the vessel responses differed significantly. In all experiments, arterial and venous rings followed the same pattern but the magnitudes were greater in arterial rings. The findings suggest that the vessel responses to insulin are altered in laminitis which could be due to insulin resistance.Grant Funding Source: Supported by Equine Health Studies Program of LSU‐SVM
Effect of exhaustive exercise on contrast sensitivity and neurovascular coupling (853.11)
Authors: Yamaguchi Yuji , Ikemura Tsukasa , Miyaji Akane , Hayashi Naoyuki 
Published: June 2021

Neurovascular coupling (NVC) is assessed as an increase response to a given visual stimulation in the blood flow velocity in the posterior cerebral artery (PCAv). To investigate whether the change in NVC with exhaustive exercise, if any, associates with contrast sensitivity, we measured the PCAv during rest and exercise in 13 healthy males while they performed a leg‐cycle exercise at 75% of maximal heat rate until exhaustion. NVC was estimated as the relative change in PCAv from the mean value obtained during 20 s of eye closing to the peak value obtained during 40 s of visual stimulation involving looking at a reversed checkerboard. The conductance index (CI) of the PCA was calculated by dividing PCAv by the mean arterial pressure. Contrast sensitivity was measured before and after the exercise. At exhaustion, PCAv response to visual stimulation significantly decreased from 16±1 (at rest; mean±SE) to 11±1%, while it significantly increased to 20±2% with a significant increase in CI response to visual stimulation at recovery period. Contrast sensitivity significantly improved after exhaustive exercise, compared to the resting baseline. These results suggest that NVC decreases by exhaustive exercise and overshoot after the exercise, and that contrast sensitivity increases by an exhaustive exercise, implying that NVC associates with a change in contrast sensitivity.Grant Funding Source: Supported by Kozuki Foundation
A Bayesian statistical model to characterize blood pressure increase in salt‐sensitive hypertension in the rat (856.6)
Authors: Dayton Alex , Ahn Kwang‐Woo , Laud Purushottam , Kurth Terry , Mattson David , Cowley Allen 
Published: June 2021

In salt‐sensitive rat models of hypertension, characteristic patterns of increase in blood pressure (BP) are observed when salt intake in the diet is increased. In this study, we used a Bayesian statistical model to quantitate these patterns and draw conclusions about the differences between sets (strains or treatments) of rats.Time‐course BP data for individual rats was fit to a mixture of two cumulative normal distributions by Gibbs sampling, a process for approximating multivariate probability distributions. The mixture was defined by seven parameters, which describe aspects of the timing and extent of BP increase. Probability distributions for each parameter describe the frequency of a certain value over all Gibbs samples. Sets of rats were assessed on a single parameter level by taking parameter values for each rat as samples from a group parameter representing all the rats, which allowed us to assess differences between experimental sets.The model precisely fit all observed BP data, and is sufficient to detect significant differences in parameters between experimental sets.This Bayesian model provides a useful tool for distinguishing sets of rats based on the character of their BP increase. These insights provided by this analysis into the timing and extent of BP increase may provide a framework for the analysis of further data generated with these rats, and the mechanisms underlying these BP increases.
Novel PKC pathway provides insight into the regulation of tone in vascular smooth muscle (865.13)
Authors: Sivilich Sarah , Trappanese Danielle , Moreland Robert 
Published: June 2021

Vascular smooth muscle (VSM) tone is the phenomenon of intrinsic force developed in the absence of a stimulus. Although the primary site of VSM regulation is on the thick filament, our research has focused on the potential role of thin filament proteins in signaling events contributing to vascular tone. We hypothesized that protein kinase C (PKC)‐dependent phosphorylation of mitogen‐activated protein kinase phosphatase‐1 (MKP‐1), an upstream mitogen activated protein kinase (MAPK) regulatory protein, would increase MKP‐1 activity and decrease MAPK activity. We used the MKP‐1 inhibitor, sanguinarine, to investigate the effect of PKC on p42/p44 MAPK in swine arterial smooth muscle. Smooth muscle strips were mounted for isometric force measurement and incubated with 3 µM Bis (PKC inhibitor), 10 µM histamine, or both, in the presence or absence of 30 µM sanguinarine. Histamine significantly increased p42/p44 MAPK activity; the p42 isoform was further enhanced by inhibition of PKC. Sanguinarine reversed the histamine and Bis‐dependent increases in p42 MAPK. MKP‐1 phosphorylation was increased by histamine and Bis, and surprisingly was further amplified in the presence of sanguinarine. These findings suggest a novel PKC pathway, which indirectly modulates MAPK activity through phosphorylation of MKP‐1. Our current studies are examining potential regulatory proteins as downstream sites of action by MAPK.Grant Funding Source: NIH DK 85734
Activation of AMP‐activated protein kinase attenuates arterial stiffening and hypertension in klotho‐deficient mice (867.1)
Authors: Lin Yi , Velury Divya , Sun Zhongjie 
Published: June 2021

