加瀬 義夫

Disruption of the hypothalamo-pituitary-adrenal (HPA) axis characterized by dysfunction of the glucocorticoid negative feedback system is frequently observed in human depressives and is thought to involve a reduction in glucocorticoid receptor (GR) function in the feedback sites including the brain. Recently, we found that chronic stress in rats induces similar HPA disruption that is caused by abolishment of feedback ability in the prefrontal cortex (PFC) and hippocampus, which involves decreased cytosolic GRs or increased nuclear GRs, respectively. Also, we found that saikokaryukotsuboreito (SRBT), a herbal medicine, prevents the chronic stress-induced HPA disruption. We therefore examined here the effects of this drug on the chronic stress-induced changes in GRs in the PFC and hippocampus. Chronic stress was induced in rats by water immersion and restraint (2 h/day) for 4 weeks. SRBT significantly prevented decreased cytosolic GRs in the PFC and increased nuclear GRs in the hippocampus in the chronically stressed rats. Moreover, SRBT significantly prevented the abolishment of feedback ability in both regions. These results suggest that the beneficial effects of SRBT on the GR level are involved in its ameliorating actions on the HPA disruption. This finding provides information important for the prevention and treatment of depression. (c) 2006 Elsevier Inc. All rights reserved.

The effects of methyleugenol, an essential oil isolated from Asiasari radix, on antinociception were examined using the formalin test in mice. Oral administration of 10 mg/kg methyleugenol significantly decreased the duration of licking and biting behavior in the second phase without affecting that of the first phase, as did diclofenac, a non-steroidal anti-inflammatory drug. Methyleugenol also inhibited pain-related behaviors induced by intrathecal injection of N-methyl-D-aspartic acid (NMDA), while diclofenac did not affect these behaviors. These effects of methyleugenol were suppressed by bicuculline, a gamma-aminobutyric acid(A) (GABA(A)) antagonist. Muscimol, a GABAA agonist, displays the same action as methyleugenol with respect to the formalin test and NMDA-induced behaviors. Methyleugenol did not affect cyclooxygenase-1 and -2 activities. These results suggest that the antinociceptive effect of methyleugenol on the second phase of formalin-induced pain may be due to the inhibition of NMDA receptor-mediated hyperalgesia via GABAA receptors. 0 2006 Elsevier B.V.. All rights reserved.

Background. Postoperative intraperitoneal adhesions are the leading cause of intestinal obstruction, but the underlying mechanisms remain incompletely understood. The aim of the current study was to investigate the involvement of intestinal ischemia/reperfusion (LIR) injury in adhesion formation in rats. Materials and methods. Rats were subjected to either a dusting of talc (15 mg/rat) over the entire small intestine or ischemia induced by clamping the superior mesenteric artery (SMA) for 30 min followed by reperfusion with or without talc dusting. On postoperative days 4, 7, and 14, the scores, lengths, and incidence of adhesions were evaluated. In addition, the contractile force of the jejunal muscle was measured at 0, 24, 48, and 96 h after the treatments using organ bath techniques under bethanechol-stimulated conditions. Results. Talc induced mild adhesions in rats. Although LIR injury alone did not produce adhesions, it markedly aggravated the talc-induced adhesions, with higher scores and longer adhesions on postoperative days 4, 7, and 14. In addition, LIR injury caused 75-88% suppression of the circular muscle contractile force and 35-52% suppression of the longitudinal muscle contractile force at 24 h after SMA occlusion. However, talc did not affect the contractions. Conclusions. Intestinal LIR injury aggravated the talc-induced adhesions, and this consequence might be due to the functional suppression of jejunal muscle contractions. This finding suggests that intestinal ischemia is an important factor in the etiology of postoperative adhesions. 0 2006 Elsevier Inc. All rights reserved.

Background. Major surgery is believed to contribute to immune dysregulation and high susceptibility to microbes. Recently, the inflammatory "two-hit" model has been accepted to elucidate development of multiple organ failure in surgical patients. Our purpose was to examine whether intestinal surgery, which causes a minor insult with no septic shock, may modify the immune response to exogenous LPS as a second stimulus. Materials and methods. Using a rat intestinal transection and anastomosis surgery model, we sequentially examined blood cell counts, body temperatures, and plasma cytokines. Rats were administered with LPS intravenously or intratracheally various days after surgery. Phagocytic activity and TNF alpha production in bronchoalveolar lavage (BAL) cells, plasma cytokines, and survival rates were evaluated. Results. The surgery itself caused no severe shock or circulating cytokine elevation, whereas the number of granulocytes in the blood was significantly elevated after surgery. LPS-induced elevation of circulating IFN-gamma attenuated 3 days after surgery. In contrast, IL-10 was enhanced 3-10 days after surgery. Hyporesponsiveness of BAL cells to LPS was observed 3 days after surgery but not the next day after surgery. However, rats intratracheally exposed to LPS 10-13 days after surgery exhibited higher mortality. Conclusions. Although our surgical procedure was not supposed to be a severe insult, it sufficiently primed rats for an altered response to a second stimulus (endotoxin), which included enhanced mortality. This study provided an improved understanding of pathophysiological changes following surgery and described a useful model for developing preventive and therapeutic strategies for complications after surgery. (c) 2006 Elsevier Inc. An rights reserved.

Background. In order to clarify the diuretic mechanisms of Saireito, a Japanese herbal medicine, the mineralcorticoid receptor antagonistic action of Saireito was evaluated in anti-glomerular basement membrane (GBM) nephritic rats. Methods. Anti-GBM nephritis was induced in rats by the intravenous, injection of anti-GBM serum, and test drugs were administered 5 days after the induction of nephritis. In addition, we also investigated aldosterone-loaded mice to clarify the effects of test drugs on aldosterone signal transduction. In an in vitro study, a mineralocorticoid receptor binding assay of the componets of Saireito was performed. Results. Saireito and spironolactone inhibited the development of proteinuria and abdominal ascites in anti-GBM nephritic rats. Saireito and spironolactone increased the urine volume and decreased the abdominal saline content in aldosterone-loaded mice. Saikosaponin H, a component of Saireito, inhibited the receptor binding of aldosterone in the in vitro assay 50% inhibitory concentration ([IC50], 22 μmol/l). Saikosaponin H also inihibited the decrease in urine volume in aldosterone-loaded mice. Conclusions. These results suggest that the diuretic action of Saireito may be partly due to an antagonistic action on the mineralocorticoid receptor, exerted by saikosaponin H. © Japanese Society of Nephrology 2006.

