Hypertension In Offspring Research Articles

Chronic placental ischemia alters amniotic fluid milieu and results in impaired glucose tolerance, insulin resistance and hyperleptinemia in young rats

Although small size at birth is associated with hypertension and associated co-morbidities such as insulin resistance and type II diabetes mellitus, many of the animal models employed to simulate this phenomenon do not closely mimic the ontogeny of growth restriction observed clinically. While intrauterine growth restriction (IUGR) is often detected near mid-pregnancy in women and persists until term, most rodent models of IUGR employ ligation of uterine arteries for a brief period during late gestation (days 19-21 of pregnancy). We hypothesized that IUGR associated with chronic reduction in uteroplacental perfusion (RUPP) and placental ischemia during the third trimester of pregnancy in the rat alters the amniotic fluid (AF) environment and results in hypertensive offspring presenting with metabolic abnormalities such as glucose intolerance and insulin resistance. Insulin-like growth factor-1 (IGF-1), IGF-2, Na(+) concentration and oxidative stress in the AF were increased, while K(+) concentration was decreased in the RUPP compared with normal pregnant (NP) fetuses. RUPP-offspring (RUPP-O) were smaller (6.1 +/- 0.2 versus 6.7 +/- 0.2 g; P < 0.05) at birth compared with NP-offspring (NP-O) groups. At nine weeks of age, mean arterial pressure (121 +/- 3 versus 107 +/- 5 mmHg; P < 0.05), fasting insulin (0.71 +/- 0.014 versus 0.30 +/- 0.08 ng/mL; P < 0.05), glucose (4.4 +/- 0.2 versus 3.1 +/- 0.3 mmol/L; P < 0.05), leptin (3.8 +/- 0.5 versus 2.3 +/- 0.3 ng/mL; P < 0.05) and the homeostasis model assessment of insulin resistance index was greater (2.9 +/- 0.6 versus 1.0 +/- 0.3; P < 0.05) in the RUPP-O compared with the NP-O rats. These data indicate that chronic placental ischemia results in numerous alterations to the fetal environment that contributes to the development of impaired glucose metabolism, insulin resistance and hyperleptinemia in young offspring.

058 Fibroblast growth factor binding protein 1 gene (FGFBP1) and hypertension — from pathway analysis to renal glomerulus

Essential hypertension is a complex, multifactorial disease with a strong genetic component. Fibroblast growth factor 1 gene (FGF1) is one of the most relevant candidates having been associated not only with familial susceptibility to hypertension but also with up-regulation within the glomerulus of the human hypertensive kidney/Circulation 2007;116:1915–24/. We have hypothesised that systematic analysis of genes interacting with FGF1 may uncover novel variants underlying essential hypertension. Seventy-nine common (minor allele frequency≥0.1) tagging (r2≥0.8) and functional single nucleotide polymorphisms (SNPs) spanning eight critical components of the FGF (fibroblast growth factor) pathway (FGF2, FGFR1, FGFR2, FGFR3, FGFR4, FGFBP1, FIBP, SPRY1) were genotyped by MALDI-TOF mass spectrometry in 629 subjects from 207 Polish hypertensive families (Silesian Hypertension Study — SHS). 83.5% of genotyped SNPs that passed quality control filters provided 92.9% genetic coverage of FGF pathway loci. Family-based analysis in SHS revealed that alleles of three SNPs (rs2956724, rs2245964 and rs16892645) in two loci (FGFR1 and FGFBP1) were transmitted to hypertensive offspring more frequently than expected by chance. However, only one association survived correction for multiple testing – major allele of rs16892645 in FGFBP1 was over-transmitted from heterozygous parents to hypertensive offspring more frequently than expected by chance(p=0.0048, false discovery rate

Chronic maternal hypertension affects placental gene expression and differentiation in rabbits

