scholarly journals Tolerance to the Behavioural and Neurochemical Effects of MDMA Following Repeated Exposure

2021 ◽  
Author(s):  
◽  
Karen Jones
Keyword(s):  
Dose Effect ◽  
Dependent Manner ◽  
Test Arena ◽  
Functional Changes ◽  
Tissue Levels ◽  
Experimental Parameters ◽  
Behavioural Tolerance ◽  
Dose Dependent ◽  
Saline Vehicle

<p>Rationale: Following repeated +/-3,4- methylenedioxymethamphetamine (MDMA) administration there is tolerance to many behavioural effects and deficits in serotonergic neurotransmission. Objectives: The present studies had three main objectives. 1. To develop a behavioural assay to examine the effects of acute and repeated MDMA exposure. 2. To use this behavioural assay to determine whether functional changes in serotonin (5-HT)2a or 5-HT2c receptors accompany tolerance to the effects of MDMA. 3. To attempt to reverse behavioural tolerance and 5-HT deficits by administering a treatment that has been shown to desensitise the 5-HT1a autoreceptor. Methods: In separate groups of rats the dose effect curves for MDMAproduced hyperactivity were determined (0.0, 1.0, 3.3, 10.0 mg/kg). In additional groups the effect of MDMA pretreatment (4 X 10mg/kg MDMA injections at 2 hour intervals) or saline vehicle on MDMA-produced hyperactivity was assessed. To determine the experimental parameters for MDMA effects in the Emergence Test (ET) separate groups of rats received MDMA (0.0, 3.3 mg/kg) and were either habituated to a hide box for various periods (15, 30, 45mins) or exposed to the test arena 3 times over a period of days (day 1, 5, 9) or injected daily in the home cage with MDMA (0.0, 3.3mg/kg) for 3 days. Emergence latency following injections of MDMA (0.0, 3.3mg/kg), the 5-HT2a /c agonistm-CPP (0.0, 0.3, 0.6 or 1.25 m/kg), the 5-HT releasing stimulant, fenfluramine (0.0, 1.0, 2.0 mg/kg), and the 5-HT2a agonist DOI (0.0, 1.0, 2.0 mg/kg) was measured. The role of 5-HT2c receptors was assessed by determining the effect of the 5-HT2c antagonist, RS102221 (0.0, 0.25, 0.5, 1.0 mg/kg). The effect of MDMA pretreatment on MDMA (0.0, 3.3 mg/kg), m-CPP (1.25 mg/kg), or fenfluramine (2.0mg/kg) induced increases in emergence latency was also assessed. The functional status of the 5-HT1a autoreceptor following MDMA pretreatment was determined by measuring the effect of the 5-HT1a agonist, 8- OHDPAT (0.0, 0.315, 0.0625, 0.125, 0.25, 0.5 mg/kg, SC), on body temperature. The ability of the 5-HT1a antagonist, WAY100635 (0.0, 0.01, 0.1, 1.0mg/kg, SC, 1 X daily for 7 days or by local injection of 0.0 or 500 ng into the dorsal raphe) to reverse the attenuation of MDMA-induced hyperactivity following MDMA pretreatment was examined. Effects of various treatments on tissue levels of 5-HT and 5-HIAA were also measured using HPLC with EC. Results: MDMA produced dose-dependent hyperactivity and tolerance was produced by MDMA pretreatment. MDMA (3.3mg/kg) increased emergence latency following a 30 minute habituation period and this effect was reduced in MDMA-pretreated rats. Fenfluramine and m-CPP but not DOI also increased emergence latency in a dose-dependent manner. RS102221 dose dependently blocked the acute effects of MDMA and m-CPP. Two weeks following MDMA pretreatment rats were tolerant to the effects of MDMA and fenfluramine, but not m-CPP. MDMA pretreatment also produced significant reductions in tissue levels of 5-HT and 5-HIAA. Subcutaneous WAY100635 administration failed to reverse the behavioural and neurochemical deficits produced by MDMA pretreatment but local administration increased MDMA-produced hyperactivity in saline and MDMA pretreated rats and reversed MDMA-produced 5-HT tissue depletions. Conclusion: The Emergence Test is a behavioural assay sensitive to the effects of acute and repeated MDMA exposure. Following MDMA pretreatment behavioural tolerance as measured by the ET is likely to be due to impaired 5-HT release rather than changes in 5-HT2a or 5-HT2c receptor responses. Because partial reversal of tolerance and 5-HT deficits following repeated MDMA administration was achieved through local DRN 5-HT1a antagonist administration the 5-HT1a autoreceptor may prove to be a clinical target for the reversal of MDMA produced deficits.</p>

scholarly journals Tolerance to the Behavioural and Neurochemical Effects of MDMA Following Repeated Exposure