Background. Anterior resection for rectal disease is associated with extrinsic autonomic denervation of the neorectum, which may influence the myenteric plexus, and subsequently the motilily/defecatory status after operation. Methods. A rat model with denervated neorectum was constructed. Colonic contractile activity in vivo, the amount of generic neuron marker (PGP 9.5) and nitric oxide synthase (NOS) were measured periodically. The responses of the muscle strip in each period to electrical field stimulation were evaluated using various neurotransmitters. Results. In rats with denervated neorectum, giant migrating contractions (GMCs) of the distal colon, the number of fecal lumps per day and their small size, significantly increased in the early phase postoperatively, although both recovered in the late-phase period. The contractile response of the muscle strip of the denervated colon to acetylcholine was reduced throughout the period; however, contraction of the denervated colon under the addition of NO inhibitor (L-NAME) was enhanced significantly in the late-phase period, and recovered to the control level by atropine. Neuronal NOS, but not PGP 9.5 concentration, in the myenteric plexus at the distal denervated colon, significantly increased in the late-phase period. None of the above items differed from the control at other colonic portions throughout the period. Conclusions. Extrinsic autonomic denervation causes abnormal hyper-motility in the neorectum, which may, be associated with multiple evacuations in the early phase postoperatively. Increased acetylcholine and the subsequent increase of neuronal NOS in the myenteric plexus may be an adaptive mechanism to compensate for such abnormal colonic motility after extrinsic denervation.

Aims: Unpito, an herbal medicine extracted from a mixture of five crude medicines (Rhei Rhizoma, Glycyrrhizae Radix, Ginseng Radix, Zingiberis Rhizoma and Aconiti Tuber), has been developed as a drug for chronic renal failure. In general, it is difficult to estimate the absorption and excretion of herbal medicines due to the presence of a wide variety of components. The purpose of the current study was to examine the systemic pharmacokinetics and elimination of Unpito in healthy volunteers following repeated administration as part of the clinical study of the medicine. Methods: Three compounds, (-) epicatechin 3-O-gallate (ECG), glycyrrhetic acid (GA) and rhein (RH) were selected as markers, to examine the clinical pharmacokinetics of Unpito based on their levels in this medicine. The disposition of each compound was evaluated in 24 healthy volunteers receiving multiple oral doses (4, 6, and 8 capsules three times a day). Results: After repeated administration, plasma ECG and GA concentrations were lower than those simulated. RH plasma concentrations were consistent with the simulation, indicating linear pharmacokinetics of RH. The potential accumulations of marker compounds were not observed from the roughly constant plasma concentrations of troughs at 72, 120, and 144 h after the first administration nor from the urinary excretions. Conclusions: This is the first study presenting pharmacokinetics of ECG, GA and RH derived from Unpito, an herbal medicine, in healthy volunteers after multiple dose administration.

Aims: Unpito, an herbal medicine extracted from a mixture of five crude medicines (Rhei Rhizoma, Glycyrrhizae Radix, Ginseng Radix, Zingiberis Rhizoma and Aconiti Tuber), has been developed as a drug for chronic renal failure. In general, it is difficult to estimate the absorption and excretion of herbal medicines due to the presence of a wide variety of components. The purpose of the current study was to examine the systemic pharmacokinetics and elimination of Unpito in healthy volunteers as part of the clinical study of the medicine. Methods: Three compounds, (-)epicatechin 3-O-gallate (ECG), glycyrrhetic acid (GA) and rhein (RH) were selected as markers, to examine the clinical pharmacokinetics of Unpito based on their levels in this medicine. The disposition of each compound was evaluated in 32 healthy volunteers receiving single oral doses (2, 4, 8, and 12 capsules). Results: After a single oral administration, ECG and RH exhibited linear pharmacokinetics in AUC and C max, while GA did not exhibit linear pharmacokinetics. A cross-over study was conducted to evaluate the effect of food at a single dose of 4 capsules. The effect of food was observed for the plasma concentrations of ECG and RH, while not for GA. The potential accumulations of δ-(3,4- dihydroxyphenyl)-γ-valerolactone (VL-2), a metabolite of ECG and RH were not observed. GA was not detected in urine. Conclusions: This is the first study presenting pharmacokinetics of ECG, GA and RH derived from Unpito, an herbal medicine, in healthy volunteers after single dose administration.

In this study, the antinociceptive effect of shakuyakukanzoto was investigated using streptozotocin-induced diabetic mice to certify its analgesic effect on diabetic patients. Shakuyakukanzoto (0.5 and 1.0 g/kg, p.o.) significantly increased the nociceptive threshold in diabetic mice. The antinociceptive activity of shakuyakukanzoto in diabetic mice was not antagonized by beta-funaltrexamine, naltrindole, or nor-binaltorphimine. The increased antinociceptive activity of (1.0 g/kg, p.o.) in diabetic mice was abolished by yohimbine (15 mu g, i.t.), but not by NAN-190 (1 mu g, i.t.), methysergide (15 mu g, i.t.), or MDL-72222 (15 mu g, i.t.). In shakuyakukanzoto diabetic mice treated with 6-hydroxydopamine (20 mu g, i.t.) chemically lesioned noradrenergic pathways, shakuyakukanzoto (1.0 g/kg, p.o.) failed to exhibit an antinociceptive effect. Furthermore, the antinociceptive activity induced by norepinephrine (0.06 - 2 mu g, i.t.) was markedly more potent in diabetic mice than in non-diabetic mice at the same dose. These results suggest that the antinociceptive effect of shakuyakukanzoto in diabetic mice is not mediated by the opioid systems and that this effect appears via selective activation of the spinal descending inhibitory alpha(2)-adrenergic systems without activating the serotonergic systems. The spinal alpha(2)-adrenoceptor-mediated analgesic mechanism was enhanced in diabetic mice, suggesting that shakuyakukanzoto exhibits its effect by activating the descending noradrenergic neurons.

In the course of our clinical studies of Kampo medicine (traditional Japanese medicines), we observed the pharmacokinetic interactions between two herbs. When Onpito (TJ-8117, Kampo medicine) containing licorice and rhubarb was administered orally to human subjects, we observed that the AUC((0-lim)) and C-max of glycyrrhetic acid (GA) in plasma were lower than those treated with other Kampo medicines containing licorice. In this study, we demonstrate the pharmacokinetic interactions of GA derived from glycyrrhizinic acid (GL) in licorice and anthraquinones derived from rhubarb. To our knowledge, this is the first report to investigate the pharmacokinetic interactions between two herbs. When GL was orally co-administrated to rats with a non-effective dose of sennoside A having purgative activity, the AUC((0-lim)) and C-max of GA decreased. In addition, sennoside A did not affect the metabolism of GL by the intestinal bacteria in vitro. In the examination using an in situ loop of rat colon, the remaining ratio of GA rose drastically by the co-administration of sennoside A, sennidin A and rhein. Observed inhibition activity of these anthraquinones on GA absorption depended on the concentration of the components added. The maximum inhibition ratio was approximately 75% by rhein, 60% by sennoside A and 25% by sennidin A. We conclude that the decrease of the pharmacokinetic parameters of GA in human plasma observed in the clinical study of TJ-8117 is attributable to an interactive action of absorption from the intestinal tract by anthraquinones contained in or derived from rhubarb.

