Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The findings presented in this paper indicate that glucocorticoids down-regulate Na(+)-Ca2+ exchanger (NCX) mRNA and activity in aortic myocytes. Serum and purified growth factors reversed NCX down-regulation. Dexamethasone, cortisol, or aldosterone decreased NCX activity by approximately 55% in 24 h. Dexamethasone was > 100 times more potent than aldosterone, indicating that a glucocorticoid receptor mediates the down-regulation of NCX activity. Dexamethasone decreased the NCX transcript to approximately 10% of the control level in 24 h without affecting plasma membrane Ca(2+)-ATPase transcripts. Fetal bovine serum increased NCX mRNA 10-fold in 4 h in dexamethasone-treated cells and restored full NCX activity in 16 h. The increase in NCX mRNA produced by serum required RNA and protein synthesis. Thrombin moderately increased NCX mRNA and partially restored NCX activity in dexamethasone-treated cells. Insulin, platelet-derived growth factor, or epidermal growth factor increased NCX mRNA similarly to thrombin. Tunicamycin, which inhibits N-linked glycosylation, prevented the restoration of NCX activity. These observations suggest that changes in the level of NCX mRNA mediate the opposing influences of glucocorticoids and growth factors on NCX activity. NCX induction by growth stimuli would increase the capacity for Ca2+ efflux and cycling between the cell and the environment.
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PMID:Regulation of sodium-calcium exchanger by glucocorticoids and growth factors in vascular smooth muscle. 796 68

Effects of a nitroxybutylester derivative of aspirin (NCX 4215) on platelet aggregation and prostanoid synthesis were compared to the effects of aspirin. NCX 4215 was approximately seven times more potent than aspirin as an inhibitor of thrombin-induced human platelet aggregation in vitro, but did not inhibit platelet thromboxane synthesis or gastric prostaglandin synthesis. NCX 4215 released nitric oxide when incubated in the presence of platelets and increased platelet levels of cGMP within 10 min of exposure, while aspirin did not. The anti-aggregatory effects of NCX 4215 in vitro were significantly attenuated by 10 microM hemoglobin. In ex vivo studies of ADP- or collagen- or thrombin-induced rat platelet aggregation, aspirin and NCX 4215 had comparable inhibitory effects 3 h after administration. Aspirin (10-120 mg/kg) caused extensive hemorrhagic erosion formation in the stomach of the rat within 3 h of oral administration, while NCX 4215 did not produce significant damage at doses of up to 300 mg/kg, nor when given daily for two weeks at 166 mg/kg. NCX 4215 did not alter systemic arterial blood pressure when administered intravenously to the rat. These studies demonstrate that NCX 4215 has comparable or enhanced anti-thrombotic activity to that of aspirin, but does not cause gastric damage or alter systemic blood pressure. The anti-thrombotic actions of NCX 4215 are, at least in part, due to generation of nitric oxide.
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PMID:Anti-thrombotic effects of a nitric oxide-releasing, gastric-sparing aspirin derivative. 867 38

The antiplatelet activity of two new nitrocompounds, chemically related to acetylsalicylic acid (NCX 4215 and NCX 4016), was studied in vitro to verify the hypothetical dual action of these drugs. Both drugs, in a dose-dependent way, inhibited arachidonic acid-induced platelet aggregation and thromboxane A2 production, measured as thromboxane B2 concentration in whole blood. These effects are likely to be related to cyclo-oxygenase inhibition. NCX 4215 and NCX 4016 in a dose-dependent way inhibited also thrombin-induced aggregation of platelets pretreated with acetylsalicylic acid. These inhibitory effects are related to nitric oxide release and cGMP increase and significantly reversed by oxyhaemoglobin and methylene blue. Either as a cyclo-oxygenase inhibitor or as a nitric oxide donor, NCX 4016 proved to be significantly more potent than NCX 4215.
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PMID:In vitro study of the anti-aggregating activity of two nitroderivatives of acetylsalicylic acid. 873 20

