Yoshikatsu Suzuki

Mechanisms underlying the reduced endothelium-dependent relaxation in human omental resistance artery in pre-eclampsia

1 In pre‐eclampsia, a functional change occurs in the role played by endothelium‐derived nitric oxide (NO) in the regulation of smooth muscle contraction in resistance arteries. We investigated the underlying mechanism in human omental resistance arteries from normotensive pregnant and pre‐eclamptic women in the presence of diclofenac (an inhibitor of cyclo‐oxygenase). 2 In endothelium‐intact strips, the sensitivity to 9,11‐epithio‐11,12‐methano‐thromboxane A2 (STA2) was significantly higher in pre‐eclampsia, and this was not modified by either NG‐nitro‐l‐arginine (l‐NNA, an inhibitor of NO synthase) or removal of the endothelium. 3 Bradykinin and substance P each produced an endothelium‐dependent relaxation of the STA2‐induced contraction in both groups, although the relaxation was significantly smaller for pre‐eclampsia. l‐NNA markedly attenuated the endothelium‐dependent relaxation in the normotensive pregnant group but not in the pre‐eclamptic group. 4 In the presence of l‐NNA, the relaxation induced by sodium nitroprusside (SNP) on the STA2 contraction was significantly smaller for pre‐eclamptic than for normotensive pregnant women. 5 In endothelium‐denuded strips, the relaxation induced by 8‐para‐ chlorophenyl thio‐guanosine‐3′,5′‐cyclic monophosphate (8‐pCPT‐cGMP) on the STA2 contraction was significantly less for pre‐eclampsia. 6 In β‐escin‐skinned strips from both groups of women, 8‐pCPT‐cGMP (1–10 μm) concentration‐dependently attenuated the contraction induced by 0.5 μm Ca2+. However, its relaxing action was significantly weaker in pre‐eclampsia. 7 It is suggested that the weaker responsiveness to NO seen in strips from pre‐eclamptic women may be partly due to a reduced smooth muscle responsiveness to cyclic GMP.

Reduced function of endothelial prostacyclin in human omental resistance arteries in pre‐eclampsia

It remains unclear in pre‐eclampsia whether or not a functional change occurs in the role played by prostacyclin in endothelium‐dependent relaxation in resistance arteries. We examined this using human omental resistance arteries (obtained from pre‐eclamptic or normotensive pregnant women) in the presence of NG‐nitro‐l‐arginine (l‐NNA, an inhibitor of nitric oxide synthase). In endothelium‐intact strips from both groups, 9,11‐epithio‐11,12‐methano‐thromboxane A2 (STA2, a thromboxane A2 mimetic) produced a contraction. Diclofenac (an inhibitor of cyclooxygenase) enhanced the STA2 contraction only in the normotensive pregnant group (1.4 times control, P < 0.01). In the presence of STA2, bradykinin (0.1 μm) produced an endothelium‐dependent relaxation in both groups, the relaxation being significantly smaller for the pre‐eclamptic group (P < 0.002). Diclofenac significantly attenuated the bradykinin‐induced relaxation only for the normotensive pregnant group (31 % inhibition, P < 0.001). The bradykinin‐induced membrane hyperpolarization consisted of diclofenac‐sensitive and ‐insensitive components. The former, but not the latter, was significantly smaller in pre‐eclampsia (‐4.3 vs.−2.6 mV, P < 0.05). The concentrations of 6‐keto‐PGF1α (a stable metabolite of prostacyclin) in these arteries were significantly lower in pre‐eclampsia in both the absence and presence of bradykinin (about 0.2‐0.4 times the normotensive pregnant value in each case, P < 0.01). By contrast, both the relaxation and the membrane hyperpolarization in response to beraprost (10 nm, a stable analogue of prostacyclin) were similar between the two groups. We conclude that, in pre‐eclampsia, a reduced part is played by prostaglandins in the endothelium‐dependent relaxation seen in resistance arteries and that this may be due to a reduced production of prostacyclin by the endothelium.

