Yasuo Makino

Regulation of ghrelin secretion during pregnancy and lactation in the rat: possible involvement of hypothalamus

We investigated the plasma concentration of ghrelin peptide during pregnancy and lactation in rats. Plasma ghrelin levels on days 10 and 15 of pregnancy were significantly lower than those of the non-pregnant rats. Thereafter, the plasma ghrelin levels on day 20 of pregnancy sharply increased to levels comparable with those in non-pregnant rats. Ghrelin peptide concentrations in the stomach did not change significantly during pregnancy. In the hypothalamus, ghrelin mRNA levels were significantly lower on day 15 of pregnancy than in the non-pregnant rats. Also, plasma ghrelin levels were significantly lower in lactating dams than non-lactating controls on days 3 and 8 of lactation. We examined the possible involvement of prolactin and oxytocin in the regulation of plasma ghrelin concentrations during lactation. Although plasma prolactin levels were decreased by the administration of bromocriptine, plasma ghrelin levels did not differ significantly between vehicle- and drug-treated lactating rats. Administration of haloperidol produced a marked increase in plasma prolactin levels as compared with the non-lactating controls. However, plasma ghrelin levels were not significantly different between vehicle- and drug-treated rats. Administration of an oxytocin antagonist into the lateral ventricle significantly inhibited the increase in the plasma oxytocin level induced by acute suckling. However, plasma ghrelin levels did not significantly between the groups. These observations indicated that the decrease in serum ghrelin is caused by a loss of the contribution of hypothalamic ghrelin. Furthermore, the present results suggested that the suckling stimulus itself, but the release of prolactin or oxytocin, is the factor most likely to be responsible for the suppression of ghrelin secretion during lactation.

Role of nitric oxide on vasorelaxation in human umbilical artery

OBJECTIVE Endothelium-derived relaxing factor (or nitric oxide) is thought to play an important role in control of blood flow in umbilical blood vessels at midgestation compared with term. Previous studies suggest that histamine releases endothelium-derived relaxing factor from umbilical arteries. In this study we intended to clarify the mechanism by which histamine releases endothelium-derived relaxing factor and causes vasorelaxation in human umbilical artery at the midstage (18 to 22 weeks) of gestation. STUDY DESIGN By means of very thin muscle strips that allow rapid diffusional access of applied drugs (in a few seconds), contractile properties of human umbilical artery were examined. Isometric tensions were measured in response to potassium chloride (39 mmol/L) or caffeine and inhibitory effects of histamine, A23187, glyceryl trinitrate, and 8-bromo-cyclic guanosine monophosphate on these contractions were also examined. RESULTS Histamine (0.01 to 0.1 mumol/L) did not inhibit 39 mmol/L K(+)-induced contractions of tissues taken at the terminal (38 to 41 weeks) stage of gestation. However, at midgestation histamine (0.01 to 0.1 mumol/L), A23187 (10 mumol/L), and 8-bromo-cyclic guanosine monophosphate (membrane-permeable analog of cyclic guanosine monophosphate, 0.1 mmol/L) inhibited 39 mmol/L K(+)-induced contractions. The inhibitory effects of histamine were antagonized by mepyramine (an H1 antagonist), L-NG-nitro arginine, methylene blue, and Ca++ depletion of the extracellular space but not by cimetidine (an H2 antagonist). Caffeine produced contractions both in the presence and absence of extracellular Ca++ possibly because of the release of Ca++ from intracellular storage sites. Glyceryl trinitrate and 8-bromo-cyclic guanosine monophosphate reduced the caffeine-induced contractions in Ca(++)-free solution. In addition, 10 mumol/L cyclic guanosine monophosphate did not attenuate the Ca++ sensitivity for contractile elements. CONCLUSION These results suggest that (1) histamine coupled to the histamine H1 receptor increases intracellular Ca++ concentration to stimulate nitric oxide synthase in human umbilical endothelial cells, (2) nitric oxide from endothelial cells activates guanylate cyclase to produce cyclic guanosine monophosphate in the umbilical smooth muscle cells, and (3) cyclic guanosine monophosphate relaxes the umbilical tissues, perhaps as a result of the activation of a Ca++ extrusion system.