Previously, we have shown that adult offspring from hypertensive rabbits develop hypertension. We aimed to determine the effects of mild (+15 mmHg) and moderate (+25 mmHg) increases in maternal blood pressure and plasma renin activity on placental differentiation and expression of components of the renin-angiotensin system and 11[beta]-hydroxysteroid dehydrogenase type 2 mRNA in rabbits. Placentas were collected from normotensive (sham), mild (2-kidney-1-cellophane wrapped; 2K-1W) and moderate (2-kidney-2-cellophane wrapped; 2K-2W) hypertensive groups at gestational age of 14, 21 and 28 days. Placental gene expression was quantified by reverse transcriptase-PCR, and morphometry was assessed by videoimage analyses of placental sections. Fetal weight was similar between groups across gestation. In the 2K-1W group at gestational age day 14, fetal-to-placental weight ratio was increased (approximately 34%) as were volumes of fetal capillaries ([up arrow]56%) and maternal blood space at gestational age day 21 ([up arrow]55%) compared with sham (all P < 0.05). In the 2K-2W group, fetal-to-placental weight ratio was increased at gestational age day 21 (approximately 25%; P < 0.01) with an accompanying reduction in placental weight, and at gestational age day 28, volume density of fetal capillaries was increased (approximately 22%; P < 0.05). Placental renin mRNA was lower in both the 2K-1W (approximately 88%) and 2K-2W (approximately 98%) groups at gestational age day 28 (all P < 0.01). Placental 11[beta]-hydroxysteroid dehydrogenase type 2 mRNA was lower in the 2K-1W (approximately 36%) and 2K-2W (approximately 31%) groups at gestational age day 14 and greater (approximately 36%) in the 2K-2W group at gestational age day 21 (all P < 0.01). Associations between placental AT1R and AT2R mRNA and placental differentiation were disturbed by hypertension. Mild and moderate maternal hypertension differentially alters placental structure and gene expression that may affect placental functional capacity and contribute to programming of hypertension in offspring.

Maternal diabetes programs hypertension and kidney injury in offspring

We investigated whether maternal diabetes programs the offspring to develop hypertension and kidney injury in adulthood and examined potential underlying mechanisms. In a murine model we studied the offspring of three groups of dams (non-diabetic, diabetic, and diabetic treated with insulin). Mean systolic blood pressure in the offspring was monitored from 8 to 20 weeks. Body and kidney weights in the offspring of diabetic mothers were significantly lower than in offspring of non-diabetic mothers. Offspring of diabetic mothers developed hypertension, microalbuminuria, and glucose intolerance. Increased accumulation of extracellular matrix proteins in the glomeruli and marked upregulation of angiotensinogen, angiotensin II type 1 receptor, angiotensin-converting enzyme, transforming growth factor beta-1 (TGF-beta1), and plasminogen activator inhibitor-1 (PAI-1) gene expression were evident in the renal cortex of hypertensive offspring of diabetic mothers. By contrast, angiotensin-converting enzyme-2 (ACE2) gene expression was lower in the hypertensive offspring of diabetic mothers than in that of non-diabetic mothers. These changes were prevented in the offspring of insulin-treated diabetic mothers. These data indicate that maternal diabetes induces perinatal programming of hypertension, renal injury, and glucose intolerance in the offspring and suggest a central role for the activation of the intrarenal renin-angiotensin system and TGF-beta1 gene expression in this process.

Epigenetic Placental Programming of Preeclampsia

Preeclampsia (PE) affects 8–10% of women in the US and long‐term consequences include development of maternal hypertension and hypertension in offspring. As methylation patterns are established during fetal life, we focused on epigenetic alterations as a plausible explanation of the heritable development of hypertension resulting from maternal PE. In this proof‐of‐principle study we determined genome‐wide CpG DNA methylation patterns in placental tissue from women with normotensive pregnancy and PE (n=3/group) by using 2.1M microarrays (NimbleGen). These arrays tile 7000 bp upstream and 3000 bp downstream a promoter in 100 bp segments and cover 28000 CpG islands. Criteria for gene selection included methylation +/−1000 bp of the respective gene's transcription start site. We identified 163 genes methylated only in PE and uploaded them to DAVID (http://david.abcc.ncifcrf.gov) where we used a classification stringency of high to determine functional annotation clusters. Cluster 1had an enrichment score of 5.59; this cluster contains the GO Terms of anatomical structure formation, angiogenesis, blood vessel development, vasculature development, and blood vessel morphogenesis. There are 12 genes total in this cluster 10 of which are common to all 5 GO Terms. This work suggests that an epigenetic mechanism may be involved in PE.Robert Wood Johnson Nurse Faculty Scholar, Sigma Theta Tau International, ARS