Is angiotensinogen gene polymorphism associated with hypertension in pregnancy

OBJECTIVE To determine whether a state of hypertension in pregnancy in the Japanese can be predicted in the early period based on detection of the M235T variant of the angiotensinogen gene, alone or with other factors. METHODS A total of 313 Japanese pregnant women were divided into 3 groups on the basis of their angiotensinogen genotype: TT, MT, and MM. Hypertension in pregnancy was diagnosed for 33 patients in all. For each group, we sought to determine what factors increased the risk of the disease. MAIN OUTCOME MEASURES The angiotensinogen M235T variant, mean arterial pressure (MAP) before the 12th gestational week, body mass index (BMI) before pregnancy, age at delivery, parity, a familial history of hypertension, and development of preeclampsia or gestational hypertension were considered. RESULTS The frequencies of the allele T were the same among preeclampsia, gestational hypertension, and normal subjects. In TT subjects, a high incidence of gestational hypertension was found for women with MAP > or = 90 mm Hg, high or low BMI before pregnancy > or = 22.0 or < 18.0, and maternal history of hypertension. In MT subjects, women who showed MAP > or = 90 mm Hg or who were above 36 years old at delivery had a high incidence of gestational hypertension. Preeclampsia could not be predicted in either group. CONCLUSIONS Hypertension in pregnancy cannot be predicted on the basis of the M235T variant of angiotensinogen gene alone. However, gestational hypertension is associated with combinations of other factors. In contrast, it is virtually impossible to predict the development of preeclampsia.

Conservative treatment by angiographic artery embolization of an 11-week cervical pregnancy after a period of heavy bleeding

OBJECTIVE To describe a rare case of conservative treatment of an 11-week cervical pregnancy after a period of heavy bleeding. DESIGN Case report. SETTING A university hospital. PATIENT(S) A 33-year-old woman was admitted to our hospital for treatment of a cervical pregnancy. Two-and-a-half years thereafter, she gave birth to a healthy baby by vaginal delivery at 38 weeks of gestation. INTERVENTION(S) Systemic methotrexate treatment, ligation of descending branches of uterine arteries, cervical cerclage, and unilateral internal iliac artery embolization. MAIN OUTCOME MEASURE(S) Transvaginal ultrasound, magnetic resonance imaging, and arteriography findings. RESULT(S) The patient was successfully treated with unilateral internal iliac artery embolization on the same side as the pregnancy in the 11th gestational week. CONCLUSION(S) After failed methotrexate and vessel ligation in cervical pregnancy, unilateral internal iliac artery embolization is an effective and conservative treatment that allows preservation of reproduction potential.

A Case of Massive Subchorionic Thrombohematoma Diagnosed by Ultrasonography and Magnetic Resonance Imaging

Massive subchorionic thrombohematoma is uncommon but associated with a poor perinatal prognosis. Placental enlargement was detected in a 25-year-old Japanese primipara woman with fetal growth retardation and oligohydramnios at 23 weeks’ gestation. Ultrasonography (USG) showed an abnormal sonolucency within the placenta at 28 weeks’ gestation, but could not give an unequivocal differentiation from placental abnormalities such as hematomas, cysts and other tumors. Magnetic resonance imaging (MRI) pointed to a large hematoma in the subchorionic region. Simultaneously, the amniotic fluid was brownish colored. From these findings, it was possible to have prenatal diagnosis of massive subchorionic thrombohematoma. At 32 weeks’ gestation, the fetus died in utero and was stillborn 3 days later. Pathological findings for the placenta revealed a large hematoma diffused between the villous chorion and the chorionic plate, with wide necrosis of placental tissue, likely due to formation of multiple thrombi. The clinical and pathological findings were compatible with massive subchorionic thrombohematoma. MRI might be useful for the detection of massive subchorionic thrombohematoma and help its clinical management in combination with USG and pulse Doppler imaging.

Evaluation Levels of Cytokines in Amniotic Fluid of Women with Intrauterine Infection in the Early Second Trimester

Amniotic fluid was obtained from 180 patients by amniocentesis at 16–22 weeks of gestation and assayed for the levels of interleukin (IL)-6, IL-8, leukocyte elastase (LE), and glucose. Ten of cases had clinical symptoms, such as uterine contraction, genital bleeding, and cervical ripening, and the other 170 were assessed for fetal chromosomal features. Four of the ten cases with uterine contraction developed abortion, while 10 of those screened had findings of fetal chromosomal anomalies, and 7 cases then underwent induced abortion artificially. In the cases of abortion, levels of IL-6, IL-8 and LE were higher than in the samples from the 160 pregnant women without clinical symptoms and a normal karyotype, while glucose in amniotic fluid was lower. Of 6 cases with clinical symptoms, but not developing abortion, 4 developed preterm labor, and in these IL-6 and IL-8 also were significantly elevated, with LE being slight high compared to normal. The results suggest that IL-6, IL-8, LE, and glucose in amniotic fluid at early second trimester can be used as markers of severe infection in the uterus, and with the first two being particularly sensitive.

Prenatal Diagnosis of Lissencephaly (Type II) by Ultrasound and Fast Magnetic Resonance Imaging

We report a case of lissencephaly which could be diagnosed by detailed examination during pregnancy. We first found bilateral enlarged ventricles in the fetus by routine abdominal ultrasonography at mid-pregnancy. Fast scanning MRI subsequently allowed confirmation of a diagnosis of lissencephaly during pregnancy.

