bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sensitization of morphine‐induced motor stimulation: age‐related differences in mice
Authors: Koek Wouter 
Published: June 2021

Given evidence for age‐related differences in effects of drugs of abuse, surprisingly few studies have explored effects of opioids in adolescents (versus adults). This study compared sensitization of morphine‐induced locomotion in adolescent and adult mice.Male C57BL/6J mice were treated with saline or morphine (10–100 mg/kg, i.p.) once per day for 4 days, and morphine (3.2–56 mg/kg)‐induced locomotion was assessed 3 days or 5 weeks later. Three days after repeated saline, morphine increased locomotion more in adolescents than in adults. Repeated morphine (minimum effective dose: 17.8 mg/kg) enhanced morphine‐induced locomotion to a similar extent in each age group (1.6 – 1.9 fold). This enhancement was still evident 5 weeks later, when the adolescents had become adult, but was smaller (1.4‐fold) and occurred at a higher dose (56 mg/kg). In animals treated repeatedly with morphine as adults, enhancing effects were no longer apparent 5 weeks later.Repeated administration of morphine produced similar short‐term enhancement of its motor stimulating effects in all age groups, but evidence for long‐term enhancement was obtained only in adolescents. These findings suggest that compared with adults, adolescents are more sensitive not only to the acute locomotor stimulating effects of morphine, but also to its long‐lasting locomotor sensitizing effects.Supported by DA23261
Antidepressant‐like effect of AMPA and ketamine combination in male Wistar ‐Kyoto rats
Authors: Akinfiresoye Luli , Lovinger D. M. , Tizabi Y. 
Published: June 2021

Studies have shown that therapeutics that act on the glutamatergic system could provide a novel mechanistic approach for the treatment of depression. We previously reported that ketamine, an NMDA antagonist, has a rapid and lasting antidepressant effect both acutely and chronically on depressive‐like behavior in Wistar‐Kyoto (WKY) rats (Soc Neurosci Abst 2008). Other studies had suggested that the antidepressant effect elicited by ketamine could be mediated through stimulation of AMPA receptors, we also sought to confirm this hypothesis in our animal model of depression. We discovered that AMPA by itself also has an antidepressant effects in WKY rats, both acutely and chronically (Biol Psych Abst 2010). In this study we examined the hypothesis that the combination of AMPA and ketamine will result in either a synergistic or additive antidepressant effect when compared to the individual treatments of AMPA or ketamine alone. Adult male WKY rats were administered the combination of AMPA (0.25 mg/kg, i.p.) and ketamine (0.25 mg/kg, i.p.) for 10 days and behavior studies were done approximately 22 hr after the last injection. Controls received saline. A 5 minute forced swim test (FST), a measure of helplessness, was used to determine the drug‐induced antidepressant effects. The combination of AMPA and ketamine resulted in a significant reduction of FST immobility compared to individual treatment of either AMPA or ketamine alone. In view of the fact that an increase in AMPA/NMDA receptor function and number may be mediating the antidepressant effects of ketamine, these results suggest that a combination of AMPA and ketamine could provide an effective therapeutic treatment for depression.Supported by NIH/NIGMS (2 SO6 GM08016‐39)
Effect of arsenic and arsenic metabolites on LTCC and BKCa expression and activities in vascular smooth muscle
Authors: McPherson Kevin , Pace Clare , Khalili Roxana , Angermann Jeff Erik 
Published: June 2021

