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Biomedical subjects

M Hori

Publications and source records attributed to M Hori.

At least 253 records · Page 14Linked to original sources
PubMed1999

B7-1 (CD80)-gene transfer combined with interleukin-12 administration elicits protective and therapeutic immunity against mouse hepatocellular carcinoma.

Human hepatocellular carcinoma (HCC) frequently recurs after primary therapy, resulting in poor prognosis. To try to find a way to prevent this, we examined the combined effectiveness of B7-1 (CD80)-gene transfer and interleukin-12 (IL-12) on the induction of protective antitumor immunity against poorly immunogenic BNL1ME A.7R. 1 (BNL) mouse HCC cells. We introduced mouse B7-1 gene into BNL1ME A. 7R.1 cells. Overexpression of B7-1 on BNL1ME A.7R.1 cells resulted in significant inhibititon of subcutaneous tumor development in syngeneic BALB/c mice, but not in complete rejection, suggesting that strong expression of B7-1 molecules may enhance the immunogenicity of BNL1ME A.7R.1 cells in immunocompetent mice. Lymphocyte study revealed that the cytolytic activity generated by immunization with B7-1 transfectants against BNL1ME A.7R.1 cells was mediated mainly by CD8(+) cytotoxic T lymphocytes (CTL). We examined the synergistic effect of IL-12 and immunization with B7-1 transfectants. The combination led to rejection of BNL1ME A.7R.1 cells in 6 of 10 tested mice and delayed tumor development in the remaining mice. Furthermore, the combined treatment against pre-established BNL1ME A.7R.1 tumors resulted in rejection in 3 of 8 tested mice or in significant inhibition of tumor growth in the remaining mice. In vivo lymphocyte subset depletion study indicated that the combined antitumor effect was dependent on the presence of both CD8(+) and CD4(+) T cells. In conclusion, the combination of immunization of B7-1-transfected HCC cells and IL-12 could induce protective and therapeutic immunity against parental HCC cells, and this combination may be therapeutically useful for suppressing recurrence of HCC.

Animals↗
PubMed1999

Pancreatoduodenectomy for locally advanced or recurrent colon cancer: report of two cases.

A 66-year-old man, who had ascending colon cancer which invaded the duodenum, pancreas, and superior mesenteric vein, underwent a curative resection including an extended right hemicolectomy, pylorus-preserving pancreatoduodenectomy, and a partial resection of the superior mesenteric vein. The pathological examination revealed adenocarcinoma of the colon, which directly invaded the duodenum and pancreas, thus causing duodenocolic fistula. Tumor infiltration to the superior mesenteric vein was not histologically proven. Two out of 40 lymph nodes were also involved. The patient is still alive and disease-free 37 months after the operation. A 72-year-old man, with a history of surgery two previous times for ascending colon cancer and its recurrence, underwent a third operation including a resection of the former ileocolic anastomosis en bloc by means of a pylorus-preserving pancreatoduodenectomy with a curative intent. The pathological examination revealed adenocarcinoma of the colon, which directly invaded the duodenum and pancreas. Seven out of 31 lymph nodes were also involved. The patient died of recurrence 24 months after the third operation. These two cases demonstrated the usefulness of a resection of the colon en bloc by means of a pancreatoduodenectomy in patients with either locally advanced colon cancer or locally advanced recurrent colon cancer.

Adenocarcinoma↗
PubMed1999

Oxidative stress induces p21 expression in pancreatic islet cells: possible implication in beta-cell dysfunction.

