G protein-coupled receptors (GPCRs) are important drug targets. Blocking angiotensin II (Ang II) type 1 receptor signaling alleviates hypertension and improves outcomes in patients with heart failure. Changes in structure and trafficking of GPCR, and desensitization of GPCR signaling induce pathophysiological processes. We investigated whether Ang II, via induction of AT1R and μ-opioid receptor (μOR) dimerization in the nucleus tractus solitarius (NTS), leads to progressive hypertension. Ang II signaling increased μOR and adrenergic receptor α2A (α2A-AR) heterodimer levels and decreased expression of extracellular signal-regulated kinases 1/2 T202/Y204 , ribosomal protein S6 kinase T359/S363 , and nNOS S1416 phosphorylation. Dimethylarginine dimethylaminohydrolase 1 (DDAH1) expression was abolished in the NTS of adult spontaneously hypertensive rats (SHRs). Endomorphin-2 was overexpressed in NTS of adult SHRs compared with that in 6-week-old Wistar-Kyoto rats (WKY). Administration of μOR agonist into the NTS of WKY increased blood pressure (BP), decreased nitric oxide (NO) production, and decreased DDAH1 activity. μOR agonist significantly reduced the activity of DDAH1 and decreased neuronal NO synthase (nNOS) phosphorylation. The AT1R II inhibitor, losartan, significantly decreased BP and abolished AT1R-induced formation of AT1R and μOR, and α2A-AR and μOR, heterodimers. Losartan also significantly increased the levels of nNOS S1416 phosphorylation and DDAH1 expression. These results show that Ang II may induce expression of endomorphin-2 and abolished DDAH1 activity by enhancing the formation of AT1R and μOR heterodimers in the NTS, leading to progressive hypertension.

Epoxyeicosatrienoic acids (EETs) and their synthetic analogs have cardiovascular protective effects. Here, we investigated the action of a novel EET analog EET-B on the progression of post-myocardial infarction (MI) heart failure in spontaneously hypertensive rats (SHR). Adult male SHR were divided into vehicle- and EET-B (10 mg/kg/day; p.o., 9 weeks)-treated groups. After 2 weeks of treatment, rats were subjected to 30-min left coronary artery occlusion or sham operation. Systolic blood pressure (SBP) and echocardiography (ECHO) measurements were performed at the beginning of study, 4 days before, and 7 weeks after MI. At the end of the study, tissue samples were collected for histological and biochemical analyses. We demonstrated that EET-B treatment did not affect blood pressure and cardiac parameters in SHR prior to MI. Fractional shortening (FS) was decreased to 18.4 ± 1.0% in vehicle-treated MI rats compared with corresponding sham (30.6 ± 1.0%) 7 weeks following MI induction. In infarcted SHR hearts, EET-B treatment improved FS (23.7 ± 0.7%), markedly increased heme oxygenase-1 (HO-1) immunopositivity in cardiomyocytes and reduced cardiac inflammation and fibrosis (by 13 and 19%, respectively). In conclusion, these findings suggest that EET analog EET-B has beneficial therapeutic actions to reduce cardiac remodeling in SHR subjected to MI.

Hypertension is a risk factor for cardiovascular disease, the leading cause of death worldwide. Although multiple factors contribute to the pathogenesis of hypertension, studies by Dr David Barker reporting an inverse relationship between birth weight and blood pressure led to the hypothesis that slow growth during fetal life increased blood pressure and the risk for cardiovascular disease in later life. It is now recognized that growth during infancy and childhood, in addition to exposure to adverse influences during fetal life, contributes to the developmental programming of increased cardiovascular risk. Numerous epidemiological studies support the link between influences during early life and later cardiovascular health; experimental models provide proof of principle and indicate that numerous mechanisms contribute to the developmental origins of chronic disease. Sex has an impact on the severity of cardiovascular risk in experimental models of developmental insult. Yet, few studies examine the influence of sex on blood pressure and cardiovascular health in low-birth weight men and women. Fewer still assess the impact of ageing on sex differences in programmed cardiovascular risk. Thus, the aim of the present review is to highlight current data about sex differences in the developmental programming of blood pressure and cardiovascular disease.

Hypertension is a major contributor to worldwide morbidity and mortality rates related to cardiovascular disease. There are important sex differences in the onset and rate of hypertension in humans. Compared with age-matched men, premenopausal women are less likely to develop hypertension. However, after age 60, the incidence of hypertension increases in women and even surpasses that seen in older men. It is thought that changes in levels of circulating ovarian hormones as women age may be involved in the increase in hypertension in older women. One of the key mechanisms involved in the development of hypertension in both men and women is an increase in sympathetic nerve activity (SNA). Brain regions important for the regulation of SNA, such as the subfornical organ, the paraventricular nucleus and the rostral ventral lateral medulla, also express specific subtypes of oestrogen receptors. Each of these brain regions has also been implicated in mechanisms underlying risk factors for hypertension such as obesity, stress and inflammation. The present review brings together evidence that links actions of oestrogen at these receptors to modulate some of the common brain mechanisms involved in the ability of hypertensive risk factors to increase SNA and blood pressure. Understanding the mechanisms by which oestrogen acts at key sites in the brain for the regulation of SNA is important for the development of novel, sex-specific therapies for treating hypertension.

Reduced nitric oxide (NO)/cGMP signalling is observed in age-related vascular disease. We hypothesize that this disturbed signalling involves effects of genomic instability, a primary causal factor in aging, on vascular smooth muscle cells (VSMCs) and that the underlying mechanism plays a role in human age-related vascular disease. To test our hypothesis, we combined experiments in mice with genomic instability resulting from the defective nucleotide excision repair gene ERCC1 ( Ercc1 d/− mice), human VSMC cultures and population genome-wide association studies (GWAS). Aortic rings of Ercc1 d/− mice showed 43% reduced responses to the soluble guanylate cyclase (sGC) stimulator sodium nitroprusside (SNP). Inhibition of phosphodiesterase (PDE) 1 and 5 normalized SNP-relaxing effects in Ercc1 d/− to wild-type (WT) levels. PDE1C levels were increased in lung and aorta. cGMP hydrolysis by PDE in lungs was higher in Ercc1 d/− mice. No differences in activity or levels of cGMP-dependent protein kinase 1 or sGC were observed in Ercc1 d/− mice compared with WT. Senescent human VSMC showed elevated PDE1A and PDE1C and PDE5 mRNA levels (11.6-, 9- and 2.3-fold respectively), which associated with markers of cellular senescence. Conversely, PDE1 inhibition lowered expression of these markers. Human genetic studies revealed significant associations of PDE1A single nucleotide polymorphisms with diastolic blood pressure (DBP; β =0.28, P =2.47×10 −5 ) and carotid intima–media thickness (cIMT; β =−0.0061, P =2.89×10 −5 ). In summary, these results show that genomic instability and cellular senescence in VSMCs increase PDE1 expression. This might play a role in aging-related loss of vasodilator function, VSMC senescence, increased blood pressure and vascular hypertrophy.

