Biomedical subjects

H C Huang

Publications and source records attributed to H C Huang.

At least 37 records · Page 2Linked to original sources

PubMed2001

Endothelin-1 induces vasoconstriction on portal-systemic collaterals of portal hypertensive rats.

Portal hypertension is associated with increased hepatic and collateral resistance to an increased portal blood flow. Endothelin-1 (ET-1) can induce intrahepatic vasoconstriction and consequently increase portal pressure. It is unknown if ET-1 also modulates portal pressure by a direct vasoconstrictive effect on collaterals. This study investigated the collateral vascular responses to ET-1, the receptors in mediation, and the regulation of ET-1 action by nitric oxide and prostaglandin. The portal-systemic collaterals of partially portal vein-ligated rats were tested by in situ perfusion. The concentration-response curves of collaterals to graded concentrations of ET-1 (10(-10)-10(-7) mol/L) with or without BQ-123 (ET(A) receptor antagonist, 2 x 10(-6) mol/L), BQ-788 (ET(B) receptor antagonist, 10(-7) mol/L) or both were recorded. In addition, the collateral responses to ET-1 with preincubation of n(omega)-nitro-L-arginine (NNA; 100 mol/L), indomethacin (INDO; 10 mol/L), or in combination were performed. ET-1 increased the perfusion pressure of collaterals and its effect was significantly suppressed by BQ-123 alone and BQ-123 plus BQ-788, but not BQ-788 alone (P <.05). Incubation with NNA, INDO, or both significantly enhanced the response of collaterals to ET-1 (P < .05). These results show that ET-1 produces a direct vasoconstrictive effect on the collateral vessels of portal hypertensive rats. This effect is mediated by ET(A,) but not ET(B), receptors. Both nitric oxide and prostaglandin modulate the collateral vascular response to ET-1 and may therefore participate in the development and maintenance of portal hypertension.

Animals↗

PubMed2001

Hepatic encephalopathy in rats with thioacetamide-induced fulminant hepatic failure: role of endotoxin and tumor necrosis factor-alpha.

BACKGROUND: Hepatic encephalopathy, a complex neuropsychiatric syndrome secondary to acute liver failure, chronic parenchymal liver disease or portal-systemic shunting, may possibly develop through mediators of endotoxin and tumor necrosis factor-alpha (TNF-alpha). However, there are no published data concerning the relationships between the severity of encephalopathy and the plasma levels of endotoxin and TNF-alpha. METHODS: Male Sprague-Dawley rats weighing about 300-350 g were used. Fulminant hepatic failure was induced by intraperitoneal injection ofthioacetamide (350 mg/kg/day) for 3 consecutive days. Severity of encephalopathy was assessed by measuring motor counts using an Opto-Varimex animal activity meter. Plasma levels of endotoxin and TNF-alpha were determined by chromogenic Limulus assay and ELISA method, respectively. RESULTS: Our study revealed that higher plasma levels of endotoxin (> 5.9 pg/ml) and TNF-alpha (> 18.8 pg/ml) were significantly associated with more blunted motor activities in rats with fulminant hepatic failure (p < 0.05). A significant correlation was observed between plasma concentrations of endotoxin and TNF-alpha (r = 0.59, p < 0.001). Plasma levels of endotoxin were weakly correlated with the total movements in an open field (r = -0.34, p = 0.032) and the counts of ambulatory (r = -0.38, p = 0.014) and vertical movements (r = -0.40, p = 0.010). There were no correlations between the motor counts and plasma levels of TNF-alpha (p > 0.05). CONCLUSIONS: In addition to endotoxin and TNF-alpha, other factors may participate in the pathogenesis of hepatic encephalopathy in rats with thioacetamide-induced fulminant hepatic failure.

Animals↗

PubMed2001

GL331 induces down-regulation of cyclin D1 expression via enhanced proteolysis and repressed transcription.

