Japanese Journal of Pharmacology

The present study was conducted to elucidate the role of oxidative stress and nuclear factor-kappaB (NF-kappaB) in the beneficial effects of angiotensin receptor blockade on obstructive nephropathy. Unilateral ureteral occlusion in rats elicited tubulo-interstitial fibrosis with concomitant macrophage infiltration and increased expression of monocyte chemoattractant protein-1. These changes were accompanied by an induction of renal cortical lipid peroxidation and activation of NF-kappaB. Both an AT(1) antagonist, candesartan, and a NF-kappaB inhibitor, pyrrolidine dithiocarbamate, markedly attenuated these changes and to a similar extent...

A polysaccharide, designated as the D-fraction, extracted from maitake (Grifola frondosa), was reported to have anti-tumor effects by activating macrophages and T cells in C3H/HeN mice in which a Th-1 dominant response was established. In this study using BALB/c mice in which a Th-2 response is genetically dominant, D-fraction reduced the expression of Th-2 cytokine interleukin (IL)-4 but markedly increased the expression of Th-1 cytokine interferon (IFN)-gamma in CD4(+) T cells and also increased IL-12p70 production as well as IFN-gamma production by antigen-presenting cells (APCs), suggesting that D-fraction promotes the differentiation into Th-1 cells of CD4(+) T cells through enhancement of IL-12p70 production by APCs...

The effects of ebastine and its active metabolite carebastine on brain dopamine uptake and the accessibility to brain were compared with those for a classical antihistaminic agent chlorpheniramine by using the microdialysis technique. Both carebastine and chlorpheniramine potently inhibited brain [(3)H]dopamine uptake and increased the extracellular concentration of dopamine in the striatum after local perfusion via microdialysis probes, although systemic injection of ebastine but not chlorpheniramine did not change the dopamine level...

We examined the effect of Ginkgo biloba extract (GBE) on hepatic drug-metabolizing enzymes, particularly cytochrome P450 (CYP), in rats. Rats were fed a GBE-containing diet or received GBE by intragastric gavage. The concentration of CYP and activity of various CYP enzymes in the liver were increased in a dose- and time-dependent manner. Significant increases in the concentration and activities of CYP enzymes were detected on day 1 of feeding of a 0.5% GBE diet and after administration of 10 mg GBE/kg body weight for 5 days by intragastric gavage...

Statins, which competitively inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity and reduce mevalonate synthesis, are believed to exert a plethora of pleiotropic effects. In this report, molecular mechanisms of the inhibitory effect on plasminogen activator inhibitor type 1 (PAI-1) expression produced by cerivastatin (CRV), the most active compound in this class, were studied using monocultures of human endothelial cell line (EA.hy 926). CRV similar to another statin, lovastatin (LOV), significantly inhibited PAI-1 expression and its release from endothelial cells, nonstimulated and stimulated with TNF-alpha...

The clinical effectiveness of the Kampo medicine Sho-seiryu-to (SST) has recently been demonstrated in a double-blind randomized study of allergic asthma and rhinitis. We investigated the effect of SST on a type 1 allergic model in mice. Ovalbumin (OVA)-induced sneezing and the total and OVA-specific IgE levels were significantly suppressed with SST at 1.0 g/kg, but that of OVA-specific IgG(2a) was not. In the splenocytes isolated from SST-administered mice, OVA-induced interleukin (IL)-4 production decreased while interferon (IFN)-gamma production was not...

We investigated the effect of hypoxia on beta-amyloid (Abeta)-induced apoptosis in rat cultured hippocampal neurons. Abeta (25 microM for 48 h) decreased the number of neuronal cells and increased the number of TUNEL-positive cells. Hypoxia (6 h) also decreased the number of neuronal cells, but did not increase the number of TUNEL-positive cells. Moreover, combined treatment with both Abeta and hypoxia (Abeta/hypoxia) significantly enhanced the decrease in the number of neuronal cells and the increase in the number of TUNEL-positive cells...

It is known that 5-HT(4) receptors in the colon of guinea pigs show a distribution similar to that in humans. Thus, we examined the effects of mosapride citrate (mosapride) and cisapride, two 5-HT(4)-receptor agonists, on colonic motility in conscious guinea pigs implanted with force transducers. Mosapride and cisapride administered intragastrically at doses of 3 - 30 mg/kg significantly enhanced the colonic motility. The enhancing effect of mosapride was antagonized by atropine or GR113808, a 5-HT(4)-receptor antagonist, but not by methysergide, a 5-HT(1)- and 5-HT(2)-receptor antagonist; ondansetron, a 5-HT(3)-receptor antagonist; or CP-99994, a tachykinin NK(1)-receptor antagonist...

The influence of interferon-beta (IFN-beta) dosing time on antiviral activity was investigated in ICR male mice under light-dark cycle conditions (lights on at 07:00, off at 19:00) with food and water available ad libitum. There was a significant dosing time-dependent change in 2',5'-oligoadenylate synthetase (2',5'-OAS) activities, as an index of antiviral activity, in liver at 12 h after IFN-beta (15 MIU/kg, i.v.) injection. IFN-beta-induced 2',5'-OAS activity was more potent after the drug injection during the late dark phase...

