Prophylactic effect of JTE-607 on LPS-induced acute lung injury in rats with CINC-1 inhibition.

OBJECTIVE AND DESIGN: JTE-607, a multiple cytokine inhibitor, was evaluated in lipopolysaccharide (LPS)-induced acute lung injury in rats in vivo and in vitro. MATERIALS AND METHODS: LPS instillation into airways of rats was performed. JTE-607 at 3-30 mg/kg and dexamethasone at 3 mg/kg were administered intravenously at 10 min and 0 min for JTE-607, and 60 min for dexamethasone prior to the LPS instillation (n = 8). Cytokine-induced neutrophil chemoattractant (CINC)-1 level and myeloperoxidase (MPO) activity in lung were measured at 4 h after LPS instillation, and at 24 h for lung wet weight measurement and histological study. LPS-induced CINC-1 production by rat alveolar macrophages were also measured in vitro. RESULTS: JTE-607 and dexamethasone showed a significant reduction of increased CINC-1 level and MPO activity in lung after LPS treatment in vivo. Increased wet weight was also significantly inhibited. Histological studies revealed that JTE-607 and dexamethasone significantly inhibited LPS-induced accumulation of peribronchial neutrophils and eosinophils, and perivascular edema. JTE-607 and dexamethasone suppressed CfNC-1 synthesis by rat alveolar macrophages in vitro with IC50 values of 12.4 microM and 2.3 nM, respectively. CONCLUSIONS: These results indicate that JTE-607 has an inhibitory effect on LPS-induced rat lung inflammation in parallel with CINC-1 reduction. The effect of JTE-607 was suggested to be through direct inhibition of CINC-1 production from rat alveolar macrophages. JTE-607 may thus be efficacious in cytokine-mediated lung inflammation such as acute respiratory distress syndrome.

Inhibitory effect of JTV-803, a new cyclic guanidine derivative, on factor Xa in vitro and in vivo.

JTV-803, 4-[(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)methyl]-1-(4-pyridinyl)piperidine-4-carboxylic acid monomethanesulfonate trihydrate showed a competitive inhibitory effect on human factor Xa, with a K(i) value of 0.019 microM. This compound was 100 times more selective in inhibiting human factor Xa as compared to its inhibitory activity against thrombin, plasmin, and trypsin. JTV-803 was also examined for its inhibitory effect on activated factor Xa obtained from plasma of various animal species. JTV-803 exerted a potent inhibitory effect on human factor Xa (IC(50): 0.081 microM). JTV-803 prolonged activated partial thromboplastin time and prothrombin time in a dose-dependent manner. Oral anticoagulant efficacy of JTV-803 was examined ex vivo for its inhibition of human factor Xa in cynomolgus monkeys. JTV-803 produced more than 20% inhibition of human factor Xa for 8 h. Taken together, the results indicate JTV-803 is a long-acting oral anticoagulant which exerts its effect via specific inhibition of human factor Xa.

A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits.

Cholesteryl ester transfer protein (CETP) is a plasma protein that mediates the exchange of cholesteryl ester in high-density lipoprotein (HDL) for triglyceride in very low density lipoprotein (VLDL). This process decreases the level of anti-atherogenic HDL cholesterol and increases pro-atherogenic VLDL and low density lipoprotein (LDL) cholesterol, so CETP is potentially atherogenic. On the other hand, CETP could also be anti-atherogenic, because it participates in reverse cholesterol transport (transfer of cholesterol from peripheral cells through the plasma to the liver). Because the role of CETP in atherosclerosis remains unclear, we have attempted to develop a potent and specific CETP inhibitor. Here we describe CETP inhibitors that form a disulphide bond with CETP, and present one such inhibitor (JTT-705) that increases HDL cholesterol, decreases non-HDL cholesterol and inhibits the progression of atherosclerosis in rabbits. Our findings indicate that CETP may be atherogenic in vivo and that JTT-705 may be a potential anti-atherogenic drug.

Effects of peroxisome proliferator-activated receptor-alpha and -gamma agonist, JTT-501, on diabetic complications in Zucker diabetic fatty rats.