GL331 is a novel podophyllotoxin-derived compound. In this study, GL331 induced human lung adenocarcinoma cell line CL1-5 growth arrest before death during the initial 24-h incubation period. We found that GL331 had no inhibitory effect on the expression of cyclins E, A, B1, CDK 4, and CDK 2; instead, its cell growth-inhibitory effect was partly attributable to an early down-regulation of cyclin D1 expression and in turn the reduction of retinoblastoma protein phosphorylation. GL331 enhanced the proteolysis of cyclin D1, and a proteasome inhibitor was able to block GL331-caused cyclin D1 reduction, suggesting that GL331-stimulated cyclin D1 degradation was through proteasomal processes. Additionally, GL331 reduced cellular cyclin D1 mRNA level down to 45% of control in 4 h and further to around 20% in 12 h. However, GL331 did not accelerate the disappearance of cyclin D1 mRNA under the condition of transcription blockage induced by actinomycin D. It was reported that a certain region in the 3'-untranslated region (UTR) of cyclin D1 mRNA mediated the mRNA degradation upon extracellular stresses. Herein, transient transfection studies demonstrated that the 3'-UTR insertion did not confer the susceptibility of luciferase reporter gene to the GL331 treatment. Together, these data suggested that GL331 did not decrease the stability of cyclin D1 mRNA. On the other hand, we found that GL331 specifically inhibited the cyclin D1 promoter-driven luciferase reporter activity. Western blot analyses showed that GL331 decreased the level of phosphorylated extracellular signal-regulated kinase (Erk), with no effect on p38 or c-Jun NH(2)-terminal kinase. Furthermore, GL331's inhibition of cyclin D1 promoter was attenuated by ectopic Erk-2 overexpression. These data suggested that GL331 inhibited cyclin D1 gene transcription via the Erk signaling pathway. In summary, we report that GL331 induced an early decline of cyclin D1 expression by dual mechanisms: 1) enhancement of protein turnover and 2) repression of Erk-mediated gene transcription.

Antineoplastic Agents, Phytogenic↗

PubMed2000

Regulation of the antioxidant response element by protein kinase C-mediated phosphorylation of NF-E2-related factor 2.

A coordinated cellular response to oxidative stress occurs in part through transcriptional regulation via a cis-acting sequence known as the antioxidant response element (ARE). NF-E2-related factor 2 (Nrf2), a member of the Cap'n'Collar family of basic region-leucine zipper (bZIP) transcription factors, has been implicated as an essential component of an ARE-binding transcriptional complex, but the signaling pathway leading to its activation has remained unclear. Using a reporter gene assay, we found that ARE-directed transcription was activated by phorbol 12-myristate 13-acetate (PMA), but completely suppressed by staurosporine and Ro-32-0432, selective inhibitors of protein kinase C (PKC). Immunocytochemistry and subcellular fractionation revealed that PMA, like tert-butylhydroquinone (tBHQ), promoted the nuclear localization of Nrf2, a process that was blocked by staurosporine or Ro-32-0432. We showed that Nrf2, a previously unidentified kinase target, was phosphorylated in HepG2 cells. PMA transiently activated Nrf2 phosphorylation, whereas the addition of tBHQ or beta-naphthoflavone (betaNF) led to a persistent stimulation, which was abolished by staurosporine, but not by U0126 and SB203580, respective inhibitors of MEK and p38 kinases. Purified Nrf2 was phosphorylated in vitro by the catalytic subunit of PKC, or by PKC immunoprecipitated from cell lysates. Significantly, PKC precipitated from tBHQ- or betaNF-treated cells showed enhanced activity against Nrf2. These findings indicate an important role of the PKC pathway in the ARE-mediated gene expression, and suggest that PKC-directed phosphorylation of Nrf2 may be a critical event for the nuclear translocation of this transcription factor in response to oxidative stress.

Animals↗

PubMed2000

The molecular chaperone DnaJ is required for the degradation of a soluble abnormal protein in Escherichia coli.