AIMS/HYPOTHESIS: Prolonged poor glycaemic control in patients with Type II (non-insulin-dependent) diabetes mellitus often causes pancreatic beta-cell dysfunction accompanied by decreases in insulin biosynthesis and beta-cell proliferation. This is well known as a clinical concept called glucose toxicity. Whereas oxidative stress is provoked under diabetic conditions, we examined the possible implication of cyclin-dependent kinase (Cdk) inhibitor p21 (WAF1/CIP1/Sdi1) in beta-cell dysfunction mediated by oxidative stress. METHODS: Oxidative stress was induced in isolated rat pancreatic islet cells by treatment with H(2)O(2) and mRNA expression of p21 and insulin was examined by northern blot analyses. Also, the expression of p21 and insulin mRNA was examined in Zucker diabetic fatty rat. In islet cells p21 was overexpressed using adenovirus and its effect on insulin gene transcription was examined. RESULTS: When oxidative stress was charged on isolated rat pancreatic islet cells, p21 mRNA expression was induced whereas insulin mRNA was decreased. Also, when diabetes developed in Zucker diabetic fatty rats, p21 expression was induced and the insulin mRNA expression was reduced. As support for the implication of p21 in impairment of beta-cell function, the p21 overexpression in the islet cells suppressed the insulin gene transcription. CONCLUSIONS/INTERPRETATION: The expression of cyclin-dependent kinase inhibitor p21, which can be induced by oxidative stress, increases in pancreatic islet cells upon development of diabetes. By suppressing cell proliferation and insulin biosynthesis, the p21 induction is likely to be implicated in the beta-cell glucose toxicity.

Animals↗
PubMed1999

Induction of glycation suppresses glucokinase gene expression in HIT-T15 cells.

AIMS/HYPOTHESIS: Chronic hyperglycaemia in patients with Type II (non-insulin-dependent) diabetes mellitus often leads to a decline in glucose-responsive insulin secretion from pancreatic beta cells, a phenomenon called glucose toxicity. Upon hyperglycaemia, glycation reaction occurs in the beta cells and induces oxidative stress. To understand the molecular basis of the beta-cell glucose toxicity, we investigated the possible effects of glycation on the expression and enzymatic activity of glucokinase, which plays a crucial part in glucose-responsive insulin secretion. METHODS: Glycation and reactive oxygen species were induced in HIT-T15 cells by treatment with D-ribose and effects on glucokinase gene transcription, glucokinase protein amount, glucose phosphorylation activity, and DNA-binding activities of putative glucokinase gene transcription factors were evaluated. RESULTS: When glycation was induced in HIT-T15 cells, the activity of the human glucokinase gene beta-cell-type promoter was suppressed substantially (83% reduction at 60 mmol/l D-ribose). Also, similar reductions in mRNA and protein amounts of glucokinase and in the Vmax of its enzymatic activity were observed. In agreement with the reduction in the promoter activity, the two major transcription factors of the glucokinase gene, the Pal-binding factor and PDX-1, reduced their binding to their target sequences in the glucokinase gene promoter in glycation-induced HIT cells. Because these effects of D-ribose were counteracted by aminoguanidine or N-acetylcysteine, reactive oxygen species, generated by the glycation reaction, appears to be involved in the phenomena. CONCLUSION/INTERPRETATION: The induction of the glycation reaction, which is known to occur in pancreatic beta cells in chronic hyperglycaemia, suppresses the glucokinase gene transcription and its enzymatic activity. Thus, hyperglycaemia-dependent inhibition of glucokinase activity could in part explain beta-cell glucose toxicity.

Acetylcysteine↗
PubMed1999

Involvement of transporter associated with antigen processing 2 (TAP2) gene polymorphisms in hepatitis C virus infection.

BACKGROUND & AIMS: Transporter associated with antigen processing (TAP) has essential roles in the antigen-presenting systems, translocating antigenic peptides from the cytosol into the endoplasmic reticulum. The aim of this study was to clarify whether TAP polymorphisms are involved in hepatitis C virus (HCV) infection. METHODS: The 145 HCV-infected Japanese patients examined in this study were categorized into two groups: 36 carriers with persistently normal alanine transaminase (ALT) values and 109 patients with chronic liver disease (CLD). TAP2 gene phenotypes were determined by means of polymerase chain reaction-restriction fragment length polymorphism, and their frequencies were compared between the two groups. RESULTS: Frequencies of TAP2*0101, *0102, and *0201 were not different between the two groups. However, TAP2*0103 frequency in carriers with normal ALT levels was significantly higher than that in patients with CLD (44% vs. 16%; P = 0.00064, Pc < 0.005). Although the TAP2*0103 allele was tightly linked with class II DRB1*1302-DQB1*0604 haplotype in this study, the TAP2*0103 frequency in the normal ALT group was also significantly higher than that in the CLD group even in DRB1*1302-DQB1*0604-negative patients (31% vs. 10%; P = 0.0076, Pc < 0.05). CONCLUSIONS: These findings suggest that TAP2*0103 may be closely associated with low serum ALT activity in HCV-infected Japanese patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Interleukin 1beta protects mice from Fas-mediated hepatocyte apoptosis and death.

