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The optimal dosage remains controversial, as misuse of oxytocin can lead to dire complications such as uterine rupture. But the authors find that high-dose oxytocin can safely shorten labor. [ABSTRACT FROM AUTHOR]

Purpose: To address whether differential regulation of the renin-angiotensin-aldosterone system occurs in pre-eclampsia, we performed an analysis of the time course of circulating and urinary profiles of the vasoconstrictor (Ang II) and the vasodilator [Ang-(1-7)] peptides in normal pregnant (NP) and pre-eclamptic (PE) women., Methods: Urine and plasma samples from 86 nulliparous women were collected prospectively; 67 subjects continued as NP and 19 developed PE. Subjects were enrolled prior to 12 weeks of gestation and plasma and spot urine samples were obtained throughout gestation. Control samples were obtained at 6 weeks postpartum (PP)., Results: Mean blood pressure (p < 0.001) was elevated at 31-37 weeks of gestation in PE subjects as compared with NP subjects. Plasma Ang I and Ang II levels were elevated in NP subjects as early as 16 weeks of gestation and maintained throughout gestation. In PE subjects both plasma Ang I and Ang II were elevated at 16-33 weeks as compared with PP levels. PE subjects showed reduced plasma Ang I and Ang II (at 35-37 weeks of gestation) compared with NP subjects. Plasma Ang-(1-7) was unchanged in both groups. All three urinary peptides increased throughout gestation in NP subjects. In PE subjects urinary Ang I was increased at 23-26 weeks and was maintained throughout gestation. Urinary Ang II was increased at 27-29 and 31-33 weeks of gestation. PE subjects had no change in urinary Ang-(1-7)., Conclusion: The activation of the RAS, particularly Ang II throughout normal gestation may contribute to the maintenance of vascular tone during normal pregnancy. However higher sensitivity to Ang II in pre-eclampsia may be potentiated by the higher circulating and urinary levels of Ang II, unopposed by local renal Ang-(1-7), and thus may contribute to the development of pre-eclampsia.

Objective: To evaluate neonatal and maternal outcomes in obese pregnant women whose weight gain differed from the Institute of Medicine (IOM) recommendations., Study Design: Maternal and neonatal outcomes associated with weight change in pregnancy were retrospectively investigated in women with obesity (body mass index (BMI) ⩾30 kg m(-2); N=10734) who gave birth at 12 hospitals. Using a 1:1:1:1 design (n=778 matched groups), we matched women with obesity who lost, maintained, gained appropriate (IOM recommended) and gained excessive weight during pregnancy by gestational age at delivery, maternal age, race/ethnicity, prepregnancy BMI, chronic hypertension, pregestational diabetes and smoking status. Regression techniques were used to adjust for confounders and compare outcomes across weight change categories., Result: Compared with IOM recommendations, weight loss was associated with twofold greater odds of low birth weight infants and a mean decrease in estimated blood loss of 30 ml; excessive weight gain was associated with doubled odds of gestational hypertension or preeclampsia, fourfold greater odds of macrosomia and a mean decrease in 5-min APGAR of 0.09. From lost to excessively gained weight, the odds of cesarean delivery increased 1.4 times and mean infant birth weight increased by 197 g. In contrast, the odds of small-for-gestational age were 1.8 times greater for women who lost than gained excessive weight., Conclusion: Weight loss in obese pregnant women is associated with increased risk for low birth weight neonates but significantly decreased or maintained risk for other maternal and neonatal morbidities, as compared with appropriate or excessive weight gain. This study supports re-evaluation of the current IOM guidelines for women with obesity.

The role of the endogenous apelin system in pregnancy is not well understood. Apelin's actions in pregnancy are further complicated by the expression of multiple forms of the peptide. Using radioimmunoassay (RIA) alone, we established the expression of apelin content in the chorionic villi of preeclamptic (PRE) and normal pregnant women (NORM) at 36-38 wk of gestation. Total apelin content was lower in PRE compared with NORM chorionic villi (49.7±3.4 vs. 72.3±9.8 fmol/mg protein; n=20-22) and was associated with a trend for lower preproapelin mRNA in the PRE. Further characterization of apelin isoforms by HPLC-RIA was conducted in pooled samples from each group. The expression patterns of apelin peptides in NORM and PRE villi revealed little or no apelin-36 or apelin-17. Pyroglutamate apelin-13 [(Pyr1)-apelin-13] was the predominant form of the peptide in NORM and PRE villi. Angiotensin-converting enzyme 2 (ACE2) activity was higher in PRE villi (572.0±23.0 vs. 485.3±24.8 pmol·mg(-1)·min(-1); n=18-22). A low dose of ANG II (1 nM; 2 h) decreased apelin release in NORM villous explants that was blocked by the ANG II receptor 1 (AT1) antagonist losartan. Moreover, losartan enhanced apelin release above the 2-h baseline levels in both NORM and PRE villi (P<0.05). In summary, these studies are the first to demonstrate the lower apelin content in human placental chorionic villi of PRE subjects using quantitative RIA. (Pyr1)-apelin-13 is the predominant form of endogenous apelin in the chorionic villi of NORM and PRE. The potential mechanism of lower apelin expression in the PRE villi may involve a negative regulation of apelin by ANG II., (Copyright © 2015 the American Physiological Society.)

Background: To understand the role of Angiotensin-(1-7) (Ang-(1-7)) in vasculature of pregnant women, we compared cardiac output (CO), total peripheral resistance (TPR) and forearm blood flow (FBF) responses to Ang-(1-7) infusion between normotensive pregnant women in their third trimester and healthy age matched non-pregnant women. The responses of skin microcirculation to Ang-(1-7) were tested in preeclamptic, normotensive pregnant and non-pregnant women. Responses to Angiotensin II (Ang II) were also determined., Methods: Non-invasive methods for systemic (bioimpedance and VascuMAP), FBF (venous occlusion strain gauge plethysmography), and skin (laser Doppler) hemodynamics assessments were used., Results: Compared to non-pregnant women, systemic infusion of Ang-(1-7) (2000 pmol/min) resulted in a greater increase in CO (9.4 ± 6.4 versus -3.3 ± 2.1%, n = 9-10) in normotensive pregnant women. Brachial local infusion of Ang-(1-7) had no effect on FBF in either group. In non-pregnant and normotensive pregnant women, local Ang II induced a dose-dependent decrease in FBF and increase in forearm resistance at 50 and 100 pmol/min (p < 0.05 versus corresponding baseline, n = 7-10). Following iontophoretic application of 5 mmol/l dose of Ang-(1-7), the change in skin flow was higher in normotensive pregnant versus preeclamptic women (182.5 ± 93 versus 15.76 ± 19.46%, n = 14-15). Skin flow was lower in normotensive pregnant versus preeclamptic women (-46.5 ± 48.7 versus 108.7 ± 49.1%, n = 14-15) following Ang II infusion at 1.0 pmol/min., Conclusion: In the third trimester of pregnancy, Ang-(1-7) induces alterations in CO and differentially regulates micro- and macro-circulations, depending on the dose. Dysregulation in skin vasculature may contribute to the development of vascular dysfunction and hypertension in preeclampsia.