This study has investigated the effects of JTT-501, a peroxisome proliferator-activated receptor (PPAR)-alpha and PPAR-gamma agonist, on the pathogenesis of diabetic complications in the Zucker diabetic fatty (ZDF) rats, a model of type 2 diabetes. Comparison is made with troglitazone, a PPAR-gamma agonist. The ZDF rats exhibited hyperglycaemia and hyperlipidaemia, and developed diabetic complications such as cataract, nephropathy, and neuropathy. Treatment with JTT-501 from the prediabetic stage controlled glycaemia and lipidaemia, and prevented the development of diabetic complications. Troglitazone was less effective in controlling serum cholesterol and neuropathy. ZDF rats developed diabetic osteopenia with reduced bone turnover, and this was prevented by JTT-501 and troglitazone, possibly mediated by increased bone turnover and bone formation. Since JTT-501 controlled glycaemia and lipidaemia in ZDF rats and prevented several diabetic complications, it is suggested that treatment with JTT-501, which activates both PPAR-alpha and PPAR-gamma, could provide a valuable therapeutic approach against diabetic complications in type 2 diabetes.

JTE-522 selectively inhibits cyclooxygenase-2-derived prostaglandin production in inflammatory tissues.

OBJECTIVE AND DESIGN: To investigate the effect of JTE-522, a selective cyclooxygenase (COX)-2 inhibitor, on prostaglandin (PG) production and COX expression in rats. SUBJECTS: Male rats (4-8 weeks old) were used for in vivo experiments, while for in vitro assay, rat peritoneal macrophages were used. TREATMENT: JTE-522 (1-100 mg/kg) and indomethacin (0.03-10 mg/kg) were administered orally. JTE-522 and reference compounds (0.01-10 microM) were subjected to COX expression. RESULTS: JTE-522 inhibited the development of carrageenin-induced paw edema and PGE2 production in inflammatory paws at a dose of 10 mg/kg. On the other hand, JTE-522 (1-100 mg/kg) did not affect A23187-stimulated thromboxane B2 release from whole blood or the PGE2 level in gastric mucosa. JTE-522 did not suppress lipopolysaccharide-induced COX-2 expression in peritoneal macrophages. CONCLUSION: These results indicate that JTE-522 selectively inhibits PG production mediated by COX-2 in inflammatory tissues. JTE-522 may thus represent a novel type of anti-inflammatory drug without adverse effects on the gastro-intestinal tract.

Suppression of polypogenesis in a new mouse strain with a truncated Apc(Delta474) by a novel COX-2 inhibitor, JTE-522.

Mutations of the adenomatous polyposis coli gene (Apc) have been implicated in the occurrence of sporadic colon cancer. Various Apc knockout strains of mice have been created to better understand the function of this gene. In the present study, using gene targeting, we disrupted the mouse Apc gene at the end of exon 10 to compare its effect with the effects of other types of Apc gene disruption, all of which are on exon 15. The mice expressed a mutant form of mRNA that encoded 474 amino acids instead of 2845 amino acids due to exon duplication. In addition, these Apc(Delta474) knockout mice developed intestinal and mammary tumors. Since the most severe cases of familial adenomatous polyposis are associated with mutations on exon 15, our mutation at exon 10 was expected to result in a mild phenotype. However, the number of polyps that our mice developed was similar to that of other Apc knockout mice such as Apc(Min) and Apc(1309) mice. Cyclooxygenase-2 (COX-2) has been implicated in colorectal carcinoma. Apc(Delta474) mice treated with JTE-522, a novel COX-2-selective inhibitor, showed a significantly reduced number of polyps. These results suggest that COX-2 plays an important role in polypogenesis and COX-2-selective inhibitors can be used as new preventive therapeutics against colorectal tumors.

JTE-607, a novel inflammatory cytokine synthesis inhibitor without immunosuppression, protects from endotoxin shock in mice.

OBJECTIVE AND DESIGN: We investigated the effect of a novel N-benzoyl-L-phenylalanine derivative compound (JTE-607) on production of various cytokines and other immune responses in vitro and on endotoxin shock in vivo. MATERIALS AND METHODS: Human, monkey, rabbit, mouse and rat peripheral blood mononuclear cells (PBMCs), and human fibroblasts, umbilical vein endothelial cells (HUVEC), mesangial cells and T cells were used in vitro. Endotoxin shock was induced by lipopolysaccharide (LPS) in Corynebacterium parvum (C. parvum) sensitized male C57BL/6 mice in vivo. RESULTS: JTE-607 inhibited inflammatory cytokine production, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, IL-8 and IL-10, from LPS-stimulated human PBMCs, with IC50 values of 11, 5.9, 8.8, 7.3 and 9.1 nM, respectively. The inhibitory effects of JTE-607 were also seen in mRNA expression of those cytokines. The potency of JTE-607 on cytokine production from PBMCs of other species, and from other human cells were much lower than that on human PBMCs. JTE-607 did not affect either LPS-stimulated microbead phagocytosis or reactive oxygen species production at 1 microM in human PBMCs but slightly suppressed expression of major histocompatibility complex class II antigen at 1 microM, although it was 100-fold less active than it was as a cytokine inhibitor. JTE-607 (0.3-10 mg/kg, i.v.) showed dose dependent inhibition of mortality after LPS challenge in C. parvum sensitized mice in accordance with a decrease of plasma TNF-alpha. CONCLUSIONS: These results suggest that JTE-607 is a multiple cytokine inhibitor specific for human PBMCs. This compound may be useful for the treatment of various cytokine mediated diseases such as septic shock without causing immunosuppression.

