Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The potential tumor-promoting effects of beraprost sodium (TRK-100), stable analogue of prostacyclin (PGI2), were investigated in rats pretreated with N-methyl-N-nitrosourea (MNU) which is a potent initiator of tumor development in a variety of organ or tissues. Male F344 rats were initially given injections of MNU (20 mg/kg b.w. i.p.) twice a week for 3 weeks, and then administered drinking water containing 6, 2, 0.7 or 0.2 ppm of beraprost sodium for the next 29 weeks. For comparison, positive control groups received N-propyl-N-nitrosourea (PNU), which is a carcinogen in hematopoietic system and small intestine on F344 rat, at the dose of 200, 50 and 12.5 ppm in their drinking water. Appropriate non-treated controls were also included. Numerous tumors were observed in many organs including the hematopoietic system, digestive tract, nervous system, Zymbal's gland (auditory sebaceous glands) and peritoneal mesothelium. However, no tumor-enhancing effects of beraprost sodium were observed. In contrast, the groups treated with PNU demonstrated increased development of tumors in the tongue, forestomach, large intestine and Zymbal's gland. These results thus indicate that beraprost sodium is not capable of modulating the development of MNU-induced tumors.
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PMID:[Modifying effects of beraprost sodium (TRK-100) on N-methyl-N-nitrosourea (MNU) carcinogenesis in F344 rats]. 250 23

Beraprost sodium (sodium (+/-)-(1R*,2R*,3aS*,8bS*)-2,3,3a,8b-tetrahydro-2- hydroxy-1-[(E)-(3S*)-3-hydroxy-4-methyl-1-octen-6-ynyl]-1H- cyclopenta[b]benzofuran-5-butyrate, TRK-100) is a chemically and biologically stable epoprostenol analogue which possesses both potent antiplatelet and peripheral vasodilating actions. Its effect on obstruction of the peripheral artery was studied in three different models: 1. acute thrombosis induced by electrical-stimulation of the femoral artery in rabbits, 2. occlusion induced by intra-arterial injection of sodium laurate in rats and 3. tail gangrene induced by subcutaneous injections of both ergotamine and epinephrine in rats. Oral administration of beraprost sodium resulted in suppression of thrombus formation in the acute thrombosis model, marked improvement of macroscopic and histological observations in the laurate-occlusion model and inhibition of tail gangrene extension. In contrast, ticlopidine improved thrombus formation in the acute thrombosis model and slightly improved histological observation in the laurate-occlusion model, but not in the tail gangrene model. Cilostazol suppressed lesions in the acute thrombosis model, but not in the tail gangrene model. These findings suggest that beraprost sodium may be very useful clinically for the therapy of peripheral circulation insufficiency diseases such as Buerger's disease and Raynaud's disease.
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PMID:Effect of beraprost sodium on peripheral circulation insufficiency in rats and rabbits. 251 Jul 41

Beraprost sodium (sodium (+/-)-(1R*,2R*,3aS*,8bS*)-2,3,3a,8b-tetrahydro-2- hydroxy-1-[(E)-(3S*)-3-hydroxy-4-methyl-1-octen-6-ynyl]-1H- cyclopenta[b]benzofuran-5-butyrate, TRK-100) is an orally active epoprostenol (prostaglandin I2, PGI2) analogue. Its effect on the central nervous system (CNS) was studied. 1. When orally administered in mice, beraprost sodium at 0.3 mg/kg caused a flush of skin, a suppression of spontaneous motility, and a fall of body temperature. At 1 mg/kg and more, it showed obvious sedation, prolongation of hexobarbital hypnosis, and analgesic action in acetic acid-induced writhing test. However, even at 3 mg/kg beraprost sodium neither induced ataxia nor had anticonvulsant activity. Hypothermia was also observed in rabbits at 1 mg/kg (p.o. and i.v.). 2. When intravenously administered, beraprost sodium exerted long-lasting action on the CNS, while its pharmacological effects resembled those of PGI2. 3. Oral administration of beraprost sodium did not inhibit aggregation toxicity induced by methamphetamine (20 mg/kg i.p.) in mice. Beraprost sodium at doses higher than 1 mg/kg enhanced aggregation toxicity induced by methamphetamine (5 mg/kg i.p.), while intracerebral ventricular administration of beraprost sodium failed to enhance it. 4. In rat spinal reflex, intravenous administration of beraprost sodium (0.1 mg/kg) slightly enhanced monosynaptic reflex and at a high dose (1 mg/kg) suppressed polysynaptic reflex. 5. In the rabbit EEG, intravenous administration of beraprost sodium at a high dose (1 mg/kg) showed some effects such as the continuous pattern of wakefulness and a fall in power of the EEG.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:General pharmacology of beraprost sodium. 1st communication: effect on the central nervous system. 251 Jul 42

