Recent studies have shown that low serum 25-hydroxyvitamin D (25[OH]D) level is a risk factor for preeclampsia. The clinical significance of in vitro findings that vitamin D regulates vascular endothelial growth factor production is unclear. We sought to determine whether there is an association between midgestation serum 25(OH)D levels and angiogenic factor activity and to compare their predictive value for the development of severe preeclampsia. We conducted a nested case-control study of women with severe preeclampsia (n=41) versus women with uncomplicated term birth (n=123) who had second trimester genetic screening (15–20 weeks). Using banked frozen serum, we measured levels of 25(OH)D, vascular endothelial growth factor, soluble fms-like tyrosine kinase 1, and placental growth factor and compared their correlations and predictive values. We found no correlation between serum 25(OH)D and angiogenic factors levels. 25(OH)D alone was comparable to vascular endothelial growth factor and soluble fms-like tyrosine kinase 1/placental growth factor ratio as a predictive marker for severe preeclampsia. A composite of both 25(OH)D level and soluble fms-like tyrosine kinase 1/placental growth factor ratio was more predictive than either alone (area under curve: 0.83 versus 0.74 and 0.67, respectively). In conclusion, combining midpregnancy 25(OH)D level with soluble fms-like tyrosine kinase 1/placental growth factor ratio provides a better prediction for the development of severe preeclampsia.

Pregnant women who subsequently develop preeclampsia are highly sensitive to infused angiotensin (Ang) II; the sensitivity persists postpartum. Activating autoantibodies against the Ang II type 1 (AT1) receptor are present in preeclampsia. In vitro and in vivo data suggest that they could be involved in the disease process. We generated and purified activating antibodies against the AT1 receptor (AT1-AB) by immunizing rabbits against the AFHYESQ epitope of the second extracellular loop, which is the binding epitope of endogenous activating autoantibodies against AT1 from patients with preeclampsia. We then purified AT1-AB using affinity chromatography with the AFHYESQ peptide. We were able to detect AT1-AB both by ELISA and a functional bioassay. We then passively transferred AT1-AB into pregnant rats, alone or combined with Ang II. AT1-AB activated protein kinase C-α and extracellular-related kinase 1/2. Passive transfer of AT1-AB alone or Ang II (435 ng/kg per minute) infused alone did not induce a preeclampsia-like syndrome in pregnant rats. However, the combination (AT1-AB plus Ang II) induced hypertension, proteinuria, intrauterine growth retardation, and arteriolosclerosis in the uteroplacental unit. We next performed gene-array profiling of the uteroplacental unit and found that hypoxia- inducible factor 1α was upregulated by Ang II plus AT1-AB, which we then confirmed by Western blotting in villous explants. Furthermore, endothelin 1 was upregulated in endothelial cells by Ang II plus AT1-AB. We show that AT1-AB induces Ang II sensitivity. Our mechanistic study supports the existence of an “autoimmune-activating receptor” that could contribute to Ang II sensitivity and possible to preeclampsia.

The current criteria for sleep-disordered breathing (SDB) in children are not based on a clinically relevant outcome. The purpose of this study was to assess the association of blood pressure with SDB in a random sample of the local elementary school children (kindergarten through grade 5) using a 2-phased strategy. During phase 1, a brief questionnaire was completed for all of the children (N=5740) with a response rate of 78.5%. During phase 2, 700 randomly selected children from phase 1 with a response rate of 70.0% were assessed with a full polysomnograph and a history/physical, including an ECG; ear, nose, and throat; and pulmonary evaluation. We observed a significantly elevated systolic blood pressure associated with the apnea hypopnea index (AHI): AHI ≥1 (2.9 mm Hg); AHI ≥3 (7.1 mm Hg); and AHI ≥5 (12.9 mm Hg). The SDB and blood pressure association remained significant after adjusting for age, sex, race, body mass index percentile or waist circumference, sleep efficiency, percentage of rapid eye movement sleep, and snoring. In addition, older age, body mass index percentile, waist circumference, and snoring were significantly associated with blood pressure, independent of SDB. Based on these findings, our study suggests that SDB is significantly associated with higher levels of systolic blood pressure in children aged 5 to 12 years even after adjusting for the various confounding factors. Clinically, the data support the threshold of AHI ≥5 for the initiation of treatment for SDB. Additional research is indicated to assess the efficacy of SDB treatment on reducing blood pressure.