Triglyceride-lowering effect of a novel insulin-sensitizing agent, JTT-501.

JTT-501, 4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-3, 5-isoxazolidinedione, is a novel insulin-sensitizing agent. We investigated the triglyceride-lowering activity of JTT-501 in a high-fat (HF) rat model. The HF rats showed insulin resistance with elevation of fasting insulin levels and reduction of insulin-stimulated glucose oxidation. There was also a tendency towards increased basal insulin and triglyceride levels. Oral administration of JTT-501 (3-30 mg kg(-1) day(-1) for 7 days) reduced basal triglyceride levels dose dependently with a minimum effective dose of 3 mg kg(-1) day(-1). Furthermore, regarding triglyceride metabolism, JTT-501 (30 mg kg(-1) day(-1) for 15 days, p.o.) decreased hepatic triglyceride output rate and serum triglyceride half-life (T1/2). In contrast, pioglitazone (30 mg kg(-1) day(-1) for 15 days, p.o.) reduced T1/2, but did not affect hepatic triglyceride output rate. We conclude that JTT-501 possesses potent triglyceride-lowering activity due to its inhibition of triglyceride secretion from the liver and enhancement of triglyceride disposal in peripheral tissues.

Glucose-dependent insulinotropic effects of JTT-608, a novel antidiabetic compound.

The effects of JTT-608 [trans-4-(4-methylcyclohexyl)-4-oxobutyric acid], a novel antidiabetic compound, on insulin secretion were investigated using mouse insulinoma cell line (MIN6 cells) and isolated, perfused rat pancreas. JTT-608 enhanced insulin secretion in MIN6 cells in a dose dependent (10-300 microM) and glucose concentration-dependent (2.8-16.7 mM) manner. Unlike sulphonylureas, JTT-608 minimally stimulated insulin secretion at low glucose concentrations but potently enhanced insulin secretion at high glucose concentrations. In isolated, perfused pancreas of normal rats, JTT-608 (100-300 microM) dose-dependently enhanced insulin secretion in the first and second phases at high glucose concentrations but minimally stimulated insulin secretion at a basal glucose concentration. In isolated, perfused pancreas of neonatally streptozotocin-induced non-insulin-dependent diabetes mellitus rats (nSTZ rats), JTT-608 (200 microM) normalized the first phase and doubled the second phase of insulin secretion. In MIN6 cells, JTT-608 did not inhibit the binding of [3H]glibenclamide to membrane fractions but enhanced K+-ATP channel-independent insulin secretion. These results suggest that JTT-608 enhances insulin secretion in a different manner and via a different mechanism from hypoglycemic sulphonylureas.

JTT-608 restores impaired early insulin secretion in diabetic Goto-Kakizaki rats.

1. We investigated the pharmacological effects of a new antidiabetic agent, JTT-608, in comparison with the sulphonylurea tolbutamide, in Goto-Kakizaki (GK) rats, a genetic model of non-obese insulin-dependent diabetes mellitus (NIDDM). 2. In isolated perfused pancreas from GK rats, JTT-608 (200 microM) enhanced 11.1 mM glucose-stimulated insulin secretion in the first and second phases, but had little effect on insulin secretion at 2.8 mM glucose. In contrast, tolbutamide (100 microM) markedly stimulated insulin secretion at 2.8 mM glucose and enhanced the second phase of insulin secretion but not the first phase at 11.1 mM glucose. 3. In vivo JTT-608 also enhanced early insulin secretion only with glucose-loading. In contrast, tolbutamide enhanced insulin secretion both with and without glucose-loading. 4. JTT-608 (10-100 mg kg(-1)) improved oral glucose tolerance with enhanced insulin secretion in a meal tolerance test (MTT). In comparison with tolbutamide, JTT-608 improved glucose tolerance more efficiently in GK rats than in Wistar rats. 5. We conclude that in diabetic GK rats JTT-608 suppressed postprandial glucose excursions with enhanced glucose-stimulated insulin secretion, especially the first phase of insulin secretion.