Hypothalamic Angiotensin Type 1 Receptors and Sodium Chloride Intake in Genetically Hypertensive Rats Raised on High Salt Diets

Spontaneously Hypertensive Rats (SHR) may have impaired titration of ingested sodium chloride. The role of Angiotensin II (AII) and hypothalamic angiotensin (AT1) receptor expression in regulating salt and water intake was evaluated in SHR raised from weaning on high salt. Female SHR were crossed with normotensive, Brown Norway (BN) males and hypertensive offspring then were sib/sib mated yielding hypertensive F2 rats that were raised to adulthood on either 4.0% (HS; n=7) or 0.8% (NS; n=8) NaCl chow. NS and HS rats were placed in metabolic pens and offered ad lib access to 2% saline, distilled H2O and sodium free chow and daily water and sodium intakes were measured. After control (2 days), AII synthesis was blocked with Captopril (1 g/L) in the saline and H2O (5 days). Blockade of AII increased NaCl ingestion in both NS (2.63 + 1.57 to 5.20 + 1.66 mmol/day) and HS (3.90 + 1.88 to 7.65 + 3.29 mmol/day) rats compared to control. Captopril decreased H2O ingested by HS rats (20.47 + 3.95 ml/day to 8.29 + 2.78 ml/day) but not by NS rats (16.39 + 4.86 ml/day vs.15.09 + 4.19 ml/day). Hypothalamic AT1 receptor density (western blot) was 60% lower in HS rats compared to NS rats (p&lt;0.05). Thus, reduced AT1 receptor expression in SHR raised on high salt intake may limit HS rats from appropriately adjusting water intake during elevated salt intake. (Funded by NSF #0437768)

Bioavailability of nitric oxide is impaired in hypertensive male IUGR offspring.

Our laboratory utilizes a rat model of placental insufficiency that results in intrauterine growth restriction (IUGR) and hypertension in male IUGR. The purpose of this study was to determine whether impaired nitric oxide (NO) bioavailability contributes to male IUGR hypertension. L‐NAME (nitro‐L‐arginine methyl ester, 10mg/kg/Day) was given in the drinking water for 40 days. Mean arterial pressure (MAP), measured in conscious chronically catheterized rats, was significantly increased in untreated IUGR relative to untreated control (133±3 vs. 122±4 mmHg, P&lt;0.05; IUGR vs. control, respectively). The increase in MAP in response to chronic L‐NAME was greater in control (Ä66 mmHg, 188±12 mmHg, P&lt;0.05 vs. untreated control) as compared to the increase in MAP observed in IUGR (Ä43 mmHg 176±14 mmHg, P&lt;0.05 vs. untreated IUGR). Therefore, these data indicate that control rats were more responsive to NO synthase (NOS) inhibition than IUGR, and that bioavailability of NO may be limited in male IUGR rats. Protein expression of the renal NOS isoforms were significantly reduced upon comparison of male IUGR to male control (eNOS: IUGR indicated 78% of Control; iNOS: IUGR 76% of Control; phosphorylated nNOS IUGR 81% of Control). Thus, these data suggest that a decrease in renal NOS isoform expression may contribute to the reduction in NO bioavailability observed in male IUGR offspring.

Maternal protein restriction leads to hyperresponsiveness to stress and salt-sensitive hypertension in male offspring.