Beraprost sodium (sodium (+/-)-(1R*,2R*,3as*,8bS*)-2,3,3a,8b-tetrahydro-2- hydroxy-1-[(E)-(3S*)-3-hydroxy-4-methyl-1-octen-6-ynyl]-1H- cyclopenta[b]benzofuran-5-butyrate, TRK-100) is an orally active epoprostenol (prostaglandin I2, PGI2) analogue. Its general pharmacological effects on peripheral organs were studied. 1. In isolated organs, beraprost sodium relaxed the trachea and increased atrial beating rate (2.4 x 10(-5) mol/l). It also dose-dependently contracted the stomach, aorta, ileum and uterus (2.4 x 10(-7)-2.4 x 10(-4) mol/l). These effects of beraprost sodium were similar, but inferior to those of PGI2 and PGE1. 2. Intravenous administration of beraprost sodium produced a dose-related decrease in blood pressure (BP), its potency being about 1/3 times that of PGI2 in anesthetized rats and dogs. Beraprost sodium and PGI2 had no effects on heart rate (HR), and enhanced respiration in conjugation with a decrease in BP. Oral administration of beraprost sodium in high doses (1-3 mg/kg in rats and 0.3 mg/kg in dogs) caused a decrease in BP. A compensatory tachycardia and an elevated plasma renin activity (PRA) occurred after low doses (0.1-0.3 mg/kg) in rats. In contrast, a change of HR and PRA in rabbits and dogs was mild. 3. Beraprost sodium produced suppression of digestive organs: markedly, gastric motility and secretion and intestinal transport; slightly, but significantly, biliary secretion. On the other hand, it enhanced ileal motility at a high dose (300 micrograms/kg i.v.). 4. Oral administration of beraprost sodium caused a decrease in urinary volume and electrolyte excretion in rats. 5. Oral administration of beraprost sodium prolonged bleeding time in mice, while it had no effect on the blood coagulation system in vitro. In addition, beraprost sodium had no hemolytic action. 6. The other effects of beraprost sodium were weak. Beraprost sodium had no local anesthetic activity and no effect on salivation, pupil size and neuromuscular transmission in the skeletal muscle. Beraprost sodium slightly contracted the uterus of non-pregnant rats in situ and dose-independently inhibited carrageenin-induced paw edema. In conclusion, beraprost sodium produced various effects on the autonomic, cardiovascular, and gastrointestinal systems. Probably, these effects may be based on its own action like PGI2.
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PMID:General pharmacology of beraprost sodium. 2nd communication: effect on the autonomic, cardiovascular and gastrointestinal systems, and other effects. 251 Jul 43

