Glucagon plays an important role in the modification of insulin secretion by leptin.

Obese people show marked hyerinsulinemia, but the exact mechanism has not been clarified. Hyperleptinemia is one of possible candidates, although there is an obvious difference in the effect of leptin on insulin secretion between isolated pancreatic islets and β-cell line. Since glucagon may modulate the effect of leptin on insulin secretion, we determined the influences of glucagon in the leptin effect on insulin secretion.

Attainment of glycaemic goals by step-up therapy with biphasic insulin aspart-70/30 in Japanese type 2 diabetic patients.

We have made step-up titration protocol with biphasic insulin aspart-70/30 (BIAsp 30), and tried to achieve glycemic goals in poorly controlled Japanese type 2 diabetic patients. We summarized all results obtained to analyze the effectiveness of our protocol. The target of glycaemic control was defined as HbA1c over 7.

Targeting by myosin phosphatase-RhoA interacting protein mediates RhoA/ROCK regulation of myosin phosphatase.

Vascular smooth muscle cell contractile state is the primary determinant of blood vessel tone. Vascular smooth muscle cell contractility is directly related to the phosphorylation of myosin light chains (MLCs), which in turn is tightly regulated by the opposing activities of myosin light chain kinase (MLCK) and myosin phosphatase. Myosin phosphatase is the principal enzyme that dephosphorylates MLCs leading to relaxation.

Incidence of β3-adrenergic receptor polymorphism and prediction of successful weight reduction with mazindol therapy in severely obese Japanese subjects.

Mazindol, a centrally acting monoamine re-uptake inhibitor, enhances satiety and supports body weight loss, but response to this drug among obese patients is very variable. The possible involvement of the Trp64Arg polymorphism of the β3-adrenergic receptor (ADRB3) gene in the development of severe obesity and weight loss response to anorexigenic drugs has not been established. In the present study, the allelic frequency of the Trp64Arg ADRB3 gene polymorphism was determined in massively obese Japanese outpatients (BMI > 35 kg/m(2)), and we investigated whether allelic differences may determine the weight loss effect of mazindol.

Tricyclic quinoxalinediones, aza-kynurenic acids, and indole-2-carboxylic acids as in vivo active NMDA-glycine antagonists.

This review article describes the development of in vivo active antagonists for the glycine binding site of the N-Methyl-D-Aspartate (NMDA) receptor. There were several difficulties in identifying a class of antagonists with in vivo efficacy and only a few compounds succeeded in emerging with activity in vivo. A series of tricyclic quinoxalinediones was highly potent glycine antagonists in vitro and the derivatives having a zwitterionic moiety including SM-18400 indeed showed in vivo activity.

M-RIP targets myosin phosphatase to stress fibers to regulate myosin light chain phosphorylation in vascular smooth muscle cells.

Vascular smooth muscle cell contraction and relaxation are directly related to the phosphorylation state of the regulatory myosin light chain. Myosin light chains are dephosphorylated by myosin phosphatase, leading to vascular smooth muscle relaxation. Myosin phosphatase is localized not only at actin-myosin stress fibers where it dephosphorylates myosin light chains, but also in the cytoplasm and at the cell membrane.

SM-31900, a novel NMDA receptor glycine-binding site antagonist, reduces infarct volume induced by permanent middle cerebral artery occlusion in spontaneously hypertensive rats.

The purpose of this study was to investigate the effect of (3S)-7-chloro-3-[2-((1R)-1-carboxyethoxy)-4-aminomethylphenyl]aminocarbonylmethyl-1,3,4,5-tetrahydrobenz[c,d]indole-2-carboxylic acid hydrochloride (SM-31900), an antagonist with high selectivity and affinity for the NMDA receptor glycine-binding site, on the cerebral infarct volume in a permanent middle cerebral artery occlusion (MCAo) model, which was constructed by electrocoagulation of a unilateral middle cerebral artery distal to the olfactory tract using spontaneously hypertensive rats (SHRs). To investigate the dose-response characteristics and the therapeutic time window of SM-31900 in this MCAo model, we conducted three experiments, in which the administration of SM-31900 was started 5min (experiment I), 30min (experiment II), or 60min (experiment III) after MCAo, respectively. In all the studies, SM-31900 was administered by intravenous bolus injection followed by continuous intravenous infusion to obtain a steady-state level of this compound in blood immediately after its administration.

In vitro and in vivo antagonistic activities of SM-31900 for the NMDA receptor glycine-binding site.

The purpose of this study was to clarify the in vitro pharmacological profile and the in vivo activity of (3S)-7-chloro-3-[2-((1R)-1-carboxyethoxy)-4-aminomethylphenyl]aminocarbonylmethyl-1,3,4,5-tetrahydrobenz[c,d]indole-2-carboxylic acid hydrochloride (SM-31900). SM-31900 inhibited the binding of [3H]glycine and [3H]5,7-dichlorokynurenic acid, radioligands for the N-methyl-D-aspartate (NMDA) receptor glycine-binding site, to rat brain membranes in a competitive manner, with K(i) values of 11+/-2 and 1.0+/-0.