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K Sueishi

Publications and source records attributed to K Sueishi.

At least 19 recordsLinked to original sources
PubMed2006

Actions of ZD0947, a novel ATP-sensitive K+ channel opener, on membrane currents in human detrusor myocytes.

BACKGROUND AND PURPOSE: ATP-sensitive K+ channels (K(ATP) channels) play important roles in regulating the resting membrane potential of detrusor smooth muscle. Actions of ZD0947, a novel KATP channel opener, on both carbachol (CCh)-induced detrusor contractions and membrane currents in human urinary bladder myocytes were investigated. EXPERIMENTAL APPROACH: Tension measurements and patch-clamp techniques were utilized to study the effects of ZD0947 in segments of human urinary bladder. Immunohistochemistry was also performed to detect the expression of the sulphonylurea receptor 1 (SUR1) and the SUR2B antigens in human detrusor muscle. KEY RESULTS: ZD0947 (> or = 0.1 microM) caused a concentration-dependent relaxation of the CCh-induced contraction of human detrusor, which was reversed by glibenclamide. The rank order of the potency to relax the CCh-induced contraction was pinacidil > ZD0947 > diazoxide. In conventional whole-cell configuration, ZD0947 (> or = 1 microM) caused a concentration-dependent inward K+ current which was suppressed by glibenclamide at -60 mV. When 1 mM ATP was included in the pipette solution, application of pinacidil or ZD0947 caused no inward K+ current at -60 mV. Gliclazide (< or =1 microM), a selective SUR1 blocker, inhibited the ZD0947-induced currents (Ki = 4.0 microM) and the diazoxide-induced currents (high-affinity site, Ki1 = 42.4 nM; low-affinity site, Ki2 = 84.5 microM) at -60 mV. Immunohistochemical studies indicated the presence of SUR1 and SUR2B proteins, which are constituents of KATP channels, in the bundles of human detrusor smooth muscle. CONCLUSIONS AND IMPLICATIONS: These results suggest that ZD0947 caused a glibenclamide-sensitive detrusor relaxation through activation of glibenclamide-sensitive KATP channels in human urinary bladder.

ATP-Binding Cassette Transporters↗
PubMed2005

Efficacy and limitations of cyclophosphamide-induced tolerance against alphaGal antigen.

In the present study, we have elucidated the efficacy of two cyclophosphamide (CP)-induced tolerance protocols for the induction of B-cell tolerance against Galalpha1-3Galbeta1-4GlcNAc (alphaGal) antigens. alpha1,3-galactosyltransferase-deficient (GalT-/-; H-2(b/d)) mice received with 1 x 10(8) AKR (alphaGal+/+ H-2k) spleen cells (SC) followed by 200 mg/kg CP, or alternatively followed by 200 mg/kg CP, 30 mg/kg Busulfan (BU) and 1 x 10(8) T-cell-depleted AKR bone marrow cells (BMC). The generation of both anti-alphaGal and anti-donor antibodies were completely suppressed, but normal antibody production against third party antigens was observed after BALB/c skin grafting in both groups of GalT-/- mice. In GalT-/- mice, treated with SC and CP, mixed chimerism was not observed. Cellular rejection was observed in grafted donor AKR hearts with an absence of humoral rejection, whereas humoral rejection was observed in untreated GalT-/- mice. On the other hand, long-term mixed chimerism and permanent acceptance of donor AKR skin graft and heart graft were achieved in GalT-/- mice treated with SC, CP, BU and BMC. These results demonstrate the efficacy of classical drug-induced tolerance in the induction of B-cell tolerance against alphaGal antigens. However, induction of stable mixed chimerism was required for the suppression of cellular rejection.

Animals↗
PubMed2004

Effects of different corticosteroids on the development of osteonecrosis in rabbits.

