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PubMed1997

YM-60828, a novel factor Xa inhibitor: separation of its antithrombotic effects from its prolongation of bleeding time.

The antithrombotic effects of intravenous infusions of YM-60828 ([N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N-[(7-amidino-2-nap hthyl)methyl]sulfamoyl]acetic acid dihydrochloride), a novel factor Xa inhibitor, argatroban, heparin and dalteparin in an arterio-venous shunt model were studied in comparison with their effects on template bleeding time. In an arterio-venous shunt model, all agents exerted antithrombotic effects in a dose-dependent manner. ID50 values of YM-60828, argatroban, heparin and dalteparin were 0.0087 mg/kg/h. 0.027 mg/kg/h, 22 IU/kg/h and 11 IU/kg/h, respectively. In bleeding time studies, all agents prolonged bleeding time in a dose-dependent manner. Doses (ED2) of YM-60828, argatroban, heparin and dalteparin, which caused 2-fold prolongation of bleeding time in the saline group, were 3.0 mg/kg/h, 0.25 mg/kg/h, 18 IU/kg/h and 26 IU/kg/h. respectively. The risk-benefit ratio (ED2/ID50) of YM-60828 was much greater than that of the other agents. These data suggest that the antithrombotic effect of YM-60828 is separate from its prolongation of bleeding time and that YM-60828 is much safer than conventional anticoagulant agents.

Animals↗
PubMed1984

Selective inhibition of thrombin by (2R,4R)-4-methyl-1-[N2-[(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl++ +) sulfonyl]-l-arginyl)]-2-piperidinecarboxylic acid.

The potency of thrombin inhibition by 4-methyl-1-[N2-[(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl)-sulfony l]- L-arginyl]-2-piperidinecarboxylic acid (MQPA) depended on the stereoconformation of the 2-piperidinecarboxylic acid moiety. Ki values for bovine alpha-thrombin were 0.019 microM with (2R,4R)-MQPA, 0.24 microM with (2R,4S)-MQPA, 1.9 microM with (2S,4R)-MQPA, and 280 microM with (2S,4S)-MQPA. (2R,4R)-MQPA of the four stereoisomers of MQPA was also the most potent inhibitor for other trypsin-like serine proteases with Ki values of 5.0 microM for trypsin, 210 microM for factor Xa, 800 microM for plasmin, and 1500 microM for plasma kallikrein. Examination of the potency of thrombin inhibition by arginine derivatives related to MQPA in structure suggested the presence of a specific binding site for the carboxamide portion (C-terminal side). The relative inhibitory potency of the four stereoisomers of MQPA for trypsin was nearly identical with that for thrombin, suggesting that the specific binding site for the carboxamide portion is present in both enzymes. Modification of thrombin by phosphopyridoxylation or the presence of heparin did not significantly alter the binding of MQPA.

Animals↗
PubMed2003

Antithrombotic effects of FK419, a novel nonpeptide platelet GPIIb/IIIa antagonist, in a guinea pig photochemically induced middle cerebral artery thrombosis model: comparison with ozagrel and argatroban.

Platelet activation and subsequent aggregation play a key role in the pathogenesis of ischemic brain damage. Recent studies revealed that enhanced platelet activation is also observed after ischemia, suggesting that secondary thrombus formation might participate in the development of cerebral infarction. The binding of platelet glycoprotein GPIIb/IIIa (integrin alpha(IIb)beta3) to fibrinogen is the final common pathway in platelet aggregation. Therefore, GPIIb/IIIa antagonists might be useful in acute ischemic stroke as well as in the secondary prevention of ischemic stroke. In the present study, we evaluated the effect of three compounds, FK419 ((S)-2-acetylamino-3-[(R)-[1-[3-(piperidin-4-yl) propionyl] piperidin-3-ylcarbonyl] amino] propionic acid trihydrate), a novel nonpeptide GPIIb/IIIa antagonist, ozagrel, a selective thromboxane A(2) synthase inhibitor, and argatroban, a thrombin inhibitor, on middle cerebral artery (MCA) patency and ischemic brain damage using photochemically induced MCA thrombosis model in guinea pigs. FK419, ozagrel, or argatroban was administered 5 min after the termination of photoirradiation. FK419 dose-dependently improved MCA patency by decreasing the total occlusion time, time to continuous reperfusion, and the number of cyclic flow reductions, at doses that inhibited ADP-induced platelet aggregation ex vivo. In contrast, ozagrel only improved total occlusion time, and argatroban showed no improvement in MCA patency. FK419 also reduced ischemic brain damage in a dose-dependent fashion, whereas ozagrel and argatroban did not. Finally, FK419 ameliorated neurological deficits, whereas ozagrel and argatroban did not. These results indicate that FK419, a GPIIb/IIIa antagonist, ameliorates ischemic brain damage by improving MCA patency after occlusion and that FK419 is a promising candidate for the treatment of acute ischemic stroke.

