Kazuo Asagiri

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.

Clinical Experience of Long-Term Transdermal Treatment with Nitric Oxide Donor for Women with Preeclampsia

Isosorbide dinitrate (ISDN), a nitric oxide donor, was applied transdermally for 4–16 days to 4 preeclamptic women with oligohydramnios, intrauterine fetal growth retardation (IUGR), and elevated resistance of blood flow in the uterine arteries. Pulsed Doppler ultrasonography revealed immediate and drastic improvement of pulsatility index (PI) of uterine arteries following treatment with ISDN. The average PI in uterine arteries of the 4 patients was reduced to approximately 67% of that of the untreated state. In 2 patients the amniotic fluid gradually increased over a few days which suggested improvement of fetoplacental circulation during administration of ISDN. This study suggests that long-term transdermal ISDN is an effective therapy, at least in a portion of preeclamptic women, to avoid maternal hypertension, fetal distress, oligohydramnios, and IUGR, and consequentially to prolong the gestational period.

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.

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).