OBJECTIVES: Osteonecrosis (ON) of the femoral head is a devastating complication occurring in patients receiving corticosteroid treatment. This study examined the effect of three corticosteroids on the development of ON in rabbits. METHODS: Thirty-nine rabbits were injected once intramuscularly with either 25 mg/kg prednisolone sodium succinate (PSL; 13 rabbits), 20 mg/kg methylprednisolone acetate (MPSL; 13 rabbits) or 20 mg/kg triamcinolone acetonide (TR; 13 rabbits). Four weeks after corticosteroid injection, the bilateral femora and humeri were examined histopathologically for the presence of ON. Haematological examinations were performed before and after corticosteroid injection. RESULTS: MPSL treatment (17/26 proximal femora, 65%) significantly increased ON incidence in the proximal femora compared with the levels seen after TR (4/26, 15%) or PSL (3/26, 12%) treatment (P < 0.01). Although not significantly increased in comparison with rabbits receiving PSL treatment (1/26 proximal humeri, 4%), ON incidence within the proximal humeri was significantly increased in MPSL-treated rabbits (6/26, 23%) in comparison with those seen in rabbits receiving TR (0/26, 0%) treatment (P < 0.05). Serum levels of cholesterol, triglyceride and free fatty acid were significantly higher 1, 2 and 4 weeks after corticosteroid treatment in rabbits treated with MPSL relative to rabbits receiving TR and rabbits with PSL treatment (P < 0.05). CONCLUSIONS: MPSL treatment significantly increased ON incidence in rabbits over levels seen after TR or PSL treatment.

Animals↗
PubMed2003

Airway-directed gene transfer of interleukin-10 using recombinant Sendai virus effectively prevents post-transplant fibrous airway obliteration in mice.

Bronchiolitis obliterans (BO) after lung transplantation prevents a satisfactory prognosis, and recent studies suggested that interleukin-10 (IL-10) gene transfer to distant organs could inhibit BO in rodent models. Although delivery of the therapeutic gene to a local airway would be favored to minimize systemic effects, current limitations include lower gene transfer efficiency to airway epithelium. As recombinant Sendai virus (SeV) can produce dramatically efficient gene transfer to airway epithelium, we determined if SeV-mediated IL-10 gene transfer to the local airway would inhibit bronchial fibrous obliteration in murine tracheal allografts. Administration of cyclosporine A (CsA) significantly promoted not only recovery of the injured airway epithelium but also SeV-mediated IL-10 expression (CsA- versus CsA+ =228+/-78 versus 3627+/-1372 pg/graft with 5 x 10(7) pfu), thereby suggesting the requirement of epithelia for efficient gene transfer. Even at the highest expression, no significant leakage of IL-10 was evident in the systemic circulation, and the induction of interferon-gamma was completely diminished on day 7 by IL-10 gene transfer. As a result, luminal loss was significantly prevented in allografts treated with SeV-IL-10 (luminal opening, all control groups: 0% respectively, and SeV-IL-10 5 x 10(7) pfu: 25.7+/-10.5%), an effect that was enhanced by short-term CsA treatment (SeV-IL-10 5 x 10(7) pfu with CsA: 63.7+/-12.7%). We propose that SeV is a useful vector that can target airway epithelium to prevent BO avoiding putative systemic effect.

Animals↗
PubMed2003

Recombinant Sendai virus provides a highly efficient gene transfer into human cord blood-derived hematopoietic stem cells.

Hematopoietic stem cells (HSCs) are a promising target for gene therapy, however, the low efficiencies of gene transfer using currently available vectors face practical limitations. We have recently developed a novel and efficient gene transfer agent, namely recombinant Sendai virus (SeV), and we have here characterized SeV-mediated gene transfer to human cord blood (CB) HSCs and primitive progenitor cells (PPC) using the jelly fish green fluorescent protein (GFP) gene. Even at a relatively low titer (10 multiplicity of infections), SeV achieved highly efficient GFP expression in CB CD34(+) cells (85.5+/-5.8%), as well as more immature CB progenitor cells, CD34(+)AC133(+) (88.2+/-3.7%) and CD34(+)CD38(-) (84.6+/-5.7%) cells, without cytokines prestimulation, that was a clear contrast to the features of gene transfer using retroviruses. SeV-mediated gene transfer was not seriously affected by the cell cycle status. In vitro cell differentiation studies revealed that gene transfer occurred in progenitor cells of all lineages (GM-CFU, 73.0+/-11.1%; BFU-E, 24.7+/-4.0%; Mix-CFU, 59+/-4.0%; and total, 50.0+/-7.0%). These findings show that SeV could prove to be a promising vector for efficient gene transfer to CB HSCs, while preserving their ability to reconstitute the entire hematopoietic series.

