Abstract P249: Angiotensin At1a Receptor Signaling In Agrp Neurons In Metabolism Control

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Kirthikaa Balapattabi ◽  
Gary Mouradian ◽  
Matthew Hodges ◽  
Curt D Sigmund ◽  
Justin L Grobe
Keyword(s):  
Neural Plasticity ◽  
Chloride Channels ◽  
Resting Metabolic Rate ◽  
Relative Proportion ◽  
Cardiovascular Responses ◽  
Inhibitory Effect ◽  
Metabolic Effects ◽  
At1a Receptor

The adverse cardiovascular responses to leptin are preserved, but beneficial metabolic effects, such asincreases in resting metabolic rate (RMR) are lost in obesity induced by high fat diet (HFD) feeding. Wepreviously reported angiotensin II (ANG) type 1a ( Agtr1a ; AT1A) receptors in a subset of AgRP neurons arecritically required for the integrative control of RMR. Understanding the mechanisms in this unique subset ofRMR controlling- AgRP neurons is the goal of this study and is critical to decipher the pathogenesis of obesity-associated hypertension. Male C57BL/6J mice were maintained on chow or HFD from 8-18 weeks of age. Cell-attached voltage clamp recording of AgRP neurons in ARC sections of Ai9(tdTomato) AgRP mice showed that ANGapplication results in three distinct cellular responses (n=65 neurons; 8 mice). In chow fed mice, ANG suppressedelectrical activity in 1/3 of AgRP neurons (ie. “Type 1” AgRP neurons) via a losartan-sensitive mechanism,indicating involvement of AT1 receptors (Firing rate; aCSF:1.23 ± 0.10 vs ANG:0.60 ± 0.08 vs ANG+LOS:1.37 ±0.11 Hz, p<0.05). ANG caused excitation in 1/3 of AgRP neurons (“Type 2” AgRP cells) which was mediatedthrough a PD-123,319-sensitive mechanism, implicating AT2 receptors (ANG:1.69 ± 0.12 vs ANG+PD:0.86 ±0.06 Hz, p<0.05). Finally, 1/3 of AgRP neurons did not respond to ANG (“Type 0” cells). Complementary to thesefindings, mice with AT1A deleted from AgRP cells (ie, Agrp -Cre x Agtr1a Flox x Ai9 mice) exhibited a completeloss of Type 1 responses but maintenance of Types 0 and 2 (n=23 cells; 4 mice). Further, pharmacologicaldissection of signaling cascades implicated a pertussis toxin-sensitive mechanism (Gαi cascade; ANG+PTX:1.00± 0.04 Hz, p<0.05) and multiple potassium + chloride channels in the ANG-mediated inhibition of Type 1 cells.Most intriguingly, the relative proportion of AgRP neurons exhibiting Type 1 (ANG -inhibited) vs Type 0 or 2responses was decreased with HFD (Type 1 cells proportion- chow: 35%,23 out of 65; HFD: 18%, 10 out of 56).These results establish a specific ANG-inhibited subtype of AgRP neuron and implicate the AT1A/Gαi signalingcascade in the inhibitory effect of ANG. Switch of Type 1 AgRP cells to Type 0 or 2 in response to HFD suggestsHFD-induced neural plasticity/adaptation.

Anatomic patterning in the expression of vestibulosympathetic reflexes

2000 ◽  
Vol 279 (1) ◽  
pp. R109-R117 ◽  
Author(s):  
I. A. Kerman ◽  
B. J. Yates ◽  
R. M. McAllen
Keyword(s):  
Relative Proportion ◽  
Vestibular Stimulation ◽  
Nerve Fibers ◽  
Spike Shape ◽  
The Face ◽  
Nerve Fascicle ◽  
The Difference ◽  
Vestibulosympathetic Reflexes