Effect of prostacyclin analogue, beraprost sodium (Sodium (+/-)-(1R*, 2R*, 3aS*, 8bS*)-2, 3,3a,8b-tetrahydro-2-hydroxy-1-[(E)-(3S*)-3-hydroxy-4-methyl-1-octen+ ++-6- ynyl]-1H-cyclopenta-[b]benzofuran-5-butyrate, TRK-100), on the cardiovascular system of the anesthetized dog was investigated. TRK-100 was injected intra-arterially and intravenously to study the vasodilating effect of the drug by a magnetic flow meter. Intra-arterial injection of TRK-100 augmented blood flow of vertebral, coronary, renal, supramesenteric, hepatic and femoral artery at a dose range of 0.0003 to 3,000 micrograms/bed. The threshold doses of TRK-100 and PGI2 in the mesenteric artery were 0.003 micrograms and 0.0003 micrograms, respectively, and the same values were obtained in the splenic artery. Those were slightly lower than those of other arteries. Intravenous injection of TRK-100 augmented mesenteric and renal arterial flow to 193 +/- 30% and 118 +/- 4%, respectively. In this system augmentation of mesenteric and renal arterial flow was 179 +/- 19% and 135 +/- 1%, respectively, while vertebral, carotid, and femoral arterial flow decreased, respectively, to 71.4 +/- 2.1%, 80.0 +/- 9.4% and 61.4 +/- 5.6% by TRK-100 and 70.6 +/- 5.6%, 79.5 +/- 6.9% and 67.1 +/- 4.7% by PGI2. Inhibitory effects on heart functions such as cardiac output, left ventricular pressure, LV dP/dt, oxygen consumption, and cardiac work were seen. The effect was similar to PGI2. Coronary vascular resistance, total peripheral resistance and systemic blood pressure were also decreased by TRK-100 and PGI2.
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PMID:[Cardiovascular effects of beraprost sodium (TRK-100), a prostacyclin analogue in the dog]. 251 28

Effects of beraprost sodium (sodium(+/-)-(1R*,2R*,3aS*,8bS*)-2,3,3a,8b-tetrahydro-2-hydr oxy-1- [(E)-(3S*)-3-hydroxy-4-methyl-octen-6-ynyl]-1H-cyclopenta[b] benzofuran- 5-butyrate, TRK-100), a stable prostacyclin analogue, on the peripheral circulatory disturbances induced by various vasoconstrictive stimuli were studied. Orally administered beraprost sodium (10, 30 micrograms/kg) caused increase in skin blood flow in anesthetized rats and rise in skin temperature in conscious rats. Intravenously administered beraprost sodium (0.01-0.3 microgram/kg) reduced the recovery time of decreased pulse pressure by topical cooling of the leg in anesthetized rats. In conscious rabbits, intravenous infusion of beraprost sodium (10 micrograms/kg/min) inhibited the fluctuation of ear artery diameter, and dilated the ear artery and vein, resulting in a rise in the ear temperature. In anesthetized dogs, intravenously administered beraprost sodium (0.313-5 micrograms/kg) caused decrease in femoral blood flow and muscle blood flow in the hindlimb, however, it caused increase in skin blood flow at the hind leg instep. Furthermore, intra-arterially administered beraprost sodium (0.1-0.3 microgram/kg/min) under stimulation of lumbar sympathetic nerve caused increase in femoral artery blood flow and selective increase in the skin blood flow without affecting muscle blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of beraprost sodium on peripheral circulatory disturbances induced by various stimuli. 251 91

Baraprost sodium (sodium (+/-)-(1R*,2R*,3aS*,8bS*)-2,3,3a.8b- tetrahydro-2-hydroxy-1-[(E)-(3S*)-3-hydroxy-4-methyl-1-octen-6- 1H-cyclopenta[b]benzo-furan-5-butyrate, TRK-100) is a novel stable epoprostenol (prostaglandin I2, PGI2) analogue having antiplatelet and vasodilating actions. Its effect on platelet aggregation in whole blood ex vivo and platelet suspension in vitro, formation of cyclic AMP(cAMP), production of malondialdehyde(MDA), and 45Ca++-influx into platelets were studied in rats. Oral administration of TRK-100 (0.3-1 mg/kg) showed a dose-dependent inhibition of platelet aggregation induced by ADP and collagen in whole blood and also inhibited in vitro thrombin-induced aggregation of platelet suspension in the presence or absence of external Ca++. Oral TRK-100 (0.3-3 mg/kg) dose-dependently increased plasma cAMP levels and this action was confirmed in vitro with platelet rich plasma in the presence or absence of theophylline. 45Ca++-influx into platelets stimulated by thrombin was dose-dependently inhibited by TRK-100 (3-100 nmol/l). TRK-100 (3-100 nmol/l) also suppressed MDA production induced by thrombin in platelet suspension but not that induced by arachidonic acid. From these results, TRK-100 which is orally active was suggested to exert its antiplatelet action through the increase of cAMP in platelets by activation of adenylate cyclase, concomitantly followed by the inhibition of Ca++-influx and thromboxane A2 formation.
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PMID:Studies on the antiplatelet effect of the stable epoprostenol analogue beraprost sodium and its mechanism of action in rats. 254 30