In addition to promoting protein folding and translocation, molecular chaperones of Hsp70/DnaJ families are essential for the selective breakdown of many unfolded proteins. It has been proposed that chaperones function in degradation to maintain the substrates in a soluble form. In Escherichia coli, a nonsecreted alkaline phosphatase mutant that lacks its signal sequence (PhoADelta2-22) fails to fold in the cytosol and is rapidly degraded at 37 degrees C. We show that PhoADelta2-22 is degraded by two ATP-dependent proteases, La (Lon) and ClpAP, and breakdown by both is blocked in a dnaJ259-ts mutant at 37 degrees C. Both proteases could be immunoprecipitated with PhoA, but to a much lesser extent in the dnaJ mutant. Therefore, DnaJ appears to promote formation of protease-substrate complexes. DnaJ could be coimmunoprecipitated with PhoA, and the extent of this association directly correlated with its rate of degradation. Although PhoA was not degraded when DnaJ was inactivated, 50% or more of the PhoA remained soluble. PhoA breakdown and solubility did not require ClpB. PhoA degradation was reduced in a thioredoxin-reductase mutant (trxB), which allowed PhoADelta2-22 to fold into an active form in the cytosol. Introduction of the dnaJ mutation into trxB cells further stabilized PhoA, increased enzyme activity, and left PhoA completely soluble. Thus, DnaJ, although not necessary for folding (or preventing PhoA aggregation), is required for PhoA degradation and must play an active role in this process beyond maintaining the substrate in a soluble form.

Adenosine Triphosphate↗

PubMed2000

Purification and cloning of cytotoxic ribonucleases from Rana catesbeiana (bullfrog).

Ribonucleases with antitumor activity are mainly found in the oocytes and embryos of frogs, but the role of these ribonucleases in frog development is not clear. Moreover, most frog ribonuclease genes have not been cloned and characterized. In the present study, a group of ribonucleases were isolated from Rana catesbeiana (bullfrog). These ribonucleases in mature oocytes, namely RC-RNase, RC-RNase 2, RC-RNase 3, RC-RNase 4, RC-RNase 5 and RC-RNase 6, as well as liver-specific ribonuclease RC-RNase L1, were purified by column chromatographs and detected by zymogram assay and western blotting. Characterization of these purified ribonucleases revealed that they were highly conserved in amino acid sequence and had a pyroglutamate residue at their N-termini, but possessed different specific activities, base specificities and optimal pH values for their activities. These ribonucleases were cytotoxic to cervical carcinoma HeLa cells, but their cytotoxicities were not closely correlated to their enzymatic specific activities. Some other amino acid residues in addition to their catalytic residues were implicated to be involved in the cytotoxicity of the frog ribonucleases to tumor cells. Because the coding regions lack introns, the ribonuclease genes were cloned by PCR using genomic DNA as template. Their DNA sequences and amino acid sequences are homologous to those of mammalian ribonuclease superfamily, approximately 50 and approximately 25%, respectively.

Amino Acid Sequence↗

PubMed2000

Optimization of separation and migration behavior of cephalosporins in capillary zone electrophoresis.

The influences of buffer pH, buffer concentration and buffer electrolyte on the migration behavior and separation of 12 cephalosporin antibiotics in capillary zone electrophoresis using three different types of buffer electrolyte, including phosphate, citrate, and 2-(N-morpholino)ethanesulfonate (MES), were investigated. The results indicate that, although buffer pH is a crucial parameter, buffer concentration also plays an important role in the separation of cephalosporins, particularly when cefuroxime and cefazolin, cephalexin and cefaclor, or cefotaxime and cephapirin are present as analytes at the same time. The electrophoretic mobility of cephalosporins and electroosmotic mobility measured in citrate and MES buffers are remarkably different from those measured in phosphate buffer. With citrate buffer, optimum buffer concentration is confined to a small range (35-40 mM), whereas buffer concentrations up to 300 mM can be used with MES buffer. Complete separations of 12 cephalosporins could be satisfactorily achieved with these three buffers under various optimum conditions. However, the separability of 12 cephalosporins with citrate or MES buffer is better than that with phosphate buffer. As a consequence of a greater electrophoretic mobility of cephalosporins than the electroosmotic mobility with citrate buffer at pH below about 5, some cephalosporins are not detectable. The cloudiness of the peak identification and of the magnitudes of the electrophoretic mobility of cefotaxime and cefuroxime reported previously are clarified. In addition, the pKa values of cephradine, cephalexin, cefaclor, and cephapirin attributed to the deprotonation of either an amino group or a pyridinium group are reported, and the migration behavior of these cephalosporins in the pH range studied is quantitatively described.

Alkanesulfonic Acids↗

PubMed2000

Transcriptional regulation of the antioxidant response element. Activation by Nrf2 and repression by MafK.

