Objective-The continued development and use of engineered nanomaterials (ENM) has given rise to concerns over the potential for human health effects. While the understanding of cardiovascular ENM toxicity is improving, one of the most complex and acutely demanding "special" circulations is the enhanced maternal system to support fetal development. The "Barker Hypothesis" proposes that fetal development within a hostile gestational environment may predispose/program future sensitivity. Therefore, the objective of this study was two-fold: 1) to determine if maternal ENM exposure alters uterine and/or fetal microvascular function and 2) test the Barker Hypothesis at the microvascular level. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.The author(s) report(s) no conflict of interest.An abstract has been accepted to present this work at the 52 nd Annual Meeting of the Society of Toxicology, San Antonio TX, to be held March 10-14, 2013. NIH Public Access Author ManuscriptAm J Obstet Gynecol. Author manuscript; available in PMC 2014 September 01. NIH-PA Author ManuscriptStudy Design-Pregnant (gestation day 10) Sprague-Dawley rats were exposed to nanotitanium dioxide aerosols (11.3±0.039 (mg/m 3 )*hour, 5 hours/day, 8.2±0.85 days) to evaluate the maternal and fetal microvascular consequences of maternal exposure. Microvascular tissue isolation (gestation day 20) and arteriolar reactivity studies (<150μm passive diameter) of the uterine premyometrial and fetal tail arteries were conducted.Results-ENM exposures led to significant maternal and fetal microvascular dysfunction which presented as robustly compromised endothelium-dependent and -independent reactivity to pharmacologic and mechanical stimuli. Isolated maternal uterine arteriolar reactivity was consistent with a metabolically impaired profile and hostile gestational environment, impacting fetal weight. The fetal microvessels isolated from exposed dams demonstrate significant impairments to signals of vasodilation specific to mechanistic signaling and shear stress.Conclusion-To our knowledge, this is the first report providing evidence that maternal ENM inhalation is capable of influencing fetal health, thereby supporting that the Barker Hypothesis is applicable at the microvascular level.

The inbred obese Zucker (ZDF/Gmi, fa/fa) rat develops severe hyperglycemia and also exhibits severe renal disease. In this study, we compared the relative benefits of long-term treatment with angiotensin-converting enzyme inhibition (ACEI) to a peroxisome proliferator-activated receptor ␥ (PPAR␥) agonist. Four groups of obese inbred Zucker rats were studied over a 6-month observation period; untreated animals, rats treated with ACEI alone, rats treated with PPAR␥ agonist alone, and rats treated with a combination of ACEI and PPAR␥ agonist. PPAR␥ agonist treatment normalized plasma glucose and led to massive increases in body weight. Both ACEI and PPAR␥ agonist were effective in reducing the proteinuria and glomerular and tubular kidney damage. However, the PPAR␥ agonist exerted superior renal protection compared with ACEI, in this model of spontaneously occurring chronic renal disease in the diabetic, obese inbred Zucker rat. Of note, although ACEI lowered blood pressure, there was no difference in glomerular blood pressure in any group at the end of the study. The glomerular filtration rate (GFR) was improved by ACEI with a borderline effect of PPAR␥ agonist alone. A mild additive protection on GFR and tubulointerstitial damage was seen with the combination. Based on the literature it is likely that the superior protection by PPAR␥ agonist versus glomerular and tubular damage as well as proteinuria extends beyond glycemic and lipidmic control and also reflects direct, protective intrarenal actions of the PPAR␥ agonists.