Adrenomedullin attenuates the hypertension in hypertensive pregnant rats induced by NG-nitro-l-arginine methyl ester

We examined the effect of adrenomedullin on the cardiovascular system of an animal model for preeclampsia. An inhibitor of nitric oxide synthase, N(G)-nitro-L-arginine methyl ester (L-NAME), was infused subcutaneously into rats at a constant rate from day 14 of pregnancy to make an animal model for preeclampsia. Adrenomedullin was continuously infused intravenously at a dose of 3 or 10 pmol/h from day 17 of pregnancy. The basal systolic blood pressure was significantly higher in the L-NAME treated rats than in the control rats. The adrenomedullin administration at day 19 of pregnancy showed a significant decrease in the blood pressure in the L-NAME treated rats than in vehicle rats during infusion. The blood pressure of normal pregnant rats did not significantly decrease by adrenomedullin infusion. The adrenomedullin decreased pup mortality of the L-NAME treated rats. Adrenomedullin attenuated the L-NAME induced hypertension and pup mortality. On the other hand, adrenomedullin administration in both pregnant rats in early gestation (5-11 days of pregnancy) and in non-pregnant rats did not show any significant effect on L-NAME-induced hypertension. The adrenomedullin mRNA level was predominantly expressed at high levels in the ovary, uterus and placenta, but at low levels in other tissues in pregnant rats in late gestation. The adrenomedullin mRNA level of the L-NAME treated rats in placenta decreased more than in the normal pregnant rats in late gestation (P < 0.05). These findings suggest that the adrenomedullin might play an important role in the regulation of the cardiovascular system of the mother and fetoplacental unit in rats.

Clinical features of fetal growth restriction complicated later by preeclampsia

Objective:  To assess the maternal and perinatal outcome of preeclampsia with fetal growth restriction (FGR) and to assess the risk factors of FGR complicated later by preeclampsia.

The effect of nitric oxide on uterine and umbilical artery flow velocity waveform in pre-eclampsia

We compared the flow velocity waveforms of uterine and umbilical arteries in normotensive and pre-eclamptic patients at mid-gestation. In a randomised controlled trial we tested the effects of isosorbide dinitrate (ISDN, nitric oxide donor) patch therapy on the flow velocity waveform of pre-eclamptic patients at mid-gestation. The resistance indices (RI) of human uterine and umbilical arteries were higher in pre-eclamptic patients compared to the normotensive patients. ISDN patch therapy significantly reduced the increased RI values of the umbilical artery in pre-eclamptic patients without any change in systemic blood pressures, but the RI values of the uterine artery were not significantly attenuated. The change of the umbilical artery might be due to the improvement of end-diastolic flow velocity. These results suggest that the feto-placental circulation in pre-eclampsia, perhaps due to the disturbance of the endothelium-dependent vaso-relaxation system, and that ISDN therapy may improve the impaired endothelium dependent nitric oxide system.

Clinical results of fetal obstructive uropathy treated by vesicoamniotic shunting

OBJECTIVES To report the clinical results of 5 fetuses after a vesicoamniotic shunting procedure (VASP). METHODS Between 1995 and 1998, 5 patients (two with prune belly syndrome, one with a cloacal anomaly, one with urethral stenosis, and one with a sacrococcygeal teratoma) underwent VASP using a double-basket catheter. We used the following selection criteria: a fetus without chromosomal defects, with oligohydramnios, and with a predicted good renal function from sequential or single fetal urinalysis (sodium concentration, chloride concentration, and osmolarity at less than 100 mEq/L, less than 90 mEq/L, and less than 210 mOsm, respectively). RESULTS The mean gestational age was 20.8 +/- 6.9 weeks at diagnosis, 24.2 +/- 6.0 weeks at VASP, and 30.6 +/- 6.2 weeks at delivery. In our study, 2 of 5 patients survived. One of the patients with prune belly syndrome was 18 months old at last follow-up, with hydrocephalus and a creatinine level of 0.2 mg/dL. The patient with the cloacal anomaly was 4 years old at last follow-up and had signs of clonic convulsion. However, psychomotor development was delayed in both. Of the 3 patients who died, 2 died after birth, and the autopsy determined death was due to pulmonary insufficiency. The patient with urethral stenosis died in utero. CONCLUSIONS Although the principal purpose of VASP is to prevent pulmonary hypoplasia and dysfunctional kidneys, VASP was not always effective, as the outcomes were poor in most of our patients. A greater standardization of patient selection and a large cohort study in the future should be considered to assess VASP.