The binding of [125I]insulin-like growth factor-I ([125I]IGF-I) to human skin fibroblasts (HSF) is regulated by multiple factors. In monolayers of HSF, IGF-I binds to both the type I IGF receptor and IGF-binding proteins (BPs) associated with the cell surface. [125I]IGF-I binding to both of these proteins depends markedly on the sodium chloride concentration of the binding buffer. In monolayers of HSF, replacing 120 mM NaCl with isoosmotic concentrations of sucrose increases binding of [125I]IGF-I by 2- to 6-fold. Enhancement of [125I]IGF-I binding in the absence of sodium chloride is also seen in HSF in suspension, in human erythrocytes, in monolayers of HEP G2 cells and FRTL5 cells, and in membranes prepared from human placentae. Kinetic analysis of [125I]IGF-I binding to HSF monolayers reveals that association rates are increased and dissociation rates are decreased in the absence of sodium chloride. The binding of [125I]alpha IR-3, a monoclonal antibody to the human type I IGF receptor, to monolayers and suspensions of HSF also depends on the sodium ion concentration; it is 5- to 7-fold higher in the absence of sodium chloride. Binding of [125I]IGF-I to monolayers of HSF also depends on NaCl under conditions where alpha IR-3 saturates the type I IGF receptor but does not affect IGF-BPs. These findings demonstrate that sodium chloride has a marked effect on the interaction of IGF-I with the type I IGF receptor in the plasma membrane and with BPs associated with the surface of intact HSFs. Since an effect is also evident in membranes prepared from intact tissues (human placenta), occurs at 4 C, and occurs with cells devoid of BPs, a mechanism involving receptor or BP translocation seems unlikely, at least as the sole explanation for these findings. Sodium ions (and other ions) may induce a conformational change in the receptor and BPs and cause decreased availability of both the IGF-I-binding site and the alpha IR-3 epitope on the receptor and the IGF-binding site on the BP.
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PMID:Multiple factors influence insulin-like growth factor-I binding to human skin fibroblasts. 254 51

1. The transport of L- and DL-2-hydroxy 4-methylthiobutanoic acid (HMB), the methionine hydroxy analogue, by brush border membrane vesicles (BBMV) from chick small intestine was the sum of a saturable Michaelian component and a diffusive term. 2. Unlike that of L- and DL-MET, uptake was Na+-independent and electroneutral. 3. The inhibition of L-HMB transport by L-lactate, a structural analogue, and D-HMB as well, was of the competitive type. 4. Preloading of BBMV with D-HMB but not with L-lactate or L-MET trans-stimulated the influx of labelled L-HMB. 5. HMB uptake by rat and chick intestinal BBMV exhibited similar characteristics but the chick nonstereospecific transport system appeared to be unable to carry out L-lactate translocation.
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PMID:Na+-independent and nonstereospecific transport of 2-hydroxy 4-methylthiobutanoic acid by brush border membrane vesicles from chick small intestine. 259 31

Actually the maximum preservation time for donor hearts is limited to 4 hours. The aim of this experimental study in dogs was to develop techniques allowing an extension of this period up to 24 hours. In the first part of the study the influence of diastolic arrest on the preservation of high energy phosphates was studied: The following methods of cardioplegic arrest were used: 1. hyperkalemic arrest 2. hyperkalemic arrest plus high magnesium 3. low sodium and calcium-free cardioplegia. In all experiments cardioplegic arrest was followed by cold storage (0.5 degrees C). Single dose K+ plus Mg2+ cardioplegia offered the least protection. The other two types of cardioplegia were better but the ATP content was still below 50% after 24 hrs preservation. Reperfusion after cardiac transplantation induced irreversible injury and function did not recover after transplantation. In the second part of the study continuous hypothermic perfusion with low sodium and calcium-free cardioplegia was studied. With this technique HEP content, myocardial structure and functional recovery were 100% after transplantation.
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PMID:[Long-term preservation of the heart in view of its transplantation. An experimental study]. 263 87


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