BackgroundArsenic (As) contamination of ground‐ and well‐water is common worldwide. Chronic As exposure can produce toxic effects including atherosclerosis and hypertension, yet mechanisms by which both inorganic As and As metabolites induce these effects are not well elucidated. Both arsenite (iAs3+) and its metabolite monomethylarsonous acid (MMAs3+) are believed to affect the activity of critical Vascular Smooth Muscle (VSM) components including the ‘L‐type’ calcium channel (LTCC), a key regulator of VSM tone, as well as the large‐conductance calcium‐activated potassium channel (BKCa), a known modulator of cell depolarization implicated in the development of hypertension and restenosis disease.Objectives and MethodsThis study examines effects of iAs3+ and MMAs3+ on expression and related activities of LTCC and BKCa in acutely isolated and primary / tissue cultured rat thoracic aorta, as well as the A7r5 rat thoracic aorta VSM cell line, using whole‐cell patch clamp, vascular contractility, RT‐QPCR, and light microscopy.ResultsInitial results indicate alterations in VSM cell morphology, viability, LTCC activity, and responsiveness to PE‐induced vasoconstriction on acute and subchronic exposure to both iAs3+ and MMA3+.ConclusionsBoth iAs3+ and MMA3+ affect activities of key effectors governing the maintenance of VSM tone. This work was supported by the Nevada INBRE and McNair Programs.
Characterization of PPARγ ligand MCC‐555 in AOM‐induced colorectal tumorigenesis
Authors: Imchen Temjenmongla , Min Kyung-Won , Baek Seung Joon 
Published: June 2021

PPARγ agonists affect cell proliferation, differentiation, and apoptosis in a PPARγ dependent and/or‐independent manner, and thereby represent a potentially important family of therapeutic compounds for cancer treatment. Dual ligands for PPARα and PPARγ, such as MCC‐555, have been developed to improve treatment of metabolic syndrome, including hyperglycemia and hyperlipidemia. Interestingly, these dual ligands also possess anti‐proliferative activities against a variety of cancer cell lines with greater potency than conventional PPARγ specific ligands. In this study, colon cancer chemopreventive properties of MCC‐555, were evaluated using azoxymethane (AOM)‐induced colonic aberrant crypt foci (ACF) in female A/J mice. 36 female mice were randomly assigned to 5 groups: (1) negative control treated with carboxymethylcellulose (vehicle); (2) positive control treated with carboxymethylcellulose plus AOM; (3) treated with 30 mg/kg MCC‐555 plus AOM; (4) treated with 60 mg/kg MCC‐555 plus AOM; (5) treated with 60 mg/kg MCC‐555. At 6 weeks of age, all animals were gavaged with carboxymethylcellulose or MCC‐555 for 5 weeks starting 1 week before initiation with AOM injection. AOM was injected i.p. once a week for 4 weeks at 10 mg/kg for groups 2, 3 and 4. Animals will be dissected, and ACF will be examined. The results will be discussed at the meeting.This work was supported by NIH grant‐R01CA108975 and University of Tennessee Center of Excellence in Livestock Diseases and Human Health grant. Temjenmongla Imchen is a recipient of National Overseas Scholarship Award [No. 11016/07/2010‐Education] from Ministry of Tribal Affairs, New Delhi, India.
Decreased Renal and Urinary Neprilysin Protein Expression in db/db Mice
Authors: Chodavarapu Harshita , Bradshaw Melissa , Salem Esam , Elased Khalid 
Published: June 2021

The renin angiotensin system (RAS) plays a pivotal role in the pathogenesis of diabetic nephropathy. Neutral endopeptidase or neprilysin (NEP) belongs to the M13 family of zinc‐containing metallopeptidases which converts Ang I to Ang (1–7). Ang (1–7) is a potential target in renal pathology because of its opposing effects on Ang II induced actions. The possible involvement of NEP in diabetic renoprotection has not been investigated; therefore, the aim of this study is to examine the role of neprilysin in the pathogenesis of diabetic nephropathy in db/db mice. db/db mouse model for type 2 diabetes was used to study the effect of diabetes on renal and urinary NEP. These mice exhibit hyperglycemia, hypertension, hyperinsulinemia, obesity and microalbuminuria. Urine was collected over 24 hours from db/db and lean control mice to measure the urinary albumin, creatinine and total protein. Our results showed that db/db mice were hyperglycemic and demonstrated an early onset of microalbuminuria. Western blot analysis revealed decreased renal and urinary NEP protein expression in db/db mice compared to lean control mice (p<0.05). Immunohistochemical staining of kidney sections revealed a decrease in NEP protein expression in the db/db mice. In conclusion, downregulation of NEP could play an important role in the development of diabetic nephropathy in db/db mice.Supported by the American Heart Association.
Ventricular epicardial repolarization pattern in diabetic rabbits
Authors: Azarov Jan E. , Ovechkin Alexey O. , Vaykshnorayte Marina A , Sedova Ksenia A. , Shmakov Dmitry N. 
Published: June 2021