The chronic inhibition of nitric oxide (NO) synthesis with N-w-nitro-L-arginine methyl ester (L-NAME) in pregnant rats induces a pre-eclampsia-like syndrome, including hypertension. We have previously reported the beneficial effects of Toki-shakuyaku-san (TS) in this model. In the present study we demonstrated the anti-hypertensive effect of TS in pre-eclampsia produced by prolonged L-NAME-infusion during the postpartum period. Analysis of blood sex steroids suggested that the level of progesterone differs between the TS-effective (gestational day 19 and postpartum day 7) and TS-ineffective (postpartum day 1) periods. Co-administration of TS and progesterone inhibited L-NAME-induced hypertension on postpartum day 1. Furthermore, the anti-hypertensive effect of TS on postpartum day 6 disappeared in the presence of a co-administered progesterone antagonist mifepristone. These data suggest that a certain level of progesterone may be an indispensable prerequisite for an anti-hypertensive effect of TS. Finally, the effects of TS are apparently unrelated to blood levels of NO, calcitonin gene-related peptide, and endothelin-1, which have been reported to modulate systolic blood pressure in the L-NAME-induced pre-eclampsia model. Thus, the use of TS may provide a new therapeutic strategy for pre-eclampsia, although elucidation of the mechanism of action of TS would be necessary to optimize treatment protocols.

TJ-8117 (Onpi-to) is a herbal medicine extracted from mixture of five crude drugs (Rhei Rhizoma, Glycyrrhizae Radix, Ginseng Radix, Zingiberis Rhizoma and Aconiti Tuber), which has been developed as a drug for chronic renal failure. (-)Epicatechin 3-O-gallate (ECG), one of the active compounds of TJ-8117, was labeled with tritium and spiked to TJ-8117. Effects of food, renal failure and repeated administration to pharmacokinetics of ECG-related radioactivity in the plasma were investigated after oral administration of TJ-8117 containing [H-3]ECG ([H-3]TJ-8117) in male rats. After oral administration of [H-3]TJ-8117, the radioactivity in the plasma in non-fasted rats was higher than that in fasted rats. AUC(0-72 h) and C-max in the non-fasted was 123 % and 248 % of those in the fasted. After oral administration of [H-3]TJ-8117, the radioactivity in the plasma in 5/6 nephrectomized rats was higher than that in sham-operated rats. AUC(0-72 h) and C-max in 5/6 nephrectomized was 332 % and 236 % of those in sham-operated. After repeated administration of TJ-8117 for 6 days, [3H]TJ-8117 was administered on 7th day. Radioactivity in plasma in first day was similar to that in 7th day. The pharmacokinetic parameters were not significantly different between single and repeated administration.

We evaluated the effects of Rikkunshi-to and several of its ingredients on the delay of gastric emptying induced by a nitric oxide (NO) synthase inhibitor, N-G-nitro-L-arginine (L-NNA). After oral administration of L-NNA to rats, the gastric emptying rate at 24 h was decreased from 82.8 +/- 2.4% to 53.3 +/- 5.7%. The decrease of the gastric emptying rate induced by L-NNA treatment was markedly ameliorated by administration of Rikkunshi-to, (250 and 500 mg/kg, p.o.) in a dose-dependent manner. To identify the active ingredient of Rikkunshi-to, the components were separated according to polarity, and the effects of the respective fractions on gastric emptying were evaluated. Significant efficacy was found in the water and methanol fractions, but not in the 50% aqueous-methanol fraction. Furthermore, hesperidin (1 - 4.29 mg/kg, p.o.) contained in the methanol fraction and L-arginine (4.5 mg/kg, p.o.) contained in the water fraction ameliorated the decrease in the gastric emptying rate induced by L-NNA treatment. These results suggest that Rikkunshi-to ameliorated abnormalities of NO-mediated gastric functions such as delayed gastric emptying, and hesperidin and L-arginine were identified as two of the active ingredients contributing to the ability of Rikkunshi-to to facilitate gastric emptying.

The antianginal effects of lercanidipine, a newly synthesized 1,4-dihydropyridine derivative calcium channel antagonist, were evaluated in experimental angina model rats and the effects were compared with those of nifedipine, benidipine and amlodipine. In the vasopressin-induced angina model, intravenous administration of lercanidipine dose-dependently suppressed vasopressin-induced ST-depression. Amlodipine barely suppressed it, while benidipine, at the same dose, completely suppressed it. Nifedipine had a potency between that of amlodipine and benidipine. Oral administration of lercanidipine showed similar effects to the intravenous administration test on ST change. High doses of amlodipine, benidipine and nifedipine suppressed ST-depression by almost 100%. In the methacholine-induced angina model, lercanidipine suppressed the ST elevation dose dependently. Amlodipine barely suppressed it, while benidipine at 30 mu g/kg effected almost total suppression. Nifedipine had a potency between that of amlodipine and benidipine. Intraduodenal administration of lercanidipine also suppressed the ST-elevation dose dependently. Nifedipine, benidipine and amlodipine at 10 mg/kg all markedly suppressed the elevation. Lercanidipine was more potent than the other calcium channel antagonists tested. In conclusion, it was explicitly demonstrated that lercanidipine exerts potent protective effects on the ischemic electrocardiography (ECG) changes in a variety of putative angina pectoris models in rats. An antispasmolytic coronary vasodilating action may be involved in the mechanism. It is expected that lercanidipine will be useful as an antianginal agent.

The effects of Keishi-bukuryo-gan on calcitonin gene-related peptide (CGRP)-induced elevation of skin temperature were investigated in gonadotropin-re leasing hormone (GnRH) analogue-treated female rats. Leupline(R) (1.0 mg/kg) as the GnRH analogue was subcutaneously (s.c.) injected into female rats. After Keishi-bukuryo-gan (100-1,000 mg/kg, p.o.) or 17beta-estradiol (0.010 mg/kg, s.c.) was administered to GnRH analogue-treated rats for 14 days, CGRP-induced skin temperature elevation, concentration of plasma 17 estradiol and pituitary gonadotropin (luteinizing hormone; LH, and follicle stimulating hormone; FSH) were measured. In addition, effects of 17beta-estradiol and Keishi-bukuryo-gan on the proliferation of estrogen-dependent human breast cancer (MCF-7) cells were investigated under in vitro conditions. GnRH analogue significantly lowered the concentrations of plasma 17beta-estradiol and pituitary gonadotropins. Tissue weights of the ovaries and uterus were also decreased by the analogue. Under the condition of estrogen deficiency, intravenous (i.v.) injection of exogenous CGRP (10 mug/kg) elevated the skin temperature of the hind paws more significantly than it did in sham-treated control rats. Estrogen supplementation inhibited this elevation of skin temperature with restoration of both the lowered plasma estrogen level and the decreased uterine weight in GnRH analogue-treated rats. On the other hand, Keishi-bukuryo-gan inhibited the elevation of skin temperature in a dose-dependent manner without restoring the plasma estrogen level and uterine weight. In addition, in an in vitro study, MCF-7 cells proliferated in a dose-dependent manner by the addition of 17 estradiol (10(-1)3-10(-8)M) to the medium. However, Keishi-bukuryo-gan (10(-6)-10(-4) mg/ml) did not activate the MCF-7 cell proliferation. These results suggest that Keishi-bukuryo-gan, which does not exhibit estrogen activity, may be useful for the treatment of hot flashes in women who are undergoing medical ovariectomy with a GnRH analogue. (C) 2005 Elsevier Inc. All rights reserved.

