Role of arachidonic acid metabolites in ethanol vasoaction in rat gastric submucosa

1988 ◽  
Vol 255 (6) ◽  
pp. G731-G737 ◽  
Author(s):  
Y. Yonei ◽  
H. Wayland ◽  
P. H. Guth
Keyword(s):  
Vessel Diameter ◽  
In Vivo Microscopy ◽  
Lipoxygenase Inhibitor ◽  
Microscopy Technique ◽  
Cyclooxygenase Activity ◽  
Microvascular Response ◽  
Acid Metabolites ◽  
Dose Dependent

By use of an in vivo microscopy technique in the anesthetized rat, the effect of 0.5-8.0% ethanol on gastric submucosal blood vessel diameter was studied. The direct application of ethanol onto the exposed submucosal vasculature caused a dose-dependent dilatation of the arterioles (9 +/- 3% by 2% ethanol) but had no effect on venular diameter. In rats pretreated with 5 mg/kg indomethacin subcutaneously to inhibit cyclooxygenase activity, the submucosal application of ethanol caused dose-dependent constriction of both arterioles and venules (2% ethanol decreasing diameters by 21 +/- 3 and 15 +/- 2%, respectively). This constriction by ethanol in indomethacin-pretreated rats was significantly inhibited by BW755C, a lipoxygenase inhibitor. Under these conditions, 2% ethanol had no significant effect on either arterioles or venules. In conclusion, ethanol appears to cause release of vasodilating prostaglandins and vasoconstricting leukotrienes that may mediate or modulate the microvascular response to ethanol.

Effect of a leukotriene receptor antagonist on LTC4 vasoconstriction in rat stomach

1990 ◽  
Vol 259 (1) ◽  
pp. G147-G154
Author(s):  
Y. Yonei ◽  
P. H. Guth
Keyword(s):  
Receptor Antagonist ◽  
In Vivo Microscopy ◽  
Leukotriene Receptor Antagonist ◽  
Rat Stomach ◽  
Cysteinyl Leukotriene ◽  
Microscopy Technique ◽  
Plot Analysis ◽  
Microvascular Response ◽  
Leukotriene Receptor

With the use of an in vivo microscopy technique in anesthetized-laparotomized rats, the effect of L660,711, a cysteinyl-leukotriene (LT) receptor antagonist, on the gastric submucosal microvascular response to leukotrienes was studied. The direct application of 50-400 nM LTC4 onto the exposed submucosal vasculature caused constriction of both arterioles (maximum constriction: 24 +/- 3%) and venules (26 +/- 3%), whereas LTD4 had no significant effect. Pretreatment with 5 mg/kg L660,711 intragastrically significantly attenuated the LTC4-induced vasoconstriction. The submucosal application of 2 x 10(-7) to 2 x 10(-2) M L660,711 dose dependently inhibited the 400 nM LTC4-induced vasoconstriction. The IC50 of L660,711, preapplied to the gastric submucosa for 15 min, was 4.4 x 10(-4) M in arterioles and 3.9 x 10(-4) M in venules, and 3.6 x 10(-5) M and 3.2 x 10(-5) M, respectively, when it was applied simultaneously with LTC4. Schild plot analysis revealed that L660,711 was not a pure competitive receptor antagonist. L660,711 had no significant effects on epinephrine- or vasopressin-induced arteriolar constriction. In conclusion, L660,711 significantly antagonizes the gastric microvascular effects of LTC4, but not those of other vasoconstrictors, and appears to be a useful new tool for studying LTC4 effects.