Animals↗
PubMed2001

Antithrombotic effects of a synthetic inhibitor of activated factor X, JTV-803, in animals.

JTV-803, 4-[(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)methyl]-1-(4-pyridinyl)piperidine-4-carboxylic acid monomethanesulfonate trihydrate, at > or = 0.1 mg/kg/h inhibited the increase in plasma thrombin-antithrombin III complex in response to continuous infusion of thromboplastin in rats. JTV-803 inhibited thrombus formation in an arteriovenous shunt model by intravenous infusion at > or = 0.3 mg/kg/h and prolonged the occlusion time of photochemically induced arterial thrombus in the middle cerebral artery at >1.5 mg/kg/0.5 h. Activated partial thromboplastin time was prolonged at 10 mg/kg/h. Intravenous administration of JTV-803 prolonged bleeding time at 30 mg/kg/h, a dose 10-100 times higher than the dose that inhibited thrombus formation. Compared with thrombin inhibitor, JTV-803 had less of an effect on the bleeding time. In the arteriovenous shunt model in cynomolgus monkey, JTV-803 prolonged the occlusion time when administered by continuous infusion at 0.3 mg/kg/h or orally at 10 mg/kg. These results suggest that the human factor Xa inhibitor JTV-803 is an orally active anticoagulant that does not affect bleeding time and is useful for the prevention of thrombus.

Animals↗
PubMed1989

Role of thrombin and thromboxane A2 in reocclusion following coronary thrombolysis with tissue-type plasminogen activator.

Reocclusion of the coronary artery occurs after thrombolytic therapy of acute myocardial infarction despite routine use of the anticoagulant heparin. However, heparin is inhibited by platelet activation, which is greatly enhanced in this setting. Consequently, it is unclear whether thrombin induces acute reocclusion. To address this possibility, we examined the effect of argatroban [MCI9038, (2R,4R)-4-methyl-1-[N alpha-(3-methyl-1,2,3,4-tetrahydro-8- quinolinesulfonyl)-L-arginyl]-2-piperidinecarboxylic acid], a specific thrombin inhibitor, on the response to tissue-type plasminogen activator in a closed-chest canine model of coronary thrombosis. MCI9038 prolonged the thrombin time and shortened the time to reperfusion (28 +/- 2 min vs. 59 +/- 7 min in controls; mean +/- SEM, n = 5, P less than 0.01). At the highest dose, 2.5 mg/kg per hr, complete reocclusion was prevented in four of the five experimental animals, whereas reocclusion occurred in all five controls. However, reperfusion was complicated by cycles of decrease flow, which were abolished by the thromboxane A2 antagonist, GR32191. GR32191 at 1 mg/kg combined with MCI9038 at 0.5 mg/kg per hr prevented reocclusion, whereas, at these doses, either drug alone was without effect. In addition, thromboxane A2 biosynthesis, determined as excretion of its metabolite 2,3-dinor-thromboxane B2, was increased after reperfusion at all doses of MCI9038. These data demonstrate that thrombin impairs thrombolysis induced by tissue-type plasminogen activator in vivo and induces acute reocclusion. Furthermore, the response to thrombin inhibition may be impaired by continued formation of thromboxane A2.

Animals↗
PubMed1990

CGS-19755, a competitive NMDA receptor antagonist, reduces calcium-calmodulin binding and improves outcome after global cerebral ischemia.