JTT-608 controls blood glucose by enhancement of glucose-stimulated insulin secretion in normal and diabetes mellitus rats.

We investigated the pharmacological effects of a new anti-hyperglycemic agent, JTT-608 [trans-4-(4-methylcyclohexyl)-4-oxobutyric acid], in normal and neonatally streptozotocin-treated rats. In normal rats, JTT-608 improved glucose tolerance at 3-30 mg/kg, doses that did not cause a decrease in fasting blood glucose levels. In contrast, tolbutamide (10-100 mg/kg) and glibenclamide (1-3 mg/kg) caused a persistent decrease in fasting blood glucose levels, and tolbutamide only improved glucose tolerance at 10-100 mg/kg. Furthermore, JTT-608 (3-30 mg/kg) enhanced insulin secretion only with glucose stimulation, but tolbutamide (10-100 mg/kg) enhanced it both with and without glucose stimulation. In neonatally streptozotocin-treated rats, JTT-608 (10-100 mg/kg) improved glucose tolerance with enhanced insulin secretion in the oral glucose tolerance test and meal tolerance test. Additionally, JTT-608 improved glucose tolerance dose dependently, but the effect of tolbutamide reached a plateau. We conclude that JTT-608 is an enhancer of glucose-stimulated insulin secretion.

Pharmacological profiles of a novel oral antidiabetic agent, JTT-501, an isoxazolidinedione derivative.

JTT-501, 4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-3,5-isoxaz olidinedione, is an isoxazolidinedione derivative which is structurally distinct from thiazolidinediones such as pioglitazone and troglitazone. We investigated the effects of JTT-501 on insulin-sensitizing activity and in rodent diabetic models. JTT-501 enhanced insulin-stimulated cell differentiation of 3T3-L1 fibroblasts with an EC50 value of 110 nM. Furthermore, JTT-501 activated peroxisome proliferator-activated (PPA) gamma and alpha receptors with the EC5-fold values of 0.28 and 5.4 microM, respectively. In the non-insulin-dependent diabetes mellitus model KK-Ay mice, JTT-501 improved hyperglycemia, hyperinsulinemia and hypertriglyceridemia, and enhanced insulin-stimulated glucose oxidation in adipose tissues. JTT-501 was also effective in the non-insulin-dependent diabetes mellitus model Zucker diabetic fatty (ZDF) rats but not in the insulin-dependent diabetes mellitus model streptozotocin-induced diabetic mice. These observations suggest that JTT-501 enhances insulin sensitivity in peripheral tissues and improves hyperglycemia, hyperinsulinemia, and hypertriglyceridemia in non-insulin dependent diabetes mellitus models. In particular, the triglyceride-lowering activity of JTT-501 is a unique characteristic compared to the thiazolidinediones. Therefore, JTT-501 may be a promising antidiabetic agent for treating non-insulin-dependent diabetes mellitus patients with insulin resistance.

Profile of JTE-522 as a human cyclooxygenase-2 inhibitor.

Inhibitory activity and the mechanism of action of JTE-522 (4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamid e), a novel selective cyclooxygenase (COX)-2 inhibitor, on human COX-1 and COX-2 were investigated and compared with those of reference compounds. In an enzyme assay, JTE-522 inhibited yeast-expressed human recombinant COX-2 with an IC50 value of 0.085 microM. In contrast, JTE-522 did not inhibit human COX-1 prepared from human platelets at concentrations up to 100 microM. In a cell-based assay, JTE-522 diminished lipopolysaccharide-induced prostaglandin E2 production in human peripheral blood mononuclear cells (COX-2) (IC50 value = 15.1 nM). On the other hand, JTE-522 was less potent at inhibiting calcium ionophore-induced thromboxane B2 production in washed human platelets (COX-1) (IC50 value = 6210 nM). JTE-522 showed highly selective inhibition of human COX-2, and its activity was more selective than that of other COX-2 inhibitors (NS-398 and SC-58635). Human recombinant COX-2 activity was attenuated by JTE-522 in a dose-dependent and time-dependent manner. In contrast, the inhibitory activity of JTE-522 on human COX-1 was not affected by preincubation time. COX-2 inhibition by JTE-522 could not be recovered by gel filtration. These results indicate that JTE-522 is a highly selective, time-dependent and irreversible inhibitor of human COX-2.