Platelet Aggregation in Whole Blood: The Role of Thromboxane A2 and Adenosine Diphosphate

1985 ◽  
Vol 54 (03) ◽  
pp. 612-616 ◽  
Author(s):  
A J Carter ◽  
S Heptinstall
Keyword(s):  
Platelet Aggregation ◽  
Whole Blood ◽  
Adenosine Diphosphate ◽  
Blood Platelet ◽  
Thromboxane B2 ◽  
Lipoxygenase Inhibitor ◽  
Thromboxane Synthase Inhibitor ◽  
Synthase Inhibitor

SummaryThe platelet aggregation that occurred in whole blood in response to several aggregating agents (collagen, arachidonic acid, adenosine diphosphate, adrenaline and thrombin) was measured using an Ultra-Flo 100 Whole Blood Platelet Counter. The amounts of thromboxane B2 produced were measured by radioimmunoassay. The effects of various inhibitors of thromboxane synthesis and the effects of apyrase, an enzyme that destroys adenosine diphosphate, were determined.Platelet aggregation was always accompanied by the production of thromboxane B2, and the amounts produced depended on the nature and concentration of the aggregating agent used. The various inhibitors of thromboxane synthesis - aspirin and flurbiprofen (cyclo-oxygenase inhibitors), BW755C (a cyclo-oxygenase and lipoxygenase inhibitor) and dazoxiben (a selective thromboxane synthase inhibitor) - did not markedly inhibit aggregation. Results obtained using apyrase showed that adenosine diphosphate contributed to the aggregation process, and that its role must be acknowledged when devising means of inhibiting platelet aggregation in vivo.

scholarly journals Endothelin 1-induced retinal ganglion cell death is largely mediated by JUN activation

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
Olivia J. Marola ◽  
Stephanie B. Syc-Mazurek ◽  
Gareth R. Howell ◽  
Richard T. Libby
Keyword(s):  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Ganglion Cells ◽  
Retinal Vessel ◽  
Vessel Diameter ◽  
Retinal Ganglion ◽  
Retinal Ganglion Cell Death ◽  
Ganglion Cell Death

Abstract Glaucoma is a neurodegenerative disease characterized by loss of retinal ganglion cells (RGCs), the output neurons of the retina. Multiple lines of evidence show the endothelin (EDN, also known as ET) system is important in glaucomatous neurodegeneration. To date, the molecular mechanisms within RGCs driving EDN-induced RGC death have not been clarified. The pro-apoptotic transcription factor JUN (the canonical target of JNK signaling) and the endoplasmic reticulum stress effector and transcription factor DNA damage inducible transcript 3 (DDIT3, also known as CHOP) have been shown to act downstream of EDN receptors. Previous studies demonstrated that JUN and DDIT3 were important regulators of RGC death after glaucoma-relevant injures. Here, we characterized EDN insult in vivo and investigated the role of JUN and DDIT3 in EDN-induced RGC death. To accomplish this, EDN1 ligand was intravitreally injected into the eyes of wildtype, Six3-cre+Junfl/fl (Jun−/−), Ddit3 null (Ddit3−/−), and Ddit3−/−Jun−/− mice. Intravitreal EDN1 was sufficient to drive RGC death in vivo. EDN1 insult caused JUN activation in RGCs, and deletion of Jun from the neural retina attenuated RGC death after EDN insult. However, deletion of Ddit3 did not confer significant protection to RGCs after EDN1 insult. These results indicate that EDN caused RGC death via a JUN-dependent mechanism. In addition, EDN signaling is known to elicit potent vasoconstriction. JUN signaling was shown to drive neuronal death after ischemic insult. Therefore, the effects of intravitreal EDN1 on retinal vessel diameter and hypoxia were explored. Intravitreal EDN1 caused transient retinal vasoconstriction and regions of RGC and Müller glia hypoxia. Thus, it remains a possibility that EDN elicits a hypoxic insult to RGCs, causing apoptosis via JNK-JUN signaling. The importance of EDN-induced vasoconstriction and hypoxia in causing RGC death after EDN insult and in models of glaucoma requires further investigation.