The purpose of the study was to find out the spatial pattern of ventricular repolarization in diabetes mellitus (DM) in heart in situ and to estimate the contribution of sympathetic tone to its development.DM was induced in rabbits with alloxan (100 mg/kg). At 4–5 week follow‐up, the ventricular electrical potentials were mapped with the 64‐electrode epicardial sock array in zoletil‐anesthetized (10 mg/kg) 13 diabetic and 8 healthy animals. Activation‐recovery intervals (ARIs) serving as repolarization duration indices were measured in each lead prior to and after the injection of esmolol (0.5 mg/kg).The left ventricular (LV) apical ARIs were shorter than the basal ARIs in controls (P<0.046), whereas the converse was found in DM (P<0.022). Additionally, an interventricular ARI gradient was found in DM group with the right ventricular (RV) ARIs being longer than the LV ARIs (P<0.022). Esmolol abrogated all the repolarization gradients within the ventricles in healthy and DM rabbits by the preferential prolongation of the initially shorter repolarization durations.Thus, DM caused the remodeling of ventricular repolarization which at least in part could be ascribed to the sympathetic dysfunction.
Characterization of innate collateral connections in the canine heart
Authors: Spaan Jos , van Horssen Pepijn , van den Wijngaard Jeroen , Siebes Maria 
Published: June 2021

BackgroundInnate coronary collateral connections may be important for recruitment as functional collateral vessels. The aim was to define the distribution of these connections and characterize their diameter and orientation.MethodsIn ex‐vivo canine hearts (n=6) the left main and right coronary artery were cannulated and filled with fluorescent resin (Batson #17). The hearts were prepared for our imaging cryomicrotome, sliced at 20 μm and block face images acquired. The stacks of about 4000 images were mathematically analyzed for vessel segments and pathways. Connections between branching subtrees were detected.ResultsIn average 400 connections per heart were found. Diameter distributions were skewed one sided to higher diameters with a mean peak value of 102.27±11.78 μm. In general orientation of these connections are parallel to the epicardium. Additionally, endocardial orientation was preferential parallel towards the longitudinal axis in contrast to midmyocard. The diameter distribution of the segments feeding a closed collateral pathway had a peak diameter of 220 μm. These segments were randomly distributed.ConclusionIn the dog, pre‐existing collateral connections are randomly distributed in the heart and therefore each coronary artery perfusion territory, large and small, has precursors for collateral vessels outgrowth.Supported by FP7‐ICT 2007224495 (euHeart)..
Differential Stiffness between Resistance Microvessels and Conduit Arteries in the Coronary Circulation of Ossabaw Swine with Metabolic Syndrome
Authors: Trask Aaron J. , Katz Paige S. , Kelly Amy P. , Cismowski Mary J. , Galantowicz Maarten L. , Neeb Zachary P. , Alloosh Mouhamad , Sturek Michael , Lucchesi Pamela A. 
Published: June 2021