BACKGROUND & AIMS: Fas-mediated apoptosis is one of the major death processes of hepatocytes in liver diseases. The aim of this study was to determine whether interleukin (IL)-1beta regulates the Fas-mediated apoptotic process of differentiated hepatocytes in vivo. METHODS: IL-1beta was injected into Balb/cA mice 5 hours before lethal challenge with agonistic anti-Fas administration. Survival and hepatocyte apoptotic process of these mice were examined. RESULTS: IL-1beta pretreatment prolonged animal survival in a dose-dependent manner, and 500 ng of IL-1beta completely protected mice from lethality. Both serum alanine aminotransferase value and hepatic DNA fragmentation were significantly suppressed by IL-1beta pretreatment. IL-1beta affected neither hepatic distribution of anti-Fas antibody nor Fas expression levels on hepatocytes but significantly suppressed Fas-induced activation of hepatic caspase 3-like protease. Suppression of Fas-induced activation of the caspase by IL-1beta was diminished by coadministration with D-galactosamine and reversed by coinjection with an excess amount of uridine. CONCLUSIONS: These results suggest that IL-1beta suppresses Fas-mediated hepatocyte apoptosis by inducing molecule(s) that suppress the apoptosis control machinery upstream of caspase 3. This observation raises the possibility that IL-1beta acts as a negative regulator of Fas-mediated hepatocyte apoptosis during liver injury.

Alanine Transaminase↗
PubMed1999

Human parathyroid hormone (1-34) increases urinary excretion of lysosomal enzymes in rats.

The kidney is the major target of parathyroid hormone (PTH), and PTH influences the urinary excretion of calcium, phosphate and hydrogen ions. It was previously reported that the urinary, excretion of N-acetyl-beta-D-glucosaminidase (NAG), a lysosomal enzyme, transiently increases after human PTH (hPTH) (1-34) infusion in normal subjects and idiopathic hypoparathyroidism patients, but not in pseudohypoparathyroidism type I patients. Here we report that intravenous infusion of hPTH(1-34) to rats transiently increased the urinary excretion of various lysosomal enzymes, such as beta-glucuronidase and acid phosphatase as well as NAG. However, it did not affect the urinary excretion of tubular brush border membrane enzymes, i.e. alkaline phosphatase, leucine aminopeptidase and gamma-glutamyl transpeptidase. Human PTH(1-34) dose-dependently increased the urinary excretion of NAG in rats with a peak at 30 min, which returned to a baseline within 60 min. The increase in the urinary NAG excretion caused by hPTH(1-34) positively correlated with the increase in the urinary cAMP excretion (r = 0.844, p < 0.01), and infusion of dibutyryl cAMP at a dose of 20 mg/kg similarly increased the urinary excretion of NAG. These results suggested that the increase in the urinary excretion of lysosomal enzymes caused by hPTH(1-34) may be a functional response to hPTH(1-34) occurring in the renal tubules via PTH signaling pathway.

Acetylglucosaminidase↗
PubMed1999

Impaired splanchnic and peripheral glucose uptake in liver cirrhosis.

BACKGROUND/AIM: Patients with liver cirrhosis are insulin-resistant and frequently glucose-intolerant. Although peripheral glucose uptake has been shown to be impaired in liver cirrhosis, little is known about the significance of splanchnic (hepatic) glucose uptake after oral glucose load. METHODS/RESULTS: We performed an oral glucose tolerance test and euglycemic hyperinsulinemic clamp with oral glucose load for eight patients with liver cirrhosis and eight patients with chronic active hepatitis. The patients with liver cirrhosis had higher plasma glucose levels 2 h after glucose load than those with chronic active hepatitis (228+/-22 mg/dl vs. 102+/-9 mg/dl, p<0.01). Using the euglycemic hyperinsulinemic clamp with oral glucose load, we simultaneously measured peripheral and splanchnic glucose uptake. Peripheral glucose uptake in liver cirrhosis was 6.1+/-0.7 mg x kg(-1) x min(-1), which was lower than that in healthy volunteers (10.5+/-0.9 mg x kg(-1) x min(-1), p<0.05) and in chronic active hepatitis (8.4+/-0.3 mg x kg(-1) x min(-1), p<0.05). Furthermore, splanchnic glucose uptake in liver cirrhosis was much lower (20.1+/-3.4%) than in healthy volunteers (36.0+/-4.0%, p<0.05) and in chronic active hepatitis (37.2+/-3.1%, p<0.05). CONCLUSION: These results suggest that glucose intolerance in patients with liver cirrhosis is caused by a defect of the glucose uptake of both splanchnic and peripheral tissues.