2021 ◽  
Author(s):  
◽  
Karen Jones
Keyword(s):  
Dose Effect ◽  
Dependent Manner ◽  
Test Arena ◽  
Functional Changes ◽  
Tissue Levels ◽  
Experimental Parameters ◽  
Behavioural Tolerance ◽  
Dose Dependent ◽  
Saline Vehicle

<p>Rationale: Following repeated +/-3,4- methylenedioxymethamphetamine (MDMA) administration there is tolerance to many behavioural effects and deficits in serotonergic neurotransmission. Objectives: The present studies had three main objectives. 1. To develop a behavioural assay to examine the effects of acute and repeated MDMA exposure. 2. To use this behavioural assay to determine whether functional changes in serotonin (5-HT)2a or 5-HT2c receptors accompany tolerance to the effects of MDMA. 3. To attempt to reverse behavioural tolerance and 5-HT deficits by administering a treatment that has been shown to desensitise the 5-HT1a autoreceptor. Methods: In separate groups of rats the dose effect curves for MDMAproduced hyperactivity were determined (0.0, 1.0, 3.3, 10.0 mg/kg). In additional groups the effect of MDMA pretreatment (4 X 10mg/kg MDMA injections at 2 hour intervals) or saline vehicle on MDMA-produced hyperactivity was assessed. To determine the experimental parameters for MDMA effects in the Emergence Test (ET) separate groups of rats received MDMA (0.0, 3.3 mg/kg) and were either habituated to a hide box for various periods (15, 30, 45mins) or exposed to the test arena 3 times over a period of days (day 1, 5, 9) or injected daily in the home cage with MDMA (0.0, 3.3mg/kg) for 3 days. Emergence latency following injections of MDMA (0.0, 3.3mg/kg), the 5-HT2a /c agonistm-CPP (0.0, 0.3, 0.6 or 1.25 m/kg), the 5-HT releasing stimulant, fenfluramine (0.0, 1.0, 2.0 mg/kg), and the 5-HT2a agonist DOI (0.0, 1.0, 2.0 mg/kg) was measured. The role of 5-HT2c receptors was assessed by determining the effect of the 5-HT2c antagonist, RS102221 (0.0, 0.25, 0.5, 1.0 mg/kg). The effect of MDMA pretreatment on MDMA (0.0, 3.3 mg/kg), m-CPP (1.25 mg/kg), or fenfluramine (2.0mg/kg) induced increases in emergence latency was also assessed. The functional status of the 5-HT1a autoreceptor following MDMA pretreatment was determined by measuring the effect of the 5-HT1a agonist, 8- OHDPAT (0.0, 0.315, 0.0625, 0.125, 0.25, 0.5 mg/kg, SC), on body temperature. The ability of the 5-HT1a antagonist, WAY100635 (0.0, 0.01, 0.1, 1.0mg/kg, SC, 1 X daily for 7 days or by local injection of 0.0 or 500 ng into the dorsal raphe) to reverse the attenuation of MDMA-induced hyperactivity following MDMA pretreatment was examined. Effects of various treatments on tissue levels of 5-HT and 5-HIAA were also measured using HPLC with EC. Results: MDMA produced dose-dependent hyperactivity and tolerance was produced by MDMA pretreatment. MDMA (3.3mg/kg) increased emergence latency following a 30 minute habituation period and this effect was reduced in MDMA-pretreated rats. Fenfluramine and m-CPP but not DOI also increased emergence latency in a dose-dependent manner. RS102221 dose dependently blocked the acute effects of MDMA and m-CPP. Two weeks following MDMA pretreatment rats were tolerant to the effects of MDMA and fenfluramine, but not m-CPP. MDMA pretreatment also produced significant reductions in tissue levels of 5-HT and 5-HIAA. Subcutaneous WAY100635 administration failed to reverse the behavioural and neurochemical deficits produced by MDMA pretreatment but local administration increased MDMA-produced hyperactivity in saline and MDMA pretreated rats and reversed MDMA-produced 5-HT tissue depletions. Conclusion: The Emergence Test is a behavioural assay sensitive to the effects of acute and repeated MDMA exposure. Following MDMA pretreatment behavioural tolerance as measured by the ET is likely to be due to impaired 5-HT release rather than changes in 5-HT2a or 5-HT2c receptor responses. Because partial reversal of tolerance and 5-HT deficits following repeated MDMA administration was achieved through local DRN 5-HT1a antagonist administration the 5-HT1a autoreceptor may prove to be a clinical target for the reversal of MDMA produced deficits.</p>