Microcirculatory changes in sodium taurocholate-induced pancreatitis in rats

1991 ◽  
Vol 260 (2) ◽  
pp. G346-G351 ◽  
Author(s):  
K. Kusterer ◽  
M. Enghofer ◽  
S. Zendler ◽  
C. Blochle ◽  
K. H. Usadel
Keyword(s):  
Acute Pancreatitis ◽  
Blood Flow ◽  
Vascular Permeability ◽  
Sodium Taurocholate ◽  
Image Analyzer ◽  
In Vivo Microscopy ◽  
Microscopy Technique ◽  
Permeability Changes ◽  
Hemorrhagic Necrosis

Using an in vivo microscopy technique, we studied the microcirculatory changes in sodium taurocholate-induced pancreatitis in rats. With a computerized image analyzer system, blood flow, vascular permeability changes, and capillary densities were measured. Intraductal infusion of 0.4 ml saline had only minor effects on the microcirculation. Various concentrations and volumes of sodium taurocholate solutions were infused into the pancreatic duct. Sodium taurocholate (0.4 ml, 4%) led to increased vascular permeability preceding stasis within 232 +/- 47 s, followed by hemorrhagic necrosis in the head of the pancreas. In the corpus close to the tail of the pancreas capillary blood flow was maintained. In conclusion, this study shows that the microcirculation of the pancreas can be excellently investigated with in vivo microscopy. With this method, tremendous distribution disturbances of the microcirculation in the pancreas can be seen in the course of acute pancreatitis. Vascular permeability changes and stasis of the microcirculation represent the primary microcirculatory events in acute pancreatitis induced by sodium taurocholate in the areas where hemorrhagic necrosis occurs.

scholarly journals Inhibition of Prostate Cancer DU-145 Cells Proliferation by Anthopleura anjunae Oligopeptide (YVPGP) via PI3K/AKT/mTOR Signaling Pathway

Marine Drugs ◽  
2018 ◽  
Vol 16 (9) ◽  
pp. 325 ◽  
Author(s):  
Xiaojuan Li ◽  
Yunping Tang ◽  
Fangmiao Yu ◽  
Yu Sun ◽  
Fangfang Huang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Signaling Pathway ◽  
Caspase 3 ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Nude Mouse Model ◽  
Dose Dependent

We investigated the antitumor mechanism of Anthopleura anjunae oligopeptide (AAP-H, YVPGP) in prostate cancer DU-145 cells in vitro and in vivo. Results indicated that AAP-H was nontoxic and exhibited antitumor activities. Cell cycle analysis indicated that AAP-H may arrest DU-145 cells in the S phase. The role of the phosphatidylinositol 3-kinase/protein kinase B/mammalian rapamycin target protein (PI3K/AKT/mTOR) signaling pathway in the antitumor mechanism of APP-H was investigated. Results showed that AAP-H treatment led to dose-dependent reduction in the levels of p-AKT (Ser473), p-PI3K (p85), and p-mTOR (Ser2448), whereas t-AKT and t-PI3K levels remained unaltered compared to the untreated DU-145 cells. Inhibition of PI3K/AKT/mTOR signaling pathway in the DU-145 cells by employing inhibitor LY294002 (10 μM) or rapamycin (20 nM) effectively attenuated AAP-H-induced phosphorylation of AKT and mTOR. At the same time, inhibitor addition further elevated AAP-H-induced cleaved-caspase-3 levels. Furthermore, the effect of AAP-H on tumor growth and the role of the PI3K/AKT/mTOR signaling pathway in nude mouse model were also investigated. Immunohistochemical analysis showed that activated AKT, PI3K, and mTOR levels were reduced in DU-145 xenografts. Western blotting showed that AAP-H treatment resulted in dose-dependent reduction in p-AKT (Ser473), p-PI3K (p85), and p-mTOR (Ser2448) levels, whereas t-AKT and t-PI3K levels remained unaltered. Similarly, Bcl-xL levels decreased, whereas that of Bax increased after AAP-H treatment. AAP-H also increased initiator (caspase 8 and 9) and executor caspase (caspase 3 and 7) levels. Therefore, the antitumor mechanism of APP-H on DU-145 cells may involve regulation of the PI3K/AKT/mTOR signaling pathway, which eventually promotes apoptosis via mitochondrial and death receptor pathways. Thus, the hydrophobic oligopeptide (YVPGP) can be developed as an adjuvant for the prevention or treatment of prostate cancer in the future.

