Early Development Of Hypertension Research Articles

241-LB: Significant Worsening of Preexisting Obesity in South Texas Children during COVID-19 Lockdown

Background: Obesity has been on the rise for the past several decades, which is associated with increased risk for comorbidities and severe consequences to the individual. In the Mexican American community, obesity has become a serious problem in children. The COVID-19 lockdown order issued in February 2020 caused further challenges for children to engage in regular physical activity. Objective: To determine if the COVID-19 lockdown impacted the weight of 95% Medicaid-insured Mexican American children at a pediatric clinic in South Texas. Design and Methods: We identified 417 new patients from March 2019 to February 2020 (with exclusion of 104 newborns) and followed them until December 2021. Height and weight were measured to estimate Body Mass Index (BMI) . The percentage of overweight or obese (OW/OB) children was calculated at the first and last visit. Results: We had a total of 346 children at the end of the study. The average stature of the whole group was at the 48th percentile with 60% of the children at or below the 50th percentile based on CDC growth charts. Boys increased BMI from the 62.7th to 71.8th percentile (p<0.01) and girls increased from the 60th to the 70th percentile (p<0.02) . The distribution of BMI of the whole group indicated that 34.5% of children were OW/OB on the first visit and 49% were OW/OB at the last visit. Conclusion (s) : Our study exemplifies that the lockdown during the COVID-19 pandemic, which was associated with decreased physical activity, increased the BMI of children and increased associated comorbidities based on lab values. We have shown in previous studies that when BMI is in the OW/OB category, children have increased blood pressure, decreased high density lipoproteins, elevated liver enzymes, increased insulin resistance, larger kidneys, and fatty liver. These indicators place children at a higher risk for early development of hypertension, renal function decline, diabetes, and cardiovascular disease. Disclosure F. J. Cervantes: None.

Elevations in arterial pressure are associated with increases in plasma angiotensin III and angiotensin 1‐9 in female obese SS rats prior to puberty

Recent studies show that prepubertal obesity is associated with increased risk of hypertension in children. Moreover, previous reports have demonstrated that there is a link between the renin-angiotensin system and obesity-related hypertension via angiotensin II (Ang II) metabolism. However, to our knowledge, studies examining AngII metabolism during the development of hypertension associated with prepubertal obesity are limited. Therefore, the current study examined whether there are sex differences in arterial pressure and AngII metabolism in lean Dahl salt-sensitive (SS) and obese SS leptin receptor mutant (SSLepRmutant) rats. Four week-old female and male lean SS and obese SSLepRmutant rats (n=5 rats per group) were implanted with telemetry transmitters to measure MAP until the rats reached 8 weeks of age. Over the course of the study, we did not detect any differences MAP between female and male SS rats (115±2 and 120±2 mmHg, respectively). MAP was similar in male SSLepRmutant rats compared to their wild-type littermates (118±6 mmHg). However, we observed a marked increase in MAP in female SSLepRmutant rats compared to the other groups (144±7 mmHg; p<0.05 vs. all groups). At the end of the study, plasma was collected and analyzed for AngII metabolites (AngII, Ang(1-7), AngIII, AngIV, Ang(1-5) and Ang(1-9); via mass spectrometry). Interestingly, we did not observe any sex or strain differences in plasma AngII levels between lean SS and obese SSLepRmutant rats. Additionally, similar results were seen when measuring the plasma levels of Ang(1-7), AngIV, and Ang(1-5). However, AngIII and Ang(1-9) levels were more than two-fold higher in female obese SSLepRmutant rats versus their lean SS littermates and male obese SSLepRmutant counterparts (p<0.05 vs. all groups). Overall, these data indicate that the elevations in arterial pressure in female obese SSLepRmutant rats is associated with alterations in angiotensin metabolism with increases in plasma levels of AngIII and Ang(1-9). Additionally, further studies are needed to investigate the roles of AngIII and Ang(1-9) and their signaling pathways in the early development of hypertension in female obese SSLepRmutant rats prior to puberty.

Clinical significance of hypertension in patients with different types of cancer treated with antiangiogenic drugs.