The antioxidant response element (ARE) mediates the transcriptional activation of many genes encoding phase II drug-metabolizing enzymes in response to oxidative stress. Recent studies using knockout mice suggest that NF-E2-related factor 2 (Nrf2), along with small Maf proteins, binds and activates the ARE. In this study, using in vitro binding assays, Nrf2/MafK heterodimers were found to interact with high affinity to the ARE. However, distinct differences were observed when this interaction was compared with that formed with nuclear proteins from H4II EC3 or HepG2 cells. Overexpression of Nrf2 activated ARE-mediated transcription in HepG2 cells, and this activation was further increased by tert-butylhydroquinone. In HeLa cells, overexpression of Nrf2 resulted in activation of the ARE, but this activation was no longer induced by tert-butylhydroquinone. Using ARE constructs with point mutations in the core sequence, we found that only mutations at the T or G nucleotides within the core (TGAC) render the ARE unresponsive to Nrf2. Overexpression of MafK led to dose-dependent repression of ARE activity. Activation of the ARE by Nrf2 was similarly antagonized by MafK. These data suggest that Nrf2 plays an important role mediating basal activity of the ARE but that small Maf proteins are repressors and not activators of ARE-mediated transcription.

Animals↗

PubMed2000

Capillary zone electrophoretic separation of neutral species of chloro-s-triazines in the presence of cationic surfactant monomers.

Chloro-s-triazines are difficult to separate by capillary zone electrophoresis (CZE), due to their low pKa values. However, these analytes can be effectively separated by CZE in the presence of cationic surfactant monomers, such as tetradecylammonium bromide (TTAB) and dodecyltrimethylammonium bromide (DTAB). The separation mechanism based on a 1:1 binding of analytes to cationic surfactant monomers is proposed. The binding constants of chloro-s-triazines to cationic surfactant monomers are estimated. The results show that the strength of the interactions of these analytes with TTAB monomers is considerably strong, whereas that of the corresponding analyte with DTAB monomers is about 12- to 14-fold weaker. A linear correlation of binding constants with log P(ow) (the logarithm of the partition coefficient of analytes between 1-octanol and aqueous phases) indicates that the migration order of these chloro-s-triazines depends primarily on their hydrophobicity. Moreover, the skewed peaks of chloro-s-triazines observed may reveal the occurrence of adsolubilization of these analytes in the adsorbed cationic surfactant layer on the capillary surface.

Cations↗

PubMed2000

The decline of porcine sperm motility by geldanamycin, a specific inhibitor of heat-shock protein 90 (HSP90).

Sperm motility is an important parameter for fertility. The molecular mechanisms of mammalian sperm motility are still largely undefined. Our previous observations suggested that heat shock protein 90 (HSP90) may be associated with porcine sperm motility. The aim of the present study was to further characterize the plausible novel function of HSP90 on sperm motility. Semen from normal, sexually mature boars with sperm motility higher than 80% was used. An HSP90-specific inhibitor, geldanamycin (GA), was added to diluted semen at 0.5, 1.0, 2.5 or 5.0 microg/mL and the semen was then incubated at 37 degrees C for 15, 30, 45 or 60 min. Sperm motility was determined by using computer-assisted semen analyzer at the end of incubation. The results indicated that GA significantly reduced sperm motility in a dose and time dependent manner. Moreover, incubation of semen with 5.0 microg/mL GA for 15 min completely stopped sperm motility. To test the reversibility of the GA effect on sperm motility, GA was removed after 30 min incubation and was replaced with fresh extender alone or with extender plus 5 mM caffeine, then incubated for another 15, 30, 45 or 60 min. The results showed that simply removing GA did not reverse the inhibitory effect on sperm motility, while adding caffeine partially reversed this inhibitory effect. However, the effect of 2.5 or 5.0 microg/mL GA was not reversed by caffeine. Considering the specificity of GA targeting to HSP90, the above observations suggested that HSP90 may play a crucial role in regulating porcine sperm motility.

Animals↗

PubMed2000

The gene coding for the Hrp pilus structural protein is required for type III secretion of Hrp and Avr proteins in Pseudomonas syringae pv. tomato.