We evaluated several doses of cis-4-(phosphonomethyl)-2-piperidine-carboxylic acid (CGS-19755), a potent competitive N-methyl-D-aspartate (NMDA) receptor antagonist, systemically administered either before or after 20 to 30 minutes of global ischemia in rats. We measured outcome by mortality, histological damage by light microscopy, and learning ability on an eight-arm maze, and determined the drug's mechanism of action by an immunohistochemical assay of calcium-calmodulin binding. High-dose treatment begun prior to ischemia resulted in reduced cellular damage in severely ischemic hippocampal tissue, but also caused high mortality due to respiratory depression. Treatment begun 30 minutes after ischemia resulted in little histological protection but significantly improved learning ability when tested 1 month after ischemia, and did not increase mortality. Furthermore, CGS-19755, 10 mg/kg intraperitoneally, begun either before or after ischemia substantially reduced calcium influx into ischemic neurons as evidenced by reduced calcium-calmodulin binding. We conclude that CGS-19755 prevents calcium entry into ischemic neurons and may be effective therapy for very acute cerebral ischemia.

Animals↗
PubMed1993

In vitro and in vivo characterization of a neutral boron-containing thrombin inhibitor.

Peptide boronic acid derivatives have proven to be very potent inhibitors of serine proteases with boroarginine derivatives being particularly potent thrombin inhibitors. The importance of the charged side chain of arginine has been investigated by synthesizing a derivative in which this side chain has been replaced by a neutral one. This boronic acid derivative, D-benzyloxycarbonyl (Z)-Phe-Pro-methoxypropylglycine-pinanediol (MpgC10H16), inhibited thrombin by a competitive mechanism with an inhibition constant (Ki) of 8.9 nM. In comparison to boroarginine derivatives, Z-D-Phe-Pro-boroMpgC10H16 displayed higher selectivity for thrombin over trypsin (Ki = 1.1 microM) and plasmin (Ki = 15.7 microM). Prolongation of thrombin time and activated partial thromboplastin time were observed with micromolar concentrations of Z-D-Phe-Pro-boroMpgC10H16. In a thrombin-dependent in vitro aggregation assay with human platelets, Z-D-Phe-Pro-boroMpgC10H16 inhibited aggregation with an IC50 of 85 nM. When tested in a thrombin-dependent platelet accumulation model in the rat, a bolus injection of (Z)-D-Phe-Pro-boroMpgC10H16 (0.3-3 mg/kg) inhibited platelet accumulation. Thus, the substitution of the charged guanidino group in the P1 side chain by the neutral methoxy group resulted in a potent and highly selective thrombin inhibitor with an interesting pharmacological profile with in vitro as well as in vivo models.

Animals↗
PubMed1994

Quantitative determination of the NMDA antagonist cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755) in human plasma using capillary gas chromatography/mass spectrometry.

An analytical method has been developed and validated for the quantitative determination of the N-methyl-D-aspartate (NMDA) antagonist cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755) in human plasma. It is a member of a new class of compounds with the potential to be neuroprotective and attenuate neuronal damage resulting from brain trauma caused by stroke and head trauma. The method is based on gas chromatography/mass spectrometry and uses stable-isotope labeled CGS 19755 as the internal standard. Samples (1 ml) were first acidified (pH 2), then extracted using a solid-phase aminopropyl ion exchange column. The drug was eluted with NH4OH and evaporated until dry. Extracts were derivatized with a mixture of pentafluoropropionic anhydride and pentafluoropropanol, and analyzed by gas chromatography/mass spectrometry. Separation was accomplished on a DB-225 capillary column (15 m x 0.32 mm) with a 0.25 micron film thickness. Mass spectrometry was carried out under negative ion ammonia chemical ionization conditions with selected ion monitoring at m/z 760 and 764 for derivatized CGS 19755 and the internal standard, respectively. Specificity was shown by the lack of interfering peaks at the retention time of CGS 19755 and internal standard. Recovery and reproducibility assessments show good accuracy, precision and linearity over the validated concentration range of 2-5000 ng ml-1.

Gas Chromatography-Mass Spectrometry↗
PubMed1995

Competitive and uncompetitive N-methyl-D-aspartate antagonist discriminations in pigeons: CGS 19755 and phencyclidine.

