In Vivo and In Vitro Studies of the Inhibitory Effect of Propofol on Human Platelet Aggregation 

1998 ◽  
Vol 88 (2) ◽  
pp. 362-370 ◽  
Author(s):  
Hiroshi Aoki ◽  
Toshiki Mizobe ◽  
Shinji Nozuchi ◽  
Noriko Hiramatsu
Keyword(s):  
Platelet Aggregation ◽  
Intracellular Calcium ◽  
Bleeding Time ◽  
Inhibitory Effect ◽  
Ion Concentration ◽  
Inhibitory Effects ◽  
Fat Emulsion ◽  
Intracellular Calcium Ion

Background The inhibitory effects of propofol on platelet aggregation are controversial because the fat emulsion used as the solvent for propofol may affect platelet function. The effects of propofol on platelet intracellular calcium ion concentration and on aggregation were investigated. Methods Platelet aggregation was measured in 10 patients who received an intravenous infusion of propofol. Intralipos, the propofol solvent, was infused in 10 healthy volunteers and platelet aggregation were measured. The in vitro effects of propofol and Intralipos on platelets were also investigated. The inhibitory effects of various concentrations of propofol were studied. The effects of propofol on the changes in intracellular calcium level using a fluorescent dye, fura-2, were also observed. Template bleeding time was measured to determine the effect of propofol in clinical use. Results Platelet aggregation was significantly inhibited by infusion of propofol, although bleeding time was not prolonged. Intralipos did not inhibit platelets either in vivo or in vitro. Propofol significantly inhibited platelet aggregation in vitro and at 5.81 +/- 2.73 microg/ml but not at 2.08 +/- 1.14 microg/ml. The increase of intracellular calcium concentration was inhibited both in influx and discharge of calcium. Conclusions Propofol inhibited platelet aggregation both in vivo and in vitro. Inhibition of platelet aggregation appeared to be caused by propofol itself and not by the fat emulsion. This inhibitory effect was also supported by the suppressed influx and discharge of calcium. No change in the bleeding time suggests that this inhibitory effect does not impair hemostasis clinically.

scholarly journals Synthesis and Thrombin, Factor Xa and U46619 Inhibitory Effects of Non-amidino and Amidino N2-Thiophenecarbonyl- and N2-Tosylanthranilamides

2017 ◽  
Author(s):  
Soo Hyun Lee ◽  
Wonhwa Lee ◽  
Nguyen Thi Ha ◽  
Il Soo Um ◽  
Jong-Sup Bae ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Ex Vivo ◽  
Factor Xa ◽  
Inhibitory Effects ◽  
Human Endothelial Cells ◽  
Antithrombotic Activity ◽  
Pharmacological Targets

Thrombin (factor IIa) and factor Xa (FXa) are key enzymes at the junction of the intrinsic and extrinsic coagulation pathways and are the most attractive pharmacological targets for the development of novel anticoagulants. Twenty non-amidino N2-thiophencarbonyl- and N2-tosyl anthranilamides 1-20 and six amidino N2-thiophencarbonyl- and N2-tosylanthranilamides 21-26 were synthesized and evaluated prothrombin time (PT) and activated partial thromboplastin time (aPTT) using human plasma at concentration 30 μg/mL in vitro. From these results, compounds 5, 9, and 21-23 were selected to study the further antithrombotic activity. The anticoagulant properties of 5, 9, and 21-23 significantly exhibited a concentration-dependent prolongation of in vitro PT and aPTT, in vivo bleeding time, and ex vivo clotting time. These compounds concentration-dependently inhibited the activities of thrombin and FXa and inhibited the generation of thrombin and FXa in human endothelial cells. In addition, data showed that 5, 9, and 21-23 significantly inhibited thrombin catalyzed fibrin polymerization and mouse platelet aggregation and inhibited platelet aggregation induced U46619 in vitro and ex vivo. N-(3'-Amidinophenyl)-2-((thiophen-2''-yl)carbonyl amino)benzamide (21) was most active.