Role Of Cyclic Amp In The Inhibition Of Human Platelet Functions By Quercetin, A Flav0N0Id That Potentiates PGI2 Effect

1981 ◽  
Author(s):  
J P Cazenave ◽  
A Beretz ◽  
A Stierlé ◽  
R Anton
Keyword(s):  
Maximum Level ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Pde Inhibitors ◽  
Pde Inhibition ◽  
Induced Aggregation ◽  
Camp Levels ◽  
Dose Dependent

Injury to the endothelium (END) and subsequent platelet (PLAT)interactions with the subEND are important steps in thrombosis and atherosclerosis. Thus,drugs that protect the END from injury and also inhibit PLAT function are of interest. It has been shown that some flavonoids(FLA), a group of compounds found in plants, prevent END desquamation in vivo, inhibit cyclic nucleotide phosphodiesterases(PDE)and inhibit PLAT function. We have studied the structure-activity relationships of 13 purified FLA on aggregation and secretion of 14c-5HT of prelabeled washed human PLAT induced by ADP, collagen(COLL) and thrombin(THR). All the FLA were inhibitors of the 3 agents tested. Quercetin(Q), was the second best after fisetin. It inhibited secretion and aggregation with I50 of 330µM against 0.1 U/ML.THR, 102µM against 5µM ADP and 40 µM against COLL. This inhibitory effect is in the range of that of other PDE inhibitors like dipyridamole or 3-isobutyl-l- methylxanthine. The aggregation induced by ADP, COLL and THR is at least mediated by 3 mechanisms that can be inhibited by increasing cAMP levels. We next investigated if Q, which is a PDE inhibitor of bovine aortic microsomes,raises PLAT cAMP levels. cAMP was measured by a protein-binding method. ADP- induced aggregation(5µM) was inhibited by PGI2 (0.1 and 0.5 nM) . Inhibition was further potentiated(l.7 and 3.3 times) by lOµM Q, which alone has no effect on aggregation. The basal level of cAMP(2.2 pmol/108PLAT) was not modified by Q (50 to 500µM). Using these concentrations of Q,the rise in cAMP caused by PGI2(0.1 and 0.5nM) was potentiated in a dose dependent manner. Q potentiated the effect of PGI2 on the maximum level of cAMP and retarded its breakdown. Thus Q and possibly other FLA could inhibit the interaction of PLAT with the components of the vessel wall by preventing END damage and by inhibiting PLAT function through a rise in cAMP secondary to PDE inhibition and potentiation of the effect of vascular PGI2 on PLAT adenylate cyclase.

scholarly journals Dynamics of intravital concentration of amino acid metabolites in human brain in post-traumatic period

2019 ◽  
Vol 484 (2) ◽  
pp. 238-242
Author(s):  
N. A. Semenova ◽  
P. E. Menshchikov ◽  
A. V. Manzhurtsev ◽  
M. V. Ublinskiy ◽  
T. A. Akhadov ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Amino Acid ◽  
Human Brain ◽  
Leading Role ◽  
Acid Metabolites ◽  
Post Traumatic ◽  
First Time

Intracellular concentrations of N acetyaspartate (NAA), aspartate (Asp) and glutamate (Glu) were determined for the first time in human brain in vivo, and the effect of severe traumatic brain injury on NAA synthesis in acute and late post-traumatic period was investigated. In MRI‑negative frontal lobes one day after injury Asp and Glu levels were found to decrease by 45 and 35%, respectively, while NAA level decreased by only 16%. A negative correlation between NAA concentration and the ratio of Asp/Glu concentrations was found. In the long-term period, Glu level returned to normal, Asp level remained below normal by 60%, NAA level was reduced by 65% relative to normal, and Asp/Glu ratio significantly decreased. The obtained results revealed leading role of the neuronal aspartate-malate shuttle in violation of NAA synthesis.