The TSOD mouse has been established as an inbred strain with spontaneous development of diabetes mellitus as the first clinical signs of diabetes. Polydipsia and polyuria are observed at about 2 months old only in male mice, after which hyperglycemia and hyperinsulinemia are detected. Following these symptoms obesity gradually develops until about 12 months old. In histopathological examination of the pancreas, severe hypertrophy of pancreatic islets was observed due to proliferation and swelling of B cells. In the kidney, thickening of the basement membrane in glomeruli and an increase of the mesangial area were observed at 18 months old. Motor neuropathy in TSOD mice began to appear at 14 months old and most male mice at 17 months old showed weakness of front and hind paws caused by neuron degeneration in the peripheral nerve. In sensory neuropathy, the threshold in the tail pressure test decreased significantly at 12 months old. Light microscopic and electron microscopic examination of sciatic nerves showed a decrease in the density of nerve fibers by the endoneural fibrosis and loss of these fibers. Degenerative changes of myelinated fibers, separation of myelin sheaths with intralamellar edema and remyelination were frequently observed. In the severely affected nerve fibers, the lamellar structure was completely destroyed and macrophages migrated around the myelin sheath or invaded the intramyelin space. Considering these findings similar to non-insulin dependent diabetes mellitus (NIDDM) in humans, the TSOD mouse should be a useful model for the pathogenic study of diabetic complications, especially of peripheral neuropathy.

Objectives. To clarify the relationship between calcitonin gene-related peptide (CGRP) and ovarian hormones (17beta-estradiol and progesterone) in hot flashes in men who undergo androgen deprivation therapy for prostate cancer, we studied the effects of ovarian hormones on CGRP-induced elevation of skin temperature in castrated male rats. The results were compared with those from rats treated with testosterone replacement. Methods. Adult male rats were castrated by either a single injection of gonadotropin-releasing hormone analogue (Leuplin, 1.0 mg/kg, subcutaneously) or bilateral orchiectomy. The castrated animals were subcutaneously injected daily for 14 days with ovarian hormones, testosterone, or olive oil as the vehicle. On the day after the final administration of the drug, the changes in skin temperature induced by exogenous CGRP (10 mug/kg intravenously), serum testosterone concentration, and prostate weight were measured. Results. The CGRP-induced elevation of skin temperature was significantly greater in the castrated rats than in the sham-treated rats. This potentiation was significantly inhibited by treatment with ovarian hormones, as well as by testosterone replacement. The testosterone replacement restored decreases in both the serum testosterone level and the prostate weight due to castration; the treatment with ovarian hormones did not affect them. Conclusions. 17beta-Estradiol and progesterone, which do not confer testosterone activity on serum, may be useful for the treatment of hot flashes in patients for whom testosterone replacement therapy is contraindicated, such as those with prostate carcinoma. In addition, we suggest that CGRP is closely involved in the amelioration of hot flashes by ovarian hormones in men who undergo androgen deprivation therapy. (C) 2004 Elsevier Inc.

The effect of Unkei-to, a traditional Japanese herbal medicine and strong in vitro releaser of cytokine-induced neutrophil chemoattractant (CINC), on the increase in locomotor activity induced by intracerebroventricular (icv) injection of corticotropin-releasing factor (CRF) in male rats in a familiar environment was investigated. Oral administration of Unkei-to (100 mg/kg) for 1 week significantly allenuated the CPF-induced increase in locomotor activity. Unkei-to also reduced the CRF-induced accumulation of hypothalamic CINC, which has a functional antagonistic action on the response to CRF; the reduction may reflect an increased release of CINC. These results suggest that Unkei-to has an alleviative effect on the action induced by brain CRF and the mechanism of this effect may partly involve CINC. (C) 2004 Elsevier Inc. All rights reserved.

Background/Purpose: Homozygous mutant Ncx/Hox11L.1-deficient (Ncx-/-) mice develop mega-ileo-ceco-colon (mega-ICC) with a caliber change in the proximal colon. The authors investigated the mechanism of intestinal dysmotility in these mice. Methods: Five-week-old Ncx-/- mice with mega ICC were compared with age-matched BDF1 control mice. Jejunum, ileum, and colon were excised from all mice and 1.0-cm-long strips of each organ, each with a resting tension of 0.5g, were suspended in an organ bath filled with Tyrode's solution at 37degreesC and bubbled with a mixture of 95% oxygen and 5% carbon dioxide. Contractile responses to acetylcholine chloride (ACh), histamine, serotonin, and barium chloride (BaCl2) were recorded isometrically. Results: For ACh, Ncx-/- mice had decreased distal colon circular muscle contraction only at lower doses and decreased distal colon longitudinal muscle contraction for all doses compared with controls (P < .05 or P < .01). In the proximal colon, Ncx-/- mice had increased circular muscle contraction only at higher doses and decreased longitudinal muscle contraction only at lower doses compared with controls (P < .01 or P < .05). ACh did not affect jejunum, and there were no significant effects on ileum. There was no response to histamine and serotonin by any part of the bowel, and the response to BaCl2 was the same for both Ncx-/- mice and controls. Conclusions: Only ACh differentially affected muscle contraction in Ncx-/- mice in the proximal and distal colon. Thus, ACh is implicated in causing the bowel dysmotility seen in Ncx-/- mice and human IND. (C) 2004 Elsevier Inc. All rights reserved.

The purpose of this study is to clarify the effect of the traditional Japanese medicine Sairei-to (TJ-114) on edema in mice with anti-glomerular basement membrane (GBM) nephritis. Sairei-to (0.38-1.5 g/kg/day) and furosemide (50mg/kg/day) were orally administered consecutively for 4 days from day 6 after an anti-GBM serum injection. Plasma volume (PV) was determined with Evans blue dye and extracellular fluid volume (ECFV) was measured using a single-injection potassium bromide technique. In the nephritic control mice, proteinuria and hyponatreuria were induced and PV, ECFV and calculated interstitial fluid volume (ISFV) were increased. Sairei-to significantly decreased ECFV and ISFV in a dose-dependent manner, but did not change PV or urinary protein excretion. A similar result was observed in the furosemide-treated mice. These results suggest that the treatment with Sairei-to was useful against nephrotic edema. © 2004, Medical and Pharmaceutical Society for WAKAN-YAKU. All rights reserved.