Background: Arterial stiffening is a progressive aging‐related disorder. Klotho is an anti‐aging protein but its role in regulation of arterial stiffening is unknown.Methods and Results: Heterozygous Klotho deficiency (KL+/‐) mice and WT littermate mice were fed on high fat diet (HFD) or normal diet (ND). Pulse wave velocity (PWV), an index of arterial stiffening, was increased in KL+/‐ mice fed on HFD for 5 weeks. Systolic blood pressure and blood glucose levels increased earlier with greater magnitudes in KL+/‐ mice fed on HFD. Notably, protein expression of collagen I, Runx2, and TGFβ1 were increased but protein expression of phosphorylated AMPKα (pAMPKα), phosphorylated eNOS (peNOS), and Mn‐SOD were decreased in aortas of KL+/‐ mice fed on HFD for 5 weeks. Interestingly, daily injection of AICAR, an activator of AMPK, abolished the increases in PWV, blood pressure, and blood glucose in KL+/‐ mice fed on HFD. AICAR not only abolished the downregulation of pAMPKα, peNOS, and Mn‐SOD levels but also attenuated the increased levels of collagen I, Runx2, TGFβ1 and superoxide, elastic lamellae breaks, and calcification in aortas in KL+/‐ mice fed on HFD.Conclusions: Klohto deficiency promotes HFD‐induced arterial stiffening and hypertension. The promoting effects of klotho deficiency on arterial stiffening may be due to downregulation of AMPKα activity.Grant Funding Source: Supported by HL105302 and HL 102074.
Direct visualisation of smooth muscle cell phenotypic plasticity and migration by long‐term imaging (867.12)
Authors: Sandison Mairi , Chalmers Susan , Dempster John , McCarron John 
Published: June 2021

An abnormal increase in the number and distribution of SMCs is a key feature of the vascular remodelling that underlies cardiovascular disease. The predominant explanation for these changes is that medial SMCs undergo phenotypic modulation followed by migration to the intima and subsequent proliferation. However, there has been no direct demonstration of this dedifferentiation process by tracking the fate of contractile SMCs and the very existence of phenotypic plasticity has been questioned. We therefore employed high‐resolution, multi‐wavelength fluorescence and simultaneous phase contrast, time‐lapse microscopy to monitor the fate of unambiguously identified, freshly isolated, mature SMCs. Phenotypic modulation of the initially contractile SMCs was clearly observed in response to serum‐containing culture media. Extensive cellular remodelling occurred, though a consistent sequence of events was observed in which spindle‐shaped SMCs initially rounded up following exposure to media. The cells remained round for varying lengths of time (1‐3 days) before spreading outwards and, at this stage, repetitive contractions occurred (measured via bursts of high speed imaging). Finally, the cells flattened further and migration began. Surprisingly, after the onset of migration, the extrusion of subcellular structures (e.g. mitochondria) from one cell and their subsequent uptake by another cell was observed. The phenotypically modulated SMCs also formed direct connections with other cells (tunnelling nanotubes). These results highlight the complexity of the remodelling process, the highly dynamic cellular interactions involved and the significant cell‐cell variation in response and will enable a detailed picture of SMC remodelling to be built.Grant Funding Source: Supported by the Wellcome Trust (092292/Z/10/Z) and the British Heart Foundation (PG/11/70/29086)
The role of adventitial resident Sca‐1+ progenitor cells in angiotensin II‐induced aortic stiffening (867.3)
Authors: Wu Jing , Hoglund Virginia , Dong Xiu , Chen Wei , Majesky Mark , Harrison David 
Published: June 2021

The aortic adventitia contains progenitor cells that express the surface marker stem cell antigen‐1 (Sca‐1). Sca‐1+ cells have been reported to transform into smooth muscle cells and promote neo‐intimal formation. We have previously found a striking deposition of adventitial collagen in mice with experimental hypertension. This fibrotic layer of collagen contributes to aortic stiffening and likely promotes systolic hypertension. Because this collagen deposition occurs at the site of Sca1+ cells, we hypothesized that Sca‐1+ progenitor cells serve as a source of adventitial collagen. Using confocal microscopy we found that chronic angiotensin II infusion causes a dramatic increase of Sca‐1+ cells in the aortic adventitial and peri‐adventitial region. Flow cytometry confirmed that aortic Sca‐1+CD31‐ cells are tripled in angiotensin II‐induced hypertension (5.6±1.6 ×103 vs. 15.9±2.4 ×103 cells/per aorta). These Sca‐1+ cells represent approximately one fourth of total adventitial cells. Angiotensin II infusion induces proliferation of these cells as evidenced by positive ki‐67 staining. We then isolated aortic Sca‐1+ cells in sham and angiotensin II‐treated mice using magnetic‐activated cell sorting and found collagen 1a1 (1.0±0.2 vs. 5.4±0.9), 3a1 (1.0±0.4 vs. 4.7±0.8), 5a1 (1.0±0.4 vs. 3.5±0.8) and fibronectin‐1 (1.0±0.3 vs. 2.7±0.4) genes were significantly upregulated in these cells. These fibrotic genes were also upregulated by 2‐3 fold in CD31+ cells suggesting endothelial to mesenchymal transition. Immunofluorescence staining demonstrated colocalization of Sca‐1 and vimentin, a marker of fibroblasts, indicating that these progenitor cells differentiate into fibroblasts during the onset of hypertension. In conclusion, resident aortic Sca‐1+ progenitor cells likely differentiate into fibroblasts in hypertension and contribute to adventitial collagen deposition and promote angiotensin II‐induced aortic stiffening.Grant Funding Source: Supported by NIH R01 grant HL105294
Prostaglandin D2‐DP1 receptor signaling inhibits sympathetic nerve activity and development of angiotensin II‐salt hypertension (874.11)
Authors: Asirvatham‐Jeyaraj Ninitha , Fink Gregory 
Published: June 2021