Animals↗
PubMed2003

Simian immunodeficiency virus-based lentivirus vector for retinal gene transfer: a preclinical safety study in adult rats.

Although lentivirus vectors hold promise for ocular gene therapy, they also have potential safety issues, particularly in the case of the current human immunodeficiency virus-based vectors. We recently developed a novel lentivirus vector derived from the nonpathogenic simian immunodeficiency virus from African green monkeys (SIVagm) to minimize these potentials. In this preclinical study, we evaluated whether SIV vector could be efficiently and safely applicable to retinal gene transfer by assessing the transgene expression, retinal function and histology over a 1-year period following subretinal injection in adult rats. The functional assessment via electroretinogram after both titers of SIV-lacZ (2.5 x 10(7) or 2.5 x 10(8) transducing units/ml) injection revealed both the dark and light adaptations to soon be impaired, in a dose-dependent manner, after a buffer injection as well, and all of them recovered to the control range by day 30. In both titers tested, the retinas demonstrated a frequent transgene expression mainly in the retinal pigment epithelium; however, the other retinal cells rarely expressed the transgene. Retinas exposed to a low titer virus showed no significant inflammatory reaction throughout the observation period, and also maintained the transgene expression over a 1-year period. In the retinas exposed to a high titer virus, however, mononuclear cell infiltration persisted in the subretinal area, and the retina that corresponded to the injected area finally underwent degeneration by around day 90. No retinal neoplastic lesions could be found in any animals over the 1-year period. We thus propose that SIV-mediated stable gene transfer might be useful for ocular gene transfer; however, more attention should be paid to avoiding complications when administering high titer lentivirus to the retina.

Animals↗
PubMed2003

Recombinant Sendai virus vectors for activated T lymphocytes.

T-lymphocyte-directed gene therapy has potential as a treatment of subjects with immunological disorders. One current limitation of this therapeutic strategy is low gene transfer efficiency, even when complex procedures are used. We report herein that a recombinant Sendai virus vector (SeV) was able to overcome this issue. Using jellyfish enhanced green fluorescent protein gene (EGFP), we found that SeV was able to transduce and express a foreign gene specifically and efficiently in activated murine and human T cells, but not in naive T cells, without centrifugation or reagents including polybrene and protamine sulfate; the present findings were in clear contrast to those demonstrated with the use of retroviruses. The transduction was selective in antigen-activated T cells, while antigen-irrelevant T cells were not transduced, even under bystander activation from specific T-cell responses by antigens ex vivo. Receptor saturation studies suggested a possible mechanism of activated T-cell-specific gene transfer, ie, SeV might attach to naive T cells but might be unable to enter their cytoplasm. We therefore propose that the SeV vector system may prove to be a potentially important alternative in the area of T-cell-directed gene therapy used in the clinical setting.

Animals↗
PubMed2003

Simian lentiviral vector-mediated retinal gene transfer of pigment epithelium-derived factor protects retinal degeneration and electrical defect in Royal College of Surgeons rats.