Isoxazolidine-3,5-dione and noncyclic 1,3-dicarbonyl compounds as hypoglycemic agents.

Isoxazolidine-3,5-dione 2 (JTT-501), one of the cyclic malonic acid derivatives, was found to decrease blood glucose at an oral dose of 38 mg/kg/day in KKAy mice and is currently undergoing evaluation in phase II clinical trials. Further studies on a series of malonic acids and related compounds showed that the 1,3-dicarbonyl structure was important for insulin-sensitizing activity. Dimethyl malonate 10, which was selected as a successor for 2, was the optimum compound in a series of 1,3-dicarbonyl compounds and was more potent than the corresponding thiazolidine-2,4-dione 1.

Inhibitory effects of JTE-522, a novel prostaglandin H synthase-2 inhibitor, on adjuvant-induced arthritis and bone changes in rats.

OBJECTIVE AND DESIGN: To investigate the effect of JTE-522, a novel selective prostaglandin H synthase (PGHS)-2 inhibitor, on adjuvant-induced arthritis and bone changes. SUBJECTS: Male Lewis rats at 8 weeks old were immunized with heat-killed mycobacteria. TREATMENT: JTE-522 (0.1-30 mg/kg) and indomethacin (0.1-3 mg/kg) were administered orally once-daily after immunization. METHODS: Paw swelling, bone changes in arthritic paws and vertebrae, urinary levels of deoxypyridinoline and pyridinium crosslinks, and the incidence of gastric lesions were determined in arthritic rats. RESULTS: JTE-522 (from 0.3 mg/kg) suppressed the development of paw swelling, and also reduced bone damage (score and bone mineral density) in arthritic paws and the urinary excretion of deoxypyridinoline and pyridinium crosslinks. However, JTE-522 did not cause gastric lesions even at 30 mg/kg in arthritic rats. CONCLUSIONS: These results suggest that JTE-522 possesses potent anti-arthritic activities and suppressive activity on inflammatory bone resorption without gastric side effects.

JTT-501, a novel oral antidiabetic agent, improves insulin resistance in genetic and non-genetic insulin-resistant models.

1. We investigated whether JTT-501 (4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-3,5-isoxa zolidinedione) would improve insulin resistance in genetic (Zucker fatty rats) and non-genetic (high-fat fed rats) rodent models of obesity. 2. JTT-501 (10-100 mg kg(-1) day(-1)) was administered orally to Zucker fatty rats for 7-21 days. In the high-fat fed rat model, JTT-501 (100 mg kg(-1) day(-1) was administered orally for 7 days. In both models, JTT-501 improved metabolic abnormalities by enhancing insulin action during the glucose tolerance test and the euglycaemic-hyperinsulinaemic clamp study. In ex vivo assays, JTT-501 ameliorated the impaired insulin-sensitive glucose oxidation and lipid synthesis in peripheral tissues. Furthermore, JTT-501 enhanced insulin receptor autophosphorylation in hindlimb muscle. 3. JTT-501 reduced serum leptin concentrations in both models, but did not affect body weight or epididymal fat weight. 4. Our observations indicate that JTT-501 improves the metabolic abnormalities in both genetic and non-genetic insulin-resistant models by enhancing insulin action in peripheral tissues. These effects of JTT-501 are due, at least in part, to enhanced insulin receptor autophosphorylation. In addition, JTT-501 is able to reduce serum leptin concentrations in hyperleptinaemia of the insulin-resistant model. We expect JTT-501 to show promise for treating non-insulin dependent diabetes mellitus patients with insulin resistance.

Pharmacological profile of JTE-522, a novel prostaglandin H synthase-2 inhibitor, in rats.