The purpose of the present studies was to examine representative uncompetitive and competitive NMDA antagonists, as well as the glycine/NMDA antagonist, HA 966, in pigeons trained to discriminate either PCP or CGS 19755 from saline. Separate groups of pigeons were trained to discriminate either the uncompetitive, phencyclidine (PCP; 0.32 and 1.0 mg/kg, IM), or the competitive, CGS 19755 (cis-4-phosphonomethyl-2-piperidine-carboxylic acid; 1.8 mg/kg, IM), NMDA antagonists from saline. Uncompetitive and competitive NMDA antagonists were examined in generalization studies, as were the racemate and the (+) and (-) stereoisomers of HA 966 (3-amino-1-hydroxypyrrolid-2-one). Dizocilpine (MK 801) was fully generalized to PCP but not to CGS 19755. All competitive NMDA antagonists tested were fully generalized to CGS 19755, but not to PCP. The competitive antagonists, however, produced > 50% PCP-appropriate responding. The (+) isomer of HA 966 was fully generalized by three of four pigeons discriminating PCP (1.0 mg/kg) or CGS 19755, whereas the racemate and the (-) isomer produced < 40% drug-appropriate responding in either group. Neither NMDA, morphine, nor pentobarbital produced > 10% drug-appropriate responding in either discrimination group. The competitive antagonists tended to produce peak drug-appropriate responding at times greater than 60 min after administration, whereas uncompetitive antagonists produced peak drug-appropriate responding at earlier times. HA 966 also had a relatively slow onset of action as compared to PCP. These results suggest that antagonists acting at different modulatory sites of the NMDA receptor complex produce similar, but not identical, discriminative stimuli.

Animals↗
PubMed1992

In vivo distribution of CGS-19755 within brain in a model of focal cerebral ischemia.

The blood-brain barrier permeability of the competitive N-methyl-D-aspartate receptor antagonist CGS-19755 [cis-4-(phosphonomethyl)-2-piperidine carboxylic acid] was assessed in normal and ischemic rat brain. The brain uptake index of CGS-19755 relative to iodoantipyrine was assessed using the Oldendorf technique in normal brain. The average brain uptake index in brain regions supplied by the middle cerebral artery was 0.15 +/- 0.35% (mean +/- SEM). The unidirectional clearance of CGS-19755 from plasma across the blood-brain barrier was determined from measurements of the volume of distribution of CGS-19755 in brain. These studies were performed in normal rats and in rats with focal cerebral ischemia produced by combined occlusion of the proximal middle cerebral artery and ipsilateral common carotid artery. In normal rats the regional plasma clearance across the blood-brain barrier was low, averaging 0.015 ml 100 g-1 min-1. In ischemic rats this clearance value averaged 0.019 ml 100 g-1 min-1 in the ischemic hemisphere and 0.009 ml 100 g-1 min-1 in the nonischemic hemisphere. No significant regional differences in plasma clearance of CGS-19755 were observed in either normal or ischemic rats except in cortex injured by electrocautery where a 14-fold increase in clearance across the blood-brain barrier was measured. We conclude that CGS-19755 crosses the blood-brain barrier very slowly, even in acutely ischemic tissue.

Animals↗
PubMed2003

Characteristics of the hemostatic action of KFA-1411, an inhibitor of coagulation factor Xa (FXa), in humans and various animals.

This study examined a low-molecular-weight factor-Xa inhibitor, KFA-1411 (3-[N-(3-amidinophenyl)-N-[N-[4-[1-(1-iminoethyl)piperidin-4- yl]phenyl]carbamoylmethyl]aminomethyl]phenoxyacetic acid monosulfonate-dihydrate). KFA-1411 selectively inhibited FXa among the serine proteases in the human blood-coagulation cascade with a Ki value of 1.73 nM, (selectivity ratio, 15000 versus its action on thrombin). The anticoagulant action of KFA-1411 in human plasma almost equaled that of the selective thrombin inhibitor, argatroban. KFA-1411 did not inhibit platelet aggregation at the concentration at which it showed an anticoagulant action. In contrast, argatroban, heparin, and low-molecular-weight heparin (LMWH; dalteparin) inhibited thrombin-induced platelet aggregation at concentrations lower than those needed for their anticoagulant actions. The FXa-inhibiting action of KFA-1411 differed among animal species, the maximum effect being seen in humans, followed by monkeys and rabbits, with rats and mice showing about one-tenth the potency seen in humans. A species variation was also observed among the values obtained for KFA-1411 in respect of anticoagulant activity in plasma (monkeys again being closest to humans). These results indicate that KFA-1411 may exhibit antithrombotic efficacy without an unwanted platelet-related action in the future treatment of various thrombotic diseases. The experimental model of monkeys is recommended for estimation of the clinical effects and safety of KFA-1411 in humans.