Hypertension is a common comorbidity in patients receiving antiangiogenic therapy. Prior studies have reported worsening or new-onset hypertension as an adverse event of antiangiogenetic therapy, which can be managed by dose reduction or discontinuation of the culprit medication. By contrast, other studies have found that the occurrence of hypertension is a potential biomarker associated with greater efficacy of antiangiogenic therapy and predicts improved survival. At present, there is no consensus on the effects of hypertension in patients treated with antiangiogenic drugs. The present study reviewed the relationship between antiangiogenic drugs and hypertension in different types of cancer. It was demonstrated that the use of antiangiogenic drugs was associated with an increased risk of hypertension in most types of solid cancers. There was no significant difference in the incidence of hypertension between monoclonal antibody and small-molecule tyrosine kinase inhibitor treatments. Hypertension was more likely to occur in patients younger than 75 years old, female, and those with no history of bevacizumab use. Discontinuation or death caused by hypertension was rare, although previous studies have reported that hypertension was a risk factor for acute and chronic cardiovascular diseases and ischemic stroke. Of note, the early development of hypertension may serve as a potential biomarker associated with greater efficacy of antiangiogenic therapy.

Reshaping commensal gut microbiota in early life lowers blood pressure potentially via a succinate mediated mechanism

Pediatric hypertension is recognized as an emerging global health concern. While new guidelines are developed for facilitating clinical management, the reasons for the prevalence of hypertension in children remain unknown. Genetics and environmental factors do not fully account for the growing incidence of pediatric hypertension. Because stable bacterial flora in early life are linked with health outcomes later in life, we hypothesized that reshaping of gut microbiota in early developmental stages of life affects blood pressure (BP) of pediatric subjects. To test this hypothesis, we administered amoxicillin (50mg/day/kg body weight with drinking water), the most commonly prescribed pediatric antibiotic, to alter gut microbiota of young, genetically hypertensive Dahl S rats (study 1) and dams during gestation and lactation to reshape microbiota of offspring (study 2). Reshaping of microbiota (determined by 16s sequencing), with reductions in Firmicutes/Bacteriodetes ratio observed in amoxicillin treated young rats and in dams. Amoxicillin treated rats (8 weeks old) also had lower blood pressure (radiotelemetry: 24‐hour average Systolic Blood Pressure in mmHg (SBP): 155±2*) compared to the untreated rats (SBP: 166±3) (n=10–12/group). In the young rats treated with amoxicillin, the BP lowering effect persisted even after the antibiotics were discontinued (10 weeks old‐last 2 weeks without Amoxicillin) (amoxicillin SBP: 196±4 vs Control SBP: 231±10*). Similarly, offspring from the dams treated with amoxicillin also showed lower systolic blood pressure (SBP: 201±4*) compared to the control rats (SBP: 222±6) (9 weeks old and n=6–8/group). Remarkably, in all cases, a decrease in BP was associated with lowering of Veillonellaceae, which are succinate‐producing bacteria. Elevated plasma succinate is reported in hypertension. Accordingly, serum succinate was measured via choloremtric assay and found lower in animals treated with amoxicillin (410±33 mg/L*) compared with control (508±30 mg/L). Our results demonstrate a direct correlation between succinate‐producing gut microbiota and early development of hypertension, and indicate that reshaping gut microbiota, especially by depleting succinate‐producing microbiota early in life may have long‐term benefits for hypertension‐prone individuals. Data presented as Mean±SEM. Non‐parametric Mann‐Whitney test*p&lt;0.05.Support or Funding InformationNational Institutes of Health (R01HL143082)

Arterial baroreflex regulation of muscle sympathetic single-unit activity in men: influence of resting blood pressure.