Sairei-to (TJ-114), a traditional Japanese medicine, has been used clinically for the treatment of various edematous disorders. The inhibitory effect of TJ-114 on edema may be dependent on the diuretic response it invokes. The present study was performed to determine the effect of TJ-114 on the anti-diuretic hormone vasopressin, which is implicated in the retention of water in various edematous disorders. TJ-114 (0.5-1.5 g/kg) was administered intra-duodenally to pentobarbital-anesthetized rats. Specimens of the renal cortex were isolated 30min after the administration and incubated in buffered Hank's balanced salt solution with vasopressin. The vasopressin-stimulated cAMP production was dose-dependently attenuated in renal tissues in rats treated with TJ-114. The inhibitory effect of TJ-114 was diminished by pretreatment with NG-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor. Therefore, TJ-114 may inhibit stimulation of the vasopressin V2 receptor which is closely related to nitric oxide production. © 2004, Medical and Pharmaceutical Society for WAKAN-YAKU. All rights reserved.

Objectives. To assess the involvement of calcitonin gene-related peptide (CGRP) in the occurrence of hot flashes in men after castration for treatment of prostate cancer, we investigated the effects of CGRP on skin temperature in surgically and medically castrated male rats. Methods. Changes in skin temperature of the hind paws after intravenous injection of 10 mug/kg of CGRP and CGRP family peptides (adrenomedullin and amylin) were measured at 5-minute intervals for 120 minutes, 3 weeks after bilateral orchiectomy or 2 weeks after subcutaneous injection of a gonadotropin-releasing hormone analogue (1.0 mg/kg Leuplin) in male rats. Antagonism with CGRP(8-37) (1000 mug/kg intravenously), a CCRP1 receptor antagonist, to the CGRP-induced response was examined by injecting it 10 minutes before injection of CGRP. The effect of testosterone replacement on castration was evaluated in each castrated rat by the administration of testosterone (1.0 mg/kg subcutaneously once a day) for 14 days before the day of the temperature analysis. Results. CGRP, but not adrenomedullin and amylin, elevated the skin temperature in surgical or medical castration-induced testosterone-deficient rats more than in the sham-treated rats. The difference was statistically significant. The CGRP-induced potentiation in the castrated rats was inhibited by pretreating with CGRP(8-37) or by supplying testosterone. Conclusions. CGRP is the most potent peptide in a family that elevates the skin temperature in male rats. The elevation of the skin temperature was more affected by the testosterone deficiency resulting from castration. These results suggest that CGRP is involved in the mechanism underlying hot flashes in men. (C) 2003 Elsevier Inc.

To assess whether peripheral changes related to skin temperature rise were induced by ovarian hormone deficiency, we investigated the effects of anaesthesia on calcitonin gene-related peptide (CGRP)- or luteinizing hormone-releasing hormone (LH-RH)-induced elevation of skin temperature in female rats. CGRP was used as an inducer of peripherally-mediated elevation of skin temperature, whereas LH-RH was used as an inducer of centrally-mediated elevation of skin temperature. Intravenous (i.v.) but not intracerebroventricular injection of CGRP (10 mug kg(-1)) or intracerebroventricular but not intravenous injection of LH-RH (10 mug/rat) elevated the skin temperature of unanaesthetized rats restrained in a Ballman's cage. The elevation with LH-RH was completely inhibited by urethane anaesthesia, whereas the elevation with CGRP was not. These results suggested that changes in skin temperature measured under anaesthesia reflected a peripherally rather than a centrally mediated mechanism. The CGRP (1.0-30 mug kg(-1), i.v.)-induced elevation of skin temperature was potentiated in ovariectomized rats and inhibited by pretreatment with a CGRP receptor antagonist CGRP(8-37) (1000 mug kg(-1), i.v.), suggesting that the potentiation may participate in peripheral factors such as a postsynaptic hypersensitivity to CGRP following ovarian hormone deficiency. Thus, measurement of skin temperature in the anaesthetized rat was a useful procedure to seek the peripheral mechanism of potentiation of skin temperature induced by CGRP, thought to be closely related to menopausal hot flashes.

A water extract of Glycyrrhizae Radix (licorice root, 甘草) showed a significant antigastric ulcer effect on the stress model by gavage in rats. Seven predominant constituents, liquiritin, liquiritin apioside, liquiritigenin, isoliquiritin, isoliquiritin apioside, isoliquiritigenin and glycyrrhizin were observed in the extract by HPLC analysis. Among these constituents, only liquiritin apioside dose-dependently improved gastric ulcer. Activity of anti-gastric ulcer effect of the extract was elucidated owing only to the effect of liquiritin apioside. Therefore the activity of anti-gastric ulcer effect of licorice should consider the content of liquiritin apioside.

The purpose of this study is to clarify the effects of 17beta-estradiol and the Japanese herbal medicine Keishi-bukuryo-gan on the release and synthesis of calcitonin gene-related peptide (CGRP) in ovariectomized (OVX) rats. The effect of ovariectomy on the release or synthesis was evaluated by measuring CGRP concentration in plasma after capsaicin (1.0 mg/kg, i.p.) injection or by measuring CGRP concentration and its mRNA expression in dorsal root ganglia in OVX rats. Ovariectomy attenuated the capsaicin-evoked increase in plasma concentration of CGRP, which was restored by treatment with 17beta-estradiol (0.010 mg/kg, s.c.) or Keishi-bukuryo-gan (1,000 mg/kg, p.o.) for 7 days after ovariectomy. However, no significant differences were observed in the CGRP concentration and the mRNA expression of dorsal root ganglia by treating the rats with ovariectomy, 17beta-estradiol, and Keishi-bukuryo-gan. These results suggest not only that estrogen deficiency attenuates CGRP release but also that 17beta-estradiol or Keishi-bukuryo-gan normalizes the attenuated release process.

