Histamine inhibits atrial myocytic ANP release via H2 receptor-cAMP-protein kinase signaling

2003 ◽  
Vol 285 (2) ◽  
pp. R380-R393 ◽  
Author(s):  
Dan Li ◽  
Jin Fu Wen ◽  
Jing Yu Jin ◽  
Hua Jin ◽  
Hai Sun Ann ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Selective Inhibitor ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Camp Analog ◽  
Induced Changes ◽  
Protein Kinase Signaling ◽  
Dose Dependent ◽  
Rabbit Atria

Changes in cyclic nucleotide production and atrial dynamics have been known to modulate atrial natriuretic peptide (ANP) release. Although cardiac atrium expresses histamine receptors and contains histamine, the role of histamine in the regulation of ANP release has to be defined. The purpose of the present study was to define the effect of histamine on the regulation of ANP release in perfused beating rabbit atria. Histamine decreased ANP release concomitantly with increases in cAMP efflux and atrial dynamics in a concentration-dependent manner. Histamine-induced decrease in ANP release was a function of an increase in cAMP production. Blockade of histamine H2 receptor with cimetidine but not of H1 receptor with triprolidine abolished the responses of histamine. Cell-permeable cAMP analog, 8-Br-cAMP, mimicked the effects of histamine, and the responses were dose-dependent and blocked by a protein kinase A (PKA)-selective inhibitor, KT5720. Nifedipine failed to modulate histamine-induced decrease in ANP release. Protein kinase nonselective inhibitor staurosporine blocked histamine-induced changes in a concentration-dependent manner. KT5720 and RP-adenosine 3′,5′-cyclic monophosphorothioate, another PKA-selective inhibitor, attenuated histamine-induced changes. These results suggest that histamine decreases atrial ANP release by H2 receptor-cAMP signaling via PKA-dependent and -independent pathways.

The P-element-induced silencing effect of KP transposons is dose dependent in Drosophila melanogaster

Genome ◽  
2011 ◽  
Vol 54 (9) ◽  
pp. 752-762 ◽  
Author(s):  
Alireza Sameny ◽  
John Locke
Keyword(s):  
Drosophila Melanogaster ◽  
Critical Role ◽  
Mutagenic Effect ◽  
P Element ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
P Elements ◽  
Single Well ◽  
Dose Dependent

Transposable elements are found in the genomes of all eukaryotes and play a critical role in altering gene expression and genome organization. In Drosophila melanogaster, transposable P elements are responsible for the phenomenon of hybrid dysgenesis. KP elements, a deletion-derivative of the complete P element, can suppress this mutagenic effect. KP elements can also silence the expression of certain other P-element-mediated transgenes in a process called P-element-dependent silencing (PDS), which is thought to involve the recruitment of heterochromatin proteins. To explore the mechanism of this silencing, we have mobilized KP elements to create a series of strains that contain single, well-defined KP insertions that show PDS. To understand the quantitative role of KP elements in PDS, these single inserts were combined in a series of crosses to obtain genotypes with zero, one, or two KP elements, from which we could examine the effect of KP gene dose. The extent of PDS in these genotypes was shown to be dose dependent in a logarithmic rather than linear fashion. A logarithmic dose dependency is consistent with the KP products interacting with heterochromatic proteins in a concentration-dependent manner such that two molecules are needed to induce gene silencing.

PKCϵ has an alcohol-binding site in its second cysteine-rich regulatory domain

2009 ◽  
Vol 421 (3) ◽  
pp. 405-413 ◽  
Author(s):  
Joydip Das ◽  
Satyabrata Pany ◽  
Ghazi M. Rahman ◽  
Simon J. Slater
Keyword(s):  
Protein Kinase ◽  
Binding Site ◽  
Maximum Effect ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Kinase C ◽  
C1 Domain ◽  
Pkc Protein Kinase C ◽  
And Function