Bacterial surface appendages called pili often are associated with DNA and/or protein transfer between cells. The exact function of pili in the transfer process is not understood and is a matter of considerable debate. The Hrp pilus is assembled by the Hrp type III protein secretion system of Pseudomonas syringae pv. tomato (Pst) strain DC3000. In this study, we show that the hrpA gene, which encodes the major subunit of the Hrp pilus, is required for secretion of putative virulence proteins, such as HrpW and AvrPto. In addition, the hrpA gene is required for full expression of genes that encode regulatory, secretion, and effector proteins of the type III secretion system. hrpA-mediated gene regulation apparently is through effect on the mRNA level of two previously characterized regulatory genes, hrpR and hrpS. Ectopic expression of the hrpRS gene operon restored gene expression, but not protein secretion, in the hrpA mutant. Three single amino acid mutations at the HrpA carboxyl terminus were identified that affect the secretion or regulatory function of the HrpA protein. These results define an essential role of the Hrp pilus structural gene in protein secretion and coordinate regulation of the type III secretion system in Pst DC3000.

Amino Acids↗

PubMed2000

A novel class of apical sodium co-dependent bile acid transporter inhibitors: the 2,3-disubstituted-4-phenylquinolines.

A series of 2,3-disubstituted-4-phenylquinolines were prepared and were found to inhibit the apical sodium co-dependent bile acid transporter (ASBT). Alkyl and ester substitution at the 3-position showed comparable activities while substitution at the 2-position was much more sensitive to the nature of the substituent. The synthesis and in vitro potency data are presented for this novel class of compounds.

Carrier Proteins↗

PubMed2000

G-33A mutation in the promoter region of thrombomodulin gene and its association with coronary artery disease and plasma soluble thrombomodulin levels.

Thrombomodulin is an endothelial glycoprotein that decreases thrombin activity and activates protein C. A recent study has shown that G-33A promoter mutation of the thrombomodulin gene occurs particularly in Asians. In this study, we analyzed the distribution of G-33A mutation in the promoter region of the thrombomodulin gene in the Chinese population and determined whether the mutation might be a risk for coronary artery disease (CAD). In addition, the influence of this mutation on plasma soluble thrombomodulin levels in patients with CAD was also examined. We studied 320 consecutive patients (mean age 63 years; 73% men) with CAD and 200 age- and sex-matched control subjects. Screening for thrombomodulin G-33A promoter mutation was conducted using polymerase chain reaction, single-strand conformation polymorphism, and direct deoxyribonucleic acid sequencing. The frequency of the G-33A mutation (GA+AA genotypes) was significantly higher in the CAD group (23.8% vs 15.5%, odds ratio [OR] 1.70, p = 0.031). Multiple logistic regression analysis showed that the mutation was an independent risk factor (OR 1.81, p = 0.016) for CAD, as was hypertension (OR 1.44, p = 0.040), diabetes mellitus (OR 2.50, p <0.001), and smoking (OR 2.15, p <0.001). In CAD patients with GG genotype, the soluble thrombomodulin level increased with the extent of CAD (36 +/- 15 vs 47 +/- 18 vs 55 +/- 36 ng/ml in 1-, 2-, or 3-vessel CAD, p <0.001). However, in CAD patients with G-33A mutation, there was no difference between the levels of soluble thrombomodulin (39 +/- 17 vs 37 +/- 15 vs 42 +/- 18 ng/ml, p = NS) in 1-, 2-, or 3-vessel CAD. Our observations suggest that there is a significant association of the G-33A mutation in thrombomodulin gene with CAD, and this mutation may influence the soluble thrombomodulin levels in patients with CAD.

Asian People↗

PubMed2000

Characterization of the alanine racemases from Pseudomonas aeruginosa PAO1.

Alanine racemases are ubiquitous, almost uniquely prokaryotic enzymes catalyzing the racemization between l- and d-alanine. The requirement for d-alanine as a necessary component of the bacterial cell wall makes this class of enzymes a logical target for the development of novel antibiotics. In an effort to better understand the structure and mechanism of these enzymes, we have cloned the two independent alanine racemases from Pseudomonas aeruginosa, an important opportunistic bacterial pathogen of humans and animals. The dadX(PA) and alr(PA) genes have been sequenced, overexpressed, and their activity was demonstrated by complementing d-alanine auxotrophs of Escherichia coli. Both gene products were purified to electrophoretic homogeneity, the enzymes were characterized biochemically, and preliminary crystals were obtained.