The arterial baroreflex has dominant control over multiunit muscle sympathetic nerve activity (MSNA) burst occurrence, but whether this extends to all single units or is influenced by resting blood pressure status is unclear. In 22 men (32 ± 8 yr), we assessed 68 MSNA single units during sequential bolus injections of nitroprusside and phenylephrine (modified Oxford). Sympathetic baroreflex sensitivity (sBRS) was quantified as the weighted negative linear regression slope between diastolic blood pressure (DBP) and single-unit spike firing probability and multiple spike firing. Strong negative linear relationships (r ≥ -0.50) between DBP and spike firing probability were observed in 63/68 (93%) single units (-2.27 ± 1.27%·cardiac cycle-1·mmHg-1 [operating range, 18 ± 8 mmHg]). In contrast, only 45/68 (66%) single units had strong DBP-multiple spike firing relationships (-0.13 ± 0.18 spikes·cardiac cycle-1·mmHg-1 [operating range, 14 ± 7 mmHg]). Participants with higher resting DBP (65 ± 3 vs. 77 ± 3 mmHg, P < 0.001) had similar spike firing probability sBRS (low vs. high, -2.08 ± 1.08 vs. -2.46 ± 1.42%·cardiac cycle-1·mmHg-1, P = 0.33), but a smaller sBRS operating range (20 ± 6 vs. 16 ± 9 mmHg, P = 0.01; 86 ± 24 vs. 52 ± 25% of total range, P < 0.001) and a higher proportion of single units without arterial baroreflex control outside this range [6/31 (19%) vs. 21/32 (66%), P < 0.001]. Participants with higher resting DBP also had fewer single units with arterial baroreflex control of multiple spike firing (79 vs. 53%, P = 0.04). The majority of MSNA single units demonstrate strong arterial baroreflex control over spike firing probability during pharmacological manipulation of blood pressure. Changes in single-unit sBRS operating range and control of multiple spike firing may represent altered sympathetic recruitment patterns associated with the early development of hypertension.NEW & NOTEWORTHY Muscle sympathetic single units can be differentially controlled during stress. In contrast, we demonstrate that 93% of single units maintain strong arterial baroreflex control during pharmacological manipulation of blood pressure. Interestingly, the operating range and proportion of single units that lose arterial baroreflex control outside of this range are influenced by resting blood pressure levels. Altered single unit, but not multiunit, arterial baroreflex control may represent changes in sympathetic recruitment patterns in early stage development of hypertension.

Exposure to Amoxicillin in Early Life Is Associated With Changes in Gut Microbiota and Reduction in Blood Pressure: Findings From a Study on Rat Dams and Offspring.

BackgroundPediatric hypertension is recognized as an emerging global health concern. Although new guidelines are developed for facilitating clinical management, the reasons for the prevalence of hypertension in children remain unknown. Genetics and environmental factors do not fully account for the growing incidence of pediatric hypertension. Because stable bacterial flora in early life are linked with health outcomes later in life, we hypothesized that reshaping of gut microbiota in early life affects blood pressure (BP) of pediatric subjects.Methods and ResultsTo test this hypothesis, we administered amoxicillin, the most commonly prescribed pediatric antibiotic, to alter gut microbiota of young, genetically hypertensive rats (study 1) and dams during gestation and lactation (study 2) and recorded their BP. Reshaping of microbiota with reductions in Firmicutes/Bacteriodetes ratio were observed. Amoxicillin treated rats had lower BP compared with untreated rats. In young rats treated with amoxicillin, the lowering effect on BP persisted even after antibiotics were discontinued. Similarly, offspring from dams treated with amoxicillin showed lower systolic BP compared with control rats. Remarkably, in all cases, a decrease in BP was associated with lowering of Veillonellaceae, which are succinate‐producing bacteria. Elevated plasma succinate is reported in hypertension. Accordingly, serum succinate was measured and found lower in animals treated with amoxicillin.ConclusionsOur results demonstrate a direct correlation between succinate‐producing gut microbiota and early development of hypertension and indicate that reshaping gut microbiota, especially by depleting succinate‐producing microbiota early in life, may have long‐term benefits for hypertension‐prone individuals.

