Teruo Yokokura

Effect of Organic Acid Absorption on Bicarbonate Transport in Rat Colon

The absorption of organic anions and the influence of these anions on the movement of HCO3− were studied in vivo in rat colon using a perfusion technique. The absorption of short chain fatty acids (SCFAs) such as acetate, propionate, and butyrate was much greater than that of succinate or lactate. With increasing initial concentration of SCFA up to 100 mmol · l−1, SCFA absorption increased linearly in correspondence with HCO3− appearance. FinalpCO2 level of the perfusion solution with SCFA was the same as the plasma level. Among the SCFAs, no significant differences in absorption or their effects on HCO3− appearance were observed. The presence of Na+ stimulated SCFA absorption, and the maximum value was obtained at more than 100 mmol · l−1 of Na+.These results suggest that a specific system for HCO3− secretion activated by SCFA exists in the colon, and that this system may control the intraluminal pH by the alkalization of intestinal contents.

Effects of prolyl endopeptidase inhibitors and neuropeptides on delayed neuronal death in rats.

We investigated the effects of the prolyl endopeptidase inhibitors 1-[1-(Benzyloxycarbonyl)-L-prolyl]prolinal (Z-Pro-Prolinal) and N-benzyloxycarbonyl-thioprolyl-thioprolinal-dimethylaceta l (ZTTA) on delayed neuronal death induced by four-vessel-occlusion transient ischemia in rats. We also examined the effects of [pGlu4, Cyt6, ArgS]vasopressin (vasopressin-(4-9)) and thyrotropin-releasing hormone (TRH) on the delayed neuronal death. Furthermore, we investigated the role of vasopressin receptors in the effects of vasopressin and prolyl endopeptidase inhibitors. Z-Pro-Prolinal, vasopressin-(4-9) and TRH protected pyramidal cells in the CA1 subfield of the rat hippocampus from delayed neuronal death after 10-min ischemia. The effect of vasopressin-(4-9) was abolished by vasopressin receptor antagonists. The effect of Z-Pro-Prolinal was also abrogated by the antagonists. These results suggest that the neuroprotective effect of prolyl endopeptidase inhibitors is mediated by neuropeptides such as [Arg8]vasopressin and TRH, and indicate the involvement of vasopressin receptors in the neuroprotective effect of vasopressin-(4-9) and prolyl endopeptidase inhibitors.

Effect of organic acid on gastrointertinal motility of rat invitro

Abstract The quantity of organic acids ( lactic acid, acetic acid, propionic acid and butyric acid ) in the content of the gastrointestinal tract of germ-free and conventional rats and the in vitro effects of the organic acid on the motility of the gastrointestinal tract of rats were investigated. Organic acids were detected only in the gastrointestinal contents of conventional rats but not in those of germ-free rats. Lactic acid detected in the stomach of rats stimulated the motility of both small and large bowel while acetic acid, propionic acid and butyric acid found in the cecum stimulated the motility of the large bowel but not of small bowel.

A major metabolite of aceclofenac, 4'-hydroxy aceclofenac, suppresses the production of interstitial pro-collagenase/proMMP-1 and pro-stromelysin-1/proMMP-3 by human rheumatoid synovial cells.

Abstract.Objective and Design: We examined the effects of aceclofenac and its metabolites on the production of pro-collagenase-1/pro-matrix metalloproteinase-1 (proMMP-1), pro-gelatinase A/proMMP-2, pro-stromelysin-1/proMMP-3 and tissue inhibitor of metalloproteinases-1 (TIMP-1) by rheumatoid synovial cells.¶Materials: Synovial cells were obtained from patients with rheumatoid arthritis.¶Treatment: Cultures of confluent cells were treated with interleukin-1β (IL-1β)(1 ng/ml) and/or test drugs (0.3-30 μM) for 48 h.¶Methods: Production of proMMPs and TIMP-1 was monitored by Western blotting or gelatin zymography. Prostaglandin E2 (PGE2) was measured by an enzyme immunoassay.¶Results: 4′-Hydroxy aceclofenac, a major metabolite of aceclofenac, down-regulated both basal and IL-1β-induced production of proMMP-1 and proMMP-3 at a concentration sufficient to suppress PGE2 production without modulating proMMP-2 or TIMP-1, whereas aceclofenac itself had no marked effect on the production of proMMPs.¶Conclusions: Down-regulation of proMMP-1 and proMMP-3 production by 4′-hydroxy aceclofenac may contribute to the therapeutic effect of aceclofenac on rheumatoid arthritis and osteoarthritis.