The Effects of Brinolase (Fibrinolytic Enzyme from Aspergillus Oryzae) on Platelet Aggregation of Dog and Man

1972 ◽  
Vol 28 (01) ◽  
pp. 031-048 ◽  
Author(s):  
W. H. E Roschlau ◽  
R Gage
Keyword(s):  
Platelet Aggregation ◽  
Aspergillus Oryzae ◽  
Degradation Products ◽  
Blood Platelet ◽  
Human Platelets ◽  
Fibrinolytic Enzyme ◽  
Inhibitory Effects ◽  
Blood Platelet Aggregation

SummaryInhibition of blood platelet aggregation by brinolase (fibrinolytic enzyme from Aspergillus oryzae) has been demonstrated with human platelets in vitro and with dog platelets in vivo and in vitro, using both ADP and collagen as aggregating stimuli. It is suggested that the optimal inhibitory effects of brinolase occur indirectly through the generation of plasma fibrinogen degradation products, without compromising platelet viability, rather than by direct proteolysis of platelet structures.

The Effect of Barbituric Acid Derivatives on Platelet Function in Vitro and in Vivo

1973 ◽  
Vol 30 (02) ◽  
pp. 315-326
Author(s):  
J. Heinz Joist ◽  
Jean-Pierre Cazenave ◽  
J. Fraser Mustard
Keyword(s):  
Platelet Aggregation ◽  
Platelet Function ◽  
Barbituric Acid ◽  
Platelet Rich Plasma ◽  
Inhibitory Effect ◽  
Primary Response ◽  
Sodium Pentobarbital ◽  
Barbituric Acid Derivatives

SummarySodium pentobarbital (SPB) and three other barbituric acid derivatives were found to inhibit platelet function in vitro. SPB had no effect on the primary response to ADP of platelets in platelet-rich plasma (PRP) or washed platelets but inhibited secondary aggregation induced by ADP in human PRP. The drug inhibited both phases of aggregation induced by epinephrine. SPB suppressed aggregation and the release reaction induced by collagen or low concentrations of thrombin, and platelet adherence to collagen-coated glass tubes. The inhibition by SPB of platelet aggregation was readily reversible and isotopically labeled SPB did not become firmly bound to platelets. No inhibitory effect on platelet aggregation induced by ADP, collagen, or thrombin could be detected in PRP obtained from rabbits after induction of SPB-anesthesia.

In vitro inhibitory effects of glucosamine, chondroitin and diacerein on human hepatic CYP2D6

2021 ◽  
Vol 36 (4) ◽  
pp. 259-270
Author(s):  
Boon Hooi Tan ◽  
Nafees Ahemad ◽  
Yan Pan ◽  
Uma Devi Palanisamy ◽  
Iekhsan Othman ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
High Performance ◽  
Inhibitory Effect ◽  
Inhibitory Effects ◽  
Time Curve ◽  
Clinical Drugs ◽  
Inhibition Potencies ◽  
P450 2D6

Abstract Objectives Glucosamine, chondroitin and diacerein are natural compounds commonly used in treating osteoarthritis. Their concomitant intake may trigger drug–natural product interactions. Cytochrome P450 (CYP) has been implicated in such interactions. Cytochrome P450 2D6 (CYP2D6) is a major hepatic CYP involved in metabolism of 25% of the clinical drugs. This study aimed to investigate the inhibitory effect of these antiarthritic compounds on CYP2D6. Methods CYP2D6 was heterologously expressed in Escherichia coli. CYP2D6–antiarthritic compound interactions were studied using in vitro enzyme kinetics assay and molecular docking. Results The high-performance liquid chromatography (HPLC)-based dextromethorphan O-demethylase assay was established as CYP2D6 marker. All glucosamines and chondroitins weakly inhibited CYP2D6 (IC50 values >300 µM). Diacerein exhibited moderate inhibition with IC50 and K i values of 34.99 and 38.27 µM, respectively. Its major metabolite, rhein displayed stronger inhibition potencies (IC50=26.22 μM and K i =32.27 μM). Both compounds exhibited mixed-mode of inhibition. In silico molecular dockings further supported data from the in vitro study. From in vitro–in vivo extrapolation, rhein presented an area under the plasma concentration-time curve (AUC) ratio of 1.5, indicating low potential to cause in vivo inhibition. Conclusions Glucosamine, chondroitin and diacerein unlikely cause clinical interaction with the drug substrates of CYP2D6. Rhein, exhibits only low potential to cause in vivo inhibition.