To investigate the possibility that expression of vestibulosympathetic reflexes (VSR) is related to a nerve's anatomic location rather than its target organ, we compared VSR recorded from the same type of postganglionic fiber [muscle vasoconstrictor (MVC)] located at three different rostrocaudal levels: hindlimb, forelimb, and face. Experiments were performed on chloralose-anesthetized cats, and vestibular afferents were stimulated electrically. Single MVC unit activity was extracted by spike shape analysis of few-fiber recordings, and unit discrimination was confirmed by autocorrelation. Poststimulus time histogram analysis revealed that about half of the neurons were initially inhibited by vestibular stimulation (type 1 response), whereas the other MVC fibers were initially strongly excited (type 2 response). MVC units with types 1 and 2 responses were present in the same nerve fascicle. Barosensitivity was equivalent in the two groups, but fibers showing type 1 responses fired significantly faster than those giving type 2 responses (0.29 ± 0.04 vs. 0.20 ± 0.02 Hz). Nerve fibers with type 1 responses were most common in the hindlimb (21 of 29 units) and least common in the face (2 of 11 units), the difference in relative proportion being significant ( P < 0.05, χ2 test). These results support the hypothesis that VSR are anatomically patterned.

Antiherpes Virus Effect of the Red Marine Alga Polysiphonia denudata

2000 ◽  
Vol 55 (9-10) ◽  
pp. 830-835 ◽  
Author(s):  
Julia Serkedjieva
Keyword(s):  
Marine Alga ◽  
Water Extract ◽  
Antiviral Effect ◽  
Inhibitory Effect ◽  
Extracellular Virus ◽  
Black Sea Coast ◽  
Red Marine Alga ◽  
Replicative Cycle

Abstract The water extract from the red marine alga Polysiphonia denudata (Dillwyn) Kütz. from the Bulgarian Black Sea coast selectively inhibited the reproduction of herpes virus type 1 and type 2 in cell cultures (EC50 = 8.7 to 47.7 mg/ml) as shown by the reduction of virusinduced cytopathic effect and viral infectivity. The virus-inhibitory effect was dose-related, strain-specific and depended on virus inoculum. The inhibition affected adsorption as well as the intracellular stages of viral replication. The presence of the extract throughout the whole replicative cycle was necessary for the full expression of the antiviral effect. In higher concentrations (MIC90 = 6.5 mg/ml) the extract exhibited strong extracellular virus inactivating activity.

Two types of leptin-responsive gastric vagal afferent terminals: an in vitro single-unit study in rats

1997 ◽  
Vol 273 (2) ◽  
pp. R833-R837 ◽  
Author(s):  
Y. H. Wang ◽  
Y. Tache ◽  
A. B. Sheibel ◽  
V. L. Go ◽  
J. Y. Wei
Keyword(s):  
Inhibitory Effect ◽  
Vagal Afferents ◽  
Neural Signals ◽  
Excitatory Effect ◽  
Leptin Sensitivity ◽  
Before And After ◽  
Afferent Terminals

In vitro gastric vagal afferents' (GVAs) unit activities were recorded from the ventral GVA nerve strands in rats. The responsiveness of 16 GVA terminals to close intra-arterial injection of vehicle (0.1 ml), leptin (350 pmol), and cholecystokinin (CCK)-8 (10 pmol) was analyzed to generate a spike count-versus-time histogram. Data of 5-min spike counts before and after each treatment were normalized by dividing the latter by the former. A quotient (Q) > 1 indicates an excitatory effect, Q < 1 indicates an inhibitory effect, and Q close to 1 indicates no effect. Two types of GVA terminals were identified. Type 1 (n = 8) responded to leptin with Q > 1; CCK-8 pretreatment did not consistently alter leptin sensitivity. In contrast, Type 2 (n = 8) responded to leptin with Q < 1 or close to 1, and CCK-8 pretreatment increased the leptin sensitivity so that the terminals responded to subsequent leptin with Q > 1. These data suggest that Type 1 and Type 2 GVA terminals may provide afferent neural signals, which, in turn, will be involved in body weight and food intake control systems, respectively.

scholarly journals Localized accumulation of angiotensin II and production of angiotensin-(1–7) in rat luteal cells and effects on steroidogenesis

2006 ◽  
Vol 291 (2) ◽  
pp. E221-E233 ◽  
Author(s):  
John R. Pepperell ◽  
Gabor Nemeth ◽  
Yuji Yamada ◽  
Frederick Naftolin ◽  
Maricruz Merino
Keyword(s):  
Angiotensin Ii ◽  
Inhibitory Effect ◽  
Ang Ii ◽  
Luteal Cells ◽  
Permeabilized Cells ◽  
Production Studies ◽  
Progesterone Production ◽  
Angiotensin Peptides