Alanine Racemase↗

PubMed2000

Effect of saikosaponin, a triterpene saponin, on apoptosis in lymphocytes: association with c-myc, p53, and bcl-2 mRNA.

1. The mechanisms involved in the apoptotic effect of saikosaponin-d, a triterpene saponin from Bupleurum falcatum L., were studied in human CEM lymphocytes and compared with those of dexamethasone (3 x 10(-7) M). 2. Saikosaponin-d (10(-8) to 10(-5) M) inhibited the serum-stimulated [(3)H]-thymidine incorporation in a concentration-dependent manner. Dexamethasone also inhibited serum-stimulated [(3)H]-thymidine incorporation. 3. Cell viability was unaffected by saikosaponin-d until 10(-5) - 10(-4) M. Dexamethasone significantly reduced the number of viable cells. 4. Following saikosaponin-d (10(-5) - 10(-4) M) treatment, flow cytometry analysis of propidium iodide-stained cells showed a significant increase in the percentage of cells in the apoptotic region. Dexamethasone also significantly increased the percentage of apoptotic cells. The supravital exposure to propidium iodide and annexin V labelling demonstrated that saikosaponin-d (10(-5) - 10(-4) M) induced apoptosis as well as necrosis. 5. The apoptotic effect of saikosaponin-d (3 x 10(-6) - 10(-4) M) was also demonstrated by TUNEL analysis and DNA laddering. The percentage of apoptotic cells induced by saikosaponin-d (3 x 10(-6) - 10(-5) M) was unaffected by the presence of Z-VAD-FMK, indicating that saikosaponin-d-induced apoptosis may not be mediated by caspase activity. However, the percentage of apoptotic cells induced by dexamethasone was significantly reduced by the presence of Z-VAD-FMK. 6. Levels of c-myc, p53, and bcl-2 mRNA were analysed by the reverse transcription-polymerase chain reaction. Levels of c-myc and p53 mRNA were significantly increased, while the level of bcl-2 mRNA was decreased, by saikosaponin-d (10(-5) M) treatment. Dexamethasone did not significantly change the expression of these genes. 7. It is suggested that the apoptotic effect of saikosaponin-d may be partly mediated by increases in c-myc and p53 mRNA levels accompanied by a decrease in bcl-2 mRNA level.

Amino Acid Chloromethyl Ketones↗

PubMed2000

G1 kinases and transforming growth factor-beta signaling are associated with a growth pattern switch in diabetes-induced renal growth.

BACKGROUND: Diabetes mellitus-induced nephromegaly is thought to involve both hyperplastic and hypertrophic proximal tubule cell growth. The temporal relationship between these growth patterns and the mechanisms that mediate them are unknown. METHODS: Renal growth was assayed in isolated renal proximal tubules harvested from diabetic rats. Diabetes mellitus was induced by streptozotocin. RESULTS: Following the induction of a diabetic state, there was a progressive increase in the kidney:body weight ratio. This was associated with an increase in 5-bromo-2-deoxyuridine incorporation (marker for hyperplastic cell growth) at day 2, which returned to baselines levels by day 4, and an increase in the protein:DNA ratio (marker for hypertrophic cell growth), which was clearly evident by day 10. Thus, diabetes-induced proximal tubule growth involved an initial hyperplastic, followed by a hypertrophic, growth period. During the hyperplastic growth period, both cdk4/cyclin D (cyclin D) and cdk2/cyclin E (cyclin E) kinase activities were increased. The switch between the growth periods was associated with continued activation of cyclin D, but inhibition of cyclin E kinase. The reduction in cyclin E kinase activity correlated with a reduction in cdk2/cyclin E complex abundance and an increased abundance of cyclin kinase inhibitors in cdk2/cyclin E complexes that did form. Also associated with the switch in growth patterns was a change in transforming growth factor-beta (TGF-beta) receptor expression. During the hyperplastic growth period, TGF-beta receptor II expression was decreased, while during the hypertrophic growth period, there was both a return of receptor II expression to baseline levels and increased expression of receptor I. Consistent with an increase in TGF-beta signaling during hypertrophy, there was an increase in Smad 2/3 protein expression and an increase in the abundance of Smad 2/4 complexes. CONCLUSIONS: Diabetes-induced proximal tubule growth involves an initial hyperplastic growth period that switches to a hypertrophic growth period within a couple of days. The pattern of G1 kinase activity associated with the growth pattern switch demonstrates that the hypertrophy is mediated by a cell cycle-dependent mechanism. Regulation of TGF-beta receptor expression and signaling activity through the Smad protein cascade possibly plays a role in the growth pattern switch.