Alcohols regulate the expression and function of PKC (protein kinase C), and it has been proposed that an alcohol-binding site is present in PKCα in its C1 domain, which consists of two cysteine-rich subdomains, C1A and C1B. A PKCϵ-knockout mouse showed a significant decrease in alcohol consumption compared with the wild-type. The aim of the present study was to investigate whether an alcohol-binding site could be present in PKCϵ. Here we show that ethanol inhibited PKCϵ activity in a concentration-dependent manner with an EC50 (equilibrium ligand concentration at half-maximum effect) of 43 mM. Ethanol, butanol and octanol increased the binding affinity of a fluorescent phorbol ester SAPD (sapintoxin-D) to PKCϵC1B in a concentration-dependent manner with EC50 values of 78 mM, 8 mM and 340 μM respectively, suggesting the presence of an allosteric alcohol-binding site in this subdomain. To identify this site, PKCϵC1B was photolabelled with 3-azibutanol and 3-azioctanol and analysed by MS. Whereas azibutanol preferentially labelled His236, Tyr238 was the preferred site for azioctanol. Inspection of the model structure of PKCϵC1B reveals that these residues are 3.46 Å (1 Å=0.1 nm) apart from each other and form a groove where His236 is surface-exposed and Tyr238 is buried inside. When these residues were replaced by alanine, it significantly decreased alcohol binding in terms of both photolabelling and alcohol-induced SAPD binding in the mutant H236A/Y238A. Whereas Tyr238 was labelled in mutant H236A, His236 was labelled in mutant Y238A. The present results provide direct evidence for the presence of an allosteric alcohol-binding site on protein kinase Cϵ and underscore the role of His236 and Tyr238 residues in alcohol binding.

The role of protein kinase C in LHRH-induced LH and FSH release and LHRH self-priming in rat anterior pituitary glands in vitro

1988 ◽  
Vol 116 (2) ◽  
pp. 231-239 ◽  
Author(s):  
M. S. Johnson ◽  
R. Mitchell ◽  
G. Fink
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Phorbol Esters ◽  
Polymyxin B ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Kinase C ◽  
Pituitary Glands

ABSTRACT We have investigated the role of protein kinase C (PKC) in LHRH-induced LH and FSH secretion and LHRH priming. Hemipituitary glands from pro-oestrous rats were incubated with agents known to affect PKC and with or without LHRH, during which time the secretion of gonadotrophins was measured. Phorbol esters and phospholipase C, activators of PKC, released LH and FSH in a concentration-dependent manner and potentiated the LHRH-induced secretion of gonadotrophins in parallel with their ability to release these hormones alone. Inhibitors of PKC had either no effect on LH release (1-(5-isoquinolinesulphonyl)-2-methylpiperazine hydrochloride) or they augmented LHRH-induced gonadotrophin release (polymyxin B and 8-(N,N-diethylamino) octyl-3,4,5-trimethoxybenzoate). Neither the activators nor the inhibitors of PKC, when present with LHRH, caused any change in LHRH priming, even though the activators alone produced a release of gonadotrophins that showed a temporal pattern similar to that produced by LHRH priming. The profiles of effects on LH and FSH secretion were always qualitatively similar. These results show that PKC may be involved in general regulation of gonadotrophin release but that it is not important in acute responses to LHRH nor in LHRH self-priming. J. Endocr. (1988) 116, 231–239

scholarly journals Inhibitory Effects of Baicalin on the Expression and Activity of CYP3A Induce the Pharmacokinetic Changes of Midazolam in Rats

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Xin Tian ◽  
Zhen-Yu Cheng ◽  
Han Jin ◽  
Jie Gao ◽  
Hai-Ling Qiao
Keyword(s):  
Liver Microsomes ◽  
Flavonoid Compound ◽  
Rat Liver Microsomes ◽  
Dependent Manner ◽  
Inhibitory Effects ◽  
Concentration Dependent Manner ◽  
Dose Dependent Decrease ◽  
Induced Changes ◽  
Regulatory Properties ◽  
Dose Dependent