These studies aim to investigate subcellular distribution of angiotensin II (ANG II) in rat luteal cells, identify other bioactive angiotensin peptides, and investigate a role for angiotensin peptides in luteal steroidogenesis. Confocal microscopy showed ANG II distributed within the cytoplasm and nuclei of luteal cells. HPLC analysis showed peaks that eluted with the same retention times as ANG-(1–7), ANG II, and ANG III. Their relative concentrations were ANG II ≥ ANG-(1–7) > ANG III, and accumulation was modulated by quinapril, an inhibitor of angiotensin-converting enzyme (ACE), Z-proprolinal (ZPP), an inhibitor of prolyl endopeptidase (PEP), and parachloromercurylsulfonic acid (PCMS), an inhibitor of sulfhydryl protease. Phenylmethylsulfonyl fluoride (PMSF), a serine protease inhibitor, did not affect peptide accumulation. Quinapril, ZPP, PCMS, and PMSF, as well as losartan and PD-123319, the angiotensin receptor type 1 (AT1) and type 2 (AT2) receptor antagonists, were used in progesterone production studies. ZPP significantly reduced luteinizing hormone (LH)-dependent progesterone production ( P < 0.05). Quinapril plus ZPP had a greater inhibitory effect on LH-stimulated progesterone than either inhibitor alone, but this was not reversed by exogenous ANG II or ANG-(1–7). Both PCMS and PMSF acutely blocked LH-stimulated progesterone, and PCMS blocked LH-sensitive cAMP accumulation. Losartan inhibited progesterone production in permeabilized but not intact luteal cells and was reversed by ANG II. PD-123319 had no significant effect on luteal progesterone production in either intact or permeabilized cells. These data suggest that steroidogenesis may be modulated by angiotensin peptides that act in part through intracellular AT1 receptors.

Cystic fibrosis-related diabetes

2015 ◽  
Author(s):  
Stephen MP O’Riordan ◽  
Antoinette Moran
Keyword(s):  
Cystic Fibrosis ◽  
Chloride Channels ◽  
Dietary Requirements ◽  
Mild Diabetes ◽  
Emerging Treatments ◽  
Infection And Inflammation ◽  
Chronic Respiratory Infection ◽  
Unique Approach

This chapter on CFRD reviews the ever-evolving topic and provides up-to-date information on how to diagnose and manage cystic fibrosis-related diabetes CFRD in the acute and chronic setting. The treatments necessary to treat and prolong life in CF, including their unique dietary requirements, must always be followed as a first priority, with diabetes care adjusted accordingly. Early intervention with insulin has been shown to reverse clinical deterioration, even in those with mild diabetes. Newly emerging treatments for CF which have the potential to restore defective chloride channels may have implications for the development and treatment of CFRD. Whilst CFRD shares features of both type 1 and type 2 diabetes, there are important differences which necessitate a unique approach to diagnosis and management. Factors specific to CF that variably affect glucose metabolism include chronic respiratory infection and inflammation, increased energy expenditure, malnutrition, glucagon deficiency, and gastrointestinal abnormalities.

scholarly journals PPARγAgonist Rosiglitazone Suppresses Renal mPGES-1/PGE2 Pathway in db/db Mice

PPAR Research ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Ying Sun ◽  
Zhanjun Jia ◽  
Gang Liu ◽  
Li Zhou ◽  
Mi Liu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Inhibitory Effect ◽  
Peroxisome Proliferator ◽  
Glomerular Injury ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Expressions ◽  
Pg E2 ◽  
Cox 1

Evidence had shown the detrimental effect of prostaglandin (PG) E2 in diabetic nephropathy (DN) of STZ-induced type-1 diabetes but its role in the development of DN of type-2 diabetes remains uncertain. The present study was undertaken to investigate the regulation of PGE2 synthetic pathway and the interaction between peroxisome proliferator-activated receptor (PPAR)γand PGE2 synthesis in the kidneys of db/db mice. Strikingly, urinary PGE2 was remarkably elevated in db/db mice paralleled with the increased protein expressions of COX-2 and mPGES-1. In contrast, the protein expressions of COX-1, mPGES-2, cPGES, and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) were not altered. Following 1-week rosiglitazone (Rosi) therapy, urinary PGE2, but not other prostanoids, was reduced by 57% in parallel with significant reduction of mPGES-1 protein and EP4 mRNA expressions. By immunohistochemistry, mPGES-1 was significantly induced in the glomeruli of db/db mice, which was almost entirely abolished by Rosi. In line with the reduction of glomerular mPGES-1, the glomerular injury score showed a tendency of improvement after 1 week of Rosi therapy. Collectively, the present study demonstrated an inhibitory effect of PPARγactivation on renal mPGES-1/PGE2/EP4 pathway in type-2 diabetes and suggested that mPGES-1 may potentially serve as a therapeutic target for treating type-2 diabetes-associated DN.