Evaluation of Prehypertension among School Going Adolescents in Chennai

Aim:- Adolescence is an important phase of life and increased stress has made them prone for early development of Metabolic disorders. Worldwide prevalence of Prehypertension is increasing and early identification of which will help to manage the development of early hypertension and its associated complications. Hence, current study aims to evaluate the prevalence of prehypertension among school going adolescents in Chennai. Methods:- The study was conducted among school going adolescents (n-264) in Chennai between the age group 15-19yrs. Anthropometric measurements were taken and stress and sleep hygiene were assessed using validated questionnaires. Blood pressure was recorded using Hawkley random zero sphygmomanometer. Results:- The overall prevalence of Prehypertension was found to be 22.3%. Prehypertension was found to be more in females (23.1%) than males (21.6%). Conclusion:- There is an increased prevalence of prehypertension among school going adolescents in Chennai. Adolescents should be taught about the importance and benefits of healthy lifestyle for a healthy future.

Amoxicillin‐responsive alterations in commensal gut microbiota are associated with lowering of blood pressure in young hypertensive rats

Pediatric hypertension is recognized as an emerging global health concern. While new guidelines are developed for facilitating clinical management, the reasons for the prevalence of hypertension in children remain unknown. We hypothesized that, similar to the known link between gut microbiota and adult hypertensives, alterations in gut microbiota that occur very early in childhood are also associated with an increased prevalence of pediatric hypertension. To test this hypothesis, we administered amoxicillin, the most commonly prescribed antibiotic to pediatric patients, to clear gut microbiota of just‐weaned, genetically hypertensive Dahl Salt‐Sensitive (S) rats. Amoxicillin treated rats had decreased BP compared to controls. This lowering effect on blood pressure persisted even after the antibiotics were discontinued. Results will be presented on the specific alterations in gut microbiota in response to amoxicillin treatment. Albeit in an experimental model, our results demonstrate the significant role of gut microbiota in the early development of hypertension and indicate that clearing dysbiotic gut microbiota early in childhood may have long‐term benefits for hypertension‐prone individuals.Support or Funding InformationFunding for this work to BJ from the NHLBI/NIH (HL143082) is gratefully acknowledged.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The association of endothelin-1 levels with renal survival in polycystic kidney disease patients

The prominent features of autosomal dominant polycystic kidney disease (ADPKD) are early development of hypertension, chronic kidney disease and cardiovascular problems. Thus, we aimed to investigate the role of endothelin, a vascular biomarker, in the clinical course of ADPKD, including renal and cardiovascular survival. In 138 patients with ADPKD and 28 healthy controls, we measured serum endothelin-1 (ET-1) levels by enzyme-linked immunosorbent assay (ELISA). Endothelium-dependent vasodilatation (flow-mediated dilatation, FMD) and endothelium-independent vasodilatation (nitroglycerin-mediated dilatation, NMD) of the brachial artery were assessed non-invasively with high-resolution ultrasound. Magnetic resonance imaging (MRI) was performed with a 1.5-T system, and total kidney volumes were calculated using mid-slice technique. To determine PKD1 and PKD2 genotype, we performed molecular and genetic tests involving the following steps: DNA isolation, next-generation sequencing (NGS) and data analysis. Endothelin levels and height-adjusted total kidney volumes (hTKV) significantly increased while the estimated glomerular filtration rate (eGFR) decreased across CKD stages 1-4. Hypertension was more frequent in ADPKD patients with high serum endothelin. At multivariate Cox analysis, endothelin level, PKD1 truncating mutation, hTKV, high-sensitive C reactive protein (hs-CRP) level and the presence of diabetes mellitus were associated with the risk of overall survival. Moreover, endothelin level, PKD1 truncating mutation, hTKV, age and presence of hypertension were associated with the risk of renal survival. Additionally, body mass index (BMI), FMD, PKD1 truncating mutation, endothelin and triglyceride levels were independently associated with hypertension. Increased serum endothelin levels independently predict hypertension in ADPKD. Serum endothelin levels are also associated with both renal and overall survival in patients with ADPKD.