We studied in vitro the antiplatelet activity of a new nitroderivative chemically related to acetylsalicylic acid: 2 acetoxybenzoate 2-[1-nitroxy-methyl]-phenyl ester (NCX 4016), in order to identify any effects due to the release of nitric oxide and the blockade of cyclo-oxygenase. The effects of scalar doses of NCX 4016 on the early phase of platelet activation, platelet aggregation and thromboxane A2 production were investigated. We observed inhibitory effects of NCX 4016 on platelet adhesion (IC50 = 7.3 x 10(-5) M), platelet cytosolic calcium concentration, assayed by fluorescent probe Fura 2, and the expression of glycoprotein IIb/IIIa (CD41/alpha IIb beta 3) (IC50 = 3.4 x 10(-5) M) and P-selectin (CD62/GMP-140) (IC50 = 4.9 x 10(-5) M) measured by flow cytometry. NCX 4016 also prevented thrombin-induced platelet aggregation (IC50 = 3.9 x 10(-5) M). None of these parameters were affected by acetylsalicylic acid. These inhibitory activities of NCX 4016 were abolished by oxyhaemoglobin and methylene blue. Intracellular cyclic GMP observed during thrombin-induced aggregation was increased by incubation with NCX 4016. These results appear to be attributable to the release of nitric oxide, which activates soluble platelet guanylylcyclase and promotes intracellular cyclic GMP increase. NCX 4016 almost completely inhibited platelet thromboxane A2 production and arachidonic acid-induced platelet aggregation. This also occurred in the presence of oxyhaemoglobin and methylene blue, indicating that its antiplatelet activity can be attributed not only to nitric oxide release but also to cyclo-oxygenase inhibition.
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PMID:The antiplatelet effects of a new nitroderivative of acetylsalicylic acid--an in vitro study of inhibition on the early phase of platelet activation and on TXA2 production. 895 Jul 92

We studied the antithrombotic activity of 2-acetoxybenzoate 2-[1-nitroxy-methyl]-phenyl ester (NCX 4016), a novel nitric oxide (NO)-releasing aspirin derivative, in vivo in different animal models of platelet-dependent and independent pulmonary thromboembolism and compared it with that of aspirin. NCX 4016 protected mice from death induced by the intravenous (i.v.) injection of collagen plus epinephrine, of 9,11-dideoxy-11alpha, 9alpha-epoxymethano-prostaglandin F(2alpha) (U46619) and of thrombin while aspirin was only active against collagen plus epinephrine. The drop in platelet count and number of lung emboli were reduced by NCX 4016 more effectively than aspirin. NCX 4016 protected mice also from mechanical pulmonary embolism (i.v. injection of hardened rat red blood cells) while aspirin was ineffective. In rabbits, NCX 4016 significantly reduced the accumulation of [111In]oxine-labeled platelets in the pulmonary vasculature induced by collagen and by thrombin while aspirin produced reductions which were significant only versus collagen. In conclusion, NCX 4016 exerts a more pronounced antithrombotic activity than aspirin in vivo in two different animal species, largely due to a deeper inhibitory effect on platelets. NCX 4016 may represent a better antithrombotic agent than aspirin.
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PMID:Prevention of pulmonary thromboembolism by NCX 4016, a nitric oxide-releasing aspirin. 1084 12