We have previously shown that individual β-amino acid substitution in angiotensin (Ang) II reduced Ang II type 1 receptor (AT 1 R) but not Ang II type 2 receptor (AT 2 R)-binding and that the heptapeptide Ang III exhibited greater AT 2 R:AT 1 R selectivity than Ang II. Therefore, we hypothesized that β-amino-acid-substituted Ang III peptide analogues would yield highly selective AT 2 R ligands, which we have tested in binding and functional vascular assays. In competition binding experiments using either AT 1 R- or AT 2 R-transfected human embryonic kidney (HEK)-293 cells, novel β-substituted Ang III analogues lacked appreciable AT 1 R affinity, whereas most compounds could fully displace 125 I-Sar 1 Ile 8 Ang II from AT 2 R. The rank order of affinity at AT 2 R was CGP42112 > Ang III > β-Pro 7 Ang III=Ang II > β-Tyr 4 Ang III ≥ PD123319 >> β-Phe 8 Ang III >> β Arg 2 Ang III=β-Val 3 Ang III >> β-Ile 5 Ang III. The novel analogue β-Pro 7 Ang III was the most selective AT 2 R ligand tested, which was >20 000-fold more selective for AT 2 R than AT 1 R. IC 50 values at AT 2 R from binding studies correlated with maximum vasorelaxation in mouse aortic rings. Given that β-Pro 7 Ang III was an AT 2 R agonist, we compared β-Pro 7 Ang III and native Ang III for their ability to reduce blood pressure in separate groups of conscious spontaneously hypertensive rats. Whereas Ang III alone increased mean arterial pressure (MAP), β-Pro 7 Ang III had no effect. During low-level AT 1 R blockade, both Ang III and β-Pro 7 Ang III, but not Ang II, lowered MAP (by ∼30 mmHg) at equimolar infusions (150 pmol/kg/min for 4 h) and these depressor effects were abolished by the co-administration of the AT 2 R antagonist PD123319. Thus, β-Pro 7 Ang III has remarkable AT 2 R selectivity determined in binding and functional studies and will be a valuable research tool for insight into AT 2 R function and for future drug development.

We examined the impact of progressive hypotension with and without hypocapnia on regional extracranial cerebral blood flow (CBF) and intracranial velocities. Participants underwent progressive lower-body negative pressure (LBNP) until pre-syncope to inflict hypotension. End-tidal carbon dioxide was clamped at baseline levels (isocapnic trial) or uncontrolled (poikilocapnic trial). Middle cerebral artery (MCA) and posterior cerebral artery (PCA) blood velocities (transcranial Doppler; TCD), heart rate, blood pressure and end-tidal carbon dioxide were obtained continuously. Measurements of internal carotid artery (ICA) and vertebral artery (VA) blood flow (ICA BF and VA BF respectively) were also obtained. Overall, blood pressure was reduced by ∼20% from baseline in both trials ( P <0.001). In the isocapnic trial, end-tidal carbon dioxide was successfully clamped at baseline with hypotension, whereas in the poikilocapnic trial it was reduced by 11.1 mmHg ( P <0.001) with hypotension. The decline in the ICA BF with hypotension was comparable between trials (−139±82 ml; ∼30%; P <0.0001); however, the decline in the VA BF was −28±22 ml/min (∼21%) greater in the poikilocapnic trial compared with the isocapnic trial ( P =0.002). Regardless of trial, the blood flow reductions in ICA (−26±14%) and VA (−27±14%) were greater than the decline in MCA (−21±15%) and PCA (−19±10%) velocities respectively ( P ≤0.01). Significant reductions in the diameter of both the ICA (∼5%) and the VA (∼7%) contributed to the decline in cerebral perfusion with systemic hypotension, independent of hypocapnia. In summary, our findings indicate that blood flow in the VA, unlike the ICA, is sensitive to changes hypotension and hypocapnia. We show for the first time that the decline in global CBF with hypotension is influenced by arterial constriction in the ICA and VA. Additionally, our findings suggest TCD measures of blood flow velocity may modestly underestimate changes in CBF during hypotension with and without hypocapnia, particularly in the posterior circulation.

The type 2 angiotensin receptor (AT 2 R) has been suggested to counterbalance the type 1 angiotensin receptor (AT 1 R) in the central regulation of blood pressure and sympathetic tone. In the present study we investigated the blood pressure responses to stimulation of central AT 2 Rs by the selective agonist Compound 21 in conscious spontaneously hypertensive rats (SHRs) and normotensive Wistar Kyoto rats (WKY rats). We also assessed the impact on noradrenaline [norepinephrine (NE)] plasma levels, autonomic function, spontaneous baroreflex sensitivity, and the possible involvement of the nitric oxide (NO) pathway and the AT 1 Rs. Chronic intracerebroventricular Compound 21 infusion lowered blood pressure and NE plasma levels in both rat strains. The night-time hypotensive effect was greater in SHRs compared with WKY rats. Compound 21 improved spontaneous baroreflex sensitivity more in SHRs than in WKY rats. These effects were abolished by co-administration of the AT 2 R antagonist PD123319 or the NO synthase inhibitor N ω -nitro- L -arginine methyl ester hydrochloride (L -NAME). Central AT 1 R blockade did not enhance the hypotensive response to Compound 21. Chronic selective stimulation of central AT 2 Rs lowers blood pressure through sympathoinhibition, and improves spontaneous baroreflex sensitivity more in SHRs than in WKY rats. These responses appear to require a functioning central NO pathway, but are not modified by central AT 1 R blockade. Collectively, the data demonstrate specific beneficial effects of stimulation of central AT 2 Rs in hypertension associated with increased sympathetic tone, and suggest that central AT 2 Rs may represent a potential new therapeutic target for the treatment of neurogenic hypertension.