Background: The aim of this study was to identify genetic variants contributing to preterm birth (PTB) using a linkage candidate gene approach., Methods: We studied 99 single-nucleotide polymorphisms (SNPs) for 33 genes in 257 families with PTBs segregating. Nonparametric and parametric analyses were used. Premature infants and mothers of premature infants were defined as affected cases in independent analyses., Results: Analyses with the infant as the case identified two genes with evidence of linkage: CRHR1 (P = 0.0012) and CYP2E1 (P = 0.0011). Analyses with the mother as the case identified four genes with evidence of linkage: ENPP1 (P = 0.003), IGFBP3 (P = 0.006), DHCR7 (P = 0.009), and TRAF2 (P = 0.01). DNA sequence analysis of the coding exons and splice sites for CRHR1 and TRAF2 identified no new likely etiologic variants., Conclusion: These findings suggest the involvement of six genes acting through the infant and/or the mother in the etiology of PTB.

The objectives were to determine whether single-nucleotide polymorphisms (SNPs) in KCNN3 (encodes the small conductance calcium-activated potassium channel subfamily N, member 3), associate with preterm birth (PTB). In all, 602 preterm families with at least 1 preterm (<37 weeks gestation) infant were studied: DNA from the infant and one or both parents were genotyped for 16 SNPs in KCNN3. A region of interest within KCNN3 was sequenced in 512 Caucasian non-Hispanic mothers (412 with preterm deliveries;100 who delivered at term). Family-based association testing was used for genotyping analysis; Fisher exact test was used for sequencing analysis. Six SNPs (rs1218585, rs4845396, rs12058931, rs1218568, rs6426985, and rs4845394) were associated with PTB (all Ps < .05). These variations were all located within the intronic region between exons 1 and 2. Maternal sequencing revealed an association of 3 SNPs with spontaneous PTB; rs1218585 (P = .007), rs1218584 (P = .05), and a novel SNP at chromosome1:153099353 (P = .02). Polymorphisms in KCNN3 are associated with PTB and investigation into the functional significance of these allelic changes is warranted.

Background: During preeclampsia, placental angiogenesis is impaired. Factors released from the placenta including vascular endothelial growth factor (VEGF), placental growth factor (PLGF), soluble VEGF receptor 1 (sFlt1), and soluble endoglin (sEng) are regulatory molecules of placental development and function. While the renin angiotensin system has been shown to regulate angiogenic factors in other research fields, these mechanisms have not been extensively studied during pregnancy., Methods: We evaluated the effects of angiotensin II (Ang II) and angiotensin-(1-7) [Ang-(1-7)] on the release of VEGF, PLGF, sFlt1, and sEng from placental chorionic villi (CV). CV were collected from nulliparous third-trimester normotensive and preeclamptic subjects. CV were incubated for 0, 2, 4, and 16 hours with or without Ang II (1 nM and 1 microM) or Ang-(1-7) (1 nM and 1 microM). The release of VEGF, PLGF, sFlt1, sEng, lactate dehydrogenase (LDH), and human placenta lactogen (HPL) was measured by ELISA., Results: The release of sFlt1, PLGF, sEng from normal and preeclamptic CV increased over time. Release of sFlt1 and sEng was significantly higher from preeclamptic CV. VEGF was below the detectable level of the assay in normal and preeclamptic CV. After 2 hours, sFlt1 release from normal CV was significantly inhibited with Ang II (1 nM and 1 microM) and Ang-(1-7) (1 nM and 1 microM). There was a time-dependent increase in HPL indicating that the CV were functioning normally., Conclusions: Our study demonstrates a critical inhibitory role of angiotensin peptides on sFlt1 in normal pregnancy. Loss of this regulation in preeclampsia may allow sFlt1 to increase resulting in anti-angiogenesis and end organ damage in the mother.

Previously, we demonstrated activation of the renin-angiotensin system in the fetal placental chorionic villi, but it is unknown whether the immediately adjacent area of the maternal uterine placental bed is regulated similarly. This study measured angiotensin peptides, renin-angiotensin system component mRNAs, and receptor binding in the fundus from nonpregnant subjects (n = 19) and in the uterine placental bed from normal (n = 20) and preeclamptic (n = 14) subjects. In the uterine placental bed from normal pregnant women, angiotensin II peptide levels and angiotensinogen, angiotensin-converting enzyme, angiotensin receptor type 1 (AT(1)), AT(2), and Mas mRNA expression were lower as compared with the nonpregnant subjects. In preeclamptic uterine placental bed, angiotensin II peptide levels and renin and angiotensin-converting enzyme mRNA expression were significantly higher than normal pregnant subjects. The AT(2) receptor was the predominant receptor subtype in the nonpregnant fundus, whereas all angiotensin receptor binding was undetectable in normal and preeclamptic pregnant uterine placental bed compared with nonpregnant fundus. These findings suggest that the maternal uterine placental bed may play an endocrine role by producing angiotensin II, which acts in the adjacent placenta to vasoconstrict fetal chorionic villi vessels where we have shown previously that AT(1) receptors predominate. This would lead to decreased maternal-fetal oxygen exchange and fetal nutrition, a known characteristic of preeclampsia.

We compared maternal and neonatal outcomes in diabetic pregnancies treated with either insulin glargine or neutral protamine Hagedorn (NPH) insulin. We performed a retrospective chart review of diabetic pregnant patients using the Diabetes Care Center of Wake Forest University during the years 2000 to 2005. Outcomes of interest included maternal hemoglobin A1C, average fasting and 2-hour postprandial blood sugars, mode of delivery, birth weight, 5-minute Apgar score < 7, umbilical artery pH < 7.20, incidence of neonatal hypoglycemia, and pregnancy complications. A total of 52 diabetic pregnant patients were included in this study. Twenty-seven women used insulin glargine. A total of 13 women used insulin glargine during the first trimester. Glycemic control was similar in women who used NPH insulin and insulin glargine, as determined by hemoglobin A1C levels and mean blood sugar values. There were no differences in mode of delivery, average birth weight, or neonatal outcomes. Maternal and fetal/neonatal outcomes appear similar in pregnant diabetic women who use either NPH insulin or insulin glargine in combination with a short-acting insulin analogue to achieve adequate glycemic control during pregnancy. Insulin glargine appears to be an effective insulin analogue for use in women whose pregnancies are complicated by diabetes.

The chorionic villi in the placenta are responsible for the regulation of fetal oxygen and nutrient transport. Although the peripheral renin-angiotensin system is activated during normal pregnancy, the regulation of the local chorionic villi renin-angiotensin system remains unknown. Therefore, placental chorionic villous tissue was collected from nulliparous third-trimester normotensive or preeclamptic subjects and was analyzed for angiotensin peptide content, angiotensinogen, renin, angiotensin-converting enzyme (ACE), ACE2, neprilysin, angiotensin II type 1 (AT(1)), angiotensin II type 2, Mas receptor mRNAs, and angiotensin receptor density and subtype. Angiotensin II in chorionic villi was significantly higher in preeclamptic subjects, whereas angiotensin (1-7) was not different. Angiotensinogen and AT(1) receptor gene expression was significantly higher in preeclamptic subjects. No differences were observed in renin, ACE, ACE2, or neprilysin gene expression. Mas receptor mRNA in preeclamptic subjects was decreased. The AT(1) receptor was the predominant receptor subtype in normal and preeclamptic chorionic villi. There was no difference in the density of the AT(1,) angiotensin II type 2, and angiotensin (1-7) receptors. These results indicate that enhanced chorionic villous expression of angiotensin II may result from increased angiotensinogen. Elevated angiotensin II, acting through the AT(1) receptor, may favor vasoconstriction in placental chorionic villi and contribute to impaired fetal blood flow and decreased fetal nutrition observed during preeclampsia.