This study was conducted to evaluate the effect of Dai-kenchu-to on chlorpromazine-induced hypoperistalsis in mice. Oral administration of Dai-kenchu-to (30-300mg/kg) dose-dependently improved small intestinal and distal colonic propulsion decreased by chlorpromazine (3 mg/kg, p.o.). Although the improvement of small intestinal propulsion due to Dai-kenchu-to was partially inhibited by atropine (I mg/kg, s.c.), this action was completely inhibited by the concomitant administration of lorglumide (10 mg/kg, i.p.), a CCKA receptor antagonist. The distal colonic propulsion-improving effect of Dai-kenchu-to was abolished by atropine (I mg/kg, s.c.). When the effects of the respective components of Dai-kenchu-to were evaluated, oral administration of Zanthoxylum Fruit improved both delayed small intestinal and distal colonic propulsion caused by chlorpromazine. On the other hand, Malt Sugar was effective against only delayed small intestinal propulsion. The action of Zanthoxylum Fruit was completely inhibited by atropine (I mg/kg, s.c.), and the effect of Malt Sugar was inhibited by lorglumide (10 mg/kg, i.p.). These results demonstrated that Dai-kenchu-to improves chlorpromazine-induced hypoperistalsis via cholinergic systems and that Zanthoxylum Fruit is the main contributor to this action of Dai-kenchu-to. In addition, endogenous CCK due to Malt Sugar may also contribute to this effect of Dai-kenchu-to. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved.

The effects of a Japanese herbal medicine, Keishi-bukuryo-gan, and 17beta-estradiol on calcitonin gene-related peptide (CGRP)-induced elevation of skin temperature were investigated in ovariectomized (OVX) rats. Ovariectomy not only potentiated CGRP-induced elevation of skin temperature and arterial vasorelaxation but also induced a lower concentration of endogenous CGRP in plasma and up-regulation of arterial CGRP receptors, suggesting that lowered CGRP in plasma due to ovarian hormone deficiency increases the number of CGRP receptors and consequently amplifies the stimulatory effects of CGRP to elevate skin temperature. Oral Keishi-bukuryo-gan (100-1000 mg/kg, once a day for 7 days) restored a series of CGRP-related responses observed in OVX rats by normalizing plasma CGRP levels in a dose-dependent manner as effectively as s.c. injection. 17beta-estradiol (0.010 mg/kg, once a day for 7 days). However, Keishi-bukuryo-gan did not affect the lower concentration of plasma estradiol and the decreased uterine weight due to ovariectomy, although the hormone replacement of 17beta-estradiol restored them. These results suggest that Keishi-bukuryo-gan, which does not confer estrogen activity on plasma, may be useful for the treatment of hot flashes in patients for whom estrogen replacement therapy is contraindicated, as well as menopausal women.

We previously clarified that Dai-kenchu-to, a Chinese prescription, was useful for improving carbachol-induced hyperperistalsis of the small intestine in vivo, and the efficacy of Ginseng Radix, a crude drug component of Dai-kenchu-to, was also confirmed. Ginseng Radix, the root of Panax ginseng C.A. Meyer, showed significant ameliorative effects on both the carbachol-induced and the BaCl2-induced accelerated small intestinal transit model in mice, suggesting that both an inhibitory effect on the cholinergic nervous system and direct suppressive effect on muscles were involved in the ameliorative effect of Ginseng Radix on the accelerated small intestinal transit. Ginsenoside Rb1 (4) and ginsenoside Rd (7), major components of Ginseng Radix, improved both animal models. These results suggest that ginsenoside Rb1 (4) and ginsenoside Rd (7) were representative compounds of Ginseng Radix for improving the accelerated movement of the small intestine and that these compounds partly contribute to the action of Dai-kenchu-to on small intestinal transit. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

The effect of rhizomes of Atractylodes lancea on gastric disorders, in particular, the delay in gastric emptying induced by N-G-nitro-L-arginine in rats, was investigated. Intragastric treatment with an aqueous extract (250 mg/kg) and its lipophilic fractions (4 mg/kg) significantly improved delayed gastric emptying. The major constituents of the lipophilic fraction were two sesquiterpens, hinesol and beta-eudesmol, and four known polyacetylenic compounds, atractylodin, atractylodinol, acetylatractylodinol and 4,6,12-tetradecatriene-8,10-diyne-1,3,14-triol. The activity was found in the four polyacetylenic compounds at a similar potency, but not in the two sesquiterpens. To clarify the effect of the four polyacetylenic compounds in this extract, we attempted to evaluate the activity of atractylodin, as representative, at a dose of 0.2 mg/kg based on the total amounts (0.2 mg/250 mg aqueous extract) of the four polyacetylenic compounds. In addition, atractylodin improved the delay in gastric emptying at between 0.1 and 0.3 mg/kg in a dose-dependent manner. These results suggest that the aqueous extract improved the delayed gastric emptying, and polyacetylenic compounds contributed to its activity. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

The pharmacological characteristics of Ryokan-kyomi-shinge-nin-to (RKS), a traditional oriental herbal (Kampo) medicine which has been used for the treatment of allergic asthma and rhinitis, were investigated. The number of sneezes by actively sensitized mice after a topical antigen challenge was significantly reduced by pretreatment with RKS (300 and 1000 mg/kg, p.o.). Although RKS did not inhibit the antigen-induced histamine release from rat peritoneal exudate cells (PEC), it significantly inhibited an increase in vascular permeability induced by histamine and serotonin. These results suggest that RKS has antiallergic activity in animals, and the functional antagonism of a histamine response may be one of the mechanisms of its effect. In addition, RKS prevented histamine hypersensitivity in actively sensitized mice. Because RKS did not affect sleeping time induced by pentobarbital in mice and did not inhibit gastric emptying in rats, the drug appears to be useful for treating allergic patients suffering from classical antihistamines side effects such as stomach discomfort or relative drowsiness.

6-Shogaol, a constituent of Zingiber officinale, improved carbachol-induced accelerated small intestinal transit in vivo, as well as improving longitudinal muscle contraction induced by low-frequency electrical stimulation of the isolated guinea pig small intestine in vitro. In addition, 6-shogaol ameliorated BaCl2-induced hyperperistalsis of the small intestine in vivo.

Zingiberis Rhizoma (Shokyo) showed significant ameliorative effect on the BaCl2-induced delay of gastric emptying in rat. Bioassay-guided fractionation of the aqueous extract of Shokyo resulted in isolation of 6-gingesulfonic acid (1) and shogasulfonic acid A (3). These compounds significantly improved the delay of gastric emptying on both BaCl2-induced and N-G-nitro-L-arginine (L-NNA)-induced model in rat. Zingiberis Siccatum Rhizoma (Kankyo) had significant efficacy against castor oil-induced diarrhea. In addition, Kankyo showed the activity increasing intestinal blood flow in normal rat.

The present study investigated the effects of the herbal medicine Dai-kenchu-to (DKCT) and its 4 individual ingredients on intestinal blood flow (IBF) in rats by laser Doppler flowmetry. Intraduodenal administration of DKCT (30, 100 and 300 mg/kg) increased IBF in a dose-dependent manner, whereas the mean arterial blood pressure was not affected. One of the ingredients in DKCT is dried ginger rhizome (150 mg/kg), whose main component is [6]-shogaol (2 mg/kg), both of which showed similar effects to those shown by DKCT, while the other ingredients in DKCT only slightly increased IBF or had no effect. The calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP (8-37), completely abolished the hyperemia induced by DKCT, dried ginger rhizome and [6]-shogaol. However, the vasoactive intestinal polypeptide (VIP) receptor antagonist, [4-Cl-DPhe6, Leu17]-VIP, and atropine were less inhibitory than CGRP (8-37), and the substance P (SP) receptor antagonist, spantide, had no effect. The present study demonstrated that DKCT and one of its active components, [6]-shogaol, produced an increase in IBF which was mainly mediated by CGRP and suggests that DKCT may be useful in the treatment of intestinal ischemia-related diseases. © 2002 Elsevier Science Inc. All rights reserved.