Recent studies have suggested a link between exposure to ambient particulate matter <2.5μm in diameter (PM2.5) and adverse cardiovascular outcomes. The objective of this study was to examine the effects of differing community-level exposure to PM2.5 on daily measures of blood pressure (BP) among an adult population. During the period May 2002 through April 2003, BP was examined at two time points for 347 adults residing in three distinct communities of Detroit, MI. Exposure to PM2.5 was assessed in each community during this period, along with multivariate associations between PM2.5 and BP. In models combining all three communities, PM2.5 was significantly associated with systolic pressure (SP); a 10 μg/m3 increase in daily PM2.5 was associated with a 3.2 mm Hg increase in SP (p=0.05). However, in models that added a location interaction, larger effects were observed for SP within the community with highest PM2.5 levels; a 10 μg/m3 increase in daily PM2.5 was associated with a 8.6 mm Hg increase in SP (p=0.01). We also found young age (<55 years) and not taking BP medications to be significant predictors of increased BP effects. Among those taking BP medications, the PM2.5 effect on BP appeared to be mitigated, partially explaining the age effect, as those participants less than 55 years were less likely to take BP medications. Short-term increases in exposure to ambient PM2.5 are associated with acute increases in BP in adults, especially within communities with elevated levels of exposure.

Short-term elevations in ambient fine particulate matter (PM2.5) may increase resting systolic (SBP) and diastolic (DBP) blood pressure, but whether PM2.5 alters hemodynamic responses to orthostatic challenge has not been studied in detail. We repeatedly measured SBP and DBP during supine rest and 1 and 3 minutes after standing among 747 elderly (aged 78.3 ± 5.3 years, mean ± SD) participants from the MOBILIZE Boston Study. We used linear mixed models to assess the association between change in SBP (ΔSBP=standing SBP − supine SBP) and DBP (ΔDBP) upon standing and mean PM2.5 levels over the preceding 1 to 28 days, adjusting for meteorological covariates, temporal trends, and medical history. We observed a 1.4 (95% confidence interval (CI): 0.0, 2.8; p=0.046) mmHg higher ΔSBP and a 0.7 (95% CI: 0.0, 1.4; p=0.053) mmHg higher ΔDBP at 1 minute of standing per interquartile range increase (3.8 μg/m3) in mean PM2.5 levels in the past 7 days. ΔSBP and ΔDBP measured 3 minutes after standing were not associated with PM2.5. Resting DBP (but not SBP or pulse pressure) was positively associated with PM2.5 at longer averaging periods. Responses were more strongly associated with black carbon than sulfate levels. These associations did not differ significantly according to hypertension status, obesity, diabetes, or gender. These results suggest that ambient particles can increase resting DBP and exaggerate blood pressure responses to postural changes in elderly people. Increased vasoreactivity during posture change may be responsible, in part, for the adverse effect of ambient particles on cardiovascular health.

Obesity is often associated with reduced plasma IGF-1 levels, oxidative stress, mitochondrial damage and cardiac dysfunction. This study was designed to evaluate the impact of IGF-1 on high fat diet-induced oxidative, myocardial, geometric and mitochondrial responses. FVB and cardiomyocyte-specific IGF-1 overexpression transgenic mice were fed a low (10%) or high fat (45%) diet to induce obesity. High fat diet feeding led to glucose intolerance, elevated plasma levels of leptin, interleukin-6, insulin and triglyceride as well as reduced circulating IGF-1 levels. Echocardiography revealed reduced fractional shortening, increased end systolic and diastolic diameter, increased wall thickness, and cardiac hypertrophy in high fat-fed FVB mice. High fat diet promoted ROS generation, apoptosis, protein and mitochondrial damage, reduced ATP content, cardiomyocyte cross-sectional area, contractile and intracellular Ca2+ dysregulation, including depressed peak shortening and maximal velocity of shortening/relengthening, prolonged duration of relengthening, and dampened intracellular Ca2+ rise and clearance. Western blot analysis revealed disrupted phosphorylation of insulin receptor, post-receptor signaling molecules IRS-1 (tyrosine/serine phosphorylation), Akt, GSK3β, Foxo3a, mTOR, as well as downregulated expression of mitochondrial proteins PPARγ coactivator 1α (PGC1α) and UCP-2. Intriguingly, IGF-1 mitigated high fat diet feeding-induced alterations in ROS, protein and mitochondrial damage, ATP content, apoptosis, myocardial contraction, intracellular Ca2+ handling and insulin signaling, but not whole body glucose intolerance and cardiac hypertrophy. Exogenous IGF-1 treatment also alleviated high fat diet-induced cardiac dysfunction. Our data revealed that IGF-1 alleviates high fat diet-induced cardiac dysfunction despite persistent cardiac remodeling, possibly due to preserved cell survival, mitochondrial function and insulin signaling.