Uterine rupture, whether in the setting of a prior uterine incision or in an unscarred uterus, is an obstetric emergency with potentially catastrophic consequences for both mother and child. Numerous studies have been published regarding various risk factors associated with uterine rupture. Despite the mounting data regarding both antepartum and intrapartum factors, it currently is impossible to predict in whom a uterine rupture will occur. This article reviews the data regarding these antepartum and intrapartum predictors for uterine rupture. The author hopes that the information presented in this article will help clinicians assess an individual's risk for uterine rupture.

The present study was designed to determine ANG peptide content [ANG I, ANG II, ANG-(1-7)], ACE2 mRNA, and the immunocytochemical distribution of ANG-(1-7) and ACE2 in the uteroembryonic unit during early and late gestation in Sprague-Dawley rats and in a rat model of pregnancy-induced hypertension, the reduced uterine perfusion pressure (RUPP) model. At early pregnancy ANG-(1-7) and ACE2 staining were localized in the primary and secondary decidual zone and luminal and glandular epithelial cells. During late gestation, ANG-(1-7) and ACE2 staining was visualized in the labyrinth placenta and amniotic and yolk sac epithelium. Uterine ANG II concentration at early pregnancy was significantly decreased by 21-55% in the implantation and interimplantation sites compared with virgin rats, whereas ANG-(1-7) levels were maintained at prepregnancy levels. At late gestation, uterine concentrations of ANG I and ANG II were significantly increased (30% and 25%, respectively). In RUPP animals, ANG-(1-7) concentration is significantly reduced in the uterus (181 +/- 16 vs. 372 +/- 74 fmol/g of tissue) and placenta (143 +/- 26 vs. 197 +/- 20 fmol/g of tissue). ACE2 mRNA increased in the uterus of early pregnant compared with virgin rats, yet within the implantation site it was downregulated. At late pregnancy, ACE2 mRNA is elevated by 58% in the uterus and decreased by 59% in RUPP animals. The regulation of ANG-(1-7) and ACE2 in early and late pregnancy supports the hypothesis that ANG-(1-7) and ACE2 may act as a local autocrine/paracrine regulator throughout pregnancy, participating in the early (angiogenesis, apoptosis, and growth) and late (uteroplacental blood flow) events of pregnancy.

Pregnancy is characterized by a progressive increase in the different components of the renin angiotensin system (RAS) including angiotensin II, a potent vasoconstrictor. Pregnant women and experimental animals are resistant to the pressor effect of increased angiotensin II concentrations during pregnancy. In normal pregnancy, maternal blood pressure (BP) begins to fall in early gestation, reaches a nadir in midgestation, and then gradually increases to nonpregnant levels before term in both humans and C57BL/6J mice. The mechanism producing these changes is unknown. The present study investigates the roles of angiotensin II subtype receptors (AT1a and AT2) in hemodynamic regulation during pregnancy in mice. Female mice genetically or pharmacologically manipulated to alter angiotensin receptor stimulation were bred to 2 strains of males. Maternal BP was measured daily throughout pregnancy. Pup weight and number were determined. Pregnancy-induced hypertension was apparent in transgenic female mice expressing the human angiotensin gene bred with males expressing human renin. This effect was not apparent in the absence of the AT1a receptor (ie, in AT1a knockout mice). The midgestation BP decline in both C56BL/6J and AT1a(-/-) females was abolished by AT2 receptor antagonism. There was a linear, inverse relationship between average BP throughout pregnancy and the average pup weight and number per litter. In summary, these findings suggest that activation of the AT2 receptor may be an important factor in promoting the midgestation BP decline that occurs in several mammalian species and, furthermore, that angiotensin is an important modulator of BP during pregnancy.

Angiotensin-(1-7) is increased in the circulation during human pregnancy, but its functional role is unknown. Recent studies suggested that it opposes angiotensin II mediated vascular growth. Because angiogenesis is critical to normal embryonic development during human pregnancy, this study assessed the in vitro effects of angiotensin-(1-7) on human umbilical vein endothelial cell tube formation. The blocking effects of the angiotensin-(1-7) receptor antagonist, D-[Alanine7]-Ang-(1-7), and angiotensin II receptor AT1 and AT2 antagonists, losartan and PD123319, on tube formation were measured by counting tube branch points. Human umbilical vein endothelial cells were cultured in EGM-2 medium and treated with angiotensin-(1-7) (0.17 nM-17 microM) for 18 h. Angiotensin-(1-7) inhibited tube formation by 24% (P < 0.01) at all doses tested. Treatment with 1.7 microM angiotensin-(1-7) plus 17 microM D-[Alanine7]-Ang-(1-7) resulted in the reversal of angiotensin-(1-7) mediated inhibition of tube formation (P < 0.05). Losartan (17 microM) also reversed the angiotensin-(1-7) mediated inhibition of tube formation (P < 0.05). Tube formation was unaffected by PD123319. These results suggest that angiotensin-(1-7) has an anti-angiogenic effect on human umbilical vein endothelial cells through a unique AT(1-7) receptor that is sensitive to losartan, indicating that angiotensin-(1-7) may play an important role in the regulation of vascular growth in the placenta during pregnancy.

We recently demonstrated that renin-angiotensin system (RAS) overactivity during late gestation in rats is associated with increased kidney and urine levels of ANG-(1-7) and enhanced kidney immunostaining of ANG-(1-7) and angiotensin-converting enzyme 2 (ACE2). To understand the temporal-spatial changes in normal and hypertensive pregnancies, the renal distribution of ANG-(1-7) and ACE2 in association with kidney angiotensin peptides and ACE2 activity was examined in virgin, normal pregnant (NP; gestational days 5, 15, and 19) and reduced uterine perfusion pressure (RUPP at day 19) pregnant Sprague-Dawley rats. ANG-(1-7) and ACE2 immunocytochemical staining increased 1.8- and 1.9-fold and 1.7- and 1.8-fold, respectively, at days 15 and 19 of NP, compared with virgin rats. ANG-(1-7) and ANG II concentrations were increased in the kidney at 19 days of gestation. ACE2 activity measured using a fluorescent substrate was increased 1.9- and 1.9-fold in the cortex and 1.9- and 1.8-fold in the medulla at days 15 and 19 of NP. In the RUPP animals, ANG-(1-7) immunostaining and concentration were significantly decreased compared with 19-day NP rats. ACE2 activity was unchanged in the cortex and medulla of RUPP rats. In conclusion, during NP, the concurrent changes of ACE2 and ANG-(1-7) suggest that ACE2 plays an important role in regulating the renal levels of ANG-(1-7) at mid to late gestation. However, the decrease in renal ANG-(1-7) content in the absence of a concomitant decrease in ACE2 implicates the participation of other ANG-(1-7) forming or degrading enzymes during hypertensive pregnancy.

Oxytocin is the most common pharmacologic agent used for the induction and augmentation of labor. Oxytocin protocols can be divided into high-dose and low-dose protocols depending on the initial dose and the amount and rate of sequential increase in dose. Despite the frequency with which oxytocin in used in clinical practice, there is little consensus regarding which protocol is most appropriate. The purpose of this chapter is to review the most current data concerning recommendations for the use of oxytocin in the induction of labor, including cases of intrauterine fetal demise and vaginal birth after cesarean.