The present study was conducted to clarify the effects of Dai-kenchu-to on accelerated small intestinal movement. We evaluated the effects of Dai-kenchu-to and its constituent herbs (dried ginger root, ginseng, zanthoxylum fruit, and malt sugar) on carbachol-accelerated mouse small intestinal transit, and contractions induced by low-frequency electrostimulation (ESC), KCI, or acetylcholine (ACh) using isolated guinea pig ileum. Dai-kenchu-to (10-300 mg/kg, p.o.) significantly improved carbachol-accelerated small intestinal transit in a dose-dependent manner. Using a concentration with the compounded rate for Dai-kenchu-to 300 mg/kg, carbachol-accelerated small intestinal transit was also significantly improved with a single dose of dried ginger root or ginseng. At a concentration of 3 x 10(-5) g/ml or less, Dai-kenchu-to, dried ginger root, and ginseng all inhibited ESC but not KCl- or ACh-induced contractions. However, at a higher concentration of Dai-kenchu-to (10(-4) g/ml) or zanthoxylum fruit (10-5 g/ml or more) the ESC were enhanced. Both Dai-kenchu-to and dried ginger root at 10(-3) g/ml remarkably inhibited the KCI-induced contractions. These results indicate that Dai-kenchu-to improves accelerated small intestinal movement and that dried ginger root and ginseng may be involved in this effect. It is also thought that the mechanisms mainly involve the direct inhibition of smooth muscle but with a contribution from neural inhibition.

The effects of both Dai-kenchu-to and PGF(2 alpha) on intestinal and uterine motility were studied in anaesthetized rabbits with force transducers implanted in the jejunum, ileum and uterus, A single intraduodenal administration of Dai-kenchu-to (300 mg/kg) enhanced the intestinal motility but not the uterine motility, However, intravenous administration of PGF(2 alpha) (20 mug/kg) enhanced both intestinal and uterine motility, The effects of Dai-kenchu-to on the spontaneous contraction and contractile response of the isolated rat uterine strips to oxytocin, PGF(2 alpha) or ACh were also studied. Oral administration of Dai-kenchu-to at 300 mg/kg for one week had no effect on either the spontaneous contraction or the contractile response of the uterus, These results indicate that Dai-kenchu-to may exert stimulatory effects on intestinal motility, as PGF(2 alpha) but has no effect on the uterine motility, suggesting a selective effect on the gastrointestinal tract, Hence, Dai-kenchu-to may be safer than PGF(2 alpha) in the treatment of postoperative adhesive ileus in women. However, more studies are needed to determine whether Dai-kenchu-to could be administered to pregnant women. Copyright (C) 2001 John Wiley & Sons, Ltd.

The mechanisms by which Dai-kenchu-to (TJ-100), a kampo medicine, enhances gastrointestinal motility was investigated using isolated guinea pig ileum. TJ-100 induced contractions accompanied by autonomous contraction at a concentration of more than 3 × 10-4 g/ml in a dose-related manner. The TJ-100-induced ileal contraction was suppressed by atropine and tetrodotoxin, but not by hexamethonium. This effect was partially suppressed in the presence of high concentrations of ICS 205-930, a serotonin 4 (5-HT4) receptor antagonist. In addition, TJ-100 showed an acetylcholine (ACh) -releasing action in the smooth muscle tissues of ileum. These results suggest that contractile response induced by TJ-100 is partially mediated by ACh released from the cholinergic nerve endings and that 5-HT4 receptors would be involved in the effect of TJ-100.

The effect of saiboku-to on gastric lesions induced by restraint water-immersion stress and ethanol has been examined in rats. Thirty minutes after oral administration of saiboku-to, the rats were placed in restraint cages and immersed in water at 23 degrees C for 7 h, or orally administered 99.5% ethanol (1 mt) and placed in normal cages for 1 h. The stress for 7 h or the ethanol treatment for Ih induced erosion in the glandular area of the stomach. Histology showed that the surface epithelial cells were desquamated and part of the lamina propria mucosae was injured. The evaluation of lesion index, the cumulative length of the gastric lesion, on the gross appearance of the stomach, revealed that saiboku-to dose-dependently inhibited both the water-immersion stress-induced gastric erosion and ethanol-induced gastric erosion. To determine whether the anti-erosion effect of saiboku-to was because of a mild irritant effect, saiboku-to or 20% ethanol, which is known as a typical mild irritant, were given orally. After 30 min a strong irritant, 99.5% ethanol, was given orally. Histological examination was performed 30 min after administration of saiboku-to or the mild irritant, and Ih after administration of the strong irritant. The mild irritant induced a reduction in surface epithelial cells 30 min after administration. Furthermore, the mild irritant protected the stomach against mucosal erosion produced by the strong irritant. Saiboku-to protected the strong irritant-induced erosion without producing mild irritation as observed in stomach treated with 20% ethanol. Pretreatment with saiboku-to also inhibited the decrease in the levels of hexosamine, gastric mucus glycoprotein, induced by the strong irritant. In pylorus-ligated rats, saiboku-to dose-dependently inhibited gastric acid secretion, a gastric aggressive factor. These results suggest that the anti-erosion effect of saiboku-to which is not a mild irritant, involves both inhibition of aggressive factors, such as gastric acid secretion, and augmentation of defensive factors, such as gastric mucus cells.

The present study was conducted to determine the characteristics of the effects of Keishi-ka-shakuyaku-to (Gui-Zhi-Jia-Shao-Yao-Tang TJ-60) on diarrhea. Significant repression was noted by TJ-60 at 1000 mg/kg, p.o. for diarrhea induced by pilocarpine, barium chloride or castor oil. Under normal conditions, TJ-60 did not influence small intestinal transit by its oral treatment even at 1000 mg/kg, however, it dose-dependently improved the acceleration of such transit caused by neostigmine. TJ-60 did not influence the resting tonus in isolated small intestine, but did selectively inhibit low frequency electrostimulated contractions. These results indicate that the antidiarrheal effects of T J-60 may be due to the inhibition of excessively accelerated small intestinal movement, and that the inhibition of acetyleholine release by parasympathetic nerves is partly involved in the mechanism of this antidiarrheal action.