Nitric oxide-releasing aspirins are new chemical entities obtained by adding a nitric oxide-releasing moiety to aspirin. NCX-4016 is the prototype of this family of molecules. NCX-4016 consists of the parent molecule (aspirin) linked to a 'spacer' via an ester linkage, which is in turn connected to a nitric oxide-releasing moiety. Both aspirin and nitric oxide moieties of NCX-4016 contribute to its effectiveness, the latter occurring via both cyclic guanosyl monophosphate-dependent and -independent mechanisms. In vitro studies have shown that NCX-4016 inhibits platelet aggregation induced by aspirin-sensitive (arachidonic acid) and aspirin-insensitive (thrombin) agonist. In contrast to aspirin, NCX-4016 exerts a multilevel regulation of inflammatory target, including caspase-1 and NF-kappaB. This broad spectrum of activities translates to an increased potency of this drug in modulating cardiovascular inflammation. Human studies have shown, that while nitric oxide-aspirin maintains its anti-thrombotic activity, it spares the gastrointestinal tract. Indeed, a 7-day course of NCX-4016 results in 90% reduction of gastric damage caused by equimolar doses of aspirin. Further studies are ongoing to define whether this superior anti-inflammatory and anti-thrombotic profile translates in clinical benefits in patients with cardiovascular diseases.
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PMID:NO-aspirin: mechanism of action and gastrointestinal safety. 1284 39

Antiplatelet therapy for the prevention and treatment of coronary artery disease (CAD) has undergone dramatic changes and improvements. Aspirin remains the first-line antiplatelet drug for clinical use. Newer platelet inhibitors such as the thienopyridine agents, ticlopidine and clopidogrel, have also been shown to be effective in treating CAD. There have been ongoing efforts to evaluate newer antiplatelet drugs, with the potential to improve clinical efficacy and safety. Some of the more promising antiplatelet agents include new adenosine diphosphate receptor antagonists such as prasugrel, cangrelor, and ticagrelor (AZD6140). In addition, a new thromboxane receptor antagonist, NCX-4016, a newly discovered protease-activated receptor antagonist that targets thrombin-induced platelet aggregation, and anti-von Willebrand factor aptamers show tremendous promise in refining antiplatelet therapy by targeting different receptors and molecules.
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PMID:Investigational antiplatelet drugs for the treatment and prevention of coronary artery disease. 1870 26

BACKGROUND AND PURPOSE The Na(+) /Ca(2+) exchanger is a bi-directional transporter that plays an important role in maintaining the concentration of cytosolic Ca(2+) ([Ca(2+) ](i) ) of quiescent platelets and increasing it during activation with some, but not all, agonists. There are two classes of Na(+) /Ca(2+) exchangers: K(+) -independent Na(+) /Ca(2+) exchanger (NCX) and K(+) -dependent Na(+) /Ca(2+) exchanger (NCKX). Platelets have previously been shown to express NCKX1. However, initial studies from our laboratory suggest that NCX may also play a role in platelet activation. The objective of this study was to determine if the human platelet expresses functional NCXs. EXPERIMENTAL APPROACH RT-PCR, DNA sequencing and Western blot analysis were utilized to characterize the human platelet Na(+) /Ca(2+) exchangers. Their function during quiescence and collagen-induced activation was determined by measuring [Ca(2+) ](i) with calcium-green/fura-red in response to: changes in the Na(+) and K(+) gradient, NCX pharmacological inhibitors (CBDMB, KB-R7943 and SEA0400) and antibodies specific to extracellular epitopes of the exchangers. KEY RESULTS Human platelets express NCX1.3, NCX3.2 and NCX3.4. The NCXs operate in the Ca(2+) efflux mode in resting platelets and also during their activation with thrombin but not collagen. Collagen-induced increase in [Ca(2+) ](i) was reduced with the pharmacological inhibitors of NCX (CBDMB, KB-R7943 or SEA0400), anti-NCX1 and anti-NCX3. In contrast, anti-NCKX1 enhanced the collagen-induced increase in [Ca(2+) ](i) . CONCLUSIONS AND IMPLICATIONS Human platelets express K(+) -independent Na(+) /Ca(2+) exchangers NCX1.3, NCX3.2 and NCX3.4. During collagen activation, NCX1 and NCX3 transiently reverse to promote Ca(2+) influx, whereas NCKX1 continues to operate in the Ca(2+) efflux mode to reduce [Ca(2+) ](i) .
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PMID:Molecular and functional characterization of the human platelet Na(+) /Ca(2+) exchangers. 2179 May 37