Early hypertension after vasopressor weaning during septic shock: associated factors and prognostic significance

During septic shock, early development of hypertension after vasopressors weaning seems paradoxical. The aim of this study was to authenticate this empirical observation, identify associated factors and document its prognostic significance. We conducted a descriptive, retrospective study in a medical ICU of a teaching hospital among adult patients with septic shock. From January 1st, 2013 to December 31st, 2014, 262 consecutive patients over 18 years of age were admitted because of septic shock; 195 of them were successfully weaned from vasopressors. Early hypertension within the 24 hours following vasopressors weaning occurred in 22% of patients (N.=43) who did not differ in terms of past history of hypertension or chronic renal insufficiency, severity scores, vasopressor doses or duration, volume resuscitation or fluid balance. In multivariate analysis, predictive factors for developing early hypertension were past history of ischemic heart disease (OR=4.25; 95% CI: 1.74-10.35, P=0.001) and invasive mechanical ventilation (OR=2.86; 95% CI: 1.26-6.51, P=0.01). Occurrence of early hypertension was independently associated with a better survival (OR=0.03; 95% CI: 0.001-0.73, P=0.03). Development of hypertension within 24 hours of vasopressor support cessation is a frequent event affecting almost a quarter of the patients who survived the initial phase of septic shock resuscitation and is independently associated with a better outcome.

OP 10 Longitudinal assessment of cardiovascular risk factors after hypertensive disorders of pregnancy – Towards identifying a window of opportunity for screening and prevention

Introduction Accumulating evidence consistently demonstrates an increased risk and accelerated development of cardiovascular disease (CVD) risk in women with a history of a hypertensive disorder of pregnancy (HDP). Guidelines emphasize the emerging need for the prevention of CVD in these women, but fail to provide uniform recommendations on commencement and time interval in screening these patients. Objective The aim of this study is to investigate development of blood pressure, lipids and fasting glucose levels over time in women with a history of HDP in order to identify a window of opportunity for screening and prevention. Methods We identified women with self-reported normotensive pregnancy and HDP (NP, n = 1811; HDP, n = 1005) within the PREVEND study, a Dutch population-based cohort with a follow-up of maximum of 5 visits with 3-year intervals. Development of blood pressure, lipids, fasting glucose and Framingham 10-years CVD scores was longitudinally assed using generalized estimating equations. Results HDP”s present with overall higher and faster increasing prevalence of hypertension (p = 0.005), dyslipidemia (p = 0.009) and glucose disturbances (p = 0.002), reflecting in the use of medication (p Conclusion Women with a history of HDP show early development of hypertension, dyslipidemia and glucose homeostasis disturbances. Based on this cohort study, calculated 10-years CVD risk and NNS indicate commencing CVRM screening in these women at age 45 would be feasible. Download : Download high-res image (385KB) Download : Download full-size image

Abstract P104: Renin Angiotensin System (RAS) Modulation in Hypertension Program by Maternal Intrauterine Malnutrition

Intrauterine malnutrition (IM) during the early stages of development can alter the function of organs and tissues and can predict a lifetime of increased risk for adverse health outcomes, such as diabetes and hypertension. The kidney plays a key role in the development of hypertension programmed by IM, with the participation of the RAS. Our objectives were to study ACE activity and angiotensin peptides levels in tissues. Pregnants Wistar rats were separated into two groups: control group (C), fed ad libitum, and malnourished group (D) submitted to food restriction (diet 50% of the amount of feed consumed by the group C). After birth the offspring were kept as experimental groups C and D, respectively. At 4 months of age, the animals were sacrificed, heart and kidney tissues were collected to quantify angiotensin peptides and ACE activity. The offspring born with low birth weight. Kidney ACE activity was higher in group D compared to group C (299 ±86.7 vs. 253.4 ±84.82 mU/mg, p&lt;0.05), differing from Heart (D versus C: 0.15 ± 0.08 vs. 0.24 ±0.09 mU/mg). Group D presented high blood pressure values compared to group C (140.6 ±2.8 vs. 124,3±2.6 mmHg). Kidney and heart Ang II levels were increased in group D being significant when compared to group C (238.26 ±25.1 vs. 161.85 ±45.6 pmol/g and 397.89±74.9 vs. 223.33±48.7 pmol/g, p&lt;0.05, respectively). The same was observed for Ang I. The vasodilator peptide Ang1-7 levels in group D from kidney and heart were lower in comparison with group C, thus emphasizing an enabling environment for hypertension (220.74 ± 48.74 vs. 288.09 ± 47 pmol/g and 152.1±41.2 pmol/g vs. 228.93±41.2 pmol/g, p&lt;0.05, respectively). Our results indicate that perturbed maternal nutritional status alters tissue RAS resulting in higher blood pressure in the offspring, demonstrated by increased renal ACE activity and Ang II levels, with reduced Ang 1-7. The increase of Ang I and II in the heart, despite low ACE activity in this tissue suggests the activation of RAS alternative pathways. This study describes for the first time that low levels of Ang 1-7 contributed to the early development of hypertension.