The aim of the current study was to determine whether coronary resistance microvessels (CRMs) undergo differential remodeling compared to coronary conduit arteries in metabolic syndrome (MetS). Ossabaw pigs were fed either normal (n=7; Lean) or atherogenic diet (n=7; MetS) for 6 months after which CRM pressure myography and intravascular ultrasound of coronary conduit arteries were performed. MetS CRMs exhibited inward hypertrophic remodeling as shown by reduced luminal diameter and increased wall thickness. Both incremental modulus of elasticity (IME, Lean: 3.6×106 ± 0.7×106 vs. MetS: 1.1×106 ± 0.2×106, p < 0.001) and beta stiffness index (BSI, Lean: 10.3 ± 0.4 vs. MetS: 7.3 ± 1.8, p < 0.001) were decreased in MetS CRMs, while CRM distensibility was augmented (Lean: 0.1 ± 0.004 vs. MetS: 0.18 ± 0.03, p < 0.05). In contrast, BSI was increased (Lean: 4.7 ± 0.8 vs. MetS: 6.7 ± 0.3, p < 0.05) and distensibility was reduced (Lean: 0.36 ± 0.05 vs. MetS: 0.17 ± 0.01, p < 0.01) in MetS coronary conduit arteries. Molecular analysis revealed reduced col1a1/elastin and col3a1/elastin mRNA ratios in MetS CRMs, while these ratios remained unchanged in the coronary conduit arteries. These data suggest that differential remodeling between CRMs and conduit arteries may reflect differential extracellular matrix expression.Support: NIH T32HL098039 to AJT; NIH HL056046, NCH to PAL; NIH HL062552, UL1 RR025761, Purina TestDiet to MS.
Targeted disruption of T‐type calcium channels attenuates NO‐dependent recovery after depolarization
Authors: Hansen Pernille B.L. , Shin Hee-Sup , Skott Ole , Jensen Boye 
Published: June 2021

Voltage‐gated calcium channels are involved in the excitation‐contraction mechanism of resistance vessels and play an essential role in regulation of blood pressure. T‐type channels (Cav3.2) are essential for the acetylcholine‐induced relaxation of coronary arteries. We investigated involvement of T‐type channels in agonist‐independent dilatation of perfused mesenteric arteries from two T‐type channel knock‐out (KO) mice strains (Cav3.1 and Cav3.2). Depolarization lead to contraction followed by a secondary dilatation to 51±11% of control diameter (recovery) in wild type (Wt) mice. The recovery was significantly diminished in both Cav3.1 KO and in Cav3.2 KO. Inhibition of eNOS by L‐NAME led to a significantly attenuated recovery in Wt mice. The NO‐donor SNP caused dilatation in preconstricted arteries from both Cav3.1 and Cav3.2 KO mice that was not different from Wt animals. Mean arterial blood pressure and heart rate were measured in conscious mice through chronic indwelling catheters before and after infusion of L‐NAME. NOS inhibition elicited a significant increase in MAP that was sustained after four days in Wt mice (12±2%) whereas no increase was observed in Cav3.2 KO (−3±5%). In conclusion, lack of T‐type channels attenuates NO‐dependent recovery after depolarization in mesenteric resistance vessels and attenuates sustained hypertension after L‐NAME infusion in mouse. The findings are consistent with the notion that endothelial calcium‐influx through T‐type calcium channels stimulates eNOS and NO production in vitro. Our findings in vivo suggest that this mechanism is important for maintaining the systemic tone of NO on the total peripheral resistance.Research Support: Lundbeck Foundation, The Danish Medical Research Council, The Danish Heart Foundation
TRPC1 and TRPV4 are expressed in sensory endings found in regions of venoatrial endocardium where atrial volume receptors are located
Authors: Shenton Fiona , Banks Robert , Pyner Susan 
Published: June 2021

Atrial volume receptors (AVRs) detect mechanical deformation as blood returns to the heart. Members of both the ENaC/Degenerin /ASIC and the Transient Receptor Potential (TRP) channel protein families have been implicated in mechanosensation. We have carried out immunohistological investigations to discover potential mechanosensitive ion channels in sensory endings of venoatrial endocardium. Synaptic‐like vesicles, commonly described in mechanosensory endings, are thought to play a key role in regulating afferent output. Double labelling was carried out with a range of anti‐channel antibodies (ENaCβ, ENaCγ, TRPC1, TRPC4/5, TRPC6, TRPV4) together with either anti‐synaptophysin as a vesicle marker or anti‐neurofilament (NF) to identify nerves. TRPC1‐like immunoreactivity (IR) was observed in ganglion cells and nerves of the epicardium, in myocytes; and also in sensory endings of the endocardium, where it was coincident with both synaptopphysin and NF‐IR. Strong TRPV4‐like IR was likewise seen in nerves and ganglion cells. It was coincident with synaptophysin‐IR in both myocardium and epicardium, however it did not appear to stain myocytes themselves. IR was not detected with any of the other anti‐channel antibodies. TRPC1 and TRPV4 channels merit further investigation as potential contributors to mechanosensation in AVRs.Research supported by EPSRC
Lung endothelial Ca2+ and permeability response to PAF is mediated by TRPC6
Authors: Samapati Rudi , Yang Yang , Yin Jun , Stoerger Christof , Arenz Christoph , Dietrich Alexander , Adam Dieter , Wu Songwei , Freichel Marc , Flockerzi Veit , Uhlig Stefan , Kuebler Wolfgang 
Published: June 2021