Retinitis pigmentosa (RP) is a heterogenous group of inherited retinal diseases resulting in adult blindness caused by mutations of various genes. Although it is difficult to cure the blindness that results from these diseases, delaying the disease progression may be of great benefit, since the majority of RP diseases are seen in middle age or later. To test a gene therapy strategy for RP using a neurotrophic factor gene, we assessed the effect of simian lentivirus (SIV)-mediated subretinal gene transfer of pigment epithelium-derived factor (PEDF), a potent neurotrophic factor, during the disease progression in Royal College of Surgeons (RCS) rats, a well-accepted animal model of RP. Regional gene transfer via SIV into the peripheral subretinal space at the nasal hemisphere was performed in all animals to monitor site-specific transgene expression as well as the therapeutic effect in each retina. Gene transfer of lacZ and PEDF was observed in the regional pigment epithelium corresponding to the regional gene transfer. Histologically, PEDF gene transfer significantly protected the loss of photoreceptor cells (PCs) corresponding to the regions of the gene transfer, compared to those of control groups during the course of the experiment. The antiapoptotic effect of PEDF on PCs is likely to be a related mechanism, because a significant reduction of terminal dUTP-nicked end labeling-positive PC numbers was found in PEDF-treated eyes compared to those of the control group (P<0.05). PEDF-treated eyes also retained a significant sensitivity to light flash during the experimental course. These findings clearly show that neuroprotective gene therapy using PEDF can protect retinal degeneration and functional defects in individuals with RP.

Animals↗
PubMed2002

Simulated microgravity culture system for a 3-D carcinoma tissue model.

An in vitro organotypic culture model is needed to understand the complexities of carcinoma tissue consisting of carcinoma cells, stromal cells, and extracellular matrices. We developed a new in vitro model of carcinoma tissue using a rotary cell culture system with four disposable vessels (RCCS-4D) that provides a simulated microgravity condition. Solid collagen gels containing human pancreatic carcinoma NOR-P1 cells and fibroblasts or minced human pancreatic carcinoma tissue were cultured under a simulated microgravity condition or a static Ig condition for seven days. NOR-P1 cultures subjected to the simulated microgravity condition showed greater numbers of mitotic, cycling (Ki-67-positive), nuclear factor-kappa B-activating cells, and a lower number of apoptotic cells than were shown by cultures subjected to the static Ig condition. In addition, human pancreatic carcinoma specimens cultured under the simulated microgravity condition maintained the heterogeneous composition and cellular activity (determined by the cycling cell ratio and mitotic index) of the original carcinoma tissue better than static culture conditions. This new 3-D rotary cell culture system with four disposal vessels may be useful for in vitro studies of complex pancreatic carcinoma tissue.

Adenocarcinoma↗
PubMed2001

Heterogeneous distribution of P53 immunoreactivity in human lung adenocarcinoma correlates with MDM2 protein expression, rather than with P53 gene mutation.

Although the tumor suppressor p53 protein (P53) immunoreactivity and its gene (p53) mutation were reported to be significant prognostic indicators for human lung adenocarcinomas, little is known regarding the relationship between the heterogeneous distribution of P53 and its genetic status in each tumor focus and the clinicopathological significance. To determine how P53 is heterogeneously stabilized in patients, we compared P53 expression to both the p53 allelic mutation in exon 2 approximately 9 by polymerase chain reaction-single strand conformation polymorphism using microdissected DNA fractions, and the immunohistochemical MDM2 expression. Of the 48 positive to P53 in 118 lung adenocarcinomas examined, 10 with heterogeneous P53 expression were closely examined. The higher P53 expression foci in 7 of 10 cases were less differentiated, histologically in respective cases, and were frequently associated with fibrous stroma. Two had genetic mutations in exon 7 of the p53 gene in both the high and low P53 expression foci of cancer tissue indicating no apparent correlation between heterogeneous P53 expression and the occurrence of gene mutation. Immunohistochemical expression of MDM2 was significantly lower in high P53 expression areas (p < 0.05, the mean labeling indices of high and low P53 expression areas being 4.2 +/- 5.4% and 13.6 +/- 12.2%, respectively). In addition, among all the 118 cases examined, MDM2 expression was significantly suppressed in cases of p53 gene mutation, simultaneously with P53 overexpression, as compared with cases without both the p53 mutation and expression (p < 0.001). These findings suggest that the heterogeneous stabilization of P53 in human lung adenocarcinomas could be partly due to suppressed MDM2 expression. The overexpression of non-mutated P53 may afford a protective mechanism in human lung adenocarcinomas.