scholarly journals Acute Hyperglycemia May Induce Renal Tubular Injury Through Mitophagy Inhibition

2020 ◽  
Vol 11 ◽  
Author(s):  
Jingyu Wang ◽  
Xiaodan Yue ◽  
Cheng Meng ◽  
Ziyan Wang ◽  
Xiaofang Jin ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Kidney Injury ◽  
Dose Effect ◽  
Dependent Manner ◽  
Tubular Epithelial Cells ◽  
Mtor Inhibition ◽  
Acute Hyperglycemia ◽  
Renal Tubular ◽  
Dose Dependent

AimAcute hyperglycemia is closely related to kidney injury. Oxidative stress activation and notable mitochondria damages were found under acute hyperglycemia treatment in our previous work. In the present study, we explored the dose-effect relationship and the pivotal role of mitophagy in acute hyperglycemia induced tubular injuries.MethodsForty non-diabetic SD rats were randomly divided and treated with different concentrations of hyperglycemia respectively during the 6-h clamp experiment. Renal morphological and functional alterations were detected. Rat renal tubular epithelial cells were treated with different concentrations of glucose for 6 h. Markers and the regulation pathway of mitophagy were analyzed.ResultsSignificant tubular injuries but not glomeruli were observed under both light and electron microscope after acute hyperglycemia treatment, which manifested as enlargement of tubular epithelial cells, disarrangement of epithelial cell labyrinths and swelling of mitochondria. Urinary microalbumin, β2-MG, CysC, NAG, GAL, and NGAL were increased significantly with the increase of blood glucose (P &lt; 0.05). ROS was activated, mitochondrial membrane potential and LC3-II/LC3-I ratio were decreased but P62 and BNIP3L/Nix were increased in hyperglycemia groups (P &lt; 0.05), which were reversed by AMPK activation or mTOR inhibition.ConclusionAcute hyperglycemia causes obvious tubular morphological and functional injuries in a dose-dependent manner. Acute hyperglycemia could inhibit mitophagy through AMPK/mTOR pathway, which would aggravate mitochondria damage and renal tubular impairment.

scholarly journals Reduction of Pulmonary Toxicity ofStachybotrys chartarum Spores by Methanol Extraction of Mycotoxins

2000 ◽  
Vol 66 (7) ◽  
pp. 2817-2821 ◽  
Author(s):  
Carol Y. Rao ◽  
Joseph D. Brain ◽  
Harriet A. Burge
Keyword(s):  
Bronchoalveolar Lavage ◽  
Pulmonary Inflammation ◽  
Lactic Dehydrogenase ◽  
Lavage Fluid ◽  
Dose Effect ◽  
Dependent Manner ◽  
Methanol Extraction ◽  
Leukocyte Counts ◽  
Dose Dependent

ABSTRACT The fungus Stachybotrys chartarum has been implicated in cases of nonspecific indoor air quality complaints in adults and in cases of pulmonary hemorrhaging in infants. The effects that have been described have been attributed to mycotoxins. Previous dose-effect studies focused on exposure to a single mycotoxin in a solvent, a strategy which is unlikely to accurately characterize the effects of inhaled spores. In this study we examined the role of mycotoxins in the pulmonary effects caused by S. chartarum spores and the dose dependency of these effects. S. chartarum spores were extracted in methanol to reduce the mycotoxin content of the spores. Then either untreated (toxin-containing) or methanol-extracted S. chartarum spores were intratracheally instilled into male 10-week-old Charles River-Dawley rats. After 24 h, the lungs were lavaged, and the bronchoalveolar lavage fluid was analyzed to determine differences in lactic dehydrogenase, albumin, hemoglobin, myeloperoxidase, and leukocyte differential counts. Weight change was also monitored. Our data show that methanol extraction dramatically reduced the toxicity of S. chartarum spores. No statistically significant effects were observed in the bronchoalveolar lavage fluids of the animals that were treated with methanol-extracted spores at any dose. Conversely, dose-dependent effects of the toxin-containing spores were observed when we examined the lactic dehydrogenase, albumin, and hemoglobin concentrations, the polymorphonuclear leukocyte counts, and weight loss. Our findings show that a single, intense exposure to toxin-containing S. chartarum spores results in pulmonary inflammation and injury in a dose-dependent manner. Importantly, the effects are related to methanol-soluble toxins in the spores.