The protective effect of ebselen, which possesses glutathione peroxidase-like activity and antioxidative and anti-inflammatory properties, against the progression of acute gastric mucosal lesions was examined in rats with a single intraperitoneal injection of compound 48/80 (0.75 mg/kg). Ebselen (50, 100 or 200 mg/kg) was orally administered 0.5 h after compound 48/80 treatment, at which time gastric mucosal lesions appeared. Post-administered ebselen suppressed gastric mucosal lesion progression at 3 h after compound 48/80 treatment dose-dependently, although no dose of ebselen affected the decreased gastric mucosal blood flow and increased serum serotonin and histamine concentrations found at 3 h after the treatment...

Null genotype of glutathione S-transferase class me (GSTM1(-)) and the plasma level of malondialdehyde (MDA) were determined in normal subjects, epileptics with good seizure control and epileptics with intractable seizure. The frequency of GSTM1(-) of the epileptics with intractable seizure was significantly higher than that of the group with good seizure control and that of the normal subjects. The average plasma level of MDA of the patients with GSTM1(-) genotype was higher than that of the subjects with GSTM1(+) in either the normal or epileptic group...

We simultaneously recorded the prostatic contractile and urethral pressure responses to electrical stimulation (ES) of the hypogastric nerves (HGNs) or phenylephrine in anesthetized rats and studied the effects of tamsulosin on these responses. At 0.01 and 0.1 mg/kg, i.v., tamsulosin inhibited the prostatic responses to ES of the HGNs in a dose-dependent manner, while at 1 microg/kg, i.v., it reduced the response to phenylephrine (0.01 mg/kg, i.v.) to about 26% of the nonantagonized level. These inhibitory effects on prostatic responses were maintained for 60 min...

The effect of the water-soluble extract (WSE) of Salvia miltiorrhiza on neutrophil-endothelial cell adhesion was investigated. Cell adhesion was evaluated by testing neutrophil myeloperoxidase activity: expression of adhesion molecules in human umbilical vein endothelial cells (HUVEC) was measured by ELISA: the neutrophil activation rate induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP) was tested by the method of nitroblue tetrazolium (NBT) reduction. The results showed that the adhesion rate of neutrophils to unstimulated HUVEC was very low...

This paper is the first report of a genetic index for morphine withdrawal in infant rats. We examined the effects of naloxone (2 mg/kg) on c-fos mRNA levels in brains of infant and adult rats following repeated treatment with morphine (20 mg/kg, once daily for 5 days). One hour after a single administration of naloxone (naloxone challenge), an increase in c-fos mRNA was observed in the olfactory bulb, hypothalamus and medulla oblongata of infant rats, and in the olfactory bulb and hypothalamus, but not in the medulla oblongata of adult rats...

The mammalian circadian clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus and in most peripheral tissues. Clock genes drive the biological clock. However, circadian expression variations of the human clock genes are still unclear. In this study, we analyzed the daily variations of mPer2 and mClock mRNA expression in both the mouse SCN and liver to evaluate the central and peripheral alterations in the rodent clock genes. We also examined whether there are the daily variations of the clock genes hPer2 and hClock in human peripheral blood mononuclear cells (PBMCs)...

Extension of axons and dendrites in neurons may compensate for and repair damaged neuronal networks in the dementia brain. To find out drugs capable of regenerating the neuronal network, we focused on several herbal drugs belonging to the genus Panax, kinds of Ginseng, and investigated neurite outgrowth activity of their extracts and compounds. We found that the methanol extracts of Ginseng (root of P. ginseng), Notoginseng (root of P. notoginseng) and Ye-Sanchi in Chinese (rhizome of a relative to P. vietnamensis) increased neurite outgrowth in SK-N-SH cells...

We investigated the effects of fragrance inhalation on sympathetic activity in normal adult subjects using both power spectral analysis of blood pressure fluctuations and measurement of plasma catecholamine levels. Fragrance inhalation of essential oils, such as pepper oil, estragon oil, fennel oil or grapefruit oil, resulted in 1.5- to 2.5-fold increase in relative sympathetic activity, representing low frequency amplitude of systolic blood pressure (SBP-LF amplitude), compared with inhalation of an odorless solvent, triethyl citrate (P<0...

Excessive glucocorticoids induce osteoporosis. However, there is some controversy regarding the mechanism of action, and even the endpoint result. The present study was carried out to obtain further insight into the action of glucocorticoids on bone formation and resorption in rats. Growing rats were injected subcutaneously with methylprednisolone (mPSL) at doses of 0, 2.5, 5, 10 or 20 mg/kg per day for 4 weeks. Bone mineral density (BMD), enchondral and periosteal bone formation, collagen synthetic activities of osteoblasts, numbers of osteoblasts and osteoclasts, and serum markers to assess bone turnover were determined...

KB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea methanesulfonate) has been used as a pharmacological tool to block the Ca(2+) influx-mode of the Na(+)/Ca(2+) exchanger, which is thought to contribute to ischemia/reperfusion and digitalis arrhythmias. We examined effects of KB-R7943 on ischemia/reperfusion arrhythmias in beagle dogs anesthetized with sodium pentobarbital. Lead II ECG and BP were measured. KB-R7943 or the solvent (10% DMSO) was injected i.v. as a bolus, and 5 min later, the left anterior descending coronary artery was occluded for 30 min followed by reperfusion...

In vascular tissues, angiotensin II is potentially cleaved from angiotensin I by chymase and angiotensin-converting enzyme (ACE). In the normal state, vascular ACE regulates local angiotensin II formation and plays a crucial role in the regulation of blood pressure, whereas chymase is stored in mast cells and has no enzymatic activity. Chymase is activated immediately upon its release into the extracellular matrix in vascular tissues after mast cells have been activated by stimuli such as vessel injury by grafting or a balloon catheter...