Reduced hyperpolarization in endothelial cells of rabbit aortic valve following chronic nitroglycerine administration

This study was undertaken to determine whether long‐term in vivo administration of nitroglycerine (NTG) downregulates the hyperpolarization induced by acetylcholine (ACh) in aortic valve endothelial cells (AVECs) of the rabbit and, if so, whether antioxidant agents can normalize this downregulated hyperpolarization. ACh (0.03–3 μM) induced a hyperpolarization through activations of both apamin‐ and charybdotoxin‐sensitive Ca2+‐activated K+ channels (KCa) in rabbit AVECs. The intermediate‐conductance KCa channel (IKCa) activator 1‐ethyl‐2‐benzimidazolinone (1‐EBIO, 0.3 mM) induced a hyperpolarization of the same magnitude as ACh (3 μM). The ACh‐induced hyperpolarization was significantly weaker, although the ACh‐induced [Ca2+]i increase was unchanged, in NTG‐treated rabbits (versus NTG‐untreated control rabbits). The hyperpolarization induced by 1‐EBIO was also weaker in NTG‐treated rabbits. The reduced ACh‐induced hyperpolarization seen in NTG‐treated rabbits was not modified by in vitro application of the superoxide scavengers Mn‐TBAP, tiron or ascorbate, but it was normalized when ascorbate was coadministered with NTG in vivo. Superoxide production within the endothelial cell (estimated by ethidium fluorescence) was increased in NTG‐treated rabbits and this increased production was normalized by in vivo coadministration of ascorbate with the NTG. It is suggested that long‐term in vivo administration of NTG downregulates the ACh‐induced hyperpolarization in rabbit AVECs, possibly through chronic actions mediated by superoxide.

Reduction of Pleural Effusion by OK-432 in a Fetus Complicated with Congenital Hydrothorax

A 29-year-old, primiparous woman was referred to our hospital at 21 weeks of gestation because of right pleural effusion in the fetus shown by routine ultrasonographic examination. Cytology revealed abundant lymphocytes, suggesting chylothorax. We removed the pleural effusion and injected OK-432 into the chest cavity at 24 and 25 weeks of gestation. Pleural effusion declined and an adhesion between the lung surface and the pleural membrane seemed to form. At 33 weeks of gestation, a female infant was born by cesarean section (1,090 g and Apgar score 6/8). Although she demonstrated slight retraction and tachypnea, management could be achieved by administration of oxygen alone without mechanical ventilation. Later, the baby was diagnosed as suffering from the Cornelia de Lange syndrome with characteristic features. OK-432 injections could thus prevent complications of chylothorax and hypoplastic lungs, without injury to either the baby or the mother.

Angiotensin II‐induced modulation of endothelium‐dependent relaxation in rabbit mesenteric resistance arteries

The role of local endogenous angiotensin II (Ang II) in endothelial function in resistance arteries was investigated using rabbit mesenteric resistance arteries. First, the presence of immunoreactive Ang II together with Ang II type‐1 receptor (AT1R) and angiotensin converting enzyme (ACE) was confirmed in these arteries. In endothelium‐intact strips, the AT1R‐blocker olmesartan (1 μm) and the ACE‐inhibitor temocaprilat (1 μm) each enhanced the ACh (0.03 μm)‐induced relaxation during the contraction induced by noradrenaline (NA, 10 μm). Similar effects were obtained using CV‐11974 (another AT1R blocker) and enalaprilat (another ACE inhibitor). The nitric‐oxide‐synthase inhibitor NG‐nitro‐l‐arginine (l‐NNA) abolished the above effect of olmesartan. In endothelium‐denuded strips, olmesartan enhanced the relaxation induced by the NO donor NOC‐7 (10 nm). Olmesartan had no effect on cGMP production (1) in endothelium‐intact strips (in the absence or presence of ACh) or (2) in endothelium‐denuded strips (in the absence or presence of NOC‐7). In β‐escin‐skinned strips, 8‐bromoguanosine 3′,5′ cyclic monophosphate (8‐Br‐cGMP, 0.01–1 μm) concentration dependently inhibited the contractions induced (a) by 0.3 μm Ca2+ in the presence of NA+GTP and (b) by 0.2 μm Ca2++GTPγS. Olmesartan significantly enhanced, while Ang II (0.1 nm) significantly inhibited, the 8‐Br‐cGMP‐induced relaxation. We propose the novel hypothesis that in these arteries, Ang II localized within smooth muscle cells activates AT1Rs and inhibits ACh‐induced, endothelium‐dependent relaxation at least partly by inhibiting the action of cGMP on these cells.