Animals↗
PubMed1988

The novel N-methyl-D-aspartate (NMDA) antagonist CGS 19755 prevents ischemia-induced reductions of adenosine A1, NMDA, and PCP receptors in gerbil brain.

Transient brain ischemia results in a selective destruction of cell bodies within the hippocampus and cortex. This cellular destruction appears to be mediated through a release of endogenous exictatory amino acids following the ischemic episode, since the neurotoxic effects of ischemia can be attenuated by compounds that have antagonist activity at N-methyl-D-aspartate (NMDA) receptors. In the present study, the protective effects of a novel NMDA receptor antagonist, CGS 19755, were further evaluated by using quantitative autoradiography to characterize adenosine A1, NMDA, PCP, and benzodiazepine receptors in ischemic gerbil brain. Bilateral carotid artery occlusion (20 minutes) resulted in marked decreases (30-60%) in adenosine A1, NMDA, and PCP, but not benzodiazepine, receptors in gerbil forebrain. Postischemic treatment with CGS 19755 was found to completely block the ischemia-induced decreases in brain adenosine and NMDA receptors. [3H]TCP binding in ischemic gerbil brain was also elevated by CGS 19755 treatment; significant differences remained, however, between the CGS 19755-treated and control gerbils. These results indicate that transient brain ischemia produces significant and selective alterations in gerbil forebrain receptor systems. The observed decreases in radioligand binding are probably reflective of an ischemia-induced destruction of forebrain structures. However, there is some evidence that transient ischemia can also cause long-term changes in the affinity of some receptor systems. The postischemic efficacy of CGS 19755 appears to be due to its ability to block the neurotoxic effects of transient ischemia.

Adenosine↗
PubMed1997

Effect of argatroban, a selective thrombin inhibitor, on animal models of cerebral thrombosis.

Argatroban, (2R,4R)-4-methyl-1-(N2 [(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl)-sulfonyl]-L-arginyl)-2-pi peridinecarboxylic acid, a selective and competitive thrombin inhibitor, was examined for effectiveness in three different experimental models of cerebral thrombosis in rats, namely, the four-vessel occlusion model, the middle cerebral artery occlusion model, and the distal middle cerebral artery occlusion model. Argatroban was demonstrated to be effective in these experimental models of thrombosis. Among these models, the distal middle cerebral artery occlusion model was the most similar to clinical cerebral thrombosis with respect to restriction of the infarction to the cerebral cortex and the accompanying stable neurologic deficits. In this model, the thrombus was generated at the Y-shaped bifurcation of the middle cerebral artery by green light irradiation through a cranial window after administration of rose bengal. Argatroban given after thrombus formation by intraperitoneal implantation of an osmotic pressure pump was shown to reduce infarct size and neurologic deficits on day 3 and microthrombi generation on day 1, and to raise the regional cerebral blood flow on day 1, at a plasma level of 0.2 to 0.6 microM supporting its clinical usefulness in the treatment of acute-phase cerebral thrombosis. Argatroban was considered to exert its effects by salvaging neuronal cells in the ischemic penumbra and suppressing extension of the infarction into the penumbra by keeping blood vessels patent, mainly through the inhibition of microthrombogenesis.

Acute Disease↗
PubMed1993

Sexual differences in N-methyl-D-aspartate receptor-mediated regulation of tuberoinfundibular dopaminergic neurons in the rat.