Administration, Oral↗
PubMed1999

Priming with G-CSF effectively enhances low-dose Ara-C-induced in vivo apoptosis in myeloid leukemia cells.

We investigated the role of apoptosis in chemotherapy for hematologic malignancies. Twelve consecutive patients with acute myelogenous leukemia (AML) or refractory anemia with excess of blasts in transformation (RAEB-t) who were not tolerable for standard-dose chemotherapy were treated with CAG regimen (low-dose cytosine arabinoside [Ara-C] plus aclarubicin with concurrent administration of granulocyte colony-stimulating factor [G-CSF]). Bone marrow mononuclear cells obtained before the commencement of the chemotherapy were cultured with various concentrations (0-10(-5) M) of Ara-C in the presence or absence of 10 ng/mL of G-CSF, and the resultant cell proliferation/cytotoxicity was assayed. In all but one patient, half killing concentration (LC50) of Ara-C was significantly reduced in the presence of G-CSF (by 400- and 1.45-fold, median: 21-fold). Furthermore, LC(50) values in responders assayed in the presence of 10 ng/mL of G-CSF were significantly lower than those in nonresponders (p = 0.02). In vitro killing tests using a G-CSF-dependent leukemic cell line suggested that addition of G-CSF potentiates Ara-C-induced cytotoxicity through the mechanism of apoptosis. We thus assayed apoptosis in peripheral blood leukemic cells during CAG chemotherapy by flow cytometry using 7-amino-actinomycin D. Peak percentages of apoptosis in responders were significantly higher than those in nonresponders (p = 0.02). These results collectively suggest that apoptosis plays an important role for eradicating leukemic cells by CAG chemo-therapy.

Aged↗
PubMed1999

DNA cleavage and proteolysis of microtubule-associated protein 2 after cerebral ischemia of different severity.

We report temporal profiles of cytoplasmic proteolysis and genomic DNA cleavage after cerebral ischemia of different severity in gerbils. Global forebrain ischemia by bilateral common carotid artery occlusion for 5 min with reperfusion, severe unilateral hemispheric ischemia by unilateral common carotid artery occlusion for 30 min with reperfusion, and complete ischemia by decapitation were used. The hippocampus was examined for proteolysis by using immunohistochemistry for microtubule-associated protein 2, DNA cleavage by using in situ nick-end labelling, and nuclear morphology by Hematoxylin staining. During evolution of delayed neuronal death after transient forebrain ischemia, loss of the immunoreaction for microtubule-associated protein 2 occurred almost in parallel with DNA cleavage in the CA1 region. In contrast, disappearance of the immunoreaction for microtubule-associated protein 2 was much faster than genomic DNA cleavage after unilateral hemispheric ischemia and reperfusion. The microtubule-associated protein 2 immunoreactivity was completely lost before development of changes in nuclear morphology or DNA cleavage after complete ischemia. The present study demonstrated the differences between necrosis and delayed neuronal death, but the nuclear morphology in the latter was not exactly the same as seen in apoptosis. Some elements of both necrotic and apoptotic machineries may work following transient ischemia, and the degree of ischemic insult may determine the character of cell death process.

Animals↗
PubMed1999

A Ca channel blocker, benidipine, increases coronary blood flow and attenuates the severity of myocardial ischemia via NO-dependent mechanisms in dogs.

