PHARMACOLOGICAL STUDIES ON A PLANT LECTIN ALOCTIN A II. INHIBITORY EFFECT OF ALOCTIN A ON EXPERIMENTAL MODELS OF INFLAMMATION IN RATS

SummaryDipyridamole inhibits platelet aggregation in whole blood at lower concentrations than in plasma. The blood cells responsible for increased effectiveness in blood are the erythrocytes. Using the impedance aggregometer we have carried out a series of pharmacological studies in vitro to elucidate the mechanism of action of dipyridamole in whole blood. Adenosine deaminase, an enzyme breaking down adenosine, reverses the inhibitory action of dipyridamole. Two different adenosine receptor antagonists, 5’-deoxy-5’-methylthioadenosine and theophylline, also partially neutralize the activity of dipyridamole in blood. Enprofylline, a phosphodiesterase inhibitor with almost no adenosine receptor antagonistic properties, potentiates the inhibition of platelet aggregation by dipyridamole. An inhibitory effect similar to that of dipyridamole can be obtained combining a pure adenosine uptake inhibitor (RE 102 BS) with a pure phosphodiesterase inhibitor (MX-MB 82 or enprofylline). Mixing the blood during preincubation with dipyridamole increases the degree of inhibition. Lowering the haematocrit slightly reduces the effectiveness.Although we did not carry out direct measurements of adenosine levels, the results of our pharmacological studies clearly show that dipyridamole inhibits platelet aggregation in whole blood by blocking the reuptake of adenosine formed from precursors released by red blood cells following microtrauma. Its slight phosphodiesterase inhibitory action potentiates the effects of adenosine on platelets.

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Biochemical and Pharmacological Properties of SANORG 34006, a Potent and Long-Acting Synthetic Pentasaccharide

Blood ◽

10.1182/blood.v91.11.4197 ◽

1998 ◽

Vol 91 (11) ◽

pp. 4197-4205 ◽

Cited By ~ 151

Author(s):

J.M. Herbert ◽

J.P. Hérault ◽

A. Bernat ◽

R.G.M. van Amsterdam ◽

J.C. Lormeau ◽

...

Keyword(s):

Thrombin Generation ◽

Ex Vivo ◽

Thrombus Formation ◽

Factor Xa ◽

Therapeutic Index ◽

Inhibitory Effect ◽

Experimental Models ◽

Treatment And Prevention ◽

Long Acting

Abstract SANORG 34006 is a new sulfated pentasaccharide obtained by chemical synthesis. It is an analog of the “synthetic pentasaccharide” (SR 90107/ ORG 31540) which represents the antithrombin (AT) binding site of heparin. SANORG 34006 showed a higher affinity to human AT than SR 90107/ORG 31540 (kd = 1.4 ± 0.3 v 48 ± 11 nmol/L), and it is a potent and selective catalyst of the inhibitory effect of AT on factor Xa (1,240 ± 15 anti–factor Xa U/mg v850 ± 27 anti-factor Xa U/mg for SR 90107/ORG 31540). In vitro, SANORG 34006 inhibited thrombin generation occurring via both the extrinsic and intrinsic pathway. After intravenous (IV) or subcutaneous (SC) administration to rabbits, SANORG 34006 displayed a long-lasting anti–factor Xa activity and inhibition of thrombin generation (TG) ex vivo. SANORG 34006 was slowly eliminated after IV or SC administration to rats, rabbits, and baboons, showed exceptionally long half-lives (between 9.2 hours in rats and 61.9 hours in baboons), and revealed an SC bioavailability near 100%. SANORG 34006 displayed antithrombotic activity by virtue of its potentiation of the anti–factor Xa activity of AT. It strongly inhibited thrombus formation in experimental models of thromboplastin/stasis-induced venous thrombosis in rats (IV) and rabbits (SC) (ED50values = 40.0 ± 3.4 and 105.0 ± 9.4 nmol/kg, respectively). The duration of its antithrombotic effects closely paralleled the ex vivo anti–factor Xa activity. SANORG 34006 enhanced rt-PA–induced thrombolysis and inhibited accretion of125I-fibrinogen onto a preformed thrombus in the rabbit jugular vein suggesting that concomitant use of SANORG 34006 during rt-PA therapy might be helpful in facilitating thrombolysis and preventing fibrin accretion onto the thrombus under lysis. Contrary to standard heparin, SANORG 34006 did not enhance bleeding in a rabbit ear incision model at a dose that equals 10 times the antithrombotic ED50 in this species and, therefore, exhibited a favorable therapeutic index. We suggest that SANORG 34006 is a promising compound in the treatment and prevention of various thrombotic diseases.