Adenocarcinoma↗
PubMed2001

Chronic rejection in H-2 matched cardiac allografts: early emergence of vasculopathy, alloantibody, and accumulation of IFN-gamma and IL-10 mRNA.

Cardiac allograft vasculopathy (CAV) is one of the crucial problems of clinical heart transplantation. We have developed a novel model of murine cardiac allograft rejection, in which chronic rejection associated with CAV occurs in its natural course. In this study we analyzed the pathogenesis of chronic cardiac allograft rejection using an H-2 matched multiple minor histocompatibility antigen-mismatched combination, AKR (H-2k) to C3H (H-2k) recipient mice. All the cardiac allografts survived for more than 100 days but were rejected within 260 days post-transplant (n = 13; mean survival times +/- standard deviation = 189.0+/-72.0; median = 210). The heartbeats of the graft became gradually weaker throughout the duration of the rejection process. Serial histological analyses with hematoxylin and eosin, elastica van Gieson or Masson trichrome staining revealed mononuclear cell infiltration and intimal thickening (i.e. CAV) which started in most grafts at 2 weeks post-transplant. These pathological changes eventually developed to severe graft fibrosis, and the severity of these changes correlated with the deterioration of the heartbeats. Production of anti-donor antibodies in most recipients was detectable by 2 weeks post-transplant, it peaked before day 100, and subsided before rejection was complete in most grafts. Intragraft expression of IFN-gamma and IL-10 mRNA was demonstrated by reverse transcriptase-polymerase chain reaction during early periods post-transplant. In this study, we demonstrate a novel model feasible for analysis of chronic cardiac allograft rejection, in which the vascular rejection processes, including fibrosis and alloantibody production, can be tested from an early stage on, after transplantation.

Animals↗
PubMed2001

Tissue factor increases in the aqueous humor of proliferative diabetic retinopathy.

BACKGROUND: Tissue factor (TF) is a cellular initiator of the coagulation cascade and is upregulated by the major factors of diabetic angiopathy, TF might thus be one of the key molecules in diabetic retinopathy (DR). PURPOSE: To measure TF in diabetic eyes and evaluate its possible role in DR. METHODS: TF concentration in the aqueous humor of the eyes in 44 patients with diabetes and 35 age-matched control patients was evaluated by ELISA. The concentration of TF in aqueous humor (AH) was compared with the grade of DR. The concentration of TF in AH was also compared with duration of diabetes, renal function, and blood glucose control. The serum TF concentration in each group was also compared. The correlation between the serum TF and aqueous TF in each patient was analyzed. The effect of vascular endothelial growth factor (VEGF) on the TF activity of cultured bovine retinal endothelial cells was evaluated. RESULTS: The mean TF concentration in AH was higher in patients with active proliferative DR (244.5 pg/ml) than in either those with non-proliferative DR (132.4 pg/ml, P<0.05) or the control patients (114.9 pg/ml, P<0.01). The serum TF concentration in active proliferative DR patients (348.3 pg/ml) was significantly higher than in either non-proliferative DR patients, (235.9 pg/ml, P<0.01) or in the controls (223.5 pg/ml, P<0.01). However, the TF concentration of AH was not significantly correlated to that of the serum in each patient. The TF concentration in AH closely correlated with the grade of DR and protein concentration. VEGF increased the biological activity of TF in vitro. CONCLUSION: The origin of TF in AH, however, is still not clearly understood. Nonetheless, TF in AH directly reflects the severity of ocular diabetic change, and the present results indicate that TF indeed plays some role in the progression of DR.

Adult↗
PubMed2001

Second nation-wide study of atherosclerosis in infants, children and young adults in Japan.