Arginine deficiency and/or increased levels of circulating nitric oxide (NO) synthesis (NOS) inhibitors can cause reduced NOS, which may contribute to hypertension in patients with end-stage renal disease (ESRD). To test these hypotheses, NO oxidation products (NO 2 + NO 3 = NO x ) and cyclic guanosine monophosphate (cGMP), the vasodilatory second messenger of NO, were measured in the blood, urine, and dialysate effluent of hemodialysis (HD) patients and compared with the blood and urine of healthy subjects. The subjects ate a controlled low-nitrate diet (∼330 μmol/d) for 48 hours before and during blood, dialysis effluent, and 24-hour urine collection. NO x output was significantly reduced in HD patients versus controls (552 ± 51 v 824 ± 96 μmol/24 h; P < 0.001), whereas cGMP output was not low versus controls. Plasma arginine level was normal and plasma levels of citrulline and the endogenous NOS inhibitor, asymmetric dimethylarginine (ADMA), were markedly elevated in patients with ESRD versus controls. Systolic blood pressure was greater in HD patients compared with controls despite concurrent antihypertensive therapy in most patients with ESRD. These studies suggest NO production is low in patients with ESRD undergoing HD, possibly because of the increased ratio of plasma ADMA to arginine. Index WordsEnd-stage renal disease; hypertension; arginine; cyclic guanosine monophosphate (cGMP); endogenous nitric oxide synthases (NOS) inhibitors Nitric oxide (NO) is a potent vasodilator made from L-arginine by the enzymatic action of several widely distributed nitric oxide synthases (NOSs). The constitutively expressed, vascular endothelial and brain-type NOSs have major roles in the physiological control of vascular tone and kidney function, and many of these actions are mediated by cyclic guanosine monophosphate (cGMP). 1,2 NO deficiency can be produced experimentally by the administration of substituted L-arginine analogues that function as competitive inhibitors of NOS. Chronic experimental NOS inhibition in animals produces hypertension, and NOS may be defective in some individuals with primary and secondary hypertension. 3 Hypertension is particularly prevalent in hemodialysis (HD) patients with end-stage renal disease (ESRD), 4-7 and there are valid reasons to suspect NO deficiency might occur and contribute to the hypertension in this population. We previously reported that patients with ESRD undergoing peritoneal dialysis (PD) produce less NO, indicated by the removal rate of the stable inert oxidation products of NO (NO 2 In addition, the plasma levels of naturally occurring compounds that inhibit the L-arginine-NO pathway accumulate in patients with ESRD. For example, plasma levels of asymmetric dimethylarginine (ADMA) increase in HD patients, possibly to concentrations that inhibit NOS, although this remains controversial. 9,10 This, together with plasma arginine levels in the low-normal range, 9,11 means the ratio of plasma levels of endogenous NOS inhibitors to Larginine is high in patients wit...

To investigate the activity of nitric oxide (NO) in control of renal hemodynamics during aging, studies were conducted on conscious Sprague-Dawley rats aged 3-5 mo (young, Y) and 18-22 mo (old, O). Blood pressure (BP) and renal vascular resistance (RVR) were higher in O vs. Y in control, and acute systemic NO synthesis inhibition (NOSI) increased BP and RVR, with an enhanced renal vasoconstrictor response in O. Infusion of the NO substrate L-arginine produced similar, selective renal vasodilation in both groups. The endothelium-dependent vasodilator acetylcholine caused similar falls in BP and RVR, whereas sodium nitroprusside produced an exaggerated depressor response in O vs. Y without falls in RVR in either age group. Urinary excretion of the stable NO oxidation products (NOx) decreased with age, suggesting a decline in the overall somatic NO production. In conclusion, basal tonically produced NO has a more pronounced role in maintenance of renal perfusion in aging, whereas L-arginine- and agonist-stimulated renal vasodilation is not impaired with age. NO production from some source may be reduced with aging, as indicated by falls in 24-h NOX excretion, although the similarity in pressor response and enhanced renal vasoconstrictor response to NOSI suggests that the role of NO in control of total peripheral and renal vascular resistance is maintained.

Chronic blockade of the endogenous EDRF system has previously been reported to produce a model of hypertension and renal damage in rats. chronically catheterized rats to compare the renal hemodynamic and blood pressure responses to pregnancy in normal rats and during chronic EDRF blockade. produced by EDRF blockade, the normal late gestational fall in blood pressure is absent and blood pressure remains elevated at term. There was no midterm renal vasodilation or increase in GFR in the chronically hypertensive rats, also proteinuria developed close to term in hypertensive animals. The normal pregnant rat shows a marked plasma volume expansion as evidenced by significant falls in hematocrit close to term. This was suppressed in the hypertensive animals, particularly in the more severely hypertensive group. The chronically EDRF blocked hypertensive animals had a relatively poor maternal and fetal outcome compared to normal rats. The present studies were conducted in consciousIn both moderate and severe hypertension INTRODUCTION Pregnancies complicated by hypertension carry an increased risk of maternal and fetal morbidity and mortality and when under-117 Copyright 0 1992 by Marcel Dekker, Inc. Hypertens Pregnancy Downloaded from informahealthcare.com by University of Otago on 07/23/15 For personal use only.