Low birth weight humans often exhibit hypertension during adulthood. Studying the offspring of rat dams fed a maternal low-protein diet is one model frequently used to study the mechanisms of low birth weight-related hypertension. It remains unclear whether this model replicates key clinical findings of hypertension and increased blood pressure responsiveness to stress or high-salt diet. We measured blood pressure via radiotelemetry in 13-wk-old male offspring of maternal normal- and low-protein dams. Neither group exhibited hypertension at baseline; however, 1 h of restraint was accompanied by a significantly greater blood pressure response in low-protein compared with normal-protein offspring. To enhance the effect of a high-salt diet on blood pressure, normal- and low-protein offspring underwent right uninephrectomy, while controls underwent sham surgery. After 5 weeks on a high-salt diet (4% NaCl), mean arterial pressure in the Low-Protein+Sham offspring was elevated by 6 +/- 2 mmHg (P < 0.05 vs. baseline), while it remained unchanged in the normal-protein offspring. In the two uninephrectomized groups, blood pressure increased further, but was of similar magnitude. Glomerular filtration rate in the low-protein uninephrectomized offspring was 50% less than that in normal-protein offspring with intact kidneys. These data indicate that, while male low-protein offspring are not hypertensive during young adulthood, their blood pressure is hyperresponsive to restraint stress and is salt sensitive, and their glomerular filtration rate is more sensitive to hypertension-causing insults. Collectively, these may predispose for the development of hypertension later in life.

Epigenetic changes in gene expression: focus on “The liver X-receptor gene promoter is hypermethylated in a mouse model of prenatal protein restriction”

the term epigenetics was first coined in 1942 by Waddington ([20][1]) to describe the interaction of genes with their environment during development that gives rise to a phenotype. Today, the term epigenetics is used when describing a phenotype that occurs in a manner outside conventional genetic

Evidence for Sympathetic Origins of Hypertension in Juvenile Offspring of Obese Rats

Maternal obesity in rodents is associated with increased adiposity, impaired glucose tolerance, and hypertension in adult offspring. In this study we investigated the influence of maternal obesity in the rat on blood pressure and blood pressure regulatory pathways in juvenile and adult offspring. Obesity was induced before pregnancy in female Sprague-Dawley rats by feeding a highly palatable energy-dense diet. In juvenile animals (30 days of age), before the onset of obesity and hyperleptinemia, basal nighttime mean arterial pressure was significantly raised in the offspring of obese dams (OffOb) relative to offspring of controls (OffCon; mean arterial pressure, males: OffOb, 121.8+/-0.6 mm Hg versus OffCon, 115.0+/-0.5 mm Hg, n=6, P<0.01; females: OffOb, 125.4+/-0.4 mm Hg versus OffCon, 114.4+/-0.5 mm Hg, n=6, P<0.001), as was the mean arterial pressure response to restraint stress (P<0.01). The pressor response to a leptin challenge was enhanced in OffOb rats (Deltamean arterial pressure: OffOb, 9.7+/-0.8 mm Hg versus OffCon, 5.3+/-1.3 mm Hg; n=8; P<0.05). Renal tissue norepinephrine content (P<0.001) and renin expression (P<0.05) were markedly raised. Analysis of heart rate variability revealed an increased low:high frequency ratio in OffOb versus OffCon rats (P<0.05). At 90 days, hypertension in OffOb rats persisted and was abolished by alpha1- and beta-adrenergic blockade, and cardiovascular responses to phenylephrine or sodium nitroprusside indicated altered baroreceptor function. The exaggerated pressor response to leptin in OffOb rats was maintained. Hypertension in the offspring of obese rats may arise from persistent sympathoexcitatory hyperresponsiveness acquired in early stages of development.