OBJECTIVES: This study was undertaken to examine whether a dihydropyridine Ca channel blocker, benidipine, increases cardiac NO levels, and thus coronary blood flow (CBF) in ischemic hearts. BACKGROUND: Benidipine protects endothelial cells against ischemia and reperfusion injury in hearts. METHODS AND RESULTS: In open chest dogs, coronary perfusion pressure (CPP) of the left anterior descending coronary artery was reduced so that CBF decreased to one-third of the control CBF, and thereafter CPP was maintained constant (103+/-8 to 42+/-1 mmHg). Both fractional shortening (FS: 6.1+/-1.0%) and lactate extraction ratio (LER: -41+/-4%) decreased. Ten minutes after the onset of an intracoronary infusion of benidipine (100 ng/kg/min), CBF increased from 32+/-1 to 48+/-4 ml/100g/ min during 20 min without changing CPP (42+/-2 mmHg). Both FS (10.7+/-1.2%) and LER (-16+/-4%) also increased. Benidipine increased cardiac NO levels (11+/-2 to 17+/-3 nmol/ml). The increases in CBF, FS, LER and cardiac NO levels due to benidipine were blunted by L-NAME. Benidipine increased cyclic GMP contents of the coronary artery of ischemic myocardium (139+/-13 to 208+/-15 fmol/mg protein), which was blunted by L-NAME. CONCLUSION: Thus, we conclude that benidipine mediates coronary vasodilation and improves myocardial ischemia through NO-cyclic GMP-dependent mechanisms.

Animals↗
PubMed1999

Intravenous nicorandil can preserve microvascular integrity and myocardial viability in patients with reperfused anterior wall myocardial infarction.

OBJECTIVES: We assessed whether the intravenous administration of nicorandil, an adenosine triphosphate (ATP)-sensitive K+ channel opener, exerts beneficial effect on microvascular function and functional and clinical outcomes in patients with acute myocardial infarction (AMI). BACKGROUND: Experimental studies documented that ATP-sensitive K+ channel opener exerts cardioprotection after prolonged ischemia. METHODS: We randomly divided 81 patients with a first anterior AMI into two groups, nicorandil (n = 40) and control groups (n = 41). All patients received successful coronary angioplasty within 12 h after the symptom onset and underwent myocardial contrast echcardiography (MCE) with the intracoronary injection of sonicated microbubbles. In the nicorandil group, we injected 4 mg of nicorandil followed by the infusion at 6 mg/h for 24 h and by oral nicorandil (15 mg/day). RESULTS: The improvement in regional left ventricular function, wall motion score and regional wall motion was significantly better in the nicorandil group then in the control group. Intractable congestive heart failure, malignant ventricular arrhythmia and pericardial effusion were more frequently found in the control group than in the nicorandil group (15% vs. 37%, 5% vs. 20% and 8% vs. 37%, p < 0.05, respectively). The frequency of sizable MCE no reflow phenomenon was significantly lower in the nicorandil group than in the control group (15% vs. 33%, p < 0.05). CONCLUSIONS: Intravenous nicorandil in conjunction with coronary angioplasty is associated with better functional and clinical outcomes compared to angioplasty alone in patients with an anterior AMI. Myocardial contrast echocardiography findings imply that an improvement in microvascular function with nicorandil may be attributable to this better outcome.

Angioplasty, Balloon, Coronary↗
PubMed1999

Pravastatin restored the infarct size-limiting effect of ischemic preconditioning blunted by hypercholesterolemia in the rabbit model of myocardial infarction.

OBJECTIVES: We tested to find out whether pravastatin restores the infarct size (IS)-limiting effect of ischemic preconditioning (IP) and if it has any effect on the IP-induced activation of adenosine producing enzyme ecto-5'-nucleotidase which plays a key role in the IP-induced cardioprotection. BACKGROUND: The IS-limiting effect of IP is blunted by hypercholesterolemia. Recently, HMG-CoA reductase inhibitors are shown to have direct cytoprotective effects. METHODS: Rabbits were fed with a normal or cholesterol (1%) added diet with or without pravastatin (5 mg/kg/day) treatment. Infarct size was measured after 30 min occlusion and 3 h reperfusion of circumflex coronary artery with or without the IP procedure (5 min occlusion and 10 min reperfusion). Additionally, ecto-5'-nucleotidase activities of ischemic and nonischemic myocardium were measured immediately after IP procedure. RESULTS: This dose of pravastatin did not normalize the increased level of serum cholesterol. The IS-limiting effect of preceding IP (IS reduced from 36.7% to 9.6%, p < 0.001) was abolished by hypercholesterolemia (from 46.1% to 31.3%, p = NS) and restored by pravastatin treatment (from 35.2% to 9.4%, p < 0.001). Pravastatin treatment did not affect IS or the effect of IP under normocholesterolemia. The activation of ecto-5'-nucleotidase presented as the activity ratio of ischemic to nonischemic myocardium (3.1-fold in normocholesterolemia) was blunted by hypercholesterolemia (1.8-fold, p < 0.05) and restored by pravastatin treatment (2.9-fold). CONCLUSIONS: Pravastatin, at the dose serum cholesterol was not normalized, restored the IS-limiting effect of IP and IP-induced ecto-5'-nucleotidase activation, which were both blunted by hypercholesterolemia. The activation of ecto-5'-nucleotidase may be worth further investigation as a possible mechanism for the hypercholesterolemia-induced retardation and pravastatin-mediated restoration of the cardioprotective effect of IP.