Platelet activating factor (PAF) increases lung vascular permeability via ceramide formation by acid sphingomyelinase (ASM). Here, we tested the role of endothelial Ca2+ signaling as key regulator of vascular barrier function in this pathway.In isolated rat and mouse lungs, we quantified endothelial [Ca2+]i by real time imaging, edema formation by lung weight gain, and isolated caveolae to probe for Ca2+ entry channels.PAF‐induced increases in lung weight gain and endothelial [Ca2+]i were abrogated by inhibitors of ASM or in ASM‐deficient mice, and replicated by exogenous ASM or C2‐ceramide. PAF increased caveolar abundance of TRPC6, which was blocked by ASM inhibition. [Ca2+]i response to PAF was lost in TRPC6 deficient mice, but not in TRPC1,4,5 triple knock‐outs. Activation of TRPC6 replicated the [Ca2+]i and edema response to PAF.In PAF‐induced lung edema, stimulation of ASM causes recruitment of TRPC6 channels to caveolae allowing for endothelial Ca2+ influx and subsequent hyperpermeability.
Attenuation of conducted vasodilatation in the skeletal muscle during hyperhomocysteinemia
Authors: Givvimani Srikanth , Narayanan Nithya , Tyagi Neethu , Tyagi Suresh 
Published: June 2021

Conduction of vasodilatation (CVD) from distal resistance arterioles to the proximal arterioles and feeding arteries during metabolic demand is mediated by intercellular gap junctions in the vascular endothelium. The role of Hyperhomocysteinemia (HHcy) in musculoskeletal system during CVD is unclear. We hypothesize that during HHcy there is impaired CVD due to decreased expression of endothelial associated connexins and thus decreases tissue perfusion to the contracting skeletal muscles.MethodsCVD studies are performed in gluteus maximus muscle preparation of wild type (C57BL6/J) and CBS‐/+ (HHcy) mice using intravital microscopy. Expression of connexins and myostatin protein is studied by western blot and Immunohistochemistry methods.ResultsThere is decreased CVD and tissue perfusion in response to Acetylcholine in the CBS‐/+ mice compared to wild type controls assessed by intravital microscopy and Laser Doppler. There is decreased expression of connexins and increased myostatin expression in CBS‐/+ mice compared to wild type controls.ConclusionOur findings suggest that CVD in skeletal muscle is decreased during hyperhomocysteinemia due to decreased expression of gap junction connexins.Source of Research support: NIH
MMP‐9 Generated Collagen I C‐propeptides Alter Cardiac Fibroblast Function
Authors: de Castro Bras Lisandra E , Dai Qiuxia , Zamilpa Rogelio , Fields Gregg B , Weintraub Susan T , Lindsey Merry L 
Published: June 2021

Heart failure is the result of adverse remodeling of the collagenous scar that replaces the damaged myocardium after myocardial infarction (MI). Post‐MI, specific matrix metalloproteinases (MMPs) increase and mediate left ventricle (LV) remodeling. Of the MMPs family members, MMP‐9 levels have been correlated with cardiovascular mortality in humans. Animal models show that MMP‐9 levels increase early post‐MI, and MMP‐9 deletion in mice attenuates remodeling. We found that C‐terminal propeptide (C‐propeptide) levels of á2(I) collagen were reduced in MMP‐9 null mice. Also, we have recently found a novel MMP‐9 recognition site that generates a C‐propeptide of 30 kDa.We used increasing doses of collagen fragments from the C‐terminus domain to stimulate cardiac fibroblasts and determine the mechanisms whereby C‐ propeptides regulate collagen function. We identified one fragment that strongly enhanced collagen I synthesis, suggesting a positive feedback loop between collagen processing and collagen synthesis. These results indicate that in addition to mediating ECM degradation, MMP‐9 may also regulate collagen I synthesis post‐MI.
LECTINIC BINDING OF CANDIDA GLABRATA TO OLIGOSACCHARIDES ON THE CORONARY LUMINAL MEMBRANE ALTERS FLOW‐INDUCED CARDIAC RESPONSES
Authors: Torres-Tirado David , Ramirez-Zavaleta Candy , De Las Peñas Alejandro , Castaño Irene , Rubio Rafael 
Published: June 2021