Haemodynamic characteristics of hypertension induced by prenatal cortisol exposure in sheep

1. Administration of glucocorticoids to ewes early in pregnancy results in offspring with hypertension in adulthood. The hypertension in female offspring exposed to dexamethasone is associated with increased cardiac output, but whether this is also true in cortisol-exposed offspring is unknown. 2. Systemic haemodynamic variables were measured under basal conditions in castrated male and female adult sheep exposed to cortisol (5 mg/h) or saline (0.19 mL/h) from 26 to 28 days of gestation. To examine the contribution of the autonomic nervous system to maintenance of basal arterial pressure in established hypertension in cortisol-exposed sheep, responses to adrenoceptor blockade (intravenous infusion of 0.15 mg/kg per h phentolamine plus 0.4 mg/kg per h propranolol) and ganglionic blockade (intravenous infusion of 125 mg/h hexamethonium) were examined in castrated male offspring. 3. Mean arterial pressure and calculated systemic vascular resistance were 9% and 17% greater, whereas cardiac output tended to be 8% less, in cortisol-compared with saline-exposed sheep. These effects were not sex dependent. The depressor response to ganglionic blockade and the initial phase of the depressor response to adrenoceptor blockade were greater in cortisol-compared with saline-exposed sheep. 4. These results indicate that hypertension in offspring exposed prenatally to cortisol is associated with increased total peripheral resistance, mimicking observations in human patients with chronic hypertension. Furthermore, the increased vascular resistance appears to be dependent, at least in part, on an increased effect of sympathetic vasomotor drive. Taken together with previous findings, the present observations suggest that prenatal cortisol and dexamethasone programme altered adult cardiovascular function via distinct mechanistic pathways.

Hypertension and kidney alterations in rat offspring from low protein pregnancies

Low birth weight contributes to the early onset of end-stage renal disease. Therefore, this study was undertaken to investigate early and late glomerular structural alterations in both sexes of Wistar rat offspring from dams submitted to severe low protein intake during gestation. Offspring from dams fed normal protein (19% of protein) or low protein (5% of protein) were studied at days 0, 10, 90 and 180 of age. Inner cortical structure showed immature (comma-shaped and S-shaped forms) and mature corpuscles in different proportions in low protein offspring (less maturity) and normal protein offspring (more maturity). At day 10 (end of the nephrogenesis period), immature corpuscles were observed only in low protein offspring. In adulthood, low protein offspring had higher blood pressure, and showed thicker glomerular basement membrane (GBM) with effacement of the pedicles, and slit diaphragm absent with some podocytes directly adhering to the basal membrane with pedicles absent. The number of renal corpuscles was lower in low protein offspring than in normal protein offspring of the same sex, all age groups (P < 0.001). No interaction was observed between sex and maternal nutrition for the same sex and all age groups. Gestational low protein leads to glomerulogenesis retardation and consequently a lower nephron number with thick GBM and structural alterations in the pedicles of podocytes.

Prenatal Cocaine Exposure Differentially Causes Vascular Dysfunction in Adult Offspring

Epidemiological studies have shown a clear association of adverse intrauterine environment and an increased risk of cardiovascular diseases and hypertension in adult life. The present study tested the hypothesis that prenatal cocaine exposure causes reprogramming of vascular reactivity, leading to an increased risk of hypertension in adult offspring. Pregnant rats received cocaine (30 mg kg(-1) day(-1)) or saline from days 15 to 21 of gestational age, and experiments were conducted in 3-month-old offspring. Cocaine had no effect on the baseline blood pressure but significantly increased norepinephrine-stimulated blood pressure and decreased the baroreflex sensitivity in male but not female offspring. The cocaine treatment significantly increased norepinephrine-induced contractions in pressurized resistance-sized mesenteric arteries but not in aortas, which was primarily because of a loss of endothelial NO synthase-mediated inhibition and an enhanced Ca(2+) sensitivity in mesenteric arteries. In addition, the cocaine treatment significantly attenuated the endothelium-dependent relaxation in mesenteric arteries in male but not female offspring. Endothelial NO synthase protein levels in aortas but not mesenteric arteries were significantly increased in the cocaine-treated animals. However, cocaine significantly decreased phosphorylation levels of endothelial NO synthase in both aortas and mesenteric arteries. The results suggest that prenatal cocaine exposure programs vascular contractility via changes in endothelial NO synthase-regulated Ca(2+) sensitivity of myofilaments in the sex- and tissue-dependent manners in resistance arteries leading to an increased risk of hypertension in male offspring.