This work was designed to study the expression of the vasodilator peptide angiotensin-(1-7) [Ang-(1-7)] and its generating enzyme (ACE2) in the uteroplacental interface. Placentas were obtained from 11 early pregnancy failures (5 miscarriages and 6 ectopic pregnancies), 15 normotensive, and 10 preeclamptic gestations. In placental villi, the main sites of immunocytochemical expression of Ang-(1-7) and ACE2 were the syncytiotrophoblast, cytotrophoblast, endothelium and vascular smooth muscle of primary and secondary villi. Syncitial Ang-(1-7) expression in samples obtained from miscarriages and ectopic pregnancies was increased compared to normal term pregnancy [2.0 (2.0-2.25 for the 25 and 75% interquartile range) vs 1.3 (1.0-1.9), p<0.01]. In the maternal stroma, Ang-(1-7) and ACE2 were expressed in the invading and intravascular trophoblast and in decidual cells in all 3 groups. Ang-(1-7) and ACE2 staining was also found in arterial and venous endothelium and smooth muscle of the umbilical cord. The expression of Ang-(1-7) and ACE2 was similar in samples obtained from normal term or preeclamptic pregnancies, except for increased expression of ACE2 in umbilical arterial endothelium in preeclampsia [0.5 (0.5-0.8) vs 0.0 (0.0-0.0), p<0.01]. The uteroplacental location of Ang-(1-7) and ACE2 in pregnancy suggests an autocrine function of Ang-(1-7) in the vasoactive regulation that characterizes placentation and established pregnancy.

Pregnancy is a physiological condition characterized by a progressive increase of the different components of the renin-angiotensin system (RAS). The physiological consequences of the stimulated RAS in normal pregnancy are incompletely understood, and even less understood is the question of how this system may be altered and contribute to the hypertensive disorders of pregnancy. Findings from our group have provided novel insights into how the RAS may contribute to the physiological condition of pregnancy by showing that pregnancy increases the expression of both the vasodilator heptapeptide of the RAS, angiotensin-(1-7) [Ang-(1-7)], and of a newly cloned angiotensin converting enzyme (ACE) homolog, ACE2, that shows high catalytic efficiency for Ang II metabolism to Ang-(1-7). The discovery of ACE2 adds a new dimension to the complexity of the RAS by providing a new arm that may counter-regulate the activity of the vasoconstrictor component, while amplifying the vasodilator component. The studies reviewed in this article demonstrate that Ang-(1-7) increases in plasma and urine of normal pregnant women. In preeclamptic subjects we showed that plasma Ang-(1-7) was suppressed as compared to the levels found in normal pregnancy. In addition, kidney and urinary levels of Ang-(1-7) were increased in pregnant rats coinciding with the enhanced detection and expression of ACE2. These findings support the concept that in normal pregnancy enhanced ACE2 may counteract the elevation in tissue and circulating Ang II by increasing the rate of conversion to Ang-(1-7). These findings provide a basis for the physiological role of Ang-(1-7) and ACE2 during pregnancy.

Angiotensin-(1-7) (Ang-[1-7]) is a bioactive component of the renin-angiotensin system, which has depressor, vasodilatory, and antihypertensive actions. In normal pregnancy, we questioned whether the known rise in plasma angiotensin II (Ang II) is counterbalanced by an increase in plasma Ang-(1-7) and whether Ang-(1-7) levels are decreased in preeclampsia and may thus be a factor involved in the development of hypertension. Nulliparous preeclamptic subjects, third-trimester normotensive pregnant subjects, and a nonpregnant group were enrolled (n = 15/group). Preeclamptic subjects had no previous history of hypertension or renal, connective-tissue, or metabolic disease, but at the time of delivery had significant hypertension (159 +/- 3/98 +/- 3 mmHg) and > or = 3+ proteinuria. Plasma Ang-(1-7) was increased by 51% in normal pregnancy (p < 0.05). Plasma Ang I, Ang II, and renin activity were also significantly elevated in normal pregnancy. In preeclamptic subjects, Ang-(1-7) was significantly decreased (p < 0.01) compared with normal pregnant subjects. All other components of the renin-angiotensin-aldosterone system, except serum angiotensin-converting enzyme, were reduced in preeclamptic subjects compared with normal pregnant subjects; only plasma Ang II remained elevated in preeclamptic compared with nonpregnant subjects. These studies demonstrate, for the first time, increased plasma Ang-(1-7) in normal pregnant subjects compared with nonpregnant subjects and decreased Ang-(1-7) in preeclamptic subjects compared with normal pregnant subjects. In preeclampsia the decreased plasma Ang-(1-7) in the presence of elevated Ang II is consistent with the development of hypertension.

Preeclampsia remains a leading cause of maternal and fetal morbidity and mortality but has an unknown etiology. Women with elevated baseline blood pressure have an increased risk of this disorder. We hypothesized that BPH/5 mice, an inbred mouse strain with mildly elevated blood pressure, would develop a pregnancy-induced hypertensive syndrome. Nonpregnant female BPH/5 and C57BL/6 mice underwent thoracic aortic implantation of telemeters. After 7 days of recovery and 5 days of baseline mean arterial blood pressure (MAP) recording, strain-matched timed matings were carried out. MAP was recorded continuously during pregnancy and for 1 week after birth. In separate mice in metabolic cages, urinary protein was tracked, followed by renal histological analysis. Before pregnancy, the BPH/5 strain had elevated baseline MAP compared with the C57BL/6 strain, but both strains had similar total urinary protein levels and renal histology. MAP remained stable in both groups during the first 2 weeks of pregnancy. However, at the start of the last trimester, MAP began to rise further in the BPH/5 mice; it rose to peak levels just before delivery and returned to prepregnancy levels by 2 days after delivery. This was accompanied by late-gestational proteinuria and progressive glomerulosclerosis. No changes were observed in the C57BL/6 group except for a small decrease in MAP at mid gestation. The BPH/5 group delivered significantly smaller litters despite normal numbers of fetuses early in gestation, and longitudinal ultrasound studies documented fetal demise before the onset of hypertension and renal disease. This is the first report of an animal model that spontaneously develops a syndrome that bears close resemblance to preeclampsia, and it should have an impact on our understanding of the pathophysiology of this disorder.

In the pathogenesis of preeclampsia, endothelial cell activation or dysfunction is a central theme, and marked dyslipidemia may contribute to endothelial cell dysfunction. The objective of this study was to evaluate the association between preeclampsia and mutations within the lipoprotein lipase (LPL) gene. DNA was extracted from whole blood or cheek swabs of 250 preeclamptic patients, 265 control subjects, and 106 offspring of preeclamptic patients (all white). Control subjects were women who had undergone >/=2 term pregnancies unaffected by preeclampsia. All samples were genotyped for 3 LPL polymorphisms with the use of polymerase chain reaction of known allelic variants. The 3 mutations studied were the following: (1) Asp9Asn substitution in exon 2, (2) T-to-G substitution at position -93 of the proximal promotor region (-93T/G), and (3) Asn291Ser substitution in exon 6. Results were analyzed with an chi(2) contingency table. The prevalences of the Asp9Asn mutation, -93T/G promotor mutation, and Asn291Ser mutation were not significantly different among the preeclamptic patients and control subjects (Asp9Asn: patients, 2.8%; control subjects, 4.0%; -93T/G: patients, 4.5%; control subjects, 5.5%; Asn291Ser: patients, 4.0%; control subject, 3.0%). In addition, there was no difference in the frequency of any of the mutations in the offspring of preeclamptic women compared with that observed in the control population. Between a small group of patients with nulliparous HELLP syndrome (a variant of severe preeclampsia: hemolysis, elevated liver enzyme, low platelets) patients (n=12) and control subjects, there was a significant difference in the prevalence of the Asn291Ser mutation (16.7% versus 3.0%, P=0.01). In this large white population, the Asp9Asn mutation, -93T/G promotor mutation, and Asn291Ser mutation were not associated with an increased risk for preeclampsia. In a small subgroup of patients, the Asn291Ser mutation was associated with an increased risk for nulliparous HELLP syndrome.