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Both M1 and M3 receptors regulate exocrine secretion by mucous acini

AJP Cell Physiology ◽

10.1152/ajpcell.1996.271.6.c1963 ◽

1996 ◽

Vol 271 (6) ◽

pp. C1963-C1972 ◽

Cited By ~ 38

Author(s):

D. J. Culp ◽

W. Luo ◽

L. A. Richardson ◽

G. E. Watson ◽

L. R. Latchney

Keyword(s):

Inhibitory Effect ◽

Exocrine Secretion ◽

Muscarinic Agonist ◽

High Affinity ◽

Muscarinic Response ◽

M1 Receptor ◽

M3 Receptors ◽

Pharmacological Studies ◽

Equilibrium Dissociation

We investigated the role of M1 and M3 receptors in regulating exocrine secretion from acini isolated from rat sublingual glands. In secretion experiments, we derived affinity values (KB) from Schild regression analysis for the antagonists pirenzepine (61.0 nM) and 4-diphenylacetoxy-N-methylpiperidine (4-DAMP; 1.06 nM). The KB for 4-DAMP is similar to its affinity value [equilibrium dissociation constant from competition studies (Ki); 1.81 nM] determined from radioligand competition experiments. In contrast, the KB for pirenzepine is between its high-affinity (17.6 nM) and low-affinity (404 nM) Ki values. In separate secretion experiments, we found that the M1 receptor antagonist, M1-toxin, induces a rightward shift in the concentration-response curve to muscarinic agonist and inhibits maximal secretion by 40%. The inhibitory effect of M1-toxin appears specific for M1 receptor blockade, since the toxin abolishes acinar high-affinity pirenzepine-binding sites and does not inhibit secretion induced by nonmuscarinic agents. Additional pharmacological studies indicate muscarinic receptors do not function through putative neural elements within isolated acini. Our combined results are consistent with both M1 and M3 receptors directly regulating mucous acinar exocrine secretion and indicate M3 receptors alone are insufficient to induce a maximal muscarinic response.

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Effects of Simvastatin on Retinoic Acid System in Primary Human Endometrial Stromal Cells and in a Chimeric Model of Human Endometriosis

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2012-3402 ◽

2013 ◽

Vol 98 (3) ◽

pp. E463-E471 ◽

Cited By ~ 21

Author(s):

Anna Sokalska ◽

MariaPia Anderson ◽

Jesus Villanueva ◽

Israel Ortega ◽

Kaylon L. Bruner-Tran ◽

...

Keyword(s):

Retinoic Acid ◽

Binding Protein ◽

Inhibitory Effect ◽

Experimental Models ◽

Nude Mouse Model ◽

Endometrial Stromal Cells ◽

Fatty Acid Binding ◽

Proliferation And Apoptosis ◽

Chimeric Model ◽

Hes Cells

Context: Retinoic acid (RA) may promote survival or apoptosis of cells, depending on the levels of binding proteins: apoptosis-inducing cellular RA binding protein 2 (CRABP2), and cell survival-promoting fatty acid binding protein 5 (FABP5). Increased cellular uptake of retinol and altered actions of RA related to reduced expression of CRABP2 may contribute to the development of endometriosis. Recently statins have been shown to inhibit growth of human endometrial stromal (HES) cells and to reduce the number and size of endometriotic implants in experimental models of this disorder. Objective: The objective of the study was to determine whether effects of simvastatin on HES cells and experimental endometriotic implants are related to the modulation of the RA system. Methods: Effects of simvastatin and RA on proliferation and apoptosis of HES cells were evaluated. Expression of stimulated by RA 6 (STRA6), CRABP2, and FABP5 was determined by real-time PCR and Western blotting. Effects of simvastatin were also evaluated in a nude mouse model of human endometriosis. Results: Simvastatin potentiated an inhibitory effect of RA on growth of HES cells. In HES cells, simvastatin induced expression of STRA6 and CRABP2 but not FABP5. Similarly, simvastatin treatment of nude mice bearing human endometrial xenografts led to an increased expression of CRABP2 and STRA6 proteins in ectopic lesions. Conclusions: Simvastatin interacts with the RA system, inducing the expression of the key protein regulating the uptake of retinol (STRA6) and the expression of apoptosis-promoting CRABP2. These effects may contribute to cooperative apoptosis-inducing effects of simvastatin and RA and support the examination of these compounds in the treatment of endometriosis.