The baroreflex plays a key role in human BP (blood pressure) regulation. Its efferent limb consists of a vagal and a sympathetic component. The Valsalva manoeuvre is widely used to quantify vagal baroreflex function [BRS_vagal (vagal baroreflex sensitivity)], but most studies have focused on the R–R interval response to BP decrement, even though the subsequent response to an increment in BP is important and different. In the present study, we sought to evaluate whether BRS_vagal can be determined from BRSvagal inc (BRS_vagal derived from the rise in BP during phases III–IV of the Valsalva manoeuvre), to assess the association between BRSvagal inc and BRSvagal dec (BRS_vagal derived from the preceeding BP decrement) and to validate BRSvagal inc as an index of autonomic function. We studied patients with severe autonomic failure ( n =49, 25 female), mild autonomic failure ( n =25, 11 female) and matched normal controls ( n =29, 15 female). BRSvagal inc and BRSvagal dec were calculated as the regression slope of R–R interval and systolic BP during phases III–IV and the early phase II of the Valsalva manoeuvre respectively, and compared these with other autonomic indices across the groups. BRSvagal inc was calculated in all subjects and correlated highly with BRSvagal dec ( r =0.72, P <0.001). BRSvagal inc also correlated significantly with BP changes during phases II and IV of the Valsalva manoeuvre and sympathetic barosensitivity. BRSvagal inc was significantly different between the groups, being highest in the controls and lowest in patients with severe autonomic failure. In conclusion, vagal BRS, determined by relating R–R interval with the BP increase following phase III, is a valuable autonomic index, provides additional information about vagal baroreflex function and reflects overall severity of autonomic failure.

Statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) reduce plasma cholesterol and improve endothelium-dependent vasodilation, inflammation and oxidative stress. A ‘pleiotropic’ property of statins receiving less attention is their effect on the autonomic nervous system. Increased central sympathetic outflow and diminished cardiac vagal tone are disturbances characteristic of a range of cardiovascular conditions for which statins are now prescribed routinely to reduce cardiovascular events: following myocardial infarction, and in hypertension, chronic kidney disease, heart failure and diabetes. The purpose of the present review is to synthesize contemporary evidence that statins can improve autonomic circulatory regulation. In experimental preparations, high-dose lipophilic statins have been shown to reduce adrenergic outflow by attenuating oxidative stress in central brain regions involved in sympathetic and parasympathetic discharge induction and modulation. In patients with hypertension, chronic kidney disease and heart failure, lipophilic statins, such as simvastatin or atorvastatin, have been shown to reduce MNSA (muscle sympathetic nerve activity) by 12–30%. Reports concerning the effect of statin therapy on HRV (heart rate variability) are less consistent. Because of their implications for BP (blood pressure) control, insulin sensitivity, arrhythmogenesis and sudden cardiac death, these autonomic nervous system actions should be considered additional mechanisms by which statins lower cardiovascular risk.

Over the last 20 years it has become recognized that low-grade inflammation plays a role in cardiovascular disease. More recently, participation of the innate and the adaptive immune response in mechanisms that contribute to inflammation in cardiovascular disease has been reported in atherosclerosis and hypertension. Different subsets of lymphocytes and their cytokines are involved in vascular remodelling in hypertension, chronic kidney disease and heart disease. Effector T-cells include Th1 (interferon-γ-producing) and Th2 (interleukin-4 producing) lymphocytes, as well as Th17 (which produce interleukin-17) and T-suppressor lymphocytes such as T reg -cells (regulatory T-cells), which express the transcription factor Foxp3 (forkhead box P3) and participate respectively as pro- and anti-inflammatory cells. Pro-inflammatory T-lymphocytes participate in mechanisms of cardiovascular disease in part by mediating the effects of angiotensin II and mineralocorticoids. Involvement of immune mechanisms in cardiac, vascular and renal changes in hypertension has been demonstrated in many experimental models, an example being the Dahl-salt sensitive rat and the spontaneously hypertensive rat. How activation of immunity is triggered remains unknown, but neo-antigens could be generated by elevated blood pressure through damage-associated molecular pattern receptors or other mechanisms. Once activated, Th1 cells may contribute to blood pressure elevation by affecting the kidney, vascular remodelling of blood vessels directly via the effects of the cytokines produced or through their effects on perivascular fat. T reg -cells protect from blood pressure elevation by acting upon similar targets. Recent data suggests that participation of these mechanisms that have been demonstrated already in murine models also occurs in humans. These novel findings may open the way for new therapeutic approaches to improve outcomes in hypertension and cardiovascular disease in humans.

SNS (sympathetic nervous system) activation is a common feature of arterial hypertension and has been demonstrated to contribute to the development and progression of the hypertensive state. Persuasive evidence suggests a strong association between SNS overactivity and variety of disease states, including chronic renal failure, insulin resistance, congestive heart failure, sleep apnoea, ventricular arrhythmias and others. Although sympatholytic agents are available to target SNS overactivity pharmacologically, they are not widely used in clinical practice, leaving the SNS unopposed in many patients. The recent introduction of catheter-based renal denervation as an alternative approach to target the SNS therapeutically has been demonstrated to result in a clinically relevant blood pressure reduction in patients with resistant hypertension, presumably through its effects on both efferent and afferent renal nerve traffic. Available data on this interventional procedure demonstrate a favourable vascular and renal safety profile. Preliminary data obtained primarily from small and mostly uncontrolled studies in related disease states often characterized by overactivity of the SNS are promising, but require confirmation in appropriately designed clinical trials. In the present paper, we briefly review the physiology of the renal nerves and their role in hypertension and other relevant disease states, summarize the data currently available from clinical studies pertaining to the safety and efficacy of renal denervation in resistant hypertension, discuss potential future implications and the available data supporting such a role for renal denervation, and describe some of the newer devices currently under investigation to achieve improved blood pressure control via renal denervation.