Objective: The purpose of this study was to evaluate the association between preeclampsia and 3 relatively common mutations that are important in the development of vascular disease and thrombosis; these are similar to conditions observed in pregnancies complicated by preeclampsia., Study Design: Deoxyribonucleic acid was extracted from whole blood or cheek swabs of 281 patients with preeclampsia and 360 control subjects (all white). Control subjects consisted of women who had undergone at least 2 term pregnancies unaffected by preeclampsia. Mutation frequencies among patients with preeclampsia and control subjects were compared by standard chi2 analysis, with P <.05 considered significant., Results: Thirty-three of 281 women with preeclampsia (11.7%) and 22 of 193 women with severe preeclampsia (11.4%) were homozygous for cytosine-to-thymine substitution at nucleotide 677 in the gene for methyltetrahydrofolate reductase (MTHFR), versus 41 of 360 control subjects (11.4%; difference not significant). Forty of 258 women with preeclampsia (15.5%) and 22 of 175 women with severe preeclampsia (12.6%) were heterozygous for the insertion of 68 bases at position 844 in the gene for cystathionine beta-synthase (CBS), versus 58 of 332 control subjects (17.5%). Fifteen of 250 women with preeclampsia (6.0%) and 11 of 169 with severe preeclampsia (6.5%) were heterozygous for the Leiden mutation (glycine-to-alanine substitution at nucleotide 1691) in the gene for factor V (F5), versus 12 of 253 control subjects (4.7%; difference not significant)., Conclusion: In this white population a missense mutation of MTHFR, an insertion mutation of CBS, and a missense mutation of F5 were not found to be associated with an increased risk for preeclampsia, either independently or in combination.

Previous work in our laboratory has demonstrated impairment of cardiopulmonary reflex control of renal sympathetic nerve activity (RSNA) during the newborn period. The present study was designed to test the hypothesis that this delayed maturation is secondary to incomplete central integration of vagal afferent input. Term fetal (135-140 days; n = 6), newborn (3-7 days of age; n = 8), and young adult (6-8 wk old; n = 8) sheep anesthetized with alpha-chloralose underwent vagal afferent nerve stimulation. All animals had undergone prior sinoaortic denervation to eliminate influences from the arterial baroreceptors. After determination of optimal stimulation parameters, RSNA responses to gradual increases in stimulation frequency (1.0-16 Hz) were recorded and compared by one-way ANOVA. RSNA decreased progressively with increased frequency of stimulation in all three groups of animals. When comparing the three groups at any given frequency of stimulation, reflex withdrawal of RSNA tended to be more pronounced in newborn lambs (P < 0.05 for 1 and 4 Hz). Heart rate (HR) was also noted to decrease significantly with vagal afferent stimulation in each of the groups, but no significant differences in the reflex decreases in HR were noted among the three groups of animals. These results demonstrate that central integration of vagal afferent input is intact in fetal and newborn sheep. These results suggest that the delayed maturation of cardiopulmonary reflex-mediated changes in RSNA seen early in development appears to depend on intrinsic alterations in baroreceptor function rather than incomplete central integration.

Objective: To test the hypothesis that high-dose oxytocin, when used in a masked fashion, would result in shorter labors and less need for cesarean delivery., Methods: We conducted randomized, double-masked trials of high-dose compared with low-dose oxytocin for augmentation and induction of labor. Patients were randomly assigned to receive oxytocin by either a low-dose protocol (1.5 mU/minute initially, increased by 1.5 mU/minute every 30 minutes) or a high-dose protocol (4.5 mU/minute initially, increased by 4.5 mU/minute every 30 minutes). Oxytocin solutions were prepared by a central pharmacy and infusion volumes (mL/hour) were identical, thus ensuring double masking., Results: A total of 1307 patients were randomized (induction, 816; augmentation, 491). In the group receiving oxytocin for induction, high-dose oxytocin was associated with a significant shortening of labor (oxytocin to complete dilatation: 9.7+/-0.3 compared with 7.8+/-0.2 hours, P<.001; oxytocin to delivery: 10.5+/-0.3 compared with 8.5+/-0.3 hours, P<.001). The cesarean delivery rate with low-dose oxytocin was 15.0%, compared with 11.3% with high-dose oxytocin (P = .17). For nulliparous women undergoing induction, cesarean delivery rates were as follows: Total 17.3% (low dose) compared with 11.7% (high dose), P = .15; cephalopelvic disproportion 11.9% (low dose) compared with 5.9% (high dose), P = .06. When used for augmentation, high-dose oxytocin again was associated with a significant shortening of labor without a significant difference in cesarean birth rates. No differences in neonatal outcomes were noted between the groups for either augmentation or induction., Conclusion: When used in a double-masked fashion, high-dose oxytocin is associated with significantly shorter labors without any demonstrable adverse fetal or neonatal effects.

Objective: It has been proposed that cesarean section improves the long-term neurologic outcome of children with meningomyelocele. On the basis of this belief, a trial of labor is not offered in many centers. We hypothesized that there is no difference in immediate or long-term outcome by route of delivery for the fetus with meningomyelocele delivered in a tertiary care center., Study Design: All fetuses (n = 60) with meningomyelocele delivered at the University of Iowa Hospitals and Clinics between 1971 and 1995 were analyzed. Thirty-six cases were available for long-term follow-up. Motor, sensory, and anatomic levels were converted to a numeric scale. Variables were compared by one-way analysis of variance, chi2 analysis, and Fisher's exact test with significance at P < .05., Results: There were no significant differences by route of delivery for gestational age of delivery, birth weight, meningomyelocele size, or neonatal mortality (vaginal: 1/22 = 4.5%, cesarean section: 2/17 = 11.8%, P = .82). An antenatal diagnosis was made with similar frequency in the two groups (vaginal: 15/21 = 71.4%, cesarean section: 13/15 = 86.7%). In addition, the length of long-term follow-up was similar (vaginal: 54.7 +/- 11.1 months, cesarean section: 33.7 +/- 8.6 months). There was no difference in long-term neurologic outcome as determined by the change in motor level, the change in sensory level, or when comparing the final motor level with the anatomic level., Conclusions: This study was unable to detect differences between either immediate or long-term outcome for the infant with isolated meningomyelocele when stratified by route of delivery. A multicenter randomized trial should be required before the acceptance of cesarean section as the optimal route of delivery for the fetus with meningomyelocele.

As both essential hypertension and hypertension associated with pregnancy (pre-eclampsia) have been determined to have strong genetic components, considerable recent research has focused on identifying genes that may predispose to the development of these disorders. Recent advances in molecular genetics and the work of the Human Genome Project have facilitated the identification of genes that may be linked to these hypertensive disorders. Although molecular genetic studies performed in humans and animals can be used to link genes or mutations in genes to hypertension (once identified), studies are needed to assess their biochemical and physiologic importance. In this review, we discuss the ever-increasing importance and use of transgenic and gene-targeted mice in modeling the genetic basis of hypertensive disorders.