Rapid Detection of Chromosome Aneuploidies by Prenatal Interphase FISH (Fluorescence in situ Hybridization) and Its Clinical Utility in Japan

Objective: The purpose of this study was to assess the accuracy, informative rate, detection rate, and clinical utility of prenatal interphase fluorescence in situ hybridization (FISH) analysis of amniotic fluid samples from Japanese women.

Risk factors associated with altered fetal growth in patients with pregestational diabetes mellitus.

Objective: To assess the risk factors for abnormal fetal growth in patients with pregestational diabetic mellitus (DM). Methods: A retrospective study was performed in 336 patients with pregestational DM. Small-for-gestational-age (SGA) and large-for-gestational-age (LGA) infants were defined as newborns with birth weights < 10th percentile and > 90th percentile, respectively. Logistic regression analysis was performed to identify risk factors for SGA and LGA. Results: Multivariate analysis of the patients with pregestational DM revealed a significant difference between patients who delivered SGA and appropriate-for-gestational-age (AGA) infants in terms of retinopathy (OR = 5.73, 95%CI = 1.39–23.59) and hemoglobin A1C (HbA1C) before delivery (OR = 0.80, 95%CI = 0.68 – 0.94, with a 0.1% increase in DCCT unit). Multivariate analysis revealed a significant difference between patients who delivered LGA and AGA infants in terms of primipara (OR = 3.40, 95%CI = 1.47–7.87) and HbA1C before delivery (OR = 1.14, 95%CI = 1.07–1.21, with a 0.1% increase in DCCT unit). Conclusions: HbA1C before delivery influenced both SGA and LGA infants in patients with pregestational DM. Tight glycemic control might be harmful to fetal growth in pregestational diabetic patients, especially when complicated with retinopathy.

Amnioreduction in patients with bulging prolapsed membranes out of the cervix and vaginal orifice in cervical cerclage.

Abstract Objective: To determine whether an amnioreduction via bulging membranes (AVBM) and cerclage could be useful in 17 women with singleton gestations demonstrating hourglass membranes bulging out of the cervix or vaginal orifice. Methods: We used the following selection criteria for AVBM under ultrasonographic guidance using a peit needle because of undetectable cervical edges: (type 1) the bag of membranes protruded beyond the inlet of the vagina; (type 2) the bag of huge membranes completely occupied the vagina. Results: Eight patients (three cases of type 1 and five of type 2) were successful in AVBM and cerclage at 22.1±2.2 weeks gestation (range 19–24 weeks), and mean birth weight was 1,048.1±801.6 g (range 302– 2,688 g). Although the diameter of the forewater by transabdominal ultrasonography (cm) was higher than in the nine patients without AVBM (6.7±1.1 versus 4.1±0.7 cm, p=0.002), the prolongation of pregnancy (32.9±46.2 days; range 2–133 days) was the same as in patients without AVBM (36.9±39.3 day, p=1.000). Conclusion: It is important that every effort should be made to perform cervical cerclage at or before 26 weeks of gestation, even in women with type 1 or 2.

Risk factors associated with preterm delivery in women with pregestational diabetes

Aim:  The primary objective of this study was to compare the rates of spontaneous and indicated preterm delivery at less than 37 weeks of gestation. A second objective was to identify prenatal events associated with preterm delivery at less than 35 weeks of gestation in women with diabetes mellitus (DM).