Baicalin, a flavonoid compound isolated fromScutellaria baicalensis, has been shown to possess antiinflammatory, antiviral, antitumour, and immune regulatory properties. The present study evaluated the potential herb-drug interaction between baicalin and midazolam in rats. Coadministration of a single dose of baicalin (0.225, 0.45, and 0.90 g/kg, i.v.) with midazolam (10 mg/kg, i.v.) in rats resulted in a dose-dependent decrease in clearance (CL) from 25%  (P<0.05)to 34%  (P<0.001)with an increase inAUC0−∞from 47%  (P<0.05)to 53%  (P<0.01). Pretreatment of baicalin (0.90 g/kg, i.v., once daily for 7 days) also reduced midazolam CL by 43%  (P<0.001), with an increase inAUC0−∞by 87%  (P<0.01). Multiple doses of baicalin decreased the expression of hepatic CYP3A2 by approximately 58%  (P<0.01)and reduced midazolam 1′-hydroxylation by 23%  (P<0.001)and 4′-hydroxylation by 21%  (P<0.01)in the liver. In addition, baicalin competitively inhibited midazolam metabolism in rat liver microsomes in a concentration-dependent manner. Our data demonstrated that baicalin induced changes in the pharmacokinetics of midazolam in rats, which might be due to its inhibition of the hydroxylation activity and expression of CYP3A in the liver.

scholarly journals N-hydroxylamine is not an intermediate in the conversion of l-arginine to an activator of soluble guanylate cyclase in neuroblastoma N1E-115 cells

1991 ◽  
Vol 273 (3) ◽  
pp. 547-552 ◽  
Author(s):  
S Pou ◽  
W S Pou ◽  
G M Rosen ◽  
E E el-Fakahany
Keyword(s):  
Guanylate Cyclase ◽  
Cyclic Gmp ◽  
Soluble Guanylate Cyclase ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Intact Cells ◽  
Relaxing Factor ◽  
Endothelium Derived Relaxing Factor ◽  
Dose Dependent

This study evaluates the role of N-hydroxylamine (NH2OH) in activating soluble guanylate cyclase in the mouse neuroblastoma clone N1E-115. It has been proposed that NH2OH is a putative intermediate in the biochemical pathway for the generation of nitric oxide (NO)/endothelium-derived relaxing factor (EDRF) from L-arginine. NH2OH caused a time- and concentration-dependent increase in cyclic GMP formation in intact cells. This response was not dependent on Ca2+. In cytosol preparations the activation of guanylate cyclase by L-arginine was dose-dependent and required Ca2+ and NADPH. In contrast, NH2OH itself did not activate cytosolic guanylate cyclase but it inhibited the basal activity of this enzyme in a concentration-dependent manner. The formation of cyclic GMP in the cytosolic fractions in response to NH2OH required the addition of catalase and H2O2. On the other hand, catalase and/or H2O2 lead to a decrease in L-arginine-induced cyclic GMP formation. Furthermore, NH2OH inhibited L-arginine- and sodium nitroprusside-induced cyclic GMP formation in the cytosol. The inhibition of L-arginine-induced cyclic GMP formation in the cytosol by NH2OH was not reversed by the addition of superoxide dismutase. These data strongly suggest that NH2OH is not a putative intermediate in the metabolism of L-arginine to an activator of guanylate cyclase.

Endogenous ACh tonically stimulates ANP secretion in rat atria

2013 ◽  
Vol 305 (7) ◽  
pp. H1050-H1056 ◽  
Author(s):  
Hye Yoom Kim ◽  
Kyung Woo Cho ◽  
Dong Yuan Xu ◽  
Dae Gill Kang ◽  
Ho Sub Lee
Keyword(s):  
Acetylcholinesterase Inhibition ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Rat Atria ◽  
Rate Limiting Step ◽  
Induced Changes ◽  
Rate Limiting ◽  
Muscarinic Ach Receptor ◽  
High Affinity Choline Transporter