This paper reports the results of the second nation-wide cooperative study of atherosclerosis in young Japanese, aged from 1 month to 39 years, who were autopsied between 1991 and 1995. Atherosclerotic lesions in 1066 aortas and 974 coronary arteries were classified into fatty streaks, fibrous plaques and complicated lesions and quantificated with the point-counting method. The results of this study were compared with those of the former study, which was conducted 13 years earlier in almost the same fashion as this study. Atherosclerosis of aorta, which was determined by surface involvement (SI) of atherosclerotic lesions and atherosclerotic index (AI), increased with age in both sexes of the former and the present studies and their tendency for the progression of the extent of atherosclerotic lesions appeared to be similar. In the coronary arteries, the mean values of SI and AI in the males of the present study were greater significantly than those in the male of the former studies and in the female of the both studies in the third and fourth decades. This difference suggests that atherosclerotic lesions are increasing in young Japanese males. It also suggests that these subjects may be increasingly susceptible to atherosclerotic cardiovascular disease with increasing age.

Adolescent↗
PubMed2001

Hypoxia-induced angiogenesis of cultured human salivary gland carcinoma cells enhances vascular endothelial growth factor production and basic fibroblast growth factor release.

The angiogenic activity of two human salivary gland tumor cell lines, ACCS from adenoid cystic carcinoma and IT-2 from mucoepidermoid carcinoma, was examined by stimulating tube formation by bovine capillary endothelial cells (BCE). ACCS and IT-2 were cultured in 20 or 3% oxygen, representing normoxic and hypoxic conditions, respectively, and conditioned medium (CM) was obtained from each culture. The BCE tubes stimulated by hypoxic CM were 1.59 (ACCS) and 1.42 (IT-2) times longer than those stimulated by normoxic CM. The tube-forming activity of CM was inhibited by preincubation with either anti-vascular endothelial growth factor (VEGF) IgG or anti-basic fibroblast growth factor (bFGF) IgG, suggesting that both VEGF and bFGF with angiogenic activity were present in the CM. This was confirmed by ELISA, which also demonstrated increased concentrations of both proteins in the hypoxic CM. Northern blot analysis showed an increased VEGF mRNA level in both carcinoma cells with hypoxia, while hypoxia did not affect the bFGF mRNA level in either cell line. The results suggest that both VEGF and bFGF are major angiogenesis factors in salivary gland tumors, and hypoxia-induced angiogenesis results from upregulation of VEGF and increased release of bFGF.

Animals↗
PubMed2001

Osteonecrosis induced by a single administration of low-dose lipopolysaccharide in rabbits.

We succeeded in developing a novel rabbit model of nonsteroid and nontraumatic osteonecrosis (ON) by use of a single- and low-dose lipopolysaccharide (LPS) injection. This model is simple and highly reproducible for the frequent development of multifocal and widespread ON lesions. Male adult Japanese white rabbits intravenously injected with a single injection of 10 microg/kg body weight of LPS were histopathologically examined in the early phase (3 [n = 3], 5 [n = 3], and 24 h [n = 3]) and at 4 weeks (n = 22). Seventy-seven percent of the rabbits developed multifocal ON 4 weeks after LPS injection. ON was also observed in the femoral and humeral condyle. The average percentage of necrotic area/total area examined was 86.7 +/- 29.1% and 78.8 +/- 16.7% in the proximal one third of both the femoral and humeral bones, respectively. Organized thrombi in the intraosseous small-sized arteries and arterioles were frequently seen in and around the necrotic tissues. In the early phase, LPS treatment prominently induced thrombocytopenia, hyperlipidemia, and increased plasma levels of plasminogen activator inhibitor-1 (PAI-1). The plasma level of PAI-1 was significantly higher in the rabbits with ON than in those without ON (p < 0.01). The immunohistochemical expression of tissue factor was exaggerated in monocytes/macrophages and adipocytes in both the femoral and humeral bones of the LPS-treated rabbits. Histologically, marrow necrosis and fibrin thrombi could be observed at 24 h. In addition, pretreatment with an anticoagulant, warfarin potassium, significantly decreased the incidence of LPS-induced ON (33%, n = 9, p < 0.05) associated with elongation of prothrombin time. The results of our study show that a single administration of low-dose lipopolysaccharide induces multifocal and widespread ON characterized by the pathophysiological participation of hypercoagulability in ON development. Therefore, this model would be useful for elucidating the pathogenesis of nonsteroid ON in humans especially inflammatory hypercoagulability-induced as well as for developing preventive and therapeutic strategies.