Animals↗

PubMed2000

Endoscopic variceal ligation plus nadolol and sucralfate compared with ligation alone for the prevention of variceal rebleeding: a prospective, randomized trial.

Both beta-blockers and endoscopic variceal ligation (EVL) have proven to be valuable alternatives to sclerotherapy in the prevention of variceal rebleeding. Sucralfate is a mucosal protector. The effects of combinations of beta-blocker, band ligation, and sucralfate (triple therapy) remain unknown. A total of 122 patients with a history of esophageal variceal bleeding were randomized to receive EVL only (group A, 62 patients) or triple therapy (group B, 60 patients). The procedure for the triple therapy included ligation with the addition of sucralfate granules until variceal obliteration. In addition, nadolol was administered during the course of the study or until death. After a median follow-up of 21 months, recurrent upper gastrointestinal bleeding developed in 29 patients (47%) in group A and 14 patients (23%) in group B (P =.005). Recurrent bleeding from esophagogastric varices occurred in 18 patients in group A and 7 patients in group B (P =.001). Twenty-one patients in group A (50%) and 12 patients (26%) in group B experienced variceal recurrence after variceal obliteration (P <.05). Treatment failure occurred in 11 patients (18%) in group A and in 4 patients (7%) in group B (P =.05). Twenty patients from group A and 10 patients from group B died (P =.08); 9 and 4 of these deaths, respectively, were attributed to variceal hemorrhage (P =.26). The combination of ligation, nadolol, and sucralfate (triple therapy) proved more effective than banding ligation alone in terms of prevention of variceal recurrence and upper gastrointestinal rebleeding as well as variceal rebleeding.

Adrenergic beta-Antagonists↗

PubMed2000

Chronic inhibition of nitric oxide ameliorates splanchnic hyposensitivity to glypressin in a hemorrhage-transfused rat model of portal hypertension.

BACKGROUND: Vasopressin given during hemorrhage is less effective than when given during a stable state in experimental portal hypertension or patients with cirrhosis (the so-called hyposensitivity phenomenon). This study investigated whether chronic inhibition of nitric oxide (NO) synthesis by NG-nitro-L-arginine methyl ester (L-NAME), a non-selective NO synthase inhibitor, could potentiate the portal-hypotensive effect of glypressin (a long-acting vasopressin analogue) in portal-hypertensive rats during acute bleeding status. METHODS: Portal hypertension was induced by partial portal vein ligation (PVL). Rats were divided to receive either L-NAME (approximately 25 mg/kg/day in tap water) or placebo (tap water) treatment orally from 2 days prior to until 14 days after the operation. At the end of treatment, L-NAME-and placebo-treated PVL rats were subdivided into without-bleeding and with-bleeding groups to assess the effects of glypressin (0.07 mg/kg) on systemic and portal hemodynamics. In rats with a hypotensive hemorrhage, 4.5 ml of blood was withdrawn and 50% of the withdrawn blood was reinfused before the administration of glypressin. RESULTS: As compared with placebo-treated rats, chronic treatment with L-NAME in PVL rats significantly increased mean arterial pressure (P < 0.001) without modulating portal pressure (P > 0.05). In placebo-treated PVL rats, glypressin resulted in a less decrease in portal pressure in rats with bleeding than in those without bleeding (P < 0.05). For PVL rats with bleeding, the portal-hypotensive effect of glypressin was significantly potentiated after chronic L-NAME treatment (P < 0.05). CONCLUSIONS: Chronic inhibition of NO alleviates the splanchnic hyposensitivity to glypressin observed in bleeding PVL rats, suggesting the pathophysiological role of nitric oxide in mediating this splanchnic hyposensitivity.

Animals↗