Transgenic mice were generated containing a 1542-base pair fragment of the kidney androgen-regulated protein (KAP) promoter fused to the human angiotensinogen (HAGT) gene with the goal of specifically targeting inducible expression of renin-angiotensin system components to the kidney. High level expression of both KAP-HAGT and endogenous KAP mRNA was evident in the kidney of male mice from two independent transgenic lines. Renal expression of the transgene in female mice was undetectable under basal conditions but could be strongly induced by administration of testosterone. Testosterone treatment did not cause a transcriptional induction in any other tissues examined. However, an analysis of six androgen target tissues in males revealed that the transgene was expressed in epididymis. No other extra-renal expression of the transgene was detected. In situ hybridization demonstrated that expression of HAGT (and KAP) mRNA in males and testosterone-treated females was restricted to proximal tubule epithelial cells in the renal cortex. Although there was no detectable human angiotensinogen protein in plasma, it was evident in the urine, consistent with a pathway of synthesis in proximal tubule cells and release into the tubular lumen. These results demonstrate that 1542 base pairs of the KAP promoter is sufficient to drive expression of a heterologous reporter gene in a tissue-specific, cell-specific, and androgen-regulated fashion in transgenic mice.

We have generated a transgenic model consisting of both the human renin and human angiotensinogen genes to study further the role played by the renin-angiotensin system in regulating arterial pressure. Transgenic mice containing either gene alone were normotensive, whereas mice containing both genes were chronically hypertensive. Plasma renin activity and plasma angiotensin II levels were both markedly elevated in the double transgenic mice compared with either single transgenic or nontransgenic controls. The elevation in blood pressure caused by the human transgenes was independent of the genotype at the endogenous renin locus and was equal in mice homozygous for the Ren-1c allele or in mice containing one copy each of Ren-1c, Ren-1d, or Ren-2. Chronic overproduction of angiotensin II in the double transgenic mice resulted in a resetting of the baroreflex control of heart rate to a higher pressure without significantly changing the gain or sensitivity of the reflex. Moreover, this change was not due to the effects of elevated pressure itself since angiotensin-converting enzyme inhibition had minimal effects on the baroreflex in spontaneously hypertensive BPH-2 control mice, which exhibit non-renin-dependent hypertension. This double transgenic model should provide an excellent tool for further studies on the mechanisms of hypertension initiated by the renin-angiotensin system.

It is generally accepted that the etiology of essential hypertension is due to a complex interplay of genetic and environmental factors. A great deal of research effort over the past ten years has been focused on the identification of genes the variants of which predispose individuals to high blood pressure. Consequently, transgenic and knockout animals have become important research tools, providing experimental systems in which defined genetic manipulations can be introduced on uniform genetic backgrounds while minimizing environmental variation. These animal models have provided the means by which candidate genes thought to be involved in blood pressure regulation have been studied. Furthermore, these models can be used to test the significance of genes and gene variants identified via genome-wide searches as potential causes of hypertension. The purpose of this review is to provide a brief discussion of transgenic and knockout methodology and its application to study the genetic basis of hypertension.

The present study was designed to characterize the maturation of cardiopulmonary reflex control of renal sympathetic nerve activity (RSNA) independent of influences from the arterial baroreflex. Studies were conducted in conscious newborn lambs (3- to 7-days-old) (n = 16) and older lambs (6- to 8-wk-old) (n = 18). All animals underwent either sinoaortic denervation (SAD) or a sham procedure. Hemodynamic, humoral, neural, and renal responses to volume expansion (6% Dextran 70, 0.7 ml.kg-1.min-1 x 60 min) were recorded. Volume expansion resulted in a significant decrease (P < 0.05) in RSNA in intact newborn (-28.1 +/- 5.3% change from control) and older lambs (-19.4 +/- 10.1%). SAD totally abolished the sympathetic inhibition seen with volume expansion in newborn lambs (-3.6 +/- 5.7%) but not in older lambs (-25.6 +/- 8.4%). Right atrial pressure increased in a similar fashion in both newborn (intact: 5.6 +/- 0.5 mmHg; SAD: 6.1 +/- 0.8 mmHg) and older lambs (intact: 5.2 +/- 0.9 mmHg; SAD: 5.3 +/- 0.9 mmHg) and was not altered by SAD. The reflex bradycardia seen with volume expansion in newborn lambs was blocked by SAD. The present study demonstrates that, during the newborn period, the RSNA and heart rate responses to volume expansion are dependent mainly on the integrity of the arterial baroreflex. Furthermore, these studies suggest that cardiopulmonary reflex control of RSNA in response to volume expansion is impaired early in life and increases with maturation.

The renin-angiotensin system is a major determinant of arterial pressure and volume homeostasis in mammals through the actions of angiotensin II, the proteolytic digestion product of angiotensinogen. Molecular genetic studies in several human populations have revealed genetic linkage between the angiotensinogen gene and both hypertension and increased plasma angiotensinogen. Transgenic mice were generated with a human angiotensinogen genomic clone to develop an animal model to examine tissue- and cell-specific expression of the gene and to determine if overexpression of angiotensinogen results in hypertension. Human angiotensinogen mRNA was expressed in transgenic mouse liver, kidney, heart, adrenal gland, ovary, brain, and white and brown adipose tissue and, in kidney, was exclusively localized to epithelial cells of the proximal convoluted tubules. Plasma levels of human angiotensinogen were approximately 150-fold higher in transgenic mice than that found normally in human plasma. The blood pressure of mice bearing the human angiotensinogen gene was normal but infusion of a single bolus dose of purified human renin resulted in a transient increase in blood pressure of approximately 30 mm Hg within 2 min. These results suggest that abnormalities in the angiotensinogen gene resulting in increased circulating levels of angiotensinogen could potentially contribute in part to the pathogenesis of essential hypertension.

Recent studies demonstrated that renal denervation had no effect on the natriuretic response to volume expansion (VE) in fetal sheep, suggesting that the sensitivity of the cardiopulmonary reflex in response to VE is impaired in the fetus. To test this hypothesis, we investigated the renal sympathetic nerve activity (RSNA) and heart rate (HR) responses to 20 and 50% intravascular VE in fetal (130-135 days gestation; term 145 days) (n = 7), newborn (n = 8), and 6- to 8-wk-old sheep (n = 9). Despite similar increases in right atrial pressure (RAP) in the three groups, 20% VE had no significant effect on RSNA and HR in fetal sheep but significantly decreased RSNA in newborn (-22.8 +/- 7.3%) and 6- to 8-wk-old sheep (-32.1 +/- 11.7%). Bradycardic responses to VE were also observed in both newborn (from 237 +/- 6 to 200 +/- 12 beats/min) and 6- to 8-wk-old sheep (from 170 +/- 9 to 140 +/- 9 beats/min). A 50% VE had no significant effect on fetal RSNA and HR, whereas it increased RAP by 6.8 +/- 0.9 mmHg. In addition, we tested the hypothesis that interactions between cardiopulmonary and arterial baroreflexes in response to VE change during development. We found that 20 and 50% VE shifted the RSNA and HR arterial baroreflex response curves to the right in the fetus but had no significant effects on the gain of the arterial baroreflex curves in either fetal, newborn, or 6- to 8-wk-old sheep.(ABSTRACT TRUNCATED AT 250 WORDS)

The present study was designed to examine the effect of direct intrarenal infusion of the alpha 1-adrenoceptor agonist, phenylephrine, on urinary flow rate (UFR) and on renal Na and Cl excretion in conscious and chronically instrumented fetal (128-133 days gestation, term 145 days), newborn (6-12 days), and adult sheep. Five different renal concentrations of phenylephrine, varying from 5 +/- 1 to 72 +/- 2 ng/ml, were studied. Low renal phenylephrine concentration (< or = 12 +/- 1 ng/ml) induced a significant renal vasoconstrictor response in fetuses but not in newborn and adult sheep. The effects of intrarenal phenylephrine infusion on UFR and fractional excretion of Na (FENa) was greater (P < 0.05) in newborn lambs than in fetal and adult sheep. At a renal concentration of phenylephrine between 9 +/- 1 and 12 +/- 1 ng/ml, the percent decrease in UFR was greater (P < 0.05) in newborn lambs (-19.1 +/- 4.7%) than in fetal (9.8 +/- 8.9%) and adult sheep (-3.3 +/- 3.9). The percent decrease in FENa at renal concentration of phenylephrine between 18 +/- 1 and 24 +/- 1 ng/ml was also significantly (P < 0.05) larger in newborn lambs (-20.2 +/- 2.8%) than in fetal (-8.0 +/- 3.1%) and adult sheep (-11.2 +/- 2.6%). In summary, the present results indicate that the fetal kidney has a limited ability to increase sodium reabsorption in response to stimulation of alpha-adrenoceptors and that the effect of renal alpha-adrenoceptor stimulation on urinary volume and urinary sodium excretion increases during the newborn period.