The purpose of the present study was to examine the effects of N-methyl-D-aspartate (NMDA) receptor blockade on the activity of tuberoinfundibular dopaminergic (TIDA) neurons in male and female rats. TIDA neuronal activity was estimated by measuring either the accumulation of 3,4-dihydroxyphenylalanine (DOPA) 30 min after the administration of the decarboxylase inhibitor NSD-1015 or the concentration of the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the median eminence. The non-competitive NMDA receptor antagonist MK-801 markedly reduced prolactin secretion in both male and female rats. MK-801 also produced a dose- and time-dependent decrease in the activity of TIDA neurons in female rats, but had no effect on the activity of TIDA neurons in either intact, orchidectomized or orchidectomized, testosterone-treated male rats. Removal of the tonic stimulatory effects of prolactin on TIDA neurons in female rats by immunoneutralization of endogenous prolactin failed to alter the responsiveness of TIDA neurons to the inhibitory effects of MK-801. On the other hand, MK-801 was unable to inhibit TIDA neurons in ovariectomized female rats, but the responsiveness of TIDA neurons to MK-801 in ovariectomized female rats was restored following estrogen replacement, even in the absence of prolactin. Like MK-801, the competitive NMDA receptor antagonist CGS-19755 produced a dose-dependent decrease in TIDA neuronal activity in female rats, which was prevented in a dose-dependent manner by the NMDA receptor agonist D,L-(tetrazol-5-yl) glycine. Taken together, these results reveal a sexual difference in the responsiveness of TIDA neurons to NMDA receptor antagonists, and suggest that estrogen positively modulates NMDA receptor-mediated, tonic stimulation of TIDA neurons in female rats by a prolactin-independent mechanism.

Animals↗
PubMed1995

GABAA agonists: resolution and pharmacology of (+)- and (-)-isoguvacine oxide.

(3SR,4RS)-3,4-Epoxypiperidine-4-carboxylic acid (isoguvacine oxide) is a potent and specific GABAA receptor agonist. Isoguvacine oxide, originally designed as a potentially alkylating agonist, turned out to interact with the GABAA receptor in a fully reversible manner. The protected form of isoguvacine oxide, benzyl (3SR,4RS)-1-(benzyl-oxycarbonyl)-3,4-epoxypiperidin e-4-carboxylate (1) (Scheme 1), has now been resolved by chiral chromatography using cellulose triacetate as a chiral stationary phase. The enantiomers of 1 (ee > or = 98.8%) were subsequently deprotected by hydrogenolysis. Whereas both enantiomers of isoguvacine oxide were inactive as inhibitors of the binding of [3H]GABA to GABAB receptor sites (IC50 > 100 microM), (+)-isoguvacine oxide (IC50 = 0.20 +/- 0.03 microM) and (-)-isoguvacine oxide (IC50 = 0.32 +/- 0.05 microM) showed comparable potencies as inhibitors of the binding of [3H]GABA to GABAA receptor sites. Furthermore, (+)-isoguvacine oxide (EC50 = 6 microM; 33% relative efficacy) and (-)-isoguvacine oxide (EC50 = 5 microM; 38% efficacy relative to 10 microM muscimol) were approximately equipotent and equiefficacious as stimulators of the binding of [3H]diazepam to the GABAA receptor-associated benzodiazepine site. This latter effect is an in vitro estimate of GABAA agonist efficacy. These pharmacological data for isoguvacine oxide and its enantiomers do not seem to support our earlier conception of the topography of the GABAA recognition site(s), derived from extensive structure-activity studies on GABAA agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2003

Argatroban, specific thrombin inhibitor, induced phenotype change of cultured rabbit vascular smooth muscle cells.

To investigate whether argatroban ((2R,4R)-4-methyl-1-[N(2)-((RS)-3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-2-piperidinecarboxylic acid hydrate, a selective thrombin inhibitor, exerts a direct action on phenotype conversion of vascular smooth muscle cells, cultured rabbit aortic vascular smooth muscle cells were employed. Myosin heavy chain isoforms (SM1, SM2, and SMemb) mRNA expressions were evaluated by in situ hybridization and reverse transcription-polymerase chain reaction (RT-PCR). After the cells were incubated in serum-free medium containing argatroban (10 and 50 microg/ml) and platelet-derived growth factor (PDGF)-BB (10 and 50 ng/ml) for 3 h, total RNA was extracted. In situ hybridization demonstrated that myosin heavy-chain isoform mRNAs were homogenously expressed in argatroban- and PDGF-BB-treated cells. RT-PCR revealed that SM1/SM2 mRNA expressions were not changed with argatroban, while SMemb mRNA expression was increased to 1.6-fold with a statistical significance (P<0.05). Treatment with argatroban (10 and 50 microg/ml) at 24 h did not change SM1/SM2 mRNA expressions. Although SMemb mRNA expression was slightly increased, there was no statistical significance. Other phenotype markers including plasminogen activator inhibitor-1 (PAI-1) and beta-actin mRNAs were also significantly increased by argatroban. In conclusion, argatroban can directly induce phenotype conversion of vascular smooth muscle cells with the resultant up-regulation of SMemb, PAI-1, and beta-actin mRNAs.