Chronic aldosterone administration increases glomerular filtration rate (GFR) while inhibition of mineralocorticoid receptors (MR) markedly attenuates glomerular hyperfiltration and hypertension associated with primary aldosteronism or obesity. However, the mechanisms by which aldosterone alters GFR regulation are poorly understood. In the present study, we hypothesized that aldosterone suppresses tubuloglomerular feedback (TGF) via activation of macula densa (MD) MR. First, we observed the expression of MR in MD cells isolated by laser capture microdissection (LCM) and by immunofluorescence in rat kidneys. Second, to investigate the effects of aldosterone on TGF in vitro, we microdissected the juxtaglomerular apparatus (JGA) from rabbit kidneys and perfused the afferent arteriole (Af-Art) and distal tubule simultaneously. Under control conditions, TGF was 2.8 ± 0.2µm. In the presence of aldosterone (10−8 mol/L), TGF was reduced by 50%. The effect of aldosterone to attenuate TGF was blocked by the MR antagonist eplerenone (10−5 mol/L). Third, to investigate the effect of aldosterone on TGF in vivo, we performed micropuncture and TGF was determined by maximal changes in stop-flow pressure Psf (ΔPsf) when tubular perfusion rate was increased from 0 to 40 nl/min. Aldosterone (10−7 mol/L) decreased ΔPsf from 10.1 ± 1.4 to 7.7 ± 1.2 mmHg. In the presence of L-NG-monomethyl arginine citrate (L-NMMA, 10−3 mol/L), this effect was blocked. We conclude that MR are expressed in MD cells and can be activated by aldosterone, which increases nitric oxide (NO) production in the MD and blunts the TGF response.

In heart failure (HF) cardiac sympathetic nerve activity (CSNA) is increased, which has detrimental effects on the heart and promotes arrhythmias and sudden death. There is evidence that the central renin angiotensin system plays an important role in stimulating renal SNA (RSNA) in HF. Since SNA to individual organs is differentially controlled, we have investigated whether central angiotensin receptor blockade decreases CSNA in HF. We simultaneously recorded CSNA and renal SNA (RSNA) in conscious normal sheep and in sheep with HF induced by rapid ventricular pacing (ejection fraction <40%). The effect of blockade of central angiotensin AT1R by intracerebroventricular infusion of losartan (1 mg/h for 5 hrs) on resting levels and baroreflex control of CSNA and RSNA was determined. In addition, the levels of angiotensin receptors in central autonomic nuclei were determined using autoradiography. Sheep in HF had a large increase in CSNA (43±2 to 88±3 bursts/100 heart beats, P<0.05) and heart rate, with no effect on RSNA. In HF, central infusion of losartan for 5 hours significantly reduced the baseline levels of CSNA (to 69±5 bursts/100 heart beats) and heart rate. Losartan had no effect in normal animals. In HF, angiotensin receptor levels were increased in the paraventricular nucleus and supraoptic nucleus, but reduced in the area postrema and nucleus tractus solitarius. In summary, infusion of losartan reduced the elevated levels of CNSA in an ovine model of HF, indicating that central angiotensin receptors play a critical role in stimulating the increased sympathetic activity to the heart.