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Physiological and Biochemical Vascular Reactivity Parameters of Angiotensin II and the Action of Biased Agonist TRV023

Advances in Pharmacological and Pharmaceutical Sciences ◽

10.1155/2020/3092721 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Marcos André Soares Leal ◽

Thanisia de Almeida ◽

João Guilherme Torres ◽

Luciene Cristina Gastalho Campos ◽

Elisardo Corral Vasquez ◽

...

Keyword(s):

Angiotensin Ii ◽

Vascular Reactivity ◽

Renin Angiotensin System ◽

Aortic Ring ◽

Experimental Models ◽

Organ Bath ◽

Angiotensin System ◽

Active Peptides ◽

Pharmacological Studies ◽

Physiological And Biochemical

Vascular reactivity experiments using isolated aortic rings have been widely used as a model for physiological and pharmacological studies since the early sixties. Here, we suggest several parameters that the researcher should pay attention to when investigating angiotensin II in their experimental models. Angiotensin II is one of the active peptides of the renin-angiotensin system and exerts its effect through the AT1 and AT2 receptors. Some studies seek to understand the effects of angiotensin II receptors at the vascular level by using vascular reactivity experiments. However, because of the large number of variations, there are only a handful of reactivity studies that seek to use this method. Thus, the objective of this study was to standardize experimental methods with angiotensin II, through vascular reactivity protocols. For this, variables such as basal tension, concentration interval, single concentration, curve concentration response, and multiple experiments using the same aortic ring were developed using the technique of vascular reactivity in an organ bath. This is the first study that has standardized the vascular reactivity protocol. In addition, we demonstrated the effects of TRV023-biased ligand of the AT1R at vascular sites.

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Study of Melatonin as Preventive Agent of Gastrointestinal Damage Induced by Sodium Diclofenac

Cells ◽

10.3390/cells9010180 ◽

2020 ◽

Vol 9 (1) ◽

pp. 180 ◽

Cited By ~ 1

Author(s):

Aroha B. Sánchez ◽

Beatriz Clares ◽

María J. Rodríguez-Lagunas ◽

María J. Fábrega ◽

Ana C. Calpena

Keyword(s):

Side Effects ◽

Redox State ◽

Ex Vivo ◽

Inhibitory Effect ◽

Experimental Models ◽

In Vivo Studies ◽

Histological Evaluation ◽

Sodium Diclofenac ◽

Cox 2

Safety profile of nonsteroidal anti-inflammatory drugs (NSAIDs) has been widely studied and both therapeutic and side effects at the gastric and cardiovascular level have been generally associated with the inhibitory effect of isoform 1 (COX-1) and 2 (COX-2) cyclooxygenase enzymes. Now there are evidences of the involvement of multiple cellular pathways in the NSAIDs-mediated-gastrointestinal (GI) damage related to enterocyte redox state. In a previous review we summarized the key role of melatonin (MLT), as an antioxidant, in the inhibition of inflammation pathways mediated by oxidative stress in several diseases, which makes us wonder if MLT could minimize GI NSAIDs side effects. So, the aim of this work is to study the effect of MLT as preventive agent of GI injury caused by NSAIDs. With this objective sodium diclofenac (SD) was administered alone and together with MLT in two experimental models, ex vivo studies in pig intestine, using Franz cells, and in vivo studies in mice where stomach and intestine were studied. The histological evaluation of pig intestine samples showed that SD induced the villi alteration, which was prevented by MLT. In vivo experiments showed that SD altered the mice stomach mucosa and induced tissue damage that was prevented by MLT. The evaluation by quantitative reverse transcription PCR (RT-qPCR) of two biochemical markers, COX-2 and iNOS, showed an increase of both molecules in less injured tissues, suggesting that MLT promotes tissue healing by improving redox state and by increasing iNOS/NO that under non-oxidative condition is responsible for the maintenance of GI-epithelium integrity, increasing blood flow and promoting angiogenesis and that in presence of MLT, COX-2 may be responsible for wound healing in enterocyte. Therefore, we found that MLT may be a preventive agent of GI damages induced by NSAIDs.

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