scholarly journals Deiodinase type 1 activity is expressed in the prostate of pubescent rats and is modulated by thyroid hormones, prolactin and sex hormones

2006 ◽  
Vol 190 (2) ◽  
pp. 363-371 ◽  
Author(s):  
Brenda Anguiano ◽  
Alejandra López ◽  
Guadalupe Delgado ◽  
Carlos Romero ◽  
Carmen Aceves
Keyword(s):  
Thyroid Hormones ◽  
Enzymatic Activity ◽  
Mrna Expression ◽  
Sex Hormones ◽  
Inhibitory Effect ◽  
Preferential Expression ◽  
Gold Thioglucose ◽  
17Β Estradiol

The aim of this study was to characterize the type of 5′-deiodinase activity in the prostate of pubescent rats (7–8 weeks), to establish its distribution in the lobes (ventral, dorsolateral, and anterior), and to analyze its modulation by prolactin (PRL), testosterone, dihydrotestosterone (DHT), and 17β-estradiol (E2). Our results showed that the enzymatic activity was highly susceptible to inhibition by 6-n-propyl-2-thiouracil and gold thioglucose, its preferential substrate was reverse tri-iodothyronine (rT3), it exhibited a low dithiothreitol requirement (5 mM), and the apparent Km and Vmax values for substrate (rT3) were approximately 0.25 μM and 9.0 pmol liberated/mg protein per hour, respectively. All these characteristics indicate the preferential expression of type 1 deiodinase (D1), which was corroborated by demonstrating the presence of D1 mRNA in prostate. D1 activity was detected in all lobes and was most abundant in the dorsolateral. Although we detected type 2 deiodinase (D2) mRNA expression, the D2 activity was almost undetectable. D1 activity was enhanced in animals with hyperthyroidism and hyperprolactinemia, in intact animals treated with finasteride (inhibitor of local DHT production), and in castrated animals with E2 replacement. In contrast, activity diminished in castrated animals with testosterone replacement. Our results suggest that thyroid hormones, PRL, and E2 exert a positive modulation on D1 activity, while testosterone and DHT exhibit an inhibitory effect. D1 activity may be associated with prostate maturation and/or function.

scholarly journals Prions from Sporadic Creutzfeldt-Jakob Disease Patients Propagate as Strain Mixtures

mBio ◽  
2020 ◽  
Vol 11 (3) ◽  
Author(s):  
Hervé Cassard ◽  
Alvina Huor ◽  
Juan-Carlos Espinosa ◽  
Jean-Yves Douet ◽  
Severine Lugan ◽  
...  
Keyword(s):  
Relative Proportion ◽  
Significant Proportion ◽  
Proteinase K ◽  
Single Patient ◽  
Prion Strain ◽  
Prion Strains ◽  
Jakob Disease ◽  
The Brain