Candida Glabrata (CG) is a yeast that may invade humans blood stream causing dead. CG surface is lectinic and binds with high affinity to oligosaccharides (O) present in cell membranes, as example, coronary endothelial luminal membrane (CELM).Conversely, coronary flow (CF) stimulates auricular‐ventricular transmission (A‐Vt). CF acts on CELM lectins (L) and O, causing a reversible L‐O complexing necessary for CF stimulation of A‐Vt. We hypothesized that CG upon binding to CELM's O prevents CF‐induced L‐O complexing; as a result inhibiting CF‐stimulation of A‐Vt.In Langendorff perfused isolated guinea pig hearts A‐Vt was determined at different CF. As CF (ml/min) increase A‐Vt (msec) decrease. (control curve). Thereafter, to study the effects of CG bound to the CELM, CG (CGM35 sir3Δ, 3.7×103 cells/ml), was intracoronary given for 5 min and wash at length for 5 min and an experimental CF‐ A‐Vt curve determined. The experimental curve was on top of the control curve i. e. CG upon binding to CELM increases the A‐Vt value at any CF. To test the effect was due to CG bound to O, CG was displaced by perfusing sugars components of O; mannose or Galactose. Perfusion of any of these sugars after CG they reverted its inhibitory effects on CF‐induced A‐Vt stimulation. Furthermore, simultaneous perfusion of CG and any of these sugars prevented the CG‐inhibitory effects, likely competing with CELM's O for CG binding. Thus, CG upon binding to CELM's O competes with L preventing CF‐induced L‐O complexing; as a result inhibits CF‐stimulation of A‐Vt.
Allergen‐induced airway constriction in guinea pig lung slices is attenuated by arginase inhibition via increased nitric oxide production
Authors: Sopi Ramadan B , Simoons Mirjam , Sanderson Michael J , Meurs Herman , Maarsingh Harm 
Published: June 2021

In a guinea pig model of allergic asthma, arginase inhibition protects against allergen‐induced airway obstruction and greatly (>30‐fold) reduces airway sensitivity towards the inhaled allergen. Since arginase regulates nitric oxide (NO) synthesis via competition with NO synthase (NOS) for the common substrate L‐arginine, we hypothesized that the anti‐allergic effect of arginase inhibition involves increased NO synthesis. Ovalbumin (OVA; 0.0001–100 μg/ml)‐induced airway constriction was measured in lung slices obtained from actively‐sensitized guinea pigs using video‐assisted microscopy, in the absence or presence of inhibitors of arginase (ABH, 1μM or nor‐NOHA, 5 μM) and/or NOS (L‐NAME, 100 μM). OVA induced a dose‐dependent airway constriction with a mean maximal effect (Emax) of 98% and a mean EC50 of 0.039 μg/ml. ABH significantly reduced the Emax of OVA to 50%, whereas the sensitivity towards OVA was reduced by >100‐fold, to 5 μg/ml. nor‐NOHA mimicked the effects of ABH, whereas L‐NAME slightly increased contractile responses towards OVA (Emax: 100%; EC50: 0.007 μg/ml). L‐NAME partially reversed the protective effect of ABH against OVA (Emax: 74%; EC50: 0.125 μg/ml). In conclusion, arginase inhibition reduces allergen‐induced contractile responses of intrapulmonary airways by increasing NO synthesis.Supported by Erasmus Mundus partnership Join EU‐SEE and NIH grant HL‐103405.