OBJECTIVE AND DESIGN: The antinociceptive, antipyretic, and anti-inflammatory effects of JTE-522, a novel selective prostaglandin H synthase (PGHS)-2 inhibitor, were examined in rats. MATERIALS: Sheep seminal vesicle PGHS-1 and placenta PGHS-2 were used for in vitro assay, while for in vivo experiments, male rats (4-8 weeks old) were used. TREATMENT: JTE-522 and reference compounds (0.01-100 microM) were subjected to enzyme assay. JTE-522 (0.3-30 mg/kg) and indomethacin (0.3-10 mg/kg) were administered orally. RESULTS: JTE-522 inhibited PGHS-2 (IC50: 0.64 microM) without affecting PGHS-1 activity at 100 microM. In rats with yeast-induced hyperalgesia, JTE-522 showed a dose-dependent antinociceptive effect (ED50: 4.4 mg/kg). In rats with yeast-induced pyrexia, JTE-522 significantly reversed the pyrexic response (ED50: 3.9 mg/kg). Orally administered JTE-522 dose-dependently inhibited carrageenin-induced rat paw edema (ED30: 4.7 mg/kg). In rats with adjuvant-induced arthritis, JTE-522 showed a significant inhibitory effect at daily doses of 0.3-3 mg/kg. JTE-522 did not cause severe gastric lesions at oral doses up to 300 mg/kg. CONCLUSIONS: Our results indicate that the selective PGHS-2 inhibitor JTE-522 may represent a novel type of anti-inflammatory drug without adverse effects on the gastrointestinal tract. JTE-522 may thus be a promising agent for treating both acute inflammatory disease and chronic inflammatory diseases such as rheumatoid arthritis.

Inhibitory effect of OP-41483.alpha-CD, a prostacyclin analog, on peripheral vascular lesion models in rats.

The effect of a chemically stable prostacyclin analog, OP-41483 alpha-cyclodextrin clathrate (OP-41483.alpha-CD), on vascular lesions, platelet aggregation and blood pressure were examined and compared with those of prostaglandin E1 alpha-cyclodextrin clathrate (PGE1.CD) in in vivo rat models. 1) In the laurate (1 mg/leg, i.a.)-induced arterial thrombotic model, OP-41483.alpha-CD (1 microgram/kg/min, i.v.) prevented the progression of femoral arterial vascular lesions and enhanced the development of collaterals in the femoral artery. PGE1.CD did not inhibit the progression of vascular damages. 2) In the model of vasoconstriction induced by epinephrine (0.05 mg/tail, s.c.) and ergotamine (2 mg/kg, s.c.), OP-41483.alpha-CD and PGE1.CD, at 1 microgram/kg/min, inhibited the progress of of tail gangrene and lessened the decrease in tail cutaneous blood flow. 3) OP-41483.alpha-CD (1 microgram/kg/min) suppressed the ADP (0.1 mg/kg/min, i.v.)-induced decrease in the number of circulating platelets without affecting the change in blood pressure. In contrast, PGE1.CD (3 micrograms/kg/min) inhibited ADP-induced thrombocytopenia with a decrease in blood pressure. These results indicate that OP-41483.alpha-CD has antiplatelet and cutaneous blood flow improving activities that are greater than its hypotensive effect and may be of therapeutic potential in peripheral vascular diseases.

[Effects of ONO-1016, inhibitor of C1-/HCO3- exchange, on the brain water content and local cerebral blood flow following cerebral ischemia in spontaneously hypertensive rats].

The effects of ONO-1016, as an inhibitor of C1-/HCO3-exchange, on the brain edema and circulatory failure following cerebral ischemia were examined in stroke-prone spontaneously hypertensive rats (SHR-SP). SHR-SP were divided into three groups: control (sham-operation), non-treated, ONO-1016 group, respectively. Cerebral ischemia was produced by bilateral carotid artery occlusion (BCAO) for 1 hr and then following reperfusion. The brain water content and local cerebral blood flow (LCBF) were determined by dry-wet method and 14C-iodoantipyrine method 2 hr after start of reperfusion. ONO-1016 was given intravenously at a dose of 100 micrograms/kg/min prior to ischemia. The brain water content increased in septum (SP), amygdala (AM) in both non-treated and ONO-1016 groups compared from those in control group. However, brain water contents in SP and midbrain were lower in ONO-1016 group than those in non-treated group. LCBFs decreased to 50-80% in SP, cerebral cortex (CT), striatum (ST), hippocampus (HC) and AM in non-treated group, while LCBFs decreased to 60-80% in SP, CT, ST, AM in ONO-1016 group when compared from those in control group. Decrease of LCBF in ST and HC in ONO-1016 group were less severe than those in non-treated group. From these results, ONO-1016 may prevent the brain edema formation associated with hypoperfusion during reperfusion period after ischemia in SHR-SP.