Significant fluctuation in heart rate (HR) and arterial pressure occur during fetal life. However, the mechanisms regulating this normal variability are not completely understood. To test the hypothesis that the normal variability in fetal HR and blood pressure are produced by intrinsic fluctuations in sympathetic outflow, we recorded HR, mean arterial blood pressure (MABP), and renal sympathetic nerve activity (RSNA) in conscious, chronically instrumented, near-term fetal sheep (n = 5; 132-137 d of gestation, term being 145 d) and correlated the relationships between RSNA and MABP, and RSNA and HR. RSNA, HR, and MABP were sampled at a frequency of 4 Hz and the values averaged by 5-min blocks over a 4-h period. Linear regression analysis demonstrated a positive correlation between RSNA and both HR and MABP in all five fetuses (p < 0.02). In a second group of fetuses (n = 5), ganglionic blockade with trimethaphan (150-250 mg/kg/min) significantly attenuated (p < 0.05) the coefficients of variation of HR (12.3 +/- 1.9% versus 1.7 +/- 0.6%) and MABP (5.8 +/- 0.6% versus 3.6 +/- 0.5%). These results demonstrate that, in the fetus, fluctuations in HR and MABP are mediated by changes in sympathetic outflow and suggest an important role for the autonomic nervous system in fetal cardiovascular regulation.

Angiotensin II (ANG II) has been shown in adults to modulate baroreflex responses in heart rate (HR) and sympathetic outflow. To test the hypothesis that high circulating levels of ANG II in the newborn period contribute to the resetting of the arterial baroreflex observed postnatally, we studied baroreflex-mediated changes in HR and renal sympathetic nerve activity (RSNA) before and after angiotensin-converting enzyme (ACE) inhibition in fetal and newborn sheep. In the newborn, administration of the ACE inhibitor enalaprilat produced significant (P < 0.05) decreases in baseline RSNA (69 +/- 5 vs. 47 +/- 7% maximum) and HR (81 +/- 3 vs. 59 +/- 4% max), as well as in the baroreflex curve midpoints for RSNA (93 +/- 4 vs. 87 +/- 3 mmHg) and HR (95 +/- 4 vs. 81 +/- 5 mmHg); no change in the sensitivities (gains) of the baroreflex responses were seen. In contrast, no significant changes in baseline RSNA, HR, baroreflex curve midpoint, or sensitivity were demonstrated in the fetus. Infusion of ANG II in newborn lambs reversed the effects of ACE inhibition on the baroreflex responses. Additional experiments evaluating the effects of ACE inhibition in vagotomized newborns again showed resetting of the baroreflex, demonstrating that vagally mediated mechanisms are not involved in regulating the changes in sympathetic outflow during the neonatal period. These results suggest that endogenous ANG II contributes to the resetting of the baroreflex observed postnatally.

This multicenter, cooperative study represents the initial United States experience using an expandable, titanium intraprostatic stent in 68 patients (60 to 93 years old). The stents were inserted under direct vision and expanded to 33F using a balloon catheter. All patients had a symptom score analysis, and underwent measurement of peak urine flow and rate and post-void residual urine volume as part of the initial evaluation. Patients were seen at approximately 1, 3, 6 and 18 months after stent insertion (mean followup 16 months). Of the 68 patients 38 presented in urinary retention. The type of anesthesia used included general anesthesia in 6 patients, spinal or epidural anesthesia in 24, intravenous sedation in 20 and intraurethral lidocaine only in 18. All patients were able to void spontaneously within 36 hours after stent insertion. Symptom scores decreased from 16.8 to 3.9, 6.3, 5.0, 5.7 and 3.2 at approximately 1, 3, 6, 12 and 18 months, respectively. Peak urine flow rate increased from 3.9 to 13.8, 11.5, 11.2, 12.4 and 14.4 ml. per second at approximately 1, 3, 6, 12 and 18 months, respectively. Post-void residual urine volume decreased from 74.4 to 30.1, 29.2, 19.8 and 40.2 ml. at approximately 1, 3, 6 and 12 months, respectively. Of the initial 68 patients 5 died of the underlying disorder (all voiding satisfactorily with the stent in place) and 17 underwent uneventful stent removal (10 for technical failure and 7 for treatment failure). Technical failures were secondary to either inaccurate positioning or improper stent sizing. Of the 58 patients with proper placement of the stent and no technical failures 46 (79%) had improvement in symptom scores and urine flow rate. Transient hematuria was noted in 43 patients (63%) and usually resolved within 48 hours. None of the 6 urinary tract infections (9%) was recurrent. In conclusion, the titanium intraprostatic stent, when properly placed, is a promising therapeutic alternative to prostatectomy or long-term catheterization in high risk obstructed patients or those in urinary retention. Studies are currently in progress to determine the long-term efficacy of this therapeutic modality.

We conducted this pilot clinical study to investigate the safety, primarily acute toxicity, of green light (514.5 nm) whole bladder photodynamic therapy (PDT) in human bladders with transitional cell carcinoma. We enrolled five patients who were scheduled to undergo radical cystectomy and urinary diversion for locally muscle invasive bladder cancer. Four patients received intravenous injection of Photofrin at 1 mg/kg, while one patient received no drug, 48 hr before undergoing green light whole bladder photoactivation with light doses of 20-60 J/cm 2. Each patient underwent radical cystectomy on day 7 following light treatment. Post-PDT evaluation included daily monitoring of voiding symptoms, cystometric measurements of bladder capacity, and gross and histopathologic examination of the excised bladders. Our results show that the intensity of acute bladder irritation and acute post-PDT loss in bladder volume depended on the light dose and extent of bladder tumor with the associated inflammation. There was no transmural bladder injury and no treatment related morbidity. These data on acute toxicity suggest that green light whole bladder PDT treatment with 1 mg/kg of Photofrin and 20-40 J/cm 2 of laser power is safe.

The present review summarizes recent studies describing the role of renal sympathetic innervation in the regulation of renal function during development. The afferent renal innervation appears early during fetal life and probably precedes the development of efferent renal nerves. There is suggestive evidence that renal nerves are required for the proper development of the kidney and that neurotrophic growth factors play an important role in renal embryogenesis and in renal tubular differentiation. Renal sympathetic innervation modulates renal hemodynamics early during development. Renal nerve stimulation during alpha-adrenoceptor blockade produces renal vasodilation in fetal and newborn animals but not in adults. Unlike the effect of renal nerves on fetal renal hemodynamics which is observed in the young fetus, the role of renal sympathetic nerves in modulating fluid and electrolyte homeostasis seems to develop during late gestation. Recent studies have also shown that renal nerves play an important role in regulating renin secretion during the transition from fetal to newborn life. For example, renal denervation during fetal life suppressed the physiological rise in plasma renin activity associated with delivery and decreased renal renin mRNA levels after birth. Taken together, these studies suggest that renal nerves influence fetal renal development and that the influence of renal sympathetic innervation on renal hemodynamics and function changes with maturation.