Inhibition of Human Platelet Aggregation by the Proteolytic Effect of Streptokinase (SK). Role of the Factor VIII Related Antigen

1975 ◽  
Author(s):  
R. Castillo ◽  
S. Maragall ◽  
J. A. Guisasola ◽  
F. Casals ◽  
C. Ruiz ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Factor Viii ◽  
Platelet Rich Plasma ◽  
Gel Filtration ◽  
Inhibitory Effect ◽  
Factor Viii Related Antigen ◽  
Human Factor Viii ◽  
Induced Aggregation

Defective ADP-induced platelet aggregation has been observed in patients treated with streptokinase. This same effect appears “in vitro” when adding SK to platelet rich plasma (PRP). Classic hemophilia and normal platelet poor plasmas (PPP) treated with SK inhibit the aggregation of washed platelets; plasmin-treated normal human serum also shows an inhibitory effect on platelet aggregation. However, von Willebrand SK-treated plasmas do not inhibit the aggregation of washed platelets. The same results appear when plasmas are previously treated with a rabbit antibody to human factor VIII.This confirms that the antiaggregating effect is mainly linked to the digested factor VIII related antigen.The inhibition of ADP-induced platelet aggregation has been proved in gel filtration-isolated and washed platelets from SK-treated PRP.Defective ristocetin-induced platelet aggregation has also been observed- This action does not appear in washed platelets from SK-treated PRP in presence of normal PPP, but it does in presence of SK-treated PPP, which suggests that the inhibition of the ristocetin-induced aggregation is due to the lack of factor VIII and not to the factor VIII-related products.Heparin, either “in vivo” or “in vitro”, has corrected the antiaggregating effect of SK.

o-Raffinose cross-linked hemoglobin improves the hemostatic defect associated with anemia and thrombocytopenia in rabbits

Blood ◽  
2000 ◽  
Vol 96 (10) ◽  
pp. 3630-3636 ◽  
Author(s):  
David H. Lee ◽  
Leslie Bardossy ◽  
Nichole Peterson ◽  
Morris A. Blajchman
Keyword(s):  
Blood Loss ◽  
Bleeding Time ◽  
Platelet Reactivity ◽  
Inhibitory Effect ◽  
Clinical Settings ◽  
No Donor ◽  
Hemostatic Effect ◽  
Circulating Levels

Abstract Several different preparations of cross-linked hemoglobin (CLHb) are being evaluated for their efficacy and safety as red cell substitutes in a variety of preclinical and clinical settings. Because CLHb is known to sequester nitric oxide (NO) and inhibit NO-mediated processes, we hypothesized that CLHb would have a hemostatic effect by enhancing platelet reactivity, inducing vasoconstriction, or both. Infusion of o-raffinose CLHb shortened the prolonged microvascular bleeding time and decreased blood loss from ear incisions in rabbits rendered anemic and thrombocytopenic. Moreover, this hemostatic effect persisted for at least 24 hours after infusion. Phenylephrine induced a degree of vasoconstriction similar to that induced by CLHb but did not shorten the bleeding time or decrease blood loss, suggesting that vasoconstriction alone cannot account for the hemostatic effect of CLHb. There was no evidence of CLHb-induced activation of coagulation in vivo, since infusion of CLHb did not increase circulating levels of thrombin-antithrombin complex. In vitro, CLHb abolished the inhibitory effect of the NO donor 3-morpholinosydnonimine on platelet aggregation and enhanced the aggregation of stimulated but not resting platelets. This potentiating effect was not attenuated by the addition of superoxide dismutase or catalase. To evaluate the potential arterial thrombogenicity of CLHb, a model of carotid artery thrombosis was developed in rabbits without thrombocytopenia or anemia. Compared with albumin infusion, CLHb infusion shortened the time to complete carotid occlusion. These data suggest that CLHb may shift the thromboregulatory balance toward clot formation, resulting in decreased bleeding in anemic and thrombocytopenic rabbits and possibly increasing arterial thrombogenicity in normal rabbits.