Cerebrospinal fluid levels of lipocalin‐prostaglandin D synthase protein (L‐PGDS) and the lipid mediator prostaglandin D2 (PGD2) are increased in early stages of AngII‐salt hypertension (AngII‐HS‐HTN) in rats. Because L‐PGDS inhibition reduces neurogenic AngII‐HS‐HTN development and its product PGD2 acts on central DP‐1 receptors (DP‐1Rs), we hypothesized that PGD2 acting through DP1‐Rs mediated AngII‐HS‐HTN development.Method: Two sets of studies were performed. First, anesthetized rats received an injection of PGD2 (50µg/5µl) intracerebroventricularly (icv). PGD2 caused a maximum 22±6 mmHg increase in BP. In other anesthetized rats the DP1‐R antagonist BW A868C (78ng/5µl) was injected icv followed by PGD2 injection; BW A868C blocked PGD2 mediated increases in BP. In the second study we tested the effect of chronic DP1‐R blockade on AngII‐salt HTN. Continuous radio‐telemetric recording of BP was used. After control BP recording, rats on 2% NaCl diet were pretreated with vehicle (n=4) or BW A868C (425nM/h, sc, n=5). All rats then received AngII (150ng/kg/min, sc) for 14 days. Ganglionic blockade with hexamethonium (30mg/kg, ip) was performed on day 10 of AngII administration to assess neurogenic pressor activity. Finally, PGD2 (50µg/5µl) was injected acutely into lateral ventricles to test if central DP‐1Rs were inhibited.Result: Compared to the control period, AngII infusion increased mean arterial pressure (MAP, mmHg) from 95±2 to143±10 (31±10 increase) in vehicle, and from 109±7 to140±1 (56±3 increase) in BW A868C treated rats (p<0.05). Neurogenic pressor activity (mmHg) was significantly higher in BW A868 (86±10) than vehicle (46±11) treated rats. Finally, central PGD2 injection failed to elicit a BP response in BW A868C treated rats confirming central DP1‐R inhibition.Conclusion: Acute icv PGD2 induced increases in BP are mediated via DP‐1R. However, chronic PGD2 signaling through central DP1‐R inhibits AngII‐HS‐HTN development and causes sympathoinhibition.Grant Funding Source: “Supported by” RO1 HL 076312 and RCO HL 060363
Dietary quercetin enrichment improves respiratory function in mdx mice (884.17)
Authors: Selsby Joshua , Ballman Christopher , Quindry John 
Published: June 2021

Duchenne muscular dystrophy (DMD) is caused by a dystrophin deficiency and results in progressive muscle injury culminating in death due to respiratory or cardiac failure. We have established that gene transfer of the exercise mimetic, PGC‐1α, will decrease disease severity and improve muscle function in skeletal muscle taken from mdx mice, the mouse model of DMD. While this approach is effective and repeatable, at present it is not readily translatable. Hence, the purpose of this project was to determine the extent to which oral delivery of quercetin, a PGC‐1α activator, would improve respiratory function in mdx mice. To address this purpose baseline respiratory function was measured in vivo in two month old C57 and mdx mice. After measurement, the mdx group was randomly assigned into groups receiving a control diet (mdx) or diet enriched with 0.2% quercetin (mdx‐Q). Respiratory function was measured again at four and six months of age. By six months of age we found that a 16% (p<0.05) increase in respiratory frequency and a 12% (p<0.05) increase in tidal volume caused a near 30% (p<0.05) increase in minute ventilation in mdx‐Q compared to mdx. Further, peak inspiratory flow was increased 20% (p<0.05) and peak expiratory flow was increased 26% (p<0.05) in mdx‐Q compared to mdx. These data suggest strongly that dietary enrichment of the orally available PGC‐1α activator, quercetin, attenuated muscle injury and improved respiratory function in a mouse model of Duchenne muscular dystrophy.Grant Funding Source: Supported by the Duchenne Alliance and its member foundations