Stress and salt sensitivity in primary hypertension.

As the development of hypertension and target organ damage becomes more prevalent, it becomes exceedingly important to determine the underlying mechanisms through which this detrimental development occurs. Specifically, our studies and others have explored mechanisms through which stress elicits a salt-sensitive response in approximately 20-30 % of the population, resulting in the early development of hypertension and target organ damage. Data associated with this stress-induced cardiovascular response pattern have recently demonstrated additional effects across the body systems including factors contributing to the development of osteoporosis, obesity, autoimmune disease, and chronic inflammation. As each of these diseases become more prevalent in conjunction with hypertension, further research may discover stress and salt sensitivity to be at the "heart" of the matter for the development of many of today's most deadly conditions.

Is the failing heart out of fuel or a worn engine running rich? A study of mitochondria in old spontaneously hypertensive rats

Hypertension now affects about 600 million people worldwide and is a leading cause of death in the Western world. The spontaneously hypertensive rat (SHR), provides a useful model to investigate hypertensive heart failure (HF). The SHR model replicates the clinical progression of hypertension in humans, wherein early development of hypertension is followed by a long stable period of compensated cardiac hypertrophy that slowly progresses to HF. Although the hypertensive failing heart generally shows increased substrate preference towards glucose and impaired mitochondrial function, the cause-and-effect relationship between these characteristics is incompletely understood. To explore these pathogenic processes, we compared cardiac mitochondrial proteomes of 20-month-old SHR and Wistar-Kyoto controls by iTRAQ-labelling combined with multidimensional LC/MS/MS. Of 137 high-scoring proteins identified, 79 differed between groups. Changes were apparent in several metabolic pathways, chaperone and antioxidant systems, and multiple subunits of the oxidative phosphorylation complexes were increased (complexes I, III and IV) or decreased (complexes II and V) in SHR heart mitochondria. Respiration assays on skinned fibres and isolated mitochondria showed markedly lower respiratory capacity on succinate. Enzyme activity assays often also showed mismatches between increased protein expression and activities suggesting elevated protein expression may be compensatory in the face of pathological stress.

Nɛ‐(Carboxymethyl)lysine during the Early Development of Hypertension

Advanced glycation end products (AGEs) are associated with hypertension. Whether N(epsilon)-(carboxymethyl)lysine (CML) contributes to the development of hypertension in young spontaneously hypertensive rats (SHR) remains to be established compared to WKY. We determined blood pressure, renal function, marker for oxidative stress (OS), and CML in young WKY rats and SHR. We found blood pressure was increased in SHR with no difference in renal function and OS compared to WKY. CML was elevated in plasma (2.3 +/- 0.3 vs. 1.3 +/- 0.2 micromol/L) and kidney (1.0 +/- 0.1 vs. 0.5 +/- 0.1 micromol/L) compared to WKY. Early CML accumulation may contribute to the development of hypertension potentially by inducing early renal inflammation independent of glomerular dysfunction or oxidative stress.