5'-Nucleotidase↗
PubMed1999

Evidence for the delayed effect in human ischemic preconditioning: prospective multicenter study for preconditioning in acute myocardial infarction.

OBJECTIVES: This study aimed to investigate prospectively the protective effect of a first preinfarction angina attack against acute myocardial infarction (AMI) in human hearts without significant collaterals. BACKGROUND: Several retrospective studies and the prospective studies have demonstrated the existence of the preconditioning (PC) effect in humans. However, collaterals were not examined in the prospective studies. In animal models, the PC effect on myocardial infarct size appears soon after PC reperfusion (classic) but disappears within 1 to 2 h. It then reappears 24 to 48 h after reperfusion (the delayed PC effect). Meanwhile, the PC effect on stunning appears 12 h after PC reperfusion (the delayed PC effect). The concept of the classic and delayed PC effects has not been investigated in human AMI studies. If the above concept is also correct in humans, the infarct size and/or impairment of the left ventricular function should be inversely correlated with the time interval between the first preinfarction angina attack and the onset of AMI when that time interval is limited to between 2 and 48 h. METHODS: The subjects were 25 patients with first AMI of the proximal left anterior descending artery who underwent successful direct percutaneous transluminal coronary angioplasty (PTCA) 2 to 6 h after the onset and with no (or poor) collateral circulation (grade 0 or 1). They were divided into two groups: preinfarction angina (PA)(+) group: 11 patients with new onset preinfarction angina from 2 to 48 h before the onset, PA(-) group: 14 patients without angina before infarction. Peak creatine kinase (CK) and cumulative CK were examined, and the left ventricular ejection fraction (LVEF) and the regional wall motion (RWM) were determined from the left ventriculograms during the acute (immediately after the coronary reperfusion) and chronic (four weeks after the onset of AMI) phases. The RWM index (RWMI) was then calculated as the mean motion of chords (standard deviation [SD]/chord) lying in the area of chords of RWM < or = -2 SD in the acute phase (ischemic risk area). RESULTS The increase in the RWMI between the acute and chronic phases was significantly larger in the PA(+) group than in the PA(-) group (1.55 +/- 1.32 and 0.69 +/- 0.75, p < 0.05, respectively) although no significant difference in the enzymatic infarct size was seen between the two groups. The increases in the LVEF and the RWMI were significantly correlated with the time interval from the first preinfarction angina attack to the onset of AMI (r = 0.622, p < 0.05 and r = 0.646, p < 0.05, respectively), but the enzymatic infarct size was not. CONCLUSIONS: The beneficial effect of preinfarction angina on left ventricular wall motion, independently of collateral flows, indicates the existence of the PC effect in humans. The greater protective effect of a longer time interval between angina pectoris and AMI suggests that the protection is due to a delayed PC effect.

Angina Pectoris↗
PubMed1999

Intracoronary administration of adenosine triphosphate increases coronary blood flow and attenuates the severity of myocardial ischemic injury in dogs.