Aerobic exercises such as running, walking and cycling are known to elicit a PEH (post-exercise hypotensive) response in both trained and UT (untrained) subjects. However, it is not known whether swim exercise produces a similar effect in normotensive individuals. The complex acute physiological responses to water immersion suggest swimming may affect BP (blood pressure) differently than other forms of aerobic exercises. We tested the hypothesis that an acute bout of swimming would fail to elicit a PEH BP response compared with an equivalent bout of stationary cycling, regardless of training state. We studied 11 UT and ten triathlon-trained young healthy normotensive [SBP/DBP (systolic BP/diastolic BP) <120/80 mmHg)] men and women (age 23±1 years) who underwent 30 min of intensity-matched cycling and swimming sessions to assess changes in BP during a 75-min seated recovery. CO (cardiac output), SV (stroke volume), TPR (total peripheral resistance), HR (heart rate), HRV (HR variability) and core and skin temperature were also assessed. In UT subjects, PEH was similar between cycling (−3.1±1 mmHg) and swimming (−5.8±1 mmHg), with the greater magnitude of PEH following swimming, reflecting a significant fall in SV between modalities ( P <0.05). Trained individuals did not exhibit a PEH response following swimming (0.3±1 mmHg), yet had a significant fall in SBP at 50 min post-cycling exercise (−3.7±1 mmHg) ( P <0.05). The absence of PEH after swimming in the trained group may reflect a higher cardiac sympathetic outflow [as indicated by the LF (low-frequency) spectral component of HRV) (25 and 50 min) ( P <0.05)] and a slower return of vagal tone, consistent with a significant increase in HR between modalities at all time points ( P <0.05). These results suggest that training may limit the potential for an effective post-exertional hypotensive response to aerobic swimming.

Pre-eclampsia is increasingly recognized as more than an isolated disease of pregnancy. Women who have had a pregnancy complicated by pre-eclampsia have a 4-fold increased risk of later cardiovascular disease. Intriguingly, the offspring of affected pregnancies also have an increased risk of higher blood pressure and almost double the risk of stroke in later life. Experimental approaches to identify the key features of pre-eclampsia responsible for this programming of offspring cardiovascular health, or the key biological pathways modified in the offspring, have the potential to highlight novel targets for early primary prevention strategies. As pre-eclampsia occurs in 2–5% of all pregnancies, the findings are relevant to the current healthcare of up to 3 million people in the U.K. and 15 million people in the U.S.A. In the present paper, we review the current literature that concerns potential mechanisms for adverse cardiovascular programming in offspring exposed to pre-eclampsia, considering two major areas of investigation: first, experimental models that mimic features of the in utero environment characteristic of pre-eclampsia, and secondly, how, in humans, offspring cardiovascular phenotype is altered after exposure to pre-eclampsia. We compare and contrast the findings from these two bodies of work to develop insights into the likely key pathways of relevance. The present review and analysis highlights the pivotal role of long-term changes in vascular function and identifies areas of growing interest, specifically, response to hypoxia, immune modification, epigenetics and the anti-angiogenic in utero milieu.

By inducing BK (bradykinin)-stimulated adrenomedullary catecholamine release, bolus injection of the β-fragment of activated plasma coagulation Factor XII (β-FXIIa) transiently elevates BP (blood pressure) and HR (heart rate) of anaesthetized, vagotomized, ganglion-blocked, captopril-treated bioassay rats. We hypothesized that intravenous infusion of β-FXIIa into intact untreated rats would elicit a qualitatively similar vasoconstrictor response. BN (Brown Norway) rats received for 60 min either: (i) saline (control; n =10); (ii) β-FXIIa (85 ng/min per kg of body weight; n =9); or (iii) β-FXIIa after 2ADX (bilateral adrenalectomy; n =9). LV (left ventricular) volume and aortic BP were recorded before (30 min baseline), during (60 min) and after (30 min recovery) the infusion. TPR (total peripheral resistance) was derived from MAP (mean arterial pressure), SV (stroke volume) and HR. Saline had no haemodynamic effects. β-FXIIa infusion increased its plasma concentration 3-fold in both groups. In adrenally intact rats, β-FXIIa infusion increased MAP by 6% (5±2 mmHg) and TPR by 45% (0.50±0.12 mmHg/ml per min), despite falls in SV (−38±8 μl) and HR [−18±5 b.p.m. (beats/min)] (all P <0.05). In 2ADX rats, β-FXIIa had no HR effect, but decreased SV (−89±9 μl) and MAP (−4±1 mmHg), and increased TPR by 66% (0.59±0.15 mmHg/ml per min) (all P <0.05). After infusion, adrenally intact rats exhibited persistent vasoconstriction (MAP, 10±1 mmHg; TPR, 0.55±0.07 mmHg/ml per min; both P <0.05), whereas in 2ADX rats, MAP remained 5±1 mmHg below baseline ( P <0.05) and TPR returned to baseline. End-study arterial adrenaline (epinephrine) concentrations in the three groups were 1.9±0.6, 9.8±4.1 and 0.6±0.2 nmol/l respectively. Thus, in neurally intact lightly anaesthetized untreated rats, β-FXIIa infusion induces both adrenal catecholamine-mediated and adrenally independent increases in peripheral resistance.

PPH (postprandial hypotension), leading to increased morbidity and mortality, is an important clinical problem, particularly in the elderly and individuals with autonomic dysfunction. The magnitude of the postprandial fall in BP (blood pressure) appears to be dependent on the rate of nutrient entry into the small intestine and may be related to changes in splanchnic blood flow and sympathetic nerve activity. We aimed at determining the comparative effects of different ID (intraduodenal) glucose loads on BP, HR (heart rate), SMA (superior mesenteric artery) flow and vascular conductance and plasma NA (noradrenaline) in ‘young’ and ‘older’ subjects. A total of 12 ‘young’ (six male and six female; age, 22.2±2.3 years) and 12 ‘older’ (six male and six female; age, 68.7±1.0 years) subjects, the latter who have been studied previously [Vanis, Gentilcore, Rayner, Wishart, Horowitz, Feinle-Bisset and Jones (2011) Am. J. Physiol. Regul. Integr. Comp. Physiol., 300 , R1524–R1531], had measurements of BP, HR, SMA flow and plasma NA before, and during, ID infusions of glucose at 1, 2 or 3 kcal/min (‘G1’, ‘G2’ and ‘G3’) (where 1 kcal≈4.184 J), or ‘S’ (saline) for 60 min. In ‘young’ subjects, there was no change in BP during any of the four infusions. In contrast, in ‘older’ subjects, SBP (systolic BP) fell during ‘G2’, and ‘G3’ ( P <0.005 for both), but not during ‘S’ or ‘G1’. In ‘young’ and ‘older’ subjects HR increased during ‘G2’ ( P <0.05) and ‘G3’ ( P <0.001), a response that was greater ( P <0.05) in the young, but not during ‘S’ or ‘G1’. The rise in SMA flow and vascular conductance in response to ID glucose were load-dependent in both ‘young’ and ‘older’ subjects ( P <0.001 for all), with no difference between them. Plasma NA rose in response to ‘G2’ and ‘G3’ ( P <0.05) in the young, but in ‘G3’ ( P <0.05) only in the ‘older’ subjects, with no difference between them. Hence, in response to small intestinal glucose infusions at 1, 2 and 3 kcal/min, ‘older’, but not ‘young’, subjects exhibit a comparable fall in BP in response to the two higher glucose loads, which may reflect an inadequate, compensatory, rise in HR, in the ‘older’ subjects, but not a greater increase in SMA conductance.