We have previously demonstrated that Na(+)/Ca(2+) exchangers (NCXs) potentiate Ca(2+) signaling evoked by thapsigargin in human platelets, via their ability to modulate the secretion of autocoids from dense granules. This link was confirmed in platelets stimulated with the physiological agonist, thrombin, and experiments were performed to examine how Ca(2+) removal by the NCX modulates platelet dense granule secretion. In cells loaded with the near-membrane indicator FFP-18, thrombin stimulation was observed to elicit an NCX-dependent accumulation of Ca(2+) in a pericellular region around the platelets. To test whether this pericellular Ca(2+) accumulation might be responsible for the influence of NCXs over platelet function, platelets were exposed to fast Ca(2+) chelators or had their glycocalyx removed. Both manipulations of the pericellular Ca(2+) rise reduced thrombin-evoked Ca(2+) signals and dense granule secretion. Blocking Ca(2+)-permeable ion channels had a similar effect, suggesting that Ca(2+) exported into the pericellular region is able to recycle back into the platelet cytosol. Single cell imaging with extracellular Fluo-4 indicated that thrombin-evoked rises in extracellular [Ca(2+)] occurred within the boundary described by the cell surface, suggesting their presence within the open canalicular system (OCS). FFP-18 fluorescence was similarly distributed. These data suggest that upon thrombin stimulation, NCX activity creates a rise in [Ca(2+)] within the pericellular region of the platelet from where it recycles back into the platelet cytosol, acting to both accelerate dense granule secretion and maintain the initial rise in cytosolic [Ca(2+)].
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PMID:Pericellular Ca(2+) recycling potentiates thrombin-evoked Ca(2+) signals in human platelets. 2430 63

Thrombin acts on the endothelium by activating protease-activated receptors (PARs). The endothelial thrombin-PAR system becomes deregulated during pathological conditions resulting in loss of barrier function and a pro-inflammatory and pro-angiogenic endothelial phenotype. We reported recently that the ion transporter Na(+)/Ca(2+) exchanger (NCX) operating in the Ca(2+)-influx (reverse) mode promoted ERK1/2 activation and angiogenesis in vascular endothelial growth factor-stimulated primary human vascular endothelial cells. Here, we investigated whether Ca(2+) influx through NCX was involved in ERK1/2 activation, angiogenesis, and endothelial barrier dysfunction in response to thrombin. Reverse-mode NCX inhibitors and RNAi-mediated NCX1 knockdown attenuated ERK1/2 phosphorylation in response to thrombin or an agonist of PAR-1, the main endothelial thrombin receptor. Conversely, promoting reverse-mode NCX by suppressing Na(+)-K(+)-ATPase activity enhanced ERK1/2 activation. Reverse-mode NCX inhibitors and NCX1 siRNA suppressed thrombin-induced primary human vascular endothelial cell angiogenesis, quantified as proliferation and tubular differentiation. Reverse-mode NCX inhibitors or NCX1 knockdown preserved barrier integrity upon thrombin stimulation in vitro. Moreover, the reverse-mode NCX inhibitor SEA0400 suppressed Evans' blue albumin extravasation to the lung and kidneys and attenuated edema formation and ERK1/2 activation in the lungs of mice challenged with a peptide activator of PAR-1. Mechanistically, thrombin-induced ERK1/2 activation required NADPH oxidase 2-mediated reactive oxygen species (ROS) production, and reverse-mode NCX inhibitors and NCX1 siRNA suppressed thrombin-induced ROS production. We propose that reverse-mode NCX is a novel mechanism contributing to thrombin-induced angiogenesis and hyperpermeability by mediating ERK1/2 activation in a ROS-dependent manner. Targeting reverse-mode NCX could be beneficial in pathological conditions involving unregulated thrombin signaling.
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PMID:Endothelial Angiogenesis and Barrier Function in Response to Thrombin Require Ca2+ Influx through the Na+/Ca2+ Exchanger. 2597 35


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