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.

scholarly journals Lumican Inhibits Osteoclastogenesis and Bone Resorption by Suppressing Akt Activity

2021 ◽  
Vol 22 (9) ◽  
pp. 4717
Author(s):  
Jin-Young Lee ◽  
Da-Ae Kim ◽  
Eun-Young Kim ◽  
Eun-Ju Chang ◽  
So-Jeong Park ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Map Kinases ◽  
Osteoclast Differentiation ◽  
Dependent Manner ◽  
Dual Action ◽  
Dose Dependent ◽  
Resorptive Activity

Lumican, a ubiquitously expressed small leucine-rich proteoglycan, has been utilized in diverse biological functions. Recent experiments demonstrated that lumican stimulates preosteoblast viability and differentiation, leading to bone formation. To further understand the role of lumican in bone metabolism, we investigated its effects on osteoclast biology. Lumican inhibited both osteoclast differentiation and in vitro bone resorption in a dose-dependent manner. Consistent with this, lumican markedly decreased the expression of osteoclastogenesis markers. Moreover, the migration and fusion of preosteoclasts and the resorptive activity per osteoclast were significantly reduced in the presence of lumican, indicating that this protein affects most stages of osteoclastogenesis. Among RANKL-dependent pathways, lumican inhibited Akt but not MAP kinases such as JNK, p38, and ERK. Importantly, co-treatment with an Akt activator almost completely reversed the effect of lumican on osteoclast differentiation. Taken together, our findings revealed that lumican inhibits osteoclastogenesis by suppressing Akt activity. Thus, lumican plays an osteoprotective role by simultaneously increasing bone formation and decreasing bone resorption, suggesting that it represents a dual-action therapeutic target for osteoporosis.

Role of extracellular calcium and calmodulin in prolactin secretion induced by hyposmolarity, thyrotropin-releasing hormone, and high K+ in GH4C1 cells

1990 ◽  
Vol 123 (2) ◽  
pp. 218-224 ◽  
Author(s):  
Xiangbing Wang ◽  
Noriyuki Sato ◽  
Monte A. Greer ◽  
Susan E. Greer ◽  
Staci McAdams
Keyword(s):  
Smooth Muscle ◽  
Muscle Relaxant ◽  
Prolactin Secretion ◽  
Thyrotropin Releasing Hormone ◽  
Dependent Manner ◽  
Cell Toxicity ◽  
High K ◽  
Dose Dependent ◽  
Smooth Muscle Relaxant

Abstract. The mechanism by which 30% medium hyposmolarity induces PRL secretion by GH4C1 cells was compared with that induced by 100 nmol/l TRH or 30 mmol/l K+. Removing medium Ca2+, blocking Ca2+ channels with 50 μmol/l verapamil, or inhibiting calmodulin activation with 20 μmol/l trifluoperazine, 10 μmol/l chlorpromazine or 10 μmol/l pimozide almost completely blocked hyposmolarity-induced secretion. The smooth muscle relaxant, W-7, which is believed relatively specific in inhibiting the Ca2+-calmodulin interaction, depressed hyposmolarity-induced PRL secretion in a dose-dependent manner (r = −0.991, p<0.01 ). The above drugs also blocked or decreased high K+-induced secretion, but had much less effect on TRH-induced secretion. Secretion induced by TRH, hyposmolarity, or high K+ was optimal at pH 7.3-7.65 and was significantly depressed at pH 6.0 or 8.0, indicating that release of hormone induced by all 3 stimuli is due to an active cell process requiring a physiologic extracellular pH and is not produced by nonspecific cell toxicity. The data suggest hyposmolarity and high K+ may share some similarities in their mechanism of stimulating secretion, which is different from that of TRH.