Patients with POTS (postural tachycardia syndrome) have excessive orthostatic tachycardia (>30 beats/min) when standing from a supine position. HR (heart rate) and BP (blood pressure) are known to exhibit diurnal variability, but the role of diurnal variability in orthostatic changes of HR and BP is not known. In the present study, we tested the hypothesis that there is diurnal variation of orthostatic HR and BP in patients with POTS and healthy controls. Patients with POTS ( n =54) and healthy volunteers ( n =26) were admitted to the Clinical Research Center. Supine and standing (5 min) HR and BP were obtained in the evening on the day of admission and in the following morning. Overall, standing HR was significantly higher in the morning (102±3 beats/min) than in the evening (93±2 beats/min; P <0.001). Standing HR was higher in the morning in both POTS patients (108±4 beats/min in the morning compared with 100±3 beats/min in the evening; P =0.012) and controls (89±3 beats/min in the morning compared with 80±2 beats/min in the evening; P =0.005) when analysed separately. There was no diurnal variability in orthostatic BP in POTS. A greater number of subjects met the POTS HR criterion in the morning compared with the evening ( P =0.008). There was significant diurnal variability in orthostatic tachycardia, with a great orthostatic tachycardia in the morning compared with the evening in both patients with POTS and healthy subjects. Given the importance of orthostatic tachycardia in diagnosing POTS, this diurnal variability should be considered in the clinic as it may affect the diagnosis of POTS.

Childhood HTN (hypertension) has become a widely investigated topic within the last decade due to its increasing prevalence. In the present review, we examine new developments and trends that have significantly contributed to aetiology, diagnosis, evaluation and management of childhood HTN. Many recent reports document an increasing prevalence of HTN, mainly essential HTN, in children worldwide. This is probably related to the increase of childhood obesity, although obesity is not the only factor. Evidence has been accumulating to suggest a rather complex interplay between obesity, uric acid level, dietary sodium intake, inflammation, inheritance and other factors, which lead to increased risk of developing HTN in childhood and adulthood. The detection and monitoring of HTN has significantly improved with the use of ABPM (ambulatory blood pressure monitoring), which allows not only for a more accurate classification and staging of HTN, but also for the calculation of more sophisticated parameters such as the AASI (ambulatory arterial stiffness index). Measurement of arterial stiffness enables assessment of arterial dysfunction, which may precede structural vascular changes evaluated by carotid intima media thickness. Sustained HTN eventually leads to end-organ damage [LVH (left ventricular hypertrophy), central nervous system], which in turn increases the risk of cardiovascular morbidity and mortality. New developments in childhood HTN, as outlined in the present review, will hopefully contribute to better screening and management of HTN in children.

GDF15 (growth-differentiation factor 15) is a novel antihypertrophic factor which is induced in the heart in response to pressure overload and plays an important regulatory role in the process of hypertrophy. In the present study, we have investigated the relationship between GDF15 gene variants and left ventricular hypertrophy in human essential hypertension. A community-based hypertensive population sample of 1527 individuals (506 men and 1021 women) was genotyped for three GDF15 genetic variants, including one tag variant −3148C>G (rs4808793) and two exonic variants +157A>T (rs1059369) and +2438C>G (rs1058587). The effects of those variants on gene expression were studied by use of luciferase reporter assays and the determination of plasma GDF15 levels. Only the tag variant −3148G was significantly associated with a lower risk of left ventricular hypertrophy [odds ratio=0.75 (95% confidence interval, 0.63–0.89); P =0.0009]. Multiple regression analyses confirmed that −3148G predicted the decrease in left ventricular end-diastolic diameter (β=−0.10, P =0.0001), end-systolic diameter (β=−0.09, P =0.0007), mass (β=−0.11, P <0.0001) and indexed mass (β=−0.12, P <0.0001). These effects were independent of conventional factors, including gender, age, body surface area, blood pressure, diabetes, cigarette smoking and alcohol consumption. The transcription activity of the −3148G-containing construct was increased 1.45-fold ( P =0.015) at baseline and 1.73-fold ( P =0.008) after stimulation with phenylephrine when compared with the −3148C construct. The −3148G allele was also associated with a significant increase in the plasma GDF15 level in hypertensive subjects ( P =0.04). In conclusion, the results show that a promoter haplotype containing the −3148G variant increases GDF15 transcription activity and is associated with favourable left ventricular remodelling in human essential hypertension.

Sympathetic nervous system activation is a hallmark of several conditions associated with an adverse prognosis, including hypertension and the metabolic syndrome. Proposed mediators of increased sympathetic drive include hyperinsulinaemia, leptin, NEFAs (non-esterified fatty acids), pro-inflammatory cytokines, baroreflex impairment and others. The role of NEFAs appears to be of particular importance given the increased levels observed in human obesity and the experimental results linking the NEFA-induced pressor response to sympathetic activation. Findings from human studies have yielded conflicting results with regards to a sympathetically mediated association between NEFAs and elevated arterial blood pressure. In the present issue of Clinical Science , Florian and Pawelczyk present some interesting results obtained from a small number of healthy normotensive lean volunteers who were exposed to NEFA infusion and cardiovascular and sympathetic monitoring using state of the art methodology that appears to be in support of such a link. However, several methodological and conceptual considerations need to be taken into account when interpreting the results from this study. Put into perspective, the case for a substantial sympathetically mediated pressor response to NEFA infusion does not appear to be a very strong one.