ATP generates nitric oxide (NO) via activation of P2y receptors, and is degraded to adenosine. This study was undertaken to examine whether ATP causes coronary hyperemic flow via purinoceptors-, NO- and adenosine-dependent mechanisms, and attenuates the severity of contractile and metabolic dysfunction in the ischemic myocardium. In the non-ischemic canine hearts, the infusions of ATP into the coronary artery dose-dependently increased coronary blood flow. The levels of adenosine and end-product of NO in coronary venous blood over the arterial blood also increased. This hyperemic flow was partially attenuated by either 8-sulfophenyltheophylline (8SPT) or L(omega)-nitro arginine methyl ester (L-NAME), and completely blocked by the treatment with 8SPT, L-NAME and suramin (SRM). During myocardial ischemia, exogenous ATP increased coronary blood flow, and attenuated myocardial metabolic and contractile dysfunction, which was completely blunted by the treatment with 8SPT, L-NAME and SRM. We conclude that exogenous ATP increases coronary blood flow in the non-ischemic and ischemic myocardium mainly via either NO- or adenosine-dependent mechanisms.

Adenosine Triphosphate↗
PubMed1999

Monophosphoryl lipid A provides biphasic cardioprotection against ischaemia-reperfusion injury in rat hearts.

1 We utilized a rat model of myocardial infarction to investigate whether cardioprotection by monophosphoryl lipid A (MLA) is provided in the early and late phases, as well as to determine whether this cardioprotection may be related to the activation of manganese superoxide dismutase (Mn-SOD), an intrinsic radical scavenger. 2 Pretreatment with MLA (0.5 or 1.0 mg kg-1, i.v.) 24 h prior to 20-min left coronary artery (LCA) occlusion and 48-h reperfusion significantly decreased the incidence of ventricular fibrillation (VF) during ischaemia, as well as infarct size. Pretreatment with lower concentrations of MLA, however, was ineffective. 3 When we examined the time course of MLA (0.5 mg kg-1)-induced cardioprotection, both infarct size and the incidence of VF were significantly reduced in rats pretreated with MLA 0.5 h and 24 h before occlusion. We observed no differences, however, 2 and 72 h after MLA treatment. 4 The activity of Mn-SOD paralleled the cardioprotective effects of MLA. Mn-SOD activity in the myocardium was significantly enhanced in rats pretreated with MLA (0.5 mg kg-1) 0.5 and 24 h before. Mn-SOD activity was not altered, however, in rats pretreated 2 or 72 h before. Lower MLA concentrations were not effective even 24 h after the treatment. 5 We conclude that MLA treatment induced a biphasic pattern of cardioprotection. The pattern of Mn-SOD activity suggests that this enzyme may play a major role in the acquisition of cardioprotection against ischaemia-reperfusion injury.

Animals↗
PubMed1999

Mechanisms underlying the impairment of endothelium-dependent relaxation in the pulmonary artery of monocrotaline-induced pulmonary hypertensive rats.

1. It has been reported that endothelium-dependent relaxation is impaired in pulmonary hypertensive vessels. The underlying mechanisms for this phenomenon, however, have not yet been identified. In this study, the mechanisms responsible for decreased endothelium-dependent relaxation in the pulmonary artery isolated from monocrotaline (MCT)-induced pulmonary hypertensive rat (MCT rat) were examined. MCT (60 mg kg-1), or its vehicle was administered by a single subcutaneous injection to 6-week-old male Sprague Dawley rats. 2. Endothelium-dependent relaxation induced by carbachol or ionomycin in the MCT rat artery was significantly smaller than that in vehicle-treated rat (control rat) artery. Cyclic GMP levels, measured by enzyme-immunoassay, under resting or stimulation with carbachol or ionomycin were also smaller in the MCT rat artery. However, sodium nitroprusside-induced cyclic GMP accumulation in the endothelium-denuded artery was similar in control and MCT rats. These results suggest that MCT treatment decreases endothelial nitric oxide (NO) production. 3. Resting endothelial Ca2+ levels ([Ca2+]i) in the fura-PE3-loaded MCT rat artery, were not different from those in the control rat. However, the increase in endothelial [Ca2+]i elicited by carbachol was attenuated in the MCT rat. 4. In quantitative RT - PCR analysis, the expression of mRNA encoding endothelial NO synthase was rather increased in the MCT rat artery, suggesting an up-regulation of eNOS expression. 5. These results provide evidence that impaired NO-mediated arterial relaxation in the MCT rat is due to dissociation between eNOS expression and NO production. This dissociation may be derived from an inhibition of receptor-mediated Ca2+ metabolism and also from the apparent decrease in Ca2+ sensitivity of eNOS.

Animals↗