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.

VCAM-1 is a CS1 peptide-inhibitable adhesion molecule expressed by lymph node high endothelium

1993 ◽  
Vol 106 (1) ◽  
pp. 109-119 ◽  
Author(s):  
M.J. May ◽  
G. Entwistle ◽  
M.J. Humphries ◽  
A. Ager
Keyword(s):  
Lymph Node ◽  
Cell Interaction ◽  
Tnf Alpha ◽  
Dependent Manner ◽  
Ifn Gamma ◽  
Lymphocyte Adhesion ◽  
Peripheral Lymph ◽  
Endothelial Surface ◽  
Dose Dependent

Previous studies have shown that unactivated lymphocytes bind to CS1 peptide and that the adhesion of these cells to high endothelium is inhibited by CS1 peptide. These results suggest that lymphocyte binding occurs via recognition of the CS1-containing splice variant of fibronectin expressed on the high endothelial surface. We have now extended these studies by determining the role of the CS1 receptor, alpha 4 beta 1 (VLA-4) and the alternative VLA-4 ligand, VCAM-1 in a rat model of lymphocyte-high endothelial cell interaction. Anti-VLA-4 antibody, HP2/1, blocked lymphocyte adhesion to resting and IFN-gamma (interferon-gamma) pretreated cultured high endothelial cells (HEC) in a dose-dependent manner with maximal inhibition of 60%. HP2/1 completely blocked the adhesion of rat lymphocytes to immobilized CS1 peptide and to a recombinant soluble (rs) form of human VCAM-1. Lymphocyte binding to rsVCAM-1 was also completely blocked by CS1 peptide. Anti-rat VCAM-1 monoclonal antibody 5F10 inhibited adhesion to untreated and IFN-gamma-treated HEC equally and its effect at 50% inhibition was slightly less than that of HP2/1. These findings suggest that a CS1 peptide-inhibitable ligand expressed by high endothelium is VCAM-1. The majority of cultured HEC expressed significant levels of VCAM-1 under basal conditions, as did HEV in peripheral lymph nodes. VCAM-1 expression by HEC was upregulated by cytokine pretreatment and the effects were ordered: IFN-gamma &gt; TNF-alpha &gt; IL-1 beta. The results described here demonstrate that rat peripheral lymph node HEC express VCAM-1, its expression is upregulated by cytokines, in particular IFN-gamma, and it supports the adhesion of unactivated lymphocytes. They also suggest that the VLA-4/VCAM-1 adhesion pathway may operate during the constitutive migration of lymphocytes into lymphoid organs. Although the mechanism of CS1 peptide inhibition was not determined, these results show that VCAM-1 is a CS1 peptide-inhibitable ligand and therefore CS1, on its own, cannot be used as a specific indicator of fibronectin activity.

PROTECTIVE ROLE OF FICUS RACEMOSA IN DIABETES INDUCED NEUROPATHY: STRUCTURAL AND FUNCTIONAL EVIDENCES

INDIAN DRUGS ◽  
2017 ◽  
Vol 54 (11) ◽  
pp. 58-60
Author(s):  
N Solanki ◽  
◽  
S. K Bhavsar
Keyword(s):  
Sciatic Nerve ◽  
Diabetic Neuropathy ◽  
Ethanolic Extract ◽  
Protective Role ◽  
Diabetic Rats ◽  
Dependent Manner ◽  
Traditional System ◽  
Ficus Racemosa ◽  
Dose Dependent

Ficus racemosa is used in traditional system of medicine for various health problems and diseases, and is commonly known as Gular fig. The main objective was to study its effects against streptozotocin induced diabetic neuropathy by structural and functional marker. Investigation of diabetic neuropathy was carried out through functional and structural assessment in streptozotocin induced in diabetic rats. Diabetic rats were treated for 28 days in dose dependent manner of Ficus racemosa aqueous extract (250 mg/kg and 500 mg/kg) and ethanolic extract (200 mg/kg and 400 mg/kg). Study showed marked protection observed by Ficus racemosa in hippocampus region of brain and sciatic nerve tissues. Ficus racemosa treatment showed improvement in functional and structural markers, which strongly suggest its protective role in diabetic neuropathy.

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.

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