Animals↗
PubMed2001

Dual action of ZD6169, a novel K(+) channel opener, on ATP-sensitive K(+) channels in pig urethral myocytes.

1. The effects of ZD6169, a novel K(+) channel opener, on both membrane and unitary currents in pig urethra were investigated using patch-clamp techniques. Its effect was also examined on currents in inside-out patches of COS7 cells expressing carboxy terminus truncated inwardly rectifying K(+) channel (Kir6.2) subunits (Kir6.2C36) which form ATP-sensitive K(+) channels (K(ATP) channels). 2. In current-clamp mode, ZD6169 (< or = 10 microM) induced a concentration-dependent membrane hyperpolarization. Higher concentrations (> or = 30 microM) caused a transient membrane hyperpolarization, followed by a gradual membrane depolarization. On removal of ZD6169, an after hyperpolarization was observed. 3. In conventional voltage-clamp configuration, at -50 mV in symmetrical 140 mM K(+) conditions, ZD6169 (100 microM) caused a transient inward current which gradually decayed. Removal of ZD6169 evoked a much larger amplitude K(+) current with a similar time course. 4. ZD6169 produced an inward glibenclamide-sensitive K(+) current, demonstrating a bell-shaped concentration-response relationship. 5. In cell-attached configuration in symmetrical 140 mM K(+) conditions, ZD6169 (< or = 30 microM) activated an K(ATP) channel which was reversibly suppressed by application of glibenclamide. In contrast, ZD6169 (100 microM) inhibited the activity of the levcromakalim-induced K(ATP) channels. 6. ZD6169 (100 microM) had no significant effect on the channel activity of Kir6.2C36 in inside-out configuration, although cibenzoline greatly suppressed the channel activity. 7. These results demonstrate that ZD6169 possesses a dual effect on the activity of the K(ATP) channel; activating at low concentration and inhibiting at higher concentration.

Adenosine Triphosphate↗
PubMed2001

Immunohistochemical localization of vascular endothelial growth factor in the rat portal hypertensive gastropathy.

BACKGROUND AND AIMS: Portal hypertensive gastropathy (PHG) is now recognized to be a distinct entity. Recently, angiogenesis has been noticed as a key factor in clarifying the pathophysiology of various diseases. Angiogenesis in the PHT of explored gastric mucosa has yet to be explored. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor. The aim of the present study was thus to investigate whether the hypoxic state exists in PHG, and whether VEGF appears more strongly in PHG than in normal gastric mucosa and, if so, what exactly is the role of the hypoxic state and VEGF in PHG. METHODS: At 1, 3, 7 and 14 days after either a portal ligation or sham operation, the portal venous pressure, the gastric mucosal blood flow volume and the blood gas were measured and, the expression of VEGF and antiproliferating cell nuclear antigen (PCNA) in gastric mucosal specimens was immunohistochemically assessed. RESULTS: The portal pressure (PP) and the gastric mucosal blood flow (GMBF) in the PHT rats were significantly greater than in the control (CTR). Both the SaO2 and PaO2 of the arterial blood gas were lower in the PHT rats than in the control rats. The percentage of VEGF expression in the PHG was found to be higher than that in the control gastric mucosa. The percentage of PCNA expression in the PHG was higher than that in the control gastric mucosa. CONCLUSION: The levels of SaO2 and PaO2 were lower in the PHT rats. There is a possibility that a kind of portal hypertensive gastric change may trigger an enhanced histochemical expression of VEGF. The increased activity of VEGF may have a possibility of the hypoxic gastric mucosal state caused by the presence of active congestion. This damaged mucosal state 'PHG' may thus facilitate the fragility in PHG and such lesions may be slow and insidious, which may therefore lead to sudden and severe anemia, thus causing massive and sometimes fatal hemorrhaging.

Animals↗