Previous studies have shown that acute increases in plasma NEFAs (non-esterified fatty acids) raise SVR (systemic vascular resistance) and BP (blood pressure). However, these studies have failed to distinguish between CNS (central nervous system) mechanisms that raise sympathetic activity and paracrine mechanisms that increase SVR directly, independent of CNS involvement. The aim of the present study was to directly determine whether the sympathetic nervous system contributes to the pressor response to NEFAs. On 2 days separated by at least 2 weeks, 17 lean healthy volunteers (ten male/seven female; age, 22±1 years; body mass index, 23±1 kg/m 2 ; values are means±S.E.M.) received a 4-h intravenous infusion of 20% Intralipid® or placebo (in a single-blind randomized balanced order). MSNA (muscle sympathetic nerve activity), HR (heart rate), BP (oscillometric brachial measurement) and (cardiac output; acetylene rebreathing) were measured before and throughout infusion. The change in HR (+8.2±1.0 and +2.4±1.2 beats/min), systolic BP (+14.0±1.6 and +3.2±2.5 mmHg) and diastolic BP (+8.2±1.0 and −0.1±1.7 mmHg) were significantly greater after the 4-h infusion of Intralipid® compared with placebo ( P <0.001). The change in BP with Intralipid® resulted from an increase in SVR ( /mean arterial pressure; P <0.001) compared with baseline, without a change in . MSNA burst frequency increased during Intralipid® infusion compared with baseline (+4.9±1.3 bursts/min; P <0.05), and total MSNA (frequency×amplitude) was augmented 65% ( P <0.001), with no change during placebo infusion. Lipid infusion increased insulin, aldosterone and F 2 -isoprostane, but not leptin, concentrations. On the basis of the concomitant increase in BP, MSNA and SVR, we conclude that central sympathetic activation contributes to the pressor response to NEFAs. Previous studies have shown that acute increases in plasma NEFAs (non-esterified fatty acids) raise SVR (systemic vascular resistance) and BP (blood pressure). However, these studies have failed to distinguish between CNS (central nervous system) mechanisms that raise sympathetic activity and paracrine mechanisms that increase SVR directly, independent of CNS involvement. The aim of the present study was to directly determine whether the sympathetic nervous system contributes to the pressor response to NEFAs. On 2 days separated by at least 2 weeks, 17 lean healthy volunteers (ten male/seven female; age, 22±1 years; body mass index, 23±1 kg/m 2 ; values are means±S.E.M.) received a 4-h intravenous infusion of 20% Intralipid® or placebo (in a single-blind randomized balanced order). MSNA (muscle sympathetic nerve activity), HR (heart rate), BP (oscillometric brachial measurement) and (cardiac output; acetylene rebreathing) were measured before and throughout infusion. The change in HR (+8.2±1.0 and +2.4±1.2 beats/min), systolic BP (+14.0±1.6 and +3.2±2.5 mmHg) and diastolic BP (+8.2±1.0 and −0.1±1.7 mmHg) were significantly greater after the 4-h infusion of Intralipid® compared with placebo ( P <0.001). The change in BP with Intralipid® resulted from an increase in SVR ( /mean arterial pressure; P <0.001) compared with baseline, without a change in . MSNA burst frequency increased during Intralipid® infusion compared with baseline (+4.9±1.3 bursts/min; P <0.05), and total MSNA (frequency×amplitude) was augmented 65% ( P <0.001), with no change during placebo infusion. Lipid infusion increased insulin, aldosterone and F 2 -isoprostane, but not leptin, concentrations. On the basis of the concomitant increase in BP, MSNA and SVR, we conclude that central sympathetic activation contributes to the pressor response to NEFAs. Previous studies have shown that acute increases in plasma NEFAs (non-esterified fatty acids) raise SVR (systemic vascular resistance) and BP (blood pressure). However, these studies have failed to distinguish between CNS (central nervous system) mechanisms that raise sympathetic activity and paracrine mechanisms that increase SVR directly, independent of CNS involvement. The aim of the present study was to directly determine whether the sympathetic nervous system contributes to the pressor response to NEFAs. On 2 days separated by at least 2 weeks, 17 lean healthy volunteers (ten male/seven female; age, 22±1 years; body mass index, 23±1 kg/m 2 ; values are means±S.E.M.) received a 4-h intravenous infusion of 20% Intralipid® or placebo (in a single-blind randomized balanced order). MSNA (muscle sympathetic nerve activity), HR (heart rate), BP (oscillometric brachial measurement) and (cardiac output; acetylene rebreathing) were measured before and throughout infusion. The change in HR (+8.2±1.0 and +2.4±1.2 beats/min), systolic BP (+14.0±1.6 and +3.2±2.5 mmHg) and diastolic BP (+8.2±1.0 and −0.1±1.7 mmHg) were significantly greater after the 4-h infusion of Intralipid® compared with placebo ( P <0.001). The change in BP with Intralipid® resulted from an increase in SVR ( /mean arterial pressure; P <0.001) compared with baseline, without a change in . MSNA burst frequency increased during Intralipid® infusion compared with baseline (+4.9±1.3 bursts/min; P <0.05), and total MSNA (frequency×amplitude) was augmented 65% ( P <0.001), with no change during placebo infusion. Lipid infusion increased insulin, aldosterone and F 2 -isoprostane, but not leptin, concentrations. On the basis of the concomitant increase in BP, MSNA and SVR, we conclude that central sympathetic activation contributes to the pressor response to NEFAs.

Diabetes aggravates the impact of elevated BP (blood pressure) on the microcirculation, and people of African ancestry with diabetes are more susceptible to microvascular damage than Europeans. In the present study, we investigated possible differences in the retinal microcirculation in people of European and African-Caribbean ethnicity with diabetes that might account for this. A total of 51 subjects with Type 2 diabetes (age 40–65 years; 25 male; 29 African-Caribbean) were studied. Clinic and 24 h ambulatory BP, and fasting glucose, insulin and lipids were measured. Digital retinal images were analysed using custom-written semi-automatic software to determine: LDR (length/diameter ratio) and AVR (arteriolar/venular diameter ratio), branching angles, vessel tortuosity and N T (number of terminal vessel branches). Arterioles were narrower in European people with diabetes than in African-Caribbean people with diabetes [mean (S.D.) arteriolar diameter, 76 (7) compared with 82 (11) μm respectively ( P =0.03); arteriolar LDR, 28.1 (8.5) compared with 23.7 (7.0) respectively ( P =0.046); and AVR, 0.66 (0.21) compared with 0.90 (0.36) respectively ( P =0.028)]. Ethnic differences in arteriolar LDR, arteriolar diameter and AVR were not explained by differences in BP, but were attenuated by adjustment for the duration of diabetes. There was no significant relationship between BP and arteriolar narrowing in the group as a whole, although the relationship between arteriolar LDR and systolic BP was stronger in Europeans than African-Caribbeans [β=0.08 (0.07) compared with β=0.03 (0.06); P =0.03]. In conclusion, in the presence of diabetes, a relationship between BP and retinal arteriolar diameter was not evident and implies impaired small artery remodelling in the presence of diabetes. African-Caribbean people with diabetes have wider retinal arterioles and this could contribute to enhanced microvascular damage in this ethnic group.