Effects of Arginine-Vasopressin Fragment 4–9 on Rodent Cholinergic Systems

Arginine-vasopressin fragment 4-9 (AVP4-9) has been demonstrated in animal studies to facilitate learning and memory. To clarify the mechanisms of this facilitation, we focused on the effects of AVP4-9 on rodent cholinergic systems. AVP4-9 (0.1 microM) enhanced the basal and the high-potassium-evoked acetylcholine (ACh) release from rat hippocampal slices (122.4 and 120.0% of control, respectively) in the presence of 1.3 mM calcium (physiological level) at 60 min after the incubation at 37 degrees C. The AVP4-9-stimulated basal ACh release was inhibited by a V1-selective antagonist ([(beta-mercapto-beta,beta-cyclopentamethylene propionic acid)1, O-methyl-Tyr2, Arg8] vasopressin), but not by a V2-selective antagonist ([adamantaneacetyl1, O-ethyl-D-Tyr2, Val4, aminobutyryl6, Arg8,9]-vasopressin). In addition, AVP4-9 did not affect the basal ACh release under the calcium-free condition at 37 degrees C or in the presence of 1.3 mM calcium at 4 degrees C. However, AVP4-9 facilitated the passive-avoidance response of scopolamine (a cholinergic blocker)-induced memory-deficient mice. These findings demonstrate that AVP4-9 stimulates ACh release via mediation by V1-like vasopressin receptors, and shows dependence on calcium ion and temperature. The results also suggest that the mechanism of the facilitative effects of AVP4-9 on learning and memory consist of the observed stimulation of cholinergic systems and other parallel pathways that would not be inhibited by cholinergic blocking.

Anti-inflammatory effect of YPE-01, a novel diarylheptanoid derivative, on dermal inflammation in mice

Objective and Design: We investigated the anti-inflammatory effect of YPE-01, a novel diarylheptanoid derivative in vitro and in vivo.¶Material: In the in vitro study, rat basophilic leukemia (RBL-1) cells were used. For the in vivo study, ICR and ddY mice (male, 7 weeks old) were used.¶Treatment: In the in vitro study, the supernatant of RBL-1 cells lysate was incubated with 50u2009μM arachidonic acid (AA) and 0.01-100u2009μM test drugs for 15u2009min. RBL-1 cells were preincubated with 0.01–100u2009μM test drugs for 10u2009min before incubation with 0.5u2009μM calcium ionophore A23187 for 10u2009min. In the in vivo study, YPE-01 (0.1–3u2009mg/ear) was applied to the ear of mice at the same time as a 12-O-tetradecanoylphorbol 13-acetate (TPA) application or 1u2009h before an AA application.¶Methods: In the in vitro study, the amounts of 5-hydroxyeicosatetraenoic acid and leukotrienes were measured by high-performance liquid chromatography and an enzyme immunoassay, respectively. In the in vivo study, a circular tissue sample from the ear of the mice was weighed. Statistical analysis was done using Dunnetts test.¶Results: YPE-01 inhibited the 5-lipoxygenase activity (IC50, 0.28u2009μM) and the leukotriene B4 (IC50, 0.035u2009μM) and C4 (IC50, 0.046u2009μM) production by RBL-1 cells without any inhibition of cyclooxygenase activity in vitro. The topical application of YPE-01 significantly suppressed both the AA- and TPA-induced ear edemas in vivo.¶Conclusions: YPE-01 is a selective 5-lipoxygenase inhibitor with a suppressive effect against dermal inflammation.