Exogenous acetylcholine (ACh) is known to stimulate atrial natriuretic peptide (ANP) secretion concomitantly with a decrease in atrial pulse pressure. However, the role of intrinsic ACh in the regulation of ANP secretion remains unknown. Recently, it was shown that nonneuronal and neuronal ACh is present in the cardiac atria. From this finding we hypothesize that endogenously released ACh is involved in the regulation of ANP secretion in an autocrine or paracrine manner in the atria. Experiments were performed in isolated beating rat atria. ANP was measured using radioimmunoassay. To increase the availability of the ACh in the extracellular space of the atrium, its degradation was inhibited with an inhibitor of acetylcholinesterase. Acetylcholinesterase inhibition with physostigmine increased ANP secretion concomitantly with a decrease in atrial dynamics in a concentration-dependent manner. Inhibitors of M2 muscarinic ACh receptor (mAChR), methoctramine, and ACh-activated K+ (KACh+) channels, tertiapin-Q, abolished the physostigmine-induced changes. The effects were not observed in the atria from rats treated with pertussis toxin. Furthermore, the physostigmine-induced effects were attenuated by an inhibitor of high-affinity choline transporter, hemicholinium-3, which is a rate-limiting step of ACh synthesis. Inhibitors of the mAChR signaling pathway and ACh synthesis also attenuated the basal levels of ANP secretion and accentuated atrial dynamics. These findings suggest that endogenously released ACh tonically stimulates ANP secretion from atrial cardiomyocytes via activation of M2 mAChR-Gi/o-KACh+ channel signaling. It is also suggested that the ACh-ANP signaling is implicated in cardiac physiology and pathophysiology.

Reversibility of increased microvessel permeability in response to VE-cadherin disassembly

2000 ◽  
Vol 279 (6) ◽  
pp. L1218-L1225 ◽  
Author(s):  
Xiaopei Gao ◽  
Panos Kouklis ◽  
Ning Xu ◽  
Richard D. Minshall ◽  
Raudel Sandoval ◽  
...  
Keyword(s):  
Surface Area ◽  
Adhesive Contact ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Concentration Dependent Manner ◽  
Permeability Surface ◽  
Microvessel Permeability ◽  
Area Product ◽  
Dose Dependent

We determined the role of vascular endothelial (VE)-cadherin complex in regulating the permeability of pulmonary microvessels. Studies were made in mouse lungs perfused with albumin-Krebs containing EDTA, a Ca2+ chelator, added to study the VE-cadherin junctional disassembly. We then repleted the perfusate with Ca2+ to restore VE-cadherin integrity. Confocal microscopy showed a disappearance of VE-cadherin immunostaining in a time- and dose-dependent manner after Ca2+ chelation and reassembly of the VE-cadherin complex within 5 min after Ca2+ repletion. We determined the125I-labeled albumin permeability-surface area product and capillary filtration coefficient ( K fc) to quantify alterations in the pulmonary microvessel barrier. The addition of EDTA increased 125I-albumin permeability-surface area product and K fc in a concentration-dependent manner within 5 min. The permeability response was reversed within 5 min after repletion of Ca2+. An anti-VE-cadherin monoclonal antibody against epitopes responsible for homotypic adhesion augmented the increase in K fc induced by Ca2+chelation and prevented reversal of the response. We conclude that the disassembled VE-cadherins in endothelial cells are mobilized at the junctional plasmalemmal membrane such that VE-cadherins can rapidly form adhesive contact and restore microvessel permeability by reannealing the adherens junctions.

Ca2+ requirement for metabolic effects of secretagogues in the amphibian gastric mucosa

1989 ◽  
Vol 257 (6) ◽  
pp. G969-G976
Author(s):  
O. Subero ◽  
P. Lobo ◽  
J. Chacin
Keyword(s):  
Gastric Mucosa ◽  
Oxygen Uptake ◽  
Metabolic Effects ◽  
Ionophore A23187 ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Exogenous Glucose ◽  
Dose Dependent ◽  
Stimulation Of