Endothelin inhibits thick ascending limb chloride flux via ETB receptor-mediated NO release

2000 ◽  
Vol 279 (2) ◽  
pp. F326-F333 ◽  
Author(s):  
Craig F. Plato ◽  
David M. Pollock ◽  
Jeffrey L. Garvin
Keyword(s):  
Intracellular Calcium ◽  
Chloride Transport ◽  
Inhibitory Effect ◽  
Thick Ascending Limb ◽  
Inhibitory Effects ◽  
Chloride Flux ◽  
Nacl Transport ◽  
No Release ◽  
Bq 610

Endothelin-1 (ET-1) inhibits transport in various nephron segments, and the thick ascending limb of the loop of Henle (TALH) expresses ET-1 receptors. In many tissues, activation of ETB receptors stimulates release of NO, and we recently reported that endogenous NO inhibits TALH chloride flux ( J Cl). However, the relationship between ET-1 and NO in the control of nephron transport has not been extensively studied. We hypothesized that ET-1 decreases NaCl transport by cortical TALHs through activation of ETBreceptors and release of NO. Exogenous ET-1 (1 nM) decreased J Cl from 118.3 ± 15.0 to 62.7 ± 13.6 pmol · mm−1 · min−1 (48.3 ± 8.2% reduction), whereas removal of ET-1 increased J Cl in a separate group of tubules from 87.6 ± 10.7 to 115.2 ± 10.3 pmol · mm−1 · min−1 (34.5 ± 6.2% increase). To determine whether NO mediates the inhibitory effects of ET-1 on J Cl, we examined the effect of inhibiting of NO synthase (NOS) with N G-nitro-l-arginine methyl ester (l-NAME) on ET-1-induced changes in J Cl. l-NAME (5 mM) completely prevented the ET-1-induced reduction in J Cl, whereas d-NAME did not. l-NAME alone had no effect on J Cl. These data suggest that the effects of ET-1 are mediated by NO. Blockade of ETBreceptors with BQ-788 prevented the inhibitory effects of 1 nM ET-1. Activation of ETB receptors with sarafotoxin S6c mimicked the inhibitory effect of ET-1 on J Cl (from 120.7 ± 12.6 to 75.4 ± 13.3 pmol · mm−1 · min−1). In contrast, ETA receptor antagonism with BQ-610 did not prevent ET-1-mediated inhibition of TALH J Cl (from 96.5 ± 10.4 to 69.5 ± 8.6 pmol · mm−1 · min−1). Endothelin increased intracellular calcium from 96.9 ± 14.0 to 191.4 ± 11.9 nM, an increase of 110.8 ± 26.1%. We conclude that exogenous endothelin indirectly decreases TALH J Cl by activating ETB receptors, increasing intracellular calcium concentration, and stimulating NO release. These data suggest that endothelin acts as a physiological regulator of TALH NO synthesis, thus inhibiting chloride transport and contributing to the natriuretic effects of ET-1 observed in vivo.