Animals↗
PubMed1988

The pharmacology of excitatory transmission in the rat olfactory cortex slice.

The pharmacology of excitatory transmission in slices of olfactory cortex of the rat, perfused with solution containing picrotoxin, has been studied by assessing the effects of cis-2,3-piperidine dicarboxylate, a nonselective antagonist of excitatory amino acid receptors, 2-amino-5-phosphonopentanoate, a selective antagonist of N-methyl-D-aspartate (NMDA) receptors and 2-amino-4-phosphonobutyrate (APB) and baclofen, which act at APB and GABAB sites, respectively, on evoked surface field potentials. Monosynaptic excitatory transmission was monitored by measuring the amplitude of the N'a'-wave, evoked on stimulation of the lateral olfactory tract, whilst di-/polysynaptic excitatory transmission was evaluated by calculating the areas of the potentials evoked on direct stimulation of the superficial and deep-lying association fibre systems. On the basis of the effects of the drugs in this and earlier studies, it is concluded that: (i) transmission at the lateral olfactory tract-pyramidal cell synapse is mediated by kainate/quisqualate but not NMDA receptors and is regulated by inhibitory APB receptors, located on the tract terminals; (ii) NMDA receptors are involved in mediating excitatory transmission at the synapses of superficial association fibres with the proximal apical dendrites of pyramidal cells with inhibitory APB receptors playing a regulatory role; (iii) transmission at synapses of association fibres with basal dendrites of pyramidal cells, is mediated in part by NMDA receptors with (presynaptic?) GABAB receptors exerting a strong inhibitory influence. These proposed roles of NMDA receptors have been confirmed in experiments in which the effects of magnesium ions on field potentials evoked in slices perfused in magnesium-free solution were monitored.

2-Amino-5-phosphonovalerate↗
PubMed1997

Antithrombotic and hemorrhagic effects of DX-9065a, a direct and selective factor Xa inhibitor: comparison with a direct thrombin inhibitor and antithrombin III-dependent anticoagulants.

(+)-2S-2-[4-[[(3S)-1-Acetimidoyl-3- pyrrolidinyl]oxy]phenyl]-3-[7-amidino-2-naphthyl]propanoic acid hydrochloride pentahydrate (DX-9065a) is an antithrombin III (AT III)-independent and selective inhibitor of activated blood coagulation factor X (FXa). The aim of the present study was to compare the antithrombotic and hemorrhagic effects of DX-9065a with a direct thrombin inhibitor and AT III-dependent anticoagulants in rat models of thrombosis and bleeding. Rats were administered intravenously DX-9065a (0.1-1 mg/kg/h), argatroban (0.1-1 mg/k/h), low molecular weight heparin (25-100 anti-XaU/kg/h), unfractionated heparin (25-100 anti-XaU/kg/h) or Orgaran (30-300 anti-XaU/kg/h) for 1 h. DX-9065a dose-dependently inhibited both thrombus formation and elevation in plasma thrombin-AT III complex (TAT) level in a copper wire-inserted arteriovenous (AV) shunt model in rats. The dose required for 50% inhibition of thrombus formation was 0.27 mg/kg/h. DX-9065a did not prolong transection bleeding time up to 7.78 mg/kg/h. Argatroban and AT III-dependent anticoagulants also inhibited both thrombus formation and TAT elevation, but prolonged bleeding time at a slightly higher dose than the effective dose. These results suggest that direct and selective inhibition of factor Xa by DX-9065a is preferable for the treatment of thrombosis in the aspect of lack of compromising primary hemostasis.

Animals↗