Patients with autonomic failure have disabling orthostatic hypotension due to impaired sympathetic activity. Norepinephrine transporter (NET) blockade with atomoxetine raises blood pressure in autonomic failure by increasing synaptic norepinephrine concentrations in postganglionic sympathetic neurons. This effect requires tonic release of norepinephrine, which is decreased in patients with low sympathetic tone. We hypothesized that increasing residual sympathetic outflow with the α-2 antagonist yohimbine would potentiate the pressor effect of NET blockade with atomoxetine, and improve orthostatic tolerance in peripheral autonomic failure. Seventeen patients received a single oral dose of either placebo, yohimbine 5.4 mg, atomoxetine 18 mg and the combination yohimbine and atomoxetine in a single blind, crossover study. Blood pressure was assessed while patients were seated and standing for up to 10 minutes before and 1 hour post-drug. Neither yohimbine nor atomoxetine significantly increased seated systolic blood pressure (SBP) or orthostatic tolerance compared to placebo. The combination, however, significantly increased seated SBP and orthostatic tolerance (P<0.001 and P=0.016, respectively) in a synergistic manner. The maximal increase in seated SBP seen with the combination was 31±33 mmHg at 60 minutes post-drug. Only the combination showed a significant improvement in orthostatic symptoms. In conclusion, the combination yohimbine and atomoxetine had a synergistic effect on blood pressure and orthostatic tolerance in peripheral autonomic failure, which may be explained by an increased release of norepinephrine in peripheral sympathetic neurons by α-2 antagonism combined with a reduced norepinephrine clearance by NET blockade. Safety studies are required to address the clinical usefulness of this pharmacological approach.

Self-reported short sleep duration is linked to higher blood pressure and incident hypertension in adults. Few studies have examined sleep and blood pressure in younger samples. We evaluated the associations between actigraphy-assessed time spent asleep and ambulatory blood pressure in adolescents. Participants were 246 black and white adolescents (mean age = 15.7) who were free from cardiovascular or kidney disease and were not taking sleep, cardiovascular, or psychiatric medications. Sleep duration and efficiency were assessed with in-home wrist actigraphy and sleep diaries across one week; ambulatory blood pressure monitoring was used to obtain 24-hour, sleep, wake blood pressure, and sleep-wake blood pressure ratios across two full days and nights. Results showed that shorter actigraphy-assessed sleep across one week was related to higher 48-hour blood pressure and higher nighttime blood pressure. Shorter sleep was also related to a higher systolic blood pressure sleep-wake ratio. These results were independent of age, race, sex, and body mass index. Follow-up analyses by race revealed that associations between sleep duration and blood pressure were largely present in white, but not black, adolescents. These data are consistent with the hypothesis that the cardiovascular consequences of short sleep may begin as early as adolescence.

Androgen levels are lower in obese men as compared to normal weight individuals. However, there are no safety data regarding the chronic use of androgen supplements in middle-aged men. The present study was undertaken to determine the cardiovascular and metabolic effects of chronic (10 weeks) testosterone treatment in male obese Zucker rats (OZR), starting at 22 weeks of age, when testosterone levels were significantly decreased. Testosterone supplements increased plasma levels, 10 fold in both OZR and lean Zucker rats (LZR). In OZR, testosterone supplements reduced body weight, plasma insulin and cholesterol levels and improved oral glucose tolerance test. None of these parameters were affected in LZR. Mean arterial pressure was significantly increased in OZR, but not LZR. Testosterone supplements increased proteinuria and accelerated renal injury in LZR only. Thus treatment of obese men with chronic testosterone supplements should be done with careful monitoring of blood pressure.

Cardiotonic steroids signaling through the basolateral sodium pump (Na/KATPase) have been shown to alter renal salt handling in intact animals. As the relationship between renal salt handling and blood pressure is a key determinant of hypertension, and patients with insulin resistance are frequently hypertensive, we chose to examine whether there might be competition for resources necessary for receptor mediated endocytosis.

In LLC-PK1 cells, the Na/K-ATPase-α1 and carcinoembryonic antigen cell adhesion molecule (CEACAM1), a plasma membrane protein that promotes receptor-mediated endocytosis, co-localized in the plasma membranes and translocated to the intracellular region in response to ouabain. Either ouabain or insulin alone caused accumulation of CEACAM1 as well as IRβ, and EGFR in early endosomes, but no synergy was demonstrable. Like ouabain, insulin also caused c-Src activation. When caveolin or Na/K-ATPase-α1 expression was knocked down with siRNA, insulin but not ouabain induced CEACAM1, IRβ, and EGFR endocytosis.

To determine whether this might be relevant to salt handling in vivo, we examined salt loading in mice with null renal CEACAM2 expression (Cc2−/−). The Cc2−/− animals demonstrated greater increases in blood pressure with increases in dietary salt than control animals.