Maternal low protein diet: Developmental origin of adult hypertension

ObjectiveWe hypothesized that maternal isocaloric, low‐protein, diet during pregnancy programs the Renin Angiotensin System in the fetus leading to hypertension in the adult. We conducted studies on pregnant mice, on isocaloric, normal or low protein diet (50% and 33% less protein).MethodsProteins and mRNA levels were measured using western blot and real time PCR technique and blood pressure was recorded by the non‐invasive tail cuff system.ResultsMaternal low protein diet (MLPD) resulted in low birth weight and rapid catch up growth in both male and female offspring. MLPD induced hypertension in female mice offspring at 11 weeks of age, whereas no hypertension was observed in male offspring by 20th week of age. Our results indicate increased AGT and ACE, but decreased AT2, expression of mRNA, with no change in the protein expression of AGT but decreased protein expression of both, ACE and AT2 receptors with MLPD. Promoter methylation analysis of ACE gene showed hypo‐methylation of the CpG islands as a consequence of maternal protein deprivation.ConclusionsOur studies establish that MLPD programs hypertension in female offspring by epigenetic programming of the renin‐angiotensin system.

Sodium Exposure Induces Stroke in a Genetically Susceptible Model

Much progress has been made since Barker and colleagues first proposed that conditions in utero influence the susceptibility to disease later in life.1 The association between fetal growth retardation and adult hypertension, cardiovascular disease and diabetes mellitus has been established by extensive epidemiology.2,3 It has also been recognized that in order to prevent pathogenic programming we need to identify and target specific maternal factors or conditions, and that maternal overnutrition, rather than undernutrition, is prevalent in the Western world. Several such factors have already been established (eg, maternal hypercholesterolemia,4–6 smoking,7 and diabetes mellitus8) and experimental models have been developed in which mechanisms and causal relationships of developmental programming can be investigated. Finally, the influence of maternal or environmental factors on adult disease is now widely accepted, and the expectation of a wave of cardiovascular disease in children of obese, hyperlipidemic, and diabetic mothers has led the US Congress and the National Institutes of Health to place great emphasis on the elucidation of specific risk factors (eg, in the National Children’s Study9). Animal models are key to identifying the mechanisms involved and finding preventive approaches that go beyond simple avoidance of risk during pregnancy or treatment of maternal dysmetabolic conditions. Article p 1501 In this regard, hypertension and stroke lag far behind. Although hypertension is a major risk factor of cardiovascular disease in adults, and fetal exposure to high salt concentrations promotes hypertension in offspring in both salt-sensitive and resistant rat strains,10,11 most of what we know about in utero modulation of hypertensive mechanisms comes from models of maternal hypercholesterolemia or obesity rather than hypertension. For example, maternal hypercholesterolemia and the ensuing increased oxidative stress not only promote atherogenesis but affect endothelial function, probably by interfering with nitric oxide–mediated vascular relaxation.12–14 Furthermore, endothelial …

Developmental programming of sex-dependent alterations in lipid metabolism: a role for long-term, sex-specific alterations in LDL-receptor expression. Focus on “Developmental programming of lipid metabolism and aortic vascular function in C57BL/6 mice: a novel study suggesting an involvement of LDL-receptor”

the nobel prize in physiology or medicine was awarded to Brown and Goldstein in 1985 for their discovery of the low-density lipoprotein (LDL) receptor and its importance in the regulation of cholesterol metabolism ([2][1]). Cholesterol, an essential component of the mammalian cell membrane, is

544: Maternal regulation of high fat nourishment during lactation period reduce a hypertension of male offspring

544: Maternal regulation of high fat nourishment during lactation period reduce a hypertension of male offspring