Randomized, Placebo-controlled, Blinded and Cross-matched Study on the Antiplatelet Effect of Inhaled Nitric Oxide in Healthy Volunteers

2000 ◽  
Vol 83 (02) ◽  
pp. 309-315 ◽  
Author(s):  
Axel Herr ◽  
Johann Motsch ◽  
Alexandra Holzmann ◽  
Jörg Weimann ◽  
Friedemann Taut ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Platelet Aggregation ◽  
Healthy Volunteers ◽  
Bleeding Time ◽  
Inhibitory Effect ◽  
Inhaled Nitric Oxide ◽  
Men And Women ◽  
Fibrinogen Binding ◽  
Matched Study

SummaryThe platelet inhibitory effect of 0-40 ppm inhaled nitric oxide (NO) was investigated in healthy men and women. In both groups, ADPand collagen-induced platelet aggregation was significantly inhibited 20 (T20) and 40 min (T40) after the beginning of inhalation of 5, 10, and 40 ppm. Moreover, in both men and women, the in vitro bleeding time was significantly prolonged at T20 and T40 during inhalation of 40 ppm. Inhalation of NO also inhibited P-selectin expression at 5, 10, and 40 ppm and fibrinogen binding to the GPIIb/IIIa-receptor at 40 ppm. In conclusion, in healthy volunteers, the platelet inhibitory effect of inhaled NO was not dose-related, since it was significant at 5 and 10 ppm but did not increase during the administration of higher NO concentrations. In addition, gender-related differences were only observed in ADP-induced platelet aggregation at 10 ppm and in bleeding time prolongation at 40 ppm.

Presynaptic inhibition of canine renal adrenergic nerves by acetylcholine in vivo

1979 ◽  
Vol 237 (3) ◽  
pp. H326-H331
Author(s):  
N. W. Robie
Keyword(s):  
Nerve Stimulation ◽  
Neurotransmitter Release ◽  
Intact Animal ◽  
Inhibitory Effect ◽  
Inhibitory Effects ◽  
Renal Vasculature ◽  
Anesthetized Dogs ◽  
Renal Sympathetic

Experiments were performed in anesthetized dogs to determine whether previously reported in vitro inhibition of sympathetic neurotransmitter release by acetylcholine could be demonstrated in the renal vasculature of the intact animal. Vasoconstrictor responses to renal sympathetic nerve stimulation at varying frequencies were compared to intra-arterial injections of norepinephrine before and during intra-arterial infusions of acetylcholine, 2.5--80 micrograms/min. The vasoconstrictor responses to nerve stimulation were inhibited to a greater extent than were responses to norepinephrine during infusions of acetylcholine. The inhibitory effects of acetylcholine on nerve stimulation were dose and frequency dependent. The inhibition was blocked by atropine but not altered by physostigmine. Changes in renal blood flow per se did not contribute to the inhibitory effect of acetylcholine, since another vasodilator agent, sodium acetate, did not affect the nerve stimulation-norepinephrine vasocontriction relationship. Thus, acetylcholine produced inhibition of in vivo renal sympathetic vasoconstrictor responses, and the receptor involved appears to be muscarinic.

Cancer-chemopreventive effects of natural sweeteners and related compounds

2002 ◽  
Vol 74 (7) ◽  
pp. 1309-1316 ◽  
Author(s):  
Takao Konoshima ◽  
Midori Takasaki
Keyword(s):  
Mouse Skin ◽  
Stevia Rebaudiana ◽  
Chemical Carcinogenesis ◽  
Inhibitory Effect ◽  
Skin Carcinogenesis ◽  
Inhibitory Effects ◽  
Chemopreventive Agents ◽  
Vitro Assay

To search for possible cancer-chemopreventive agents from natural resources, several natural sweeteners were screened by the in vitro assay indicated by the inhibitory effects of Epstein-Barr virus early antigen (EBV-EA) induction. Of active compounds that showed the remarkable inhibitory effects on the EBV-EA induction, stevioside, from the leaves of Stevia rebaudiana, and mogroside V, from the fruits of Momordica grosvenori, exhibited significant inhibitory effects on the two-stage mouse skin carcinogenesis in vivo induced by 7,12-dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). The inhibitory effect of stevioside is stronger than that of glycyrrhizin, which had been known as an antitumor-promoter in chemical carcinogenesis. Furthermore, stevioside also inhibited mouse skin carcinogenesis initiated by peroxynitrite. These results suggest that stevioside and mogroside V might be valuable as chemopreventive agents for chemical carcinogenesis.

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