ABSTRACT Sporadic Creutzfeldt-Jakob disease (sCJD) cases are currently classified according to the methionine/valine polymorphism at codon 129 of the PRNP gene and the proteinase K-digested abnormal prion protein (PrPres) isoform identified by Western blotting (type 1 or type 2). Converging evidence led to the view that MM/MV1, VV/MV2, and VV1 and MM2 sCJD cases are caused by distinct prion strains. However, in a significant proportion of sCJD patients, both type 1 and type 2 PrPres were reported to accumulate in the brain, which raised questions about the diversity of sCJD prion strains and the coexistence of two prion strains in the same patient. In this study, a panel of sCJD brain isolates (n = 29) that displayed either a single or mixed type 1/type 2 PrPres were transmitted into human-PrP-expressing mice (tgHu). These bioassays demonstrated that two distinct prion strains (M1CJD and V2CJD) were associated with the development of sCJD in MM1/MV1 and VV2/MV2 patients. However, in about 35% of the investigated VV and MV cases, transmission results were consistent with the presence of both M1CJD and V2CJD strains, including in patients who displayed a “pure” type 1 or type 2 PrPres. The use of a highly sensitive prion in vitro amplification technique that specifically probes the V2CJD strain revealed the presence of the V2CJD prion in more than 80% of the investigated isolates, including isolates that propagated as a pure M1CJD strain in tgHu. These results demonstrate that at least two sCJD prion strains can be present in a single patient. IMPORTANCE sCJD occurrence is currently assumed to result from spontaneous and stochastic formation of a misfolded PrP nucleus in the brains of affected patients. This original nucleus then recruits and converts nascent PrPC into PrPSc, leading to the propagation of prions in the patient’s brain. Our study demonstrates the coexistence of two prion strains in the brains of a majority of the 23 sCJD patients investigated. The relative proportion of these sCJD strains varied both between patients and between brain areas in a single patient. These findings strongly support the view that the replication of an sCJD prion strain in the brain of a patient can result in the propagation of different prion strain subpopulations. Beyond its conceptual importance for our understanding of prion strain properties and evolution, the sCJD strain mixture phenomenon and its frequency among patients have important implications for the development of therapeutic strategies for prion diseases.

Organ-specific effects of 3,5,3'-triiodothyroacetic acid in rats

1997 ◽  
pp. 537-544 ◽  
Author(s):  
H Liang ◽  
CE Juge-Aubry ◽  
M O'Connell ◽  
AG Burger
Keyword(s):  
Resting Metabolic Rate ◽  
Heart Weight ◽  
Mrna Levels ◽  
Specific Effects ◽  
Organ Specific ◽  
Serum T3 ◽  
Type 3 ◽  
Serum Tsh

In order to compare the effect of 3,5,3'-triiodothyroacetic acid (TRIAC) with those of triiodothyronine (T3) and thyroxine (T4), severely hypothyroid rats (n=56) were infused over 13 days with 1, 2 or 4 nmol/100 g body weight (BW) per day of T3 or 2, 4 or 8 nmol/100 g BW per day of T4 or TRIAC. The 8 nmol/100 g BW per day of T4 or TRIAC induced the same increase in resting metabolic rate, yet 4 nmol/100 g BW per day of T3 was more potent (P < 0.05). For inhibiting serum TSH levels, 2 nmol/100 g BW per day of TRIAC were significantly less active than 2 nmol/100 g BW per day of T4 or 1 nmol/100 g BW per day of T3 (TRIAC, serum TSH 35.5 +/- 5.7; T3 2.58 +/- 0.91; T4 2.12 +/- 0.59 ng/ml). At higher doses serum TSH and beta-TSH mRNA were unmeasurable. Using serum T3 levels as covariate, the action of T3 and T4 was identical on cardiac monodeiodinase type 1 (5'D1) activity and hepatic malic enzyme (Me) mRNA levels and similar for hepatic 5'D1 activity. The effect of TRIAC was compared with T3 by using increasing doses of 1, 2 and 4 nmol/100 g BW per day of T3 and 2, 4 and 8 nmol/100 g BW per day of TRIAC. ANOVA indicated that there was no major difference between the effects of the hormones since with increasing doses the response of hepatic 5'D1 mRNA levels and enzyme activity and Me mRNA remained parallel. However, when studying the effect on cardiac 5'D1 activity there was not only a difference for type of treatment (T3 > TRIAC) but this difference became greater with each increment in dose. Interestingly there was also only a small effect of TRIAC on increase in heart weight compared with T3 and T4. Brain cortex monodeiodinase type 2 (5'D2) was mainly inhibited by T4 infusions. Monodeiodinase type 3 (5'D3) was stimulated by T4, less so by TRIAC and least by T3, expressing probably the local T3 and TRIAC concentrations. In conclusion, despite apparently similar effects of TRIAC and T3 and T4 on hepatic parameters of thyroid hormone action, TRIAC differs considerably in terms of its effects on cardiac 5'D1 activity and possibly on other fundamental effects of thyroid hormones on the heart since heart weight increased significantly less with TRIAC than with T3 or T4.

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