EARLY RENAL DENERVATION PREVENTS DEVELOPMENT OF HYPERTENSION IN GROWTH‐RESTRICTED OFFSPRING

1. Low birth weight is associated with an increased risk for the development of hypertension. Our laboratory uses a model of reduced uterine perfusion in the pregnant rat that results in intrauterine growth-restricted (IUGR) offspring that develop hypertension at a prepubertal age. Although hypertension develops in both prepubertal male and female IUGR offspring, only male IUGR offspring remain hypertensive after puberty. We reported previously that bilateral renal denervation abolishes hypertension in adult male IUGR offspring, indicating an important role for the renal nerves in the maintenance of established IUGR-induced hypertension. We also reported that angiotensin-converting enzyme inhibition abolishes hypertension in adult male IUGR offspring. However, activation of the renin-angiotensin system does not occur in male IUGR offspring until after puberty, or after the development of established IUGR-induced hypertension. Therefore, the mechanisms involved in the development of IUGR-induced hypertension may differ from those involved in the maintenance of established IUGR-induced hypertension. Thus, the purpose of the present study was to determine whether the renal nerves play a causative role in the early development of IUGR-induced hypertension in prepubertal IUGR offspring. 2. Intrauterine growth-restricted and control offspring were subjected to either bilateral renal denervation or sham denervation, respectively, at 4 weeks of age. Mean arterial pressure (MAP) was determined at 6 weeks of age in conscious, chronically instrumented animals. Adequacy of renal denervation was verified by renal noradrenaline content. 3. Whereas renal denervation had no effect on MAP in control offspring (103 +/- 2 vs 102 +/- 3 mmHg for sham vs denervated, respectively), it reduced blood pressure in growth-restricted offspring (114 +/- 3 vs 104 +/- 1 mmHg for sham vs denervated, respectively; P < 0.01). Renal noradrenaline content was significantly reduced in denervated animals relative to sham operated rats. 4. Thus, the data indicate a role for the renal nerves in the aetiology of IUGR-induced hypertension and suggest that the renal nerves may participate in the early development of hypertension in IUGR offspring in addition to established hypertension observed in adult male IUGR offspring.

Gene Polymorphisms of the Renin-Angiotensin System and Early Development of Hypertension

A case-control association study was conducted to investigate a possible involvement of polymorphisms of three renin-angiotensin system genes: ACE (I/D and T-3892C), AGT (M235T and T174M), and AT1R (A1166C) in the early development of hypertension. One hundred nineteen hypertensive and 125 normotensive participants aged 18 to 40 years were selected from a broader sample representative of the general population of Croatia. The selection criteria for hypertensive cases were systolic blood pressure (BP) higher than 140 mm Hg or diastolic BP higher than 90 mm Hg and a history of hypertension according to patient interview. Among the polymorphisms investigated, only those located on the ACE gene were associated with hypertension. For ACE I/D, the odds ratio for hypertension of DD versus II homozygote individuals was 2.50 (95% confidence interval [CI] 1.19-5.25) and for ACE T-3892C, the odds ratio of CC versus TT individuals was 2.32 (95% CI 1.05-5.10). Both polymorphisms of the ACE gene were in tight linkage disequilibrium. Of the investigated risk factors for hypertension, only body mass index (BMI) showed an influence on the early development of hypertension, acting independently of the ACE polymorphism. Their additive effect gives rise to 86% of hypertensives in subjects having both the DD genotype and BMI >or=30 kg/m(2). The present study provides evidence of the association of the ACE gene polymorphisms and premature hypertension. In addition, BMI proved to be another important predictor of the disorder acting independently of the ACE gene.

Altered subcellular distribution of Na+,K+-ATPase in proximal tubules in young spontaneously hypertensive rats.

During early development of hypertension, the spontaneously hypertensive rat (SHR) demonstrates increased proximal tubule sodium reabsorption. Our previous observations of reduced Na+,K+-ATPase catalytic alpha1 and gamma subunit transcript abundance in SHR proximal tubule led us to test the hypothesis that increased proximal tubule sodium reabsorption may be attributable to altered subunit protein abundance, post-translational modification, or a shift in subcellular alpha1 and gamma distribution toward the basolateral membrane. We now extend previous gene expression studies by analyzing total cellular alpha1 and gamma protein abundance in proximal tubule from SHR compared with matched Wistar-Kyoto (WKY) controls. We also used sucrose density-gradient centrifugation to isolate basolateral, early, and late endosomal membrane-enriched fractions as well as cell surface biotinylation to test the hypothesis of altered subunit subcellular distribution in the SHR proximal tubule. At 4 weeks of age, significantly greater amounts of alpha1 were present in basolateral membrane-enriched fractions of SHR than WKY (21.1+/-1.8% versus 12.3+/-1.8%; P<0.005), and there was a concomitant reduction of alpha1 in late endosomal membrane-enriched fractions of SHR (63.3+/-2.7% versus 74.8+/-4.3%; P<0.05). This finding was confirmed in cell surface biotinylation studies that showed higher alpha1 (1.45+/-0.1-fold greater; P<0.05) and gamma-subunit (3.48+/-0.7-fold greater; P<0.01) abundance in 4-week-old SHR proximal tubule plasma membrane compared with matched WKY samples. These studies support the hypothesis that development of hypertension in SHR may involve an altered subcellular distribution of proximal tubule Na+,K+-ATPase subunits.