Giant prostatic hyperplasia (GPH) is an uncommon pathologic entity with only 10 reported cases of prostate glands exceeding 500 g. We report the uncomplicated removal of a 526-g prostatic adenoma by simple retropubic prostatectomy.

Endotracheal suctioning of intubated infants produces profound changes in cardiovascular and cerebral hemodynamics, but the mechanisms regulating these changes are not fully understood. To determine the role of the autonomic nervous system in regulating these physiologic changes, we investigated the effects of endotracheal suctioning on heart rate (HR), mean arterial blood pressure (MABP), and renal sympathetic nerve activity (RSNA) in nine ventilated newborn lambs. In the first part of the study (n = 6), ventilation was interrupted for suctioning. With suctioning (15 s), HR decreased by 39 +/- 6% (p < 0.05), whereas MABP and RSNA increased significantly (p < 0.05) by 36 +/- 5% and 68 +/- 8%, respectively. These changes were significantly (p < 0.05) larger than changes observed during disconnection from the ventilator (15 s) without suctioning. Administration of atropine (0.02 mg/kg) blocked the HR response to suctioning without altering MABP or RSNA changes. After bilateral vagotomy, suctioning produced no changes in any parameter. When a closed tracheal suction system was used and ventilation was maintained, suctioning again resulted in significant (p < 0.05) increases in MABP (+10 +/- 3%) and RSNA (+34 +/- 5%) and a decrease in HR (-15 +/- 4%). These data suggest that suctioning stimulates sympathoexcitatory receptors localized in large airways whose afferent fibers course within the vagus, resulting in increased sympathetic activity, which induces peripheral vasoconstriction and elevates MABP. In contrast, the HR response appears to be mediated by increased parasympathetic activity as this is abolished by atropine.

The purpose of this study was to characterize the developmental changes in baroreflex function during fetal and postnatal life in sheep. Resting mean arterial blood pressure increased significantly from 55 +/- 2 mmHg in fetuses to 86 +/- 3 mmHg in newborn lambs and to 105 +/- 4 mmHg in 4- to 6-wk-old lambs. The sensitivity (gain) of the renal sympathetic nerve activity (RSNA) response to baroreceptor stimulation was greater (P < 0.05) in fetuses (-7.7 +/- 1.9%/mmHg) than in newborn (-2.9 +/- 0.1%/mmHg) and 4- to 6-wk-old lambs (-2.2 +/- 0.2%/mmHg). The threshold and saturation pressures for the baroreflex function curve were lower (P < 0.05) in fetuses (44 +/- 2 and 61 +/- 2 mmHg) than in newborn (59 +/- 4 and 106 +/- 5 mmHg) or 4- to 6-wk-old lambs (78 +/- 5 and 132 +/- 6 mmHg). Similar findings were observed when the heart rate response to baroreceptor stimulation was examined. Additional experiments were performed in newborn and 4- to 6-wk-old lambs to determine whether the rise in arterial blood pressure associated with postnatal maturation contributed to baroreflex resetting. Sustained elevation of arterial blood pressure by 15-20 mmHg for over 90 min did not reset the baroreflex function curve in either newborn or 4- to 6-wk-old lambs.(ABSTRACT TRUNCATED AT 250 WORDS)

Fetal therapy continues to be an exciting yet controversial field. In utero treatment of a variety of fetal conditions is discussed: parvovirus B19 infection, fetal thyroid dysfunction, fetal ovarian cysts, twin-twin transfusion syndrome, and fetal hemolytic disease. Fetal surgery continues to be controversial. Despite considerable publicity, fetal surgery appears to be rarely, if ever, truly indicated. A new area of fetal therapy, ie, antenatal transplantation of fetal liver stem cells, is discussed.

Patient satisfaction with the Mentor inflatable penile prosthesis was assessed by sending a thirty-six-item questionnaire to 251 patients who had undergone implantation of the device by the senior author (D.C.M.). A total of 152 (61%) of the patients responded. Recovery time, satisfaction, reasons for dissatisfaction, perceptions of erection quality, and psychosexual parameters were evaluated. Eight-eight percent of the patients were engaging in regular sexual activity. Depending on the definition of satisfaction, 81-89 percent of the respondents reported that they were satisfied with the prosthesis. Sixty-eight percent of the survey group were satisfied with the length, width, and firmness of their prosthetic-induced erection. The majority of patients reported improvement in psychosexual functioning after implantation. Reasons for dissatisfaction included inadequate penile length, insufficient firmness, and difficulty with inflation and deflation of the penile cylinders.

Present-day whole bladder photodynamic therapy (WBPDT) is cumbersome and time consuming because cystoscopic and ultrasonic manipulations are necessary to position the light emitter within the bladder. More important, WBPDT is inherently unsafe and often ineffective since neither uniform photoirradiation nor accurate light dosimetry can be achieved with the techniques employed to photoirradiate the bladder wall. The intravesical laser catheter (IVLC) eliminates the need for cystoscopy and ultrasonography because passage of the treatment fiber into the catheter's central lumen automatically positions its light-diffusing tip within the center of the bladder. Use of the IVLC delivery system also assures accurate photoirradiation of the bladder wall since inflation of the catheter's balloon transforms the asymmetric bladder into a sphere of known diameter. The light sensor incorporated in the balloon wall provides a method to monitor light fluence and measure total light dose. When provided the parameters of bladder volume, laser energy output, and desired light dose, the computerized control system calculates treatment time and automatically adjusts the period of photoirradiation to compensate for variations in laser light production, energy losses during transmission, and for variations in light intensity resulting from the integrating sphere effect of the bladder wall. This delivery system also increases the safety of WBPDT since the monitor automatically discontinues treatment if any unsafe situation, with respect to light fluence, develops during photoirradiation.

Previous studies have suggested that acute elevations of arginine vasopressin (AVP) may result in an extravascular to intravascular shift of fluid independent of any change in total body H2O (TBW). The present studies examined the chronic influence of elevated AVP on fluid volume distribution in five splenectomized, sodium-deprived conscious dogs (avg body wt = 18.9 +/- 0.7 kg). During 4 days of continuous intravenous AVP infusion (0.36 ng X kg-1 X min-1), the computerized average 24-h total body weight was maintained within 110 g of the control value by means of a sensitive servo-controlled scale device. Urine flow and urine osmolality averaged 335 +/- 52 ml/day and 637 +/- 36 mosmol/kg during the preinfusion period and changed to levels averaging 151 +/- 14 and 1,377 +/- 121 with elevated AVP (P less than 0.05). Chromium-51-labeled red cell volume (51Cr RBC), plasma volume (Evans blue), TBW (3H2O), calculated total blood volume (using 51Cr RBC and Hct), and mean arterial pressure averaged 22 +/- 1 ml/kg, 54 +/- 7 ml/kg, 0.62 +/- 0.04 l/kg, 68 +/- 3 ml/kg, and 99 +/- 3 mmHg, respectively, during the control period and remained unchanged during the AVP infusion period. Plasma protein, sodium, and osmolality averaged 6.4 +/- 0.1 g/dl, 145.7 +/- 0.8 meq/l, and 295.0 +/- 1.5 mosmol/kg during the preinfusion period and also remained unchanged with elevated AVP. We conclude from the present studies that AVP has minimal or no chronic influence on internal volume redistribution.