Soichi Noguchi

Nafamostat mesilate, a serine protease inhibitor, suppresses lipopolysaccharide-induced nitric oxide synthesis and apoptosis in cultured human trophoblasts

We investigated the effects of nafamostat mesilate, a synthetic protease inhibitor clinically used for patients with pancreatitis or disseminated intravascular coagulopathy, on NO synthesis and apoptosis in lipopolysaccharide (LPS)-treated human trophoblasts. Nafamostat mesilate or aminoguanidine, an inhibitor of NO synthase, suppressed NO synthesis and apoptosis in trophoblasts induced by LPS. Both agents also suppressed matrix metalloproteinase-2 activity induced by LPS. LPS also stimulated secretion of IL-6 and IL-8 in cultured trophoblasts, which was suppressed by nafamostat mesilate. Protease inhibitors including nafamostat mesilate may be therapeutic agents for chorioamnionitis and various diseases including septic shock, ischemia-reperfusion injury in brain and heart, graft rejection, and acute phase inflammatory diseases, in which overproduction of NO or peroxynitrite is involved in tissue injury.

A long-term transdermal nitric oxide donor improves uteroplacental circulation in women with preeclampsia.

Objective. To determine the effects of long‐term transdermal administration (range, 4–30 days; mean ± SD, 11.1 ± 7.2 days) of isosorbide dinitrate, a nitric oxide donor, in preeclamptic women. Methods. We studied uterine and fetoplacental circulation of 12 preeclamptic women with oligohydramnios and an elevated pulsatility index in the uterine arteries. Results. Transdermal isosorbide dinitrate significantly suppressed the blood pressure of patients. Pulsed Doppler ultrasonography revealed that the average pulsatility index in the uterine arteries was significantly reduced by treatment with isosorbide dinitrate (P < .003). The average pulsatility index in the umbilical artery was also significantly reduced (P < .004). Furthermore, the size of the amniotic fluid pocket increased approximately 4‐fold by treatment with isosorbide dinitrate. Conclusions. Long‐term transdermal administration of isosorbide dinitrate improves fetoplacental circulation and may be effective therapy for avoiding maternal hypertension and oligohydramnios in some preeclamptic women.

Bisphenol A stimulates NO synthesis through a non-genomic estrogen receptor-mediated mechanism in mouse endothelial cells

Biological actions of bisphenol A (BPA), an environmental chemical, have not been fully elucidated. We studied effect of BPA on nitric oxide (NO) synthesis in the murine endothelial cell line, MSS31. BPA (1-100 microM) increased nitrite/nitrate, a stable metabolites of NO, levels in culture medium of MSS31. However, Western blotting showed that the level of endothelial NO synthase protein was not increased by 16 h of treatment with BPA (10 microM). ICI 182,780 (10 microM), an estrogen receptor (ER) antagonist, suppressed BPA-induced NO synthesis while actinomycin D (1 microg/ml), a transcription inhibitor, or cycloheximide (40 microM), a protein synthesis inhibitor, exhibited no effect on BPA-induced NO synthesis. These results indicate that BPA stimulates NO synthesis through a non-genomic ER-mediated mechanism. Short-term effects of BPA on NO synthesis were weak but similar to 17beta-estradiol.

Nafamostat mesilate suppresses NF-κB activation and NO overproduction in LPS-treated macrophages

Nafamostat mesilate (NM), a clinically used serine protease inhibitor, suppressed the overproduction of nitric oxide (NO) and the expression of inducible nitric oxide synthase (iNOS) in RAW264.7 murine macrophages treated with lipopolysaccharide (LPS, 100 ng/ml); however, it had little effect on endothelial NOS (eNOS) in human umbilical vein endothelial cells (HUVEC). Electrophoretic mobility shift assay (EMSA) revealed that LPS activated nuclear factor-kappaB (NF-kappaB) in RAW264.7 cells and that this activation was suppressed by nafamostat mesilate. Western blotting showed that nafamostat mesilate suppressed the phosphorylation and degradation of inhibitor kappaB-alpha (IkappaB-alpha), which holds NF-kappaB in the cytoplasm in an inactivated state. Our observations suggest that nafamostat mesilate is a candidate agent for various diseases such as ischemia-reperfusion, graft rejection, inflammatory diseases, and autoimmune diseases, in which iNOS and/or NF-kappaB are upregulated.

Impaired uterine perfusion associated with metabolic disorders in women with polycystic ovary syndrome

Background.  Risk factors for cardiovascular disease, including chronic anovulation, obesity, hyperandrogenism, hyperinsulinemia, and dyslipidemia, are commonly observed in women with polycystic ovary syndrome (PCOS). We evaluated uterine perfusion and its correlation with clinical and biochemical parameters in women with PCOS.

Involvement of peroxynitrite in LPS‐induced apoptosis of trophoblasts

Objective:  To examine whether or not peroxynitrite was involved in trophoblastic apoptosis induced by a bacterial endotoxin, lipopolysaccharide (LPS).

Increased plasma adrenomedullin in women with recurrent pregnancy loss

OBJECTIVE To evaluate vascular changes and uterine perfusion in women with recurrent pregnancy loss. METHODS We measured plasma levels of adrenomedullin of 100 pregnant women in the midluteal phase of a nonpregnant cycle (control group: n = 62; recurrent pregnancy loss group: n = 38). We measured the pulsatility index (PI) in the uterine arteries by transvaginal pulsed Doppler ultrasonography at the same time. RESULTS The plasma level of adrenomedullin in women with recurrent pregnancy loss (5.6 ± 1.9, mean ± standard deviation) was significantly higher (P > .001) than that in control women (3.6 ± 1.7). Uterine arterial PI of women with recurrent pregnancy loss (2.70 ± 0.47) was significantly higher (P > .001) than that in control women (2.09 ± 0.39). Plasma level of adrenomedullin had a significant positive correlation with uterine arterial PI both in the control group (r = .58, P < .001) and in the recurrent pregnancy loss group (r = .78, P < .001). Both plasma adrenomedullin concentration (7.2 ± 2.3) and uterine arterial PI (3.06 ± 0.36) were significantly high in women with antiphospholipid antibodies. CONCLUSION Plasma adrenomedullin may serve as a useful biochemical marker for recurrent pregnancy loss caused by impaired uterine perfusion.