Spontaneous fluctuations in BP (blood pressure) and subsequent change in CBFV (cerebral blood flow velocity) in the MCA (middle cerebral artery) can be used to assess dynamic cerebral autoregulation using transfer function analysis; however, the reliability of this technique has not been assessed, in particular the contribution of intra-subject variability relative to inter-subject variability. Three bilateral CBFV, BP and RR interval recordings were performed in ten healthy volunteers on four separate occasions over a 2-week period. Data were analysed to provide the ARI (autoregulatory index), CBFV, RAP (resistance-area product) and CrCP (critical closing pressure). We also measured systolic and diastolic BP, and resting HR (heart rate). We calculated the SEM (standard error of measurement) and the ICC (intra-class correlation coefficient) and their 95% CIs (confidence intervals) for each parameter to assess their absolute (intra-subject) and relative (inter-subject) reliability. The CV (coefficient of variation) of SEM ranged from 1.7% (for CBFV) to 100.0% (for RAP), whereas the ICC was <0.5 for ARI, rising to >0.8 for CBFV and diastolic BP. These data demonstrate excellent absolute and relative reliability of CBFV, whereas ARI is of comparable reliability with the measurement of HR. Using these results it is possible to determine the sample size required to demonstrate a change in ARI, with a sample of 45 subjects in each group required to show a change in ARI of 1, whereas to detect a change in ARI >2 would require only 11 subjects per group. The results of the present study could be valuable to the future planning of cerebral autoregulation studies, but more work is needed to understand the determinants of intra-subject variability in autoregulatory parameters.

Understanding the mechanisms that underlie BP (blood pressure) variation in humans and animal models may provide important clues for reducing the burden of uncontrolled hypertension in industrialized societies. High BP is often associated with increased signalling via G-protein-coupled receptors. Three members of the RGS (regulator of G-protein signalling) superfamily RGS2, RGS4 and RGS5 have been implicated in the attenuation of G-protein signalling pathways in vascular and cardiac myocytes, as well as cells of the kidney and autonomic nervous system. In the present review, we discuss the current state of knowledge regarding their differential expression and function in cardiovascular tissues, and the likelihood that one or more of these alleles are candidate hypertension genes. Together, findings from the studies described herein suggest that development of methods to modulate the expression and function of RGS proteins may be a possible strategy for the treatment and prevention of hypertension and cardiovascular disease.

Both antioxidant supplementation and exercise training have been identified as interventions which may reduce oxidative stress and thus improve cardiovascular health, but the interaction of these interventions on arterial BP (blood pressure) and vascular function has not been studied in older humans. Thus in six older (71±2 years) mildly hypertensive men, arterial BP was evaluated non-invasively at rest and during small muscle mass (knee-extensor) exercise with and without a pharmacological dose of oral antioxidants (vitamins C and E, and α-lipoic acid). The efficacy of the antioxidant intervention to decrease the plasma free radical concentration was verified via EPR (electron paramagnetic resonance) spectroscopy, while changes in endothelial function in response to exercise training and antioxidant administration were evaluated via FMD (flow-mediated vasodilation). Subjects were re-evaluated after a 6-week aerobic exercise training programme. Prior to training, acute antioxidant administration did not change resting arterial BP or FMD. Six weeks of knee-extensor exercise training reduced systolic BP (from 150±8 mmHg at pre-training to 138±3 mmHg at post-training) and diastolic BP (from 91±5 mmHg at pre-training to 79±3 mmHg at post-training), and improved FMD (1.5±1 to 4.9±1% for pre- and post-training respectively). However, antioxidant administration after exercise training negated these improvements, returning subjects to a hypertensive state and blunting training-induced improvements in FMD. In conclusion, the paradoxical effects of these interventions suggest a need for caution when exercise and acute antioxidant supplementation are combined in elderly mildly hypertensive individuals.

Interval exercise training has now been examined in a wide variety of individuals, ranging from elite athletes to patients with severe cardiovascular disease. The advantages of interval exercise training programmes in comparison with constant intensity exercise programmes are that they appear to deliver superior improvements in several cardiovascular risk factors, fitness and performance. Depending on the design, some interval exercise programmes result in a range of benefits, even though the time commitment may be dramatically less than more traditional continuous intensity programmes. In the present issue of Clinical Science , a study by Tjønna and co-workers demonstrates that aerobic interval training may also be a powerful tool in combating the increased cardiovascular risk observed in overweight adolescents.

The aim of the present study was to compare the effects of a multidisciplinary approach (MTG) and aerobic interval training (AIT) on cardiovascular risk factors in overweight adolescents. A total of 62 overweight and obese adolescents from Trøndelag County in Norway, referred to medical treatment at St Olav's Hospital, Trondheim, Norway, were invited to participate. Of these, 54 adolescents (age, 14.0±0.3 years) were randomized to either AIT (4×4 min intervals at 90% of maximal heart rate, each interval separated by 3 min at 70%, twice a week for 3 months) or to MTG (exercise, dietary and psychological advice, twice a month for 12 months). Follow-up testing occurred at 3 and 12 months. V ̇ O 2max (maximal oxygen uptake) increased more after AIT compared with MTG, both at 3 months (11 compared with 0%; P <0.01) and 12 months (12 compared with −1%; P <0.01). AIT enhanced endothelial function compared with MTG at both 3 months (absolute change, 5.1 compared with 3.9%; P <0.01) and 12 months (absolute change, 6.3 compared with 1.0%; P <0.01). AIT was favourable compared with MTG in reducing BMI (body mass index), percentage of fat, MAP (mean arterial blood pressure) and increasing peak oxygen pulse. In addition, AIT induced a more favourable regulation of blood glucose and insulin compared with MTG. In conclusion, the novel findings of the present proof-of-concept study was that 3 months of twice weekly high-intensity exercise sessions reduced several known cardiovascular risk factors in obese adolescents more than that observed after a multitreatment strategy, which was initiated as hospital treatment. Follow-up at 12 months confirmed that AIT improved or maintained these risk factors to a better degree than MTG.