To determine the mechanisms by which Hange-shashin-to (TJ-14) reduces prostaglandin E2 (PGE2) levels, the effects on blood corticosterone levels were examined in vivo and the effects on cyclooxygenase (COX) activity in vitro assessed. TJ-14, orally administered to rats at dose levels between 125 and 1000 mg/kg, caused a dose-dependent increase in blood corticosterone levels. We also showed that Glycyrrhizae Radix and Ginseng Radix, constituents of TJ-14, are involved in the increase in blood corticosterone. The activity of COX-1 was not inhibited by TJ-14 even at a dose of 1000 μg/ml, while COX-2 was inhibited at dose levels between 10 and 1000 μg/ml. The constituents Scutellariae Radix, Glycyrrhizae Radix and Coptidis Rhizoma were believed to be involved in COX-2 inhibition. These results suggest that the effect of TJ-14 in decreasing PGE2 is partially mediated by corticosterone and inhibition of COX-2.

The effects of Hange-shashin-to (TJ-14) on cholera toxin-induced intestinal fluid secretion were studied to elucidate the mechanism by which this kampo medicine manifests antidiarrheal effects. TJ-14 suppressed the intestinal fluid secretion induced by cholera toxin (1 μg/rat) in a dose- dependent manner at doses between 125 and 1000 mg/kg. It also inhibited the luminal prostaglandin E2 (PGE2) level. On the other hand, serotonin (5-HT) release was not affected by TJ-14. Subcutaneous injection of indomethacin at 10 mg/kg or ondansetron at 100 kg significantly suppressed intestinal secretion. The luminal PGE22 level was also inhibited by indomethacin (10 mg]kg, s.c.). TJ-14, even at 102-4 g/ml, had little effect on the phasic contraction of isolated guinea pig ileum induced by 5-HT (2 x 102-6 g/ml), while ondansetron suppressed the phasic contraction caused by 5-HT. These results indicate that TJ-14 is useful in suppressing cholera toxin- stimulated intestinal fluid secretion, and that this effect is partially due to its suppressive action on the PGE2 level.

The possible preventive effect of Kampo medicine Hange-shashin-to (TJ-14) on chronic diarrheal symptoms induced by the administration of the anticancer agent irinotecan hydrochloride (CPT-11) was investigated in the rat. Repeated oral administrations of TJ-14 at 125 and 500 mg/kg significantly prevented the reduction in body weight and the onset of chronic diarrheal symptoms due to CPT-11 in a dose-dependent manner, even though it failed to show a definite effect on acute diarrheal symptoms. In addition, treatment with TJ-14 accelerated the healing of the intestinal tract injured by repeated dosing of CPT-11 and inhibited significantly the increase of colonic prostaglandin E-2 (PGE(2)) which is closely related to the onset of diarrhea. TJ-14 also improved colonic water absorption impaired by repeated dosing of CPT-11 in rats. These results demonstrate that TJ-14 is an effective medicine for the prevention and/or treatment of CPT-ll-induced chronic diarrheal symptoms.

The effects of ''Hange-shashin-to (TJ-14)'' on gastric function were examined in comparison with ''Sho-saiko-to (TJ-9)''. Oral treatment with TJ-14 (125-500 mg/kg) caused dose-dependent suppression of ethanol-induced gastric injury, while it did not suppress gastric lesions induced by water-immersion stress. TJ-9 (125-500 mg/kg, p.o.) suppressed both water-immersion stress-induced gastric lesions and ethanol-induced gastric injury in a dose-dependent manner. Intraduodenal administration of TJ-14 even at 500 mg/kg did not affect gastric juice secretion, while TJ-9 at 125 to 500 mg/kg dose-dependently suppressed gastric juice secretion. TJ-14 (125-500 mg/kg, p.o.) accelerated gastric emptying in normal rats and improved the delayed gastric emptying induced by BaCl2 in a dose-dependent manner, whereas such effect was not noted with TJ-9. Oral treatment with TJ-14 at 500 mg/kg significantly suppressed apomorphine-induced vomiting, but it did not affect copper sulfate-induced vomiting. These results suggest that TJ-14 exhibits an anti-ulcer action (probably based on its ability to protect the gastric mucosa), improvement of gastric emptying and an anti-emetic action. TJ-9 also showed anti-ulcer effects, probably based on its ability to suppress gastric secretion and to protect the gastric mucosa. Thus, the present study demonstrated the effectiveness of TJ-14 and TJ-9 against gastric disease, and provided basic data which explain the differences in clinical application between these tao kampo medicines.

The effects of Hange-shashin-to (TJ-14) were examined regarding the amount of prostaglandin E-2 (PGE(2)) and the water absorbing capacity in the large intestine of rats. Repeated oral administration of TJ-14 at doses of 125 to 1000 mg/kg revealed a significant decrease in PGE(2) content in the colonic mucosa and also the promotion of colonic water absorption in a dose dependent manner. However, there was no remarkable influence on the concentrations of aldosterone and electrolytes in the serum, even at 1000 mg/kg. From these results, it was considered that some of the anti-diarrheal effects of TJ-14 might be based on a repression of the increase in the amount of PGE(2) as well as promotion of the water absorbing capacity of the large intestine. Moreover, it was also suggested that it is possible, by the application of TJ-14, to prevent the loss of water content caused by diarrhea.

We attempted to characterize the antidiarrheal action of Hange-shashin-to (TJ-14), a kampo medicine, by comparing its action with that of loperamide, The oral administration of TJ-14 caused the dose-dependent suppression of castor oil-induced diarrhea at 250 to 1000 mg/kg, No significant repression was noted by TJ-14 even at 1000 mg/kg, p.o. for diarrhea induced by pilocarpine, serotonin or barium chloride. Oral treatment with loperamide at 5 mg/kg markedly suppressed diarrhea induced by castor oil and barium chloride. Contractions of isolated guinea pig ileum in response to acetylcholine (1 x 10(-7) g/ml), histamine (1 x 10(-7) g/ml) or barium chloride (3 x 10(-4) g/ml) mere little affected by TJ-14 at 10(-4) g/ml, The responses elicited by the three contractive drugs were dose-dependently suppressed by loperamide. TJ-14 did not affect the small intestinal transit even at an oral dose of 1000 mg/kg, On the other hand, the small intestinal transit was significantly suppressed by loperamide (5 mg/kg, p.o.), These results indicate that TJ-14 can effectively control castor oil-induced diarrhea, and that its antidiarrheal action was not based on the suppression of intestinal motility.

A new dibenzocyclooctadiene lignan, isoschizandrin was isolated from the fruits of Schizandra chinensis. The structure was elucidated on the basis of the spectral analysis and chemical correlation with schizandrin and (+)- deoxyschizandrin. In experiments using rats, schizandrin and its derivatives, including isoschizandrin, showed inhibitory effects on stress-induced gastric ulceration (p.o.). © 1988.