These data demonstrate that cardiotonic steroids and insulin compete for cellular endocytosis resources and suggest that under conditions where circulating insulin concentrations are high, cardiotonic steroid mediated natriuresis could be impaired.

Experiments were performed to test the hypothesis that oxidative stress underlies the enhanced tonic dilator impact of inward-rectifier K+ (KIR) channels on renal afferent arterioles of rats with streptozotocin-induced diabetes. Sham and diabetic rats were left untreated or provided tempol in their drinking water for 26±1 days, after which afferent arteriolar lumen diameter and its responsiveness to K+ channel blockade were measured using the in vitro blood-perfused juxtamedullary nephron technique. Afferent diameter averaged 19.4±0.8 μm in sham rats and 24.4±0.8 μm in diabetic rats (P<0.05). The decrease in diameter evoked by Ba2+ (KIR channel blocker) was 3-times greater in diabetic rats than in sham rats. Glibenclamide (KATP channel blocker) and tertiapin-Q (Kir1.1/Kir3.x channel blocker) decreased afferent diameter in diabetic rats, but had no effect on arterioles from sham rats. Chronic tempol treatment prevented diabetes-induced increases in both renal vascular dihydroethidium staining and baseline afferent arteriolar diameter. Moreover, tempol prevented the exaggeration of afferent arteriolar responses to Ba2+, tertiapin-Q, and glibenclamide otherwise evident in diabetic rats. Preglomerular microvascular smooth muscle cells expressed mRNA encoding Kir1.1, Kir2.1 and Kir6.1. Neither diabetes nor tempol altered Kir1.1, Kir2.1, Kir6.1 or SUR2B protein levels in renal cortical microvessels. To the extent that the effects of tempol reflect its antioxidant actions, our observations indicate that oxidative stress contributes to the exaggerated impact of Kir1.1, Kir2.1 and KATP channels on afferent arteriolar tone during diabetes and that this phenomenon involves post-translational modulation of channel function.

Interindividual variation in the ability of aspirin to inhibit platelet cyclooxygenase-1 (COX-1) could account for some on-treatment cardiovascular events. Here, we sought to determine whether there are clinical phenotypes that are associated with a suboptimal pharmacological effect of aspirin. In a prospective, 2-week study, we evaluated the effect of aspirin 81 mg on platelet COX-1 in 135 patients with stable CAD by measuring serum thromboxane B2 (sTxB2) as an indicator of inhibition of platelet COX-1. A nested randomized study compared enteric-coated with immediate-release formulations of aspirin. We found that sTxB2 was systematically higher among the 83 patients with metabolic syndrome than among the 52 patients without (median 4.0 ng/mL vs. 3.02 ng/mL, P=0.013). Twelve (14%) patients with metabolic syndrome, but none without metabolic syndrome, had sTxB2 levels consistent with inadequate inhibition of COX (sTxB2 ≥13 ng/mL). In linear regression models, metabolic syndrome (but none of its individual components) significantly associated with higher levels of log-transformed sTxB2 (P=0.006). Higher levels of sTxB2 associated with greater residual platelet function measured by aggregometry-based methods. Among the randomized subset, sTxB2 levels were systematically higher among patients receiving enteric-coated aspirin. Last, urinary 11-dehydrothromboxane B2 did not correlate with sTxB2, suggesting that the former should not be used to quantitate aspirin’s pharmacological effect on platelets. In conclusion, metabolic syndrome, which places patients at high risk for thrombotic cardiovascular events, strongly and uniquely associates with less effective inhibition of platelet COX-1 by aspirin.

In vivo, the enzyme 11β-hydroxysteroid dehydrogenase type 2 influences ligand access to the mineralocorticoid receptor. Ablation of the encoding gene, HSD11B2, causes the hypertensive syndrome of Apparent Mineralocorticoid Excess. Studies in humans and experimental animals have linked reduced 11β-hydroxysteroid dehydrogenase type 2 activity and salt-sensitivity of blood pressure. In the present study, renal mechanisms underpinning salt-sensitivity were investigated in Hsd11b2+/− mice fed low, standard and high sodium diets.