PRENATAL EXPOSURE TO ZYMOSAN RESULTS IN HYPERTENSION IN ADULT OFFSPRING RATS

1. Events in utero appear to have a significant role in the development of cardiovascular dysfunction in adulthood. In the present study, we evaluated the effects of prenatal exposure to zymosan, a non-infectious and non-bacterial agent capable of inducing inflammation, on mean systolic arterial pressure (MSAP) in rat offspring at 6-66 weeks of age. 2. Pregnant rats were divided into three groups: (i) a control group, administered 0.5 mL, i.p., saline on gestation Days 8, 10 and 12; (ii) a zymosan-treated group, given 2.37 mg/kg, i.p., zymosan on gestation Days 8, 10 and 12; and (iii) a pyrrolidine dithiocarbamate (PDTC) + zymosan-treated group, which was given 100 mg/kg, i.p., PDTC 1 h before zymosan. At 6, 16, 26, 36, 56 and 66 weeks of age, MSAP was determined in rat offspring from all three groups. Serum levels of tumour necrosis factor (TNF)-alpha were determined in dams, as well as in offspring at 24 and 56 weeks of age. In addition, protein levels of nuclear factor (NF)-kappaB (p65) in the myocardium and kidney of offspring were determined at 24 weeks of age. 3. The results showed that MSAP and NF-kappaB (p65) levels in the myocardium and kidney of offspring from the zymosan-treated group were increased significantly compared with control. This increase was inhibited by concomitant treatment with PDTC. Serum TNF-alpha levels in dams exposed to zymosan and in their offspring at 56 weeks of age (but not at 24 weeks of age) were significantly increased compared with levels in the control group. Following lipopolysaccharide treatment (1 mg/kg, i.p.) of adult rat offspring at 24 weeks of age, there was a further increase in serum TNF-alpha levels in offspring in the zymosan-treated group compared with the other two groups. 4. The findings of the present study suggest that non-bacterial inflammation during gestation can lead to hypertension in offspring and that NF-kappaB signalling may play a critical role in this process.