Magnetic resonance measurements of renal blood flow as a marker of disease severity in autosomal-dominant polycystic kidney disease

Autosomal-dominant polycystic kidney disease (ADPKD) is an inherited disorder characterized by renal cyst growth, early development of hypertension, and late occurrence of renal insufficiency. Despite evidence for the importance of nephroangiosclerosis in the progression of renal insufficiency in ADPKD, evaluation of renal blood flow (RBF) as a surrogate marker of disease severity has received little attention. Flow phantoms and repeat RBF measurements assessed accuracy and reproducibility. One hundred twenty-seven ADPKD subjects with creatinine clearances >70 mL/min underwent measurements of RBF, total, and cyst renal volumes, and % cyst volumes by magnetic resonance (MR) and of glomerular filtration rate (GFR). Renal vascular resistance (RVR) was calculated. MR blood flow sequences utilized a two-dimensional cine phase-contrast breath-hold pulse sequence perpendicular to the renal arteries. Flow rates were calculated utilizing FLOW software. Volumetric analysis was performed using stereology and region-based thresholding. Excellent accuracy and intraobserver and interobserver reproducibility were demonstrated. Anatomic (total kidney volume, total cyst volume, and % cyst volume), hemodynamic (RBF and RVR), and functional (GFR) parameters were strongly correlated. Left polycystic kidneys were larger and had more severe disease. Regression analysis showed that age, diagnosis of hypertension, anatomic parameters and hemodynamic parameters were significant predictors of GFR. Multiple linear regression analysis identified age and hemodynamic parameters only as separate predictors of GFR. Anatomic, hemodynamic, and functional parameters discriminated between normotensive and hypertensive subjects despite antihypertensive treatments. Renal hemodynamic parameters measured by MR correlate with anatomic and functional indices of disease severity, are the strongest predictors of renal function, and deserve further consideration as an outcome measure in clinical trials to guide therapy in ADPKD.

Early changes in proteoglycans production by resistance arteries smooth muscle cells of hypertensive rats

Several functional and structural modifications at the vascular level have been described in spontaneously hypertensive rats (SHR) during the early development of hypertension. In this study, we hypothesize that changes in the extracellular matrix (ECM) could precede the development of hypertension. Synthesis of secreted and membrane-bound sulfated proteoglycans (S-PG) by cultured vascular smooth muscle cells (VSMC) obtained from young spontaneously hypertensive rats (pSHR) mesenteric resistance arteries, during the period preceding the elevation of blood pressure (BP) was tested. After 24 h of stimulation with angiotensin II (Ang II), 10% fetal calf serum (FCS), or 0.1% FCS as control, medium and cell layer S-PG synthesis was evaluated by labeling sulfated disaccharides with [ 35S]sodium sulfate. To relate this variable with cell proliferation, DNA synthesis was measured by incorporation of [ 3H]thymidine in the cell lysate. The VSMC from pSHR synthesized more secreted and membrane-bound S-PG than age-matched Wistar rat (pW) cells in the nonstimulated (0.1% FCS) and stimulated (Ang II or 10% FCS) experimental groups. When data were expressed as percent of their own control value, both Ang II and 10% FCS lowered basal secreted and cell-associated S-PG content in VSMC from pSHR, whereas in pW rat cells, these agents produced a small increase or no change. An inverse relationship between proliferation and total S-PG production (secreted plus membrane-bound) was found in pSHR cells, but not in pW cells. In conclusion, the present study demonstrates that changes in S-PG synthesis by VSMC of resistance arteries precede the vascular dysfunction associated with the development of hypertension in SHR.