In wild-type mice, there was a strong correlation between dietary sodium content and fractional sodium excretion, but not blood pressure. High sodium feeding abolished amiloride-sensitive sodium reabsorption, consistent with down-regulation of the epithelial sodium channel. In Hsd11b2+/− mice, the natriuretic response to increased dietary sodium content was blunted and epithelial sodium channel activity persisted. High sodium diet also reduced renal blood flow and increased blood pressure in Hsd11b2+/− mice. Aldosterone was modulated by dietary sodium in both genotypes and salt-sensitivity in Hsd11b2+/− mice was associated with increased plasma corticosterone levels. Chronic administration of an epithelial sodium channel blocker or a glucocorticoid receptor antagonist prevented salt-sensitivity in Hsd11b2+/− mice, whereas mineralocorticoid receptor blockade with spironolactone did not.

This study shows that reduced 11β-hydroxysteroid dehydrogenase type 2 causes salt-sensitivity of blood pressure due to impaired renal natriuretic capacity. This reflects deregulation of epithelial sodium channels and increased renal vascular resistance. The phenotype is not caused by illicit activation of mineralocorticoid receptors by glucocorticoids, but by direct activation of glucocorticoid receptors.

The National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents recently recommended staging hypertension (HTN) in children and adolescents based on blood pressure severity. The use of blood pressure staging and its corresponding therapeutic approach was examined in this pooled analysis assessing the risk for end-organ damage, specifically left ventricular hypertrophy among hypertensive adolescents stratified by working group criteria. Newly diagnosed hypertensive adolescents and normotensive control subjects similar in age, race/ethnicity, gender, and body mass index completed casual and 24-hour ambulatory blood pressure measurements, M-mode echocardiography, and fasting serum laboratories. Hypertensive subjects had higher insulin and cholesterol but similar glucose levels as compared with control subjects. Among subjects with stage 1 HTN by casual blood pressure, 34% had white-coat HTN as opposed to 15% of stage 2 hypertensive subjects. Of the subjects with normal casual measurements, 20% had HTN by ambulatory monitoring. Subjects with stage 2 HTN by casual measurement alone (odds ratio: 4.13; 95% CI: 1.04 to 16.48) and after 24-hour ambulatory confirmation (odds ratio: 7.23; 95% CI: 1.28 to 40.68) had increased odds for left ventricular hypertrophy. In addition, the risk for left ventricular hypertrophy was similar for subjects with masked and confirmed stage 1 HTN, whereas subjects with white-coat HTN had a risk comparable to normotensive subjects. Thus, recommendations that adolescents with stage 2 HTN by casual measurements alone receive medication initially along with therapeutic lifestyle counseling are reasonable, though ambulatory blood pressure monitoring remains a valuable tool for evaluating children with stage 2 HTN, because >10% have white-coat HTN.

Hyperinsulinemia increases sympathetic nerve activity and contributes to cardiovascular dysfunction in obesity and diabetes. Neurons of the hypothalamic paraventricular nucleus regulate sympathetic nerve activity through mono- and poly-synaptic connections to preganglionic neurons in the spinal cord. The purpose of the present study was to determine whether hypothalamic paraventricular nucleus neurons mediate the sympathetic response to insulin. Hyperinsulinemic-euglycemic clamps were performed in α-chloralose-anesthetized, male Sprague-Dawley rats (280–420 g) by an infusion of insulin (3.75 mU/kg/min) and 50% dextrose (0.75–2.0 ml/h) for 120 min. At 90 min, insulin significantly increased lumbar sympathetic nerve activity without any change in renal sympathetic nerve activity, heart rate, or blood glucose levels. Inhibition of the hypothalamic paraventricular nucleus with bilateral injection of the GABAA receptor agonist muscimol completely reversed the sympathoexcitatory response. However, direct injection of insulin into the hypothalamic paraventricular nucleus did not alter lumbar sympathetic nerve activity and thereby suggests insulin activates neurons upstream of the hypothalamic paraventricular nucleus. Interestingly, the sympathetic response to insulin was eliminated by hypothalamic paraventricular nucleus injection of the melancortin 3/4 receptor antagonist SHU9119 but unaffected by the angiotensin II type 1 receptor antagonist losartan. A final set of experiments suggests activation of hypothalamic paraventricular nucleus neurons during hyperinsulinemia increases glutamatergic drive to the rostral ventrolateral medulla. Collectively, these findings indicate insulin activates a melanocortin-dependent pathway to the hypothalamic paraventricular nucleus that increases glutamatergic drive to the rostral ventrolateral medulla and alter cardiovascular function.