To be or not to be … hypertensive: That is the question

‘Measure what is measurable and make measurable what is not so’. Galileo's dictum may easily be applied to the history of the measurement of blood pressure – the force at the point of measurement (usually in mmHg) within the cardiovascular system (i.e. the pressure exerted by the blood on the wall of the blood vessel). Blood pressure (BP) is created through the opposing forces generated by the pumping of the heart – within a closed circulatory system – against the resistance offered by the peripheral vasculature. The first recorded measurement of BP in an animal (a horse in 1733) required a brass pipe being directly inserted into a major artery (by the Rev Stephen Hales). Thankfully, techniques for blood pressure measurement have been refined but invasive cannulation remains the gold standard (e.g. radiotelemetry). Non-invasive sphygmomanometry (developed ∼1881) had much greater clinical application and very soon it was clear that the blood pressure distribution in a given population was normal (Gaussian), where a defined rightward shift identified individuals as being ‘hypertensive’, i.e. a statistical term denoting a significant shift away from the median for the population from which the individual was drawn. For man, this shift is ∼20 mmHg (from an optimal systolic blood pressure of 120 mmHg to stage I hypertensive of > 140 mmHg; Verdecchia & Angeli, 2003). Sphygmomanometry was readily applied to animals from rodents (Pfeffer et al. 1971) to horses (Giussani et al. 2003), but has always attracted criticism (Gross & Luft, 2003), due mainly to experimental error or being ‘stressful’ and therefore representing ‘resting’ BP (Tonkiss et al. 1998). Consequently, a number of studies have sought to validate the procedure (e.g. Pfeffer et al. 1971; Bunag, 1973). The paradigm of the developmental origins of health and disease is an active area of research that has brought the methods for measurement of BP into focus and stimulated much related debate. Fourteen years ago it was shown that a maternal low protein (MLP) diet fed to young Wistar rats (i.e. 90 versus 180 g kg−1) increased the systolic blood pressure of their adult offspring (Langley & Jackson, 1994), as assessed by tail-cuff sphygmomanometry. To my knowledge, and surprisingly, no further study since has sought to corroborate these data with radiotelemetry and with some groups reporting similar increases in BP (Woods et al. 2001), no change (Martin et al. 2004) or reduced BP (after global nutrient restriction; Brennan et al. 2008), the field appears confusing, in part, because of the different methods used for measurement of BP. Does a maternal low protein diet lead to hypertensive offspring or alternatively, offspring more ‘stressed’ by the tail-cuff procedure (Tonkiss et al. 1998)? Rodford et al. (2008) in the current issue of The Journal of Physiology, revisit the MLP paradigm and report no change in tail-cuff measured systolic blood pressure in the offspring from 4 to 16 weeks of age, in contrast to much of the published literature. Rather, they observe marked effects on the structure and function of the endothelium that is, in part, sex specific. They interpret the data as an adaptation to the less than optimal prenatal environment that may mark ‘prehypertensives' (rats after all may live > 100 weeks). An optimal functioning endothelium is crucial to stable blood pressure control (e.g. through tonic generation of nitric-oxide and endothelins) and has one of the largest active surface areas of any organ in the body. The authors rightly argue that the lack of effect on resting (or stimulated) blood pressure measured by tail-cuff sphygmomanometry is perhaps not important; rather, demonstration of hypertension (relative to a contemporaneous control population) is a useful tool for demonstrating proof-of-principle (i.e. that the prenatal environment has delayed effects) but may not be symptomatic of clinical disease. Indeed, rats rarely, if ever, suffer cardiovascular disease. As the authors point out, in robust epidemiological studies the inverse relationship between low birth weight (an outcome often observed after MLP) and adult blood pressure is less clear cut than with clinical cardiovascular outcomes (Curhan et al. 1996). While the study of Rodford et al. focuses attention on the endothelium as a potentially important marker of prehypertension, many questions remain. How does MLP in utero affect endothelial remodelling? Is the adaptive response prenatal or postnatal (unresolved in the current study as the offspring were not cross-fostered)? Why the sex specificity? Fetal growth is supply driven; cut the supply (e.g. of nutrients) and growth slows, the available blood volume may redistribute to provide substrate for growth in essential organ beds (e.g. the brain and heart) leaving the peripheral cardiovascular network susceptible at a developmentally sensitive time (Berry, 1978; Folkow, 1993). In another 14 years perhaps these will be answered and the data can be translated into clinical practice.

Increased sympathetic activity in normotensive offspring of malignant hypertensive parents compared to offspring of normotensive parents

Malignant hypertension seems to be the consequence of very high blood pressure. Furthermore, an increase in sympathetic and renin-angiotensin system activity is considered to be the main mechanisms producing malignant hypertension. In the present study, 10 offspring of malignant hypertensive (OMH) parents (age 28 +/- 5 years, 7 males, 3 females, 2 white and 8 non-white) and 10 offspring of normotensive (ONT) parents (age 28 +/- 6 years, 2 males, 8 females, 3 white and 7 non-white) were evaluated. The OMH group had significantly higher (P < 0.05) casual blood pressure (125 +/- 10/81 +/- 5 mmHg) compared with ONT (99 +/- 13/67 +/- 5 mmHg). The increase in blood pressure was greater in OMH (Delta SBP = 17 +/- 2 vs Delta SBP = 9 +/- 1 mmHg in ONT) during cold pressor testing, but they had a lower increase in heart rate (Delta HR = 13 +/- 2 vs Delta HR = 20 +/- 3 bpm in ONT) during isometric exercise(handgrip test). Sympathetic activity, measured by microneurography, was significantly higher (P < 0.05) before exercise in OMH (17 +/- 6 vs 11 +/- 4 burst/min in ONT) and exhibited a greater increase (Delta = 18 +/- 10 vs Delta = 8 +/- 3 burst/min in ONT) during isometric exercise. This study showed increased sympathetic activity in OMH before exercise and a greater response during isometric exercise, suggesting an autonomic abnormality before exercise and a greater sympathetic response to physical stress in OMH compared to ONT.