The role of extracellular Ca2+ in metabolic effects induced by theophylline and histamine was investigated in the isolated toad gastric mucosa. Primary and secondary effects on metabolism were differentiated by using K(+)-free solutions, which blocked the secretory responses but not the metabolic ones. The stimulation of respiration induced by theophylline and histamine was dose dependent and was significantly decreased by Ca2(+)-free solutions. In the presence of 1.8 mM Ca2+, the rate of glycogen breakdown was increased by theophylline in a dose-dependent manner and the dose-response curve was somewhat similar to that obtained with oxygen uptake. This effect was inhibited by incubation in Ca2(+)-free solutions. Ca2+ stimulated the rate of glycogen utilization in a concentration-dependent manner. The rates of oxidation of exogenous glucose and pyruvate were significantly inhibited by Ca2(+)-free solutions in theophylline- and histamine-stimulated mucosa, whereas the rates of oxidation of butyrate and acetate were not significantly affected. The Ca2+ ionophore A23187 significantly stimulated the rate of oxygen uptake and this response was not blocked by omeprazole and Sch 28080, two specific inhibitors of gastric H(+)-K(+)-ATPase. The results indicate that Ca2+ is required for optimal stimulation of carbohydrate catabolism in the toad gastric mucosa.

Atractylodin inhibited the migration and induced autophagy in cholangiocarcinoma cells via PI3K/AKT/mTOR and p38MAPK signalling pathways

2021 ◽  
Author(s):  
Bishwanath Acharya ◽  
Wanna Chaijaroenkul ◽  
Kesara Na-Bangchang
Keyword(s):  
Protein Kinase ◽  
Molecular Mechanisms ◽  
Mammalian Target Of Rapamycin ◽  
Bioactive Compound ◽  
Mitogen Activated Protein Kinase ◽  
Signalling Pathways ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Dose Dependent

Abstract Objectives The effects of atractylodin (ATD), the bioactive compound from Atractylodes lancea, on migration and autophagy status of cholangiocarcinoma cell line were investigated. Methods Cytotoxic activity and effects on cell migration and invasion were evaluated by MTT and trans-well assay, respectively. Autophagy and underlying molecular mechanisms were investigated using flow cytometry and western blot analysis. Key findings ATD regulated the activity of PI3K/AKT/mTOR and p38MAPK signalling pathways which contributed to autophagy induction. HuCCT-1 cell growth was inhibited by ATD in a time- and dose-dependent manner. ATD inhibited the migration and invasion of HuCCT1 cells in a concentration-dependent manner. It also induced autophagy in HuCCT1 cells in a time- and dose-dependent manner. The SB202190 (autophagy inducer) and 3-MA (autophagy inhibitor) significantly increased and decreased the rate of ATD-induced autophagy, respectively. The 24 h exposure of ATD inhibited the phosphorylation of phosphatidylinositol-3-kinase (PI3K), protein kinase B (AKT), mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (p38MAPK) and increased Beclin-1 expression and LC3 conversion. It also reduced p-AKT/AKT, p-mTOR/mTOR and p-p38MAPK/p38MAPK. Conclusions ATD inhibits the proliferation and induces CCA cell autophagy via regulating PI3K/AKT/mTOR and p38MAPK signalling pathways.

Amelioration of Carbon Tetrachloride-Induced Liver Injury by Citrus Leaf Extract

2019 ◽  
Vol 17 (4) ◽  
pp. 426-431
Author(s):  
Jin Xuezhu ◽  
Li Jitong ◽  
Nie Leigang ◽  
Xue Junlai
Keyword(s):  
Carbon Tetrachloride ◽  
Leaf Extract ◽  
Hepatic Injury ◽  
The Body ◽  
Dependent Manner ◽  
Weight Changes ◽  
Citrus Leaf ◽  
Dose Dependent ◽  
And Oxidative Stress

The main purpose of this study is to investigate the role of citrus leaf extract in carbon tetrachloride-induced hepatic injury and its potential molecular mechanism. Carbon tetrachloride was used to construct hepatic injury animal model. To this end, rats were randomly divided into 4 groups: control, carbon tetrachloride-treated, and two carbon tetrachloride + citrus leaf extract-treated groups. The results show that citrus leaf extract treatment significantly reversed the effects of carbon tetrachloride on the body weight changes and liver index. Besides, treatment with citrus leaf extract also reduced the levels of serum liver enzymes and oxidative stress in a dose-dependent manner. H&E staining and western blotting suggested that citrus leaf extract could repair liver histological damage by regulating AMPK and Nrf-2.

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