Preeclampsia is a heterogeneous syndrome affecting 3–5% of all pregnancies. An imbalance of the anti and pro-angiogenic factors, soluble receptor fms-like tyrosine kinase 1 (sFLT1) and placental growth factor (PGF), are thought to contribute to the pathophysiology of preeclampsia. Maternal plasma PGF and sFLT1 were quantified by specific immunoassays in cross-sectional samples from 130 preeclamptic subjects and 342 normotensive controls at delivery, and longitudinally in samples from 50 women who developed preeclampsia and 250 normotensive controls. Among women who developed preeclampsia, 46% (n=23) evidenced a pattern of consistently low maternal PGF across pregnancy below the lower 95%CI of controls from 15 weeks gestation to term. In contrast, the remaining 54% (n=27) women who developed preeclampsia had maternal PGF concentrations similar to or above (n=7) those of normotensive controls. Subjects with low PGF across pregnancy who developed preeclampsia evidenced significantly higher blood pressure in early pregnancy (p<0.05), and after diagnosis, earlier gestational age at delivery (p<0.05), and more preterm birth (p<0.05) compared to preeclamptic patients with high PGF. A significant subset of women who develop preeclampsia evidence consistently low PGF across pregnancy. Low PGF with preeclampsia was associated with preterm delivery compared to preeclamptic patients with high PGF. Identifying women with consistently low plasma PGF during pregnancy may provide a greater understanding of preeclampsia pathophysiology, and may provide more focused research and clinical activities.

Chronic heart failure (CHF) is characterized by increased sympathetic tone. The glutamatergic input in the rostral ventrolateral medulla (RVLM), which is a key region involved in sympathetic outflow, seems not to be involved in the generation of sympathetic tone in the normal state. The aim of this study was to determine the role of the RVLM glutamate receptors in generation of sympathetic tone in CHF. CHF was produced by left coronary artery ligation. Bilateral microinjection of the glutamate receptor antagonist kynurenic acid (KYN), the N-methyl-D-aspartate (NMDA) receptor antagonist D-AP5, or the non-NMDA receptor antagonist CNQX into the RVLM dose-dependently reduced resting blood pressure and renal sympathetic nerve activity in CHF but not in sham rats. Picoinjection of KYN (100 pmol in 5 nl) significantly decreased the basal discharge by 47% in 25 RVLM presympathetic neurons in CHF rats, In contrast, KYN had no effect on the discharge in all 22 RVLM presympathetic neurons tested in sham rats. These data suggest that upregulated glutamate receptors, including NMDA and non-NMDA, in the RVLM are involved in tonic control of elevated sympathetic tone in CHF.

The hypothalamic paraventricular nucleus (PVN) plays an important role in the sympathoexcitatory response to elevated plasma angiotensin II (Ang II). However, the mechanism by which Ang II influences sympathetic activity is not fully understood. In this study, we tested the hypothesis that GABA(γ-aminobutyric acid)-ergic function in the PVN is reduced by peripheral infusion of Ang II. To accomplish this, rats received either intravenous Ang II (12 ng/kg per minute) or vehicle (D5W) for 7 days, and renal sympathetic nerve activity (SNA), mean arterial pressure (MAP), and heart rate (HR) responses were recorded after unilateral PVN microinjection of the GABA-A receptor antagonist bicuculline methiodide (BMI, 0.1 nmol). Results indicate that in contrast to a significant increase in renal SNA, MAP, and HR observed in vehicle-infused rats (P<0.05), BMI injection into the PVN of Ang II–infused animals was without effect on all recorded variables. In a separate groups of animals, ganglionic blockade produced a significantly greater fall in MAP (P<0.01) in Ang II–infused rats than in vehicle-infused control rats, indicating that the contribution of SNA to the maintenance of blood pressure was elevated in the Ang II–infused group. Overall, these data indicate that cardiovascular and sympathoexcitatory responses to acute GABA-A receptor antagonism in the PVN are significantly blunted in rats after 7 days of intravenous infusion of Ang II. We conclude that an Ang II–induced reduction in GABAergic inhibition within the PVN may contribute to elevated SNA observed in this study.