Effect of histamine on microvascular permeability in the rat stomach

1983 ◽  
Vol 245 (2) ◽  
pp. G201-G207
Author(s):  
H. Nagata ◽  
P. H. Guth
Keyword(s):  
Histamine Receptors ◽  
Microvascular Permeability ◽  
In Vivo Microscopy ◽  
Rat Stomach ◽  
Serosal Surface ◽  
H2 Antagonist ◽  
H1 Antagonist ◽  
Dose Dependent ◽  
Muscularis Externa

The effect of histamine on gastric microvascular permeability to macromolecules in the rat was studied using fluorescent in vivo microscopy. Histamine was applied topically to the serosal surface for study of the muscularis externa, to the submucosa, and to the superficial mucosa, and the area of leaks of a fluorescein-albumin conjugate from microvessels was quantitated. In the muscularis externa both histamine and an H1-agonist, but not an H2-agonist, caused dose-dependent leak of conjugate from venules. An H1-antagonist, but not an H2-antagonist, decreased the histamine-induced leak. In the submucosa histamine caused dose-dependent dilatation of arterioles but not leak of conjugate. In contrast, bradykinin caused both dose-dependent dilatation of arterioles and leak of conjugate from venules. In the superficial mucosa histamine did not cause any leak. In conclusion, topical histamine 1) increased microvascular permeability to macromolecules from venules in the muscularis externa via H1-receptors, 2) did not affect microvascular permeability in the submucosa (this may be due to lack of histamine receptors on the venules as bradykinin increased venular permeability), and 3) did not affect microvascular permeability in the superficial mucosa, but there might not have been adequate histamine backdiffusion.

scholarly journals 5-LIPOXYGENASE INHIBITOR (ZILEUTON) PRODUCES ANTI-DEPRESSION EFFECT IN STRESS INDUCE CRS MICE MODEL

2019 ◽  
pp. 154-162
Author(s):  
SAPTARSHI PANIGRAHI ◽  
SOMNATH SURAI ◽  
HAO HONG
Keyword(s):  
Caspase 3 ◽  
Molecular Level ◽  
Behavioral Tests ◽  
Mice Model ◽  
Lipoxygenase Inhibitor ◽  
Treatment Groups ◽  
Tnf Α ◽  
Crs Model

Objective: The experiment aimed to find out the effectiveness of Zileuton, a 5-LOX inhibitor on depressive behavior and neuroinflammation in vivo. Method: Male ICR mice (25-30g) randomly distributed Veh+Veh, CRS+Vehicle, CRS+ZIL50, and CRS+ZIL100. Zileuton was orally given in the treatment groups for 21 days after 3 weeks of stress induce CRS model. Starting from the day 1, in CRS model, mice were immobilized 8 hr/day for consecutive 21 days to induce stress. After completing the drug administration, subjected the mice for behavioral tests, and then performed histopathological & Western Blotting. Result: Stress induces CRS model guide to the significant depressive-like behavior of the mice in behavioral tests which was united by adverse changes at the cellular/molecular level responsible for regulation of inflammatory and apoptotic processes. CRS triggered Microglial over activation in the DG of the hippocampus, which was successfully inhibited by Zileuton post-treatment at the dose of 100mg/kg than 50mg/kg. Level of TNF-α, IL- 1β, nuclear NF-κB p65, Bax, and cleaved Caspase-3 was high and Bcl-2 expression was low in the stress induce CRS -treated mice which were found to be opposite in the Zileuton (100mg/kg). However, the dose of 50mg/kg less to mimic the effects as exhibited more by the 100mg/kg dose of Zileuton. Conclusion: It can be concluded that selective 5-lipoxygenase inhibitor Zileuton can efficiently inhibit the depressive-like behavior/activity in CRS-induced depressive mouse model. The study is the first to show the role of 5-lipoxygenase enzyme in and Chronic Restraint Stress (CRS)-induced mice models of stress, anxiety or depression.

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