Hypertension and Type 2 diabetes are co-morbid diseases that lead to the development of nephropathy. sEH (soluble epoxide hydrolase) inhibitors are reported to provide protection from renal injury. We hypothesized that the sEH inhibitor AUDA [12-(3-adamantan-1-yl-ureido)-dodecanoic acid] protects the kidney from the development of nephropathy associated with hypertension and Type 2 diabetes. Hypertension was induced in spontaneously diabetic GK (Goto–Kakizaki) rats using AngII (angiotensin II) and a high-salt diet. Hypertensive GK rats were treated for 2 weeks with either AUDA or its vehicle added to drinking water. MAP (mean arterial pressure) increased from 118±2 mmHg to 182±20 and 187±6 mmHg for vehicle and AUDA-treated hypertensive GK rats respectively. AUDA treatment did not alter blood glucose. Hypertension in GK rats resulted in a 17-fold increase in urinary albumin excretion, which was decreased with AUDA treatment. Renal histological evaluation determined that AUDA treatment decreased glomerular and tubular damage. In addition, AUDA treatment attenuated macrophage infiltration and inhibited urinary excretion of MCP-1 (monocyte chemoattractant protein-1) and kidney cortex MCP-1 gene expression. Taken together, these results provide evidence that sEH inhibition with AUDA attenuates the progression of renal damage associated with hypertension and Type 2 diabetes.

There is a considerable debate about the potential influence of ‘fetal programming’ on cardiovascular diseases in adulthood. In the present prospective epidemiological cohort study, the relationship between birthweight and arterial elasticity in 472 children between 5 and 8 years of age was assessed. LAEI (large artery elasticity index), SAEI (small artery elasticity index) and BP (blood pressure) were assessed using the HDI/PulseWave™ CR-2000 CardioVascular Profiling System. Blood concentrations of glucose, total cholesterol and its fractions [LDL (low-density lipoprotein)-cholesterol and HDL (high-density lipoprotein)-cholesterol] and triacylglycerols (triglycerides) were determined by automated enzymatic methods. Insulin was assessed by a chemiluminescent method, insulin resistance by HOMA (homoeostasis model assessment) and CRP (C-reactive protein) by immunonephelometry. Two linear regression models were applied to investigate the relationship between the outcomes, LAEI and SAEI, and the following variables: birthweight, gestational age, glucose, LDL-cholesterol, HDL-cholesterol, triacylglycerols, insulin, CRP, HOMA, age, gender, waist circumference, per capita income, SBP (systolic BP) and DBP (diastolic BP). LAEI was positively associated with birthweight ( P =0.036), waist circumference ( P <0.001) and age ( P <0.001), and negatively associated with CRP ( P =0.024) and SBP ( P <0.001). SAEI was positively associated with birthweight ( P =0.04), waist circumference ( P =0.001) and age ( P <0.001), and negatively associated with DBP ( P <0.001). Arterial elasticity was decreased in apparently healthy children who had lower birthweights, indicating an earlier atherogenetic susceptibility to cardiovascular diseases in adolescence and adult life. Possible explanations for the results include changes in angiogenesis during critical phases of intrauterine life caused by periods of fetal growth inhibition and local haemodynamic anomalies as a way of adaptation to abnormal pressure and flow.

Type 2 diabetes is associated with an increased risk of endothelial dysfunction and microvascular complications with impaired autoregulation of tissue perfusion. Both microvascular disease and cardiovascular autonomic neuropathy may affect cerebral autoregulation. In the present study, we tested the hypothesis that, in the absence of cardiovascular autonomic neuropathy, cerebral autoregulation is impaired in subjects with DM+ (Type 2 diabetes with microvascular complications) but intact in subjects with DM− (Type 2 diabetes without microvascular complications). Dynamic cerebral autoregulation and the steady-state cerebrovascular response to postural change were studied in subjects with DM+ and DM−, in the absence of cardiovascular autonomic neuropathy, and in CTRL (healthy control) subjects. The relationship between spontaneous changes in MCA V mean (middle cerebral artery mean blood velocity) and MAP (mean arterial pressure) was evaluated using frequency domain analysis. In the low-frequency region (0.07–0.15 Hz), the phase lead of the MAP-to-MCA V mean transfer function was 52±10 ° in CTRL subjects, reduced in subjects with DM− (40±6 °; P <0.01 compared with CTRL subjects) and impaired in subjects with DM+ (30±5 °; P <0.01 compared with subjects with DM−), indicating less dampening of blood pressure oscillations by affected dynamic cerebral autoregulation. The steady-state response of MCA V mean to postural change was comparable for all groups (−12±6% in CTRL subjects, −15±6% in subjects with DM− and −15±7% in subjects with DM+). HbA 1c (glycated haemoglobin) and the duration of diabetes, but not blood pressure, were determinants of transfer function phase. In conclusion, dysfunction of dynamic cerebral autoregulation in subjects with Type 2 diabetes appears to be an early manifestation of microvascular disease prior to the clinical expression of diabetic nephropathy, retinopathy or cardiovascular autonomic neuropathy.

Oxidative stress has been associated with mechanisms of EH (essential hypertension). The aim of the present study was to test the hypothesis that the antioxidant properties of vitamins C and E are associated with a decrease in BP (blood pressure) in patients with EH. A randomized double-blind placebo-controlled clinical trial was conducted in 110 men with grade 1 EH (35–60 years of age without obesity, dyslipidaemia and diabetes mellitus, non-smokers, not undergoing vigorous physical exercise, without the use of any medication and/or high consumption of fruit and vegetables). Participants were randomly assigned to receive either vitamins C+E [vitamin C (1 g/day) plus vitamin E (400 international units/day)] or placebo for 8 weeks. Measurements included 24 h ambulatory BP and blood analysis of oxidative-stress-related parameters in erythrocytes (GSH/GSSH ratio, antioxidant enzymes and malondialdehyde) and plasma [FRAP (ferric reducing ability of plasma)], and levels of 8-isoprostane, vitamins C and E were measured at baseline and after treatment. Following administration of vitamins C+E, patients with EH had significantly lower systolic BP, diastolic BP and mean arterial BP and higher erythrocyte and serum antioxidant capacity compared with either placebo-treated patients with EH or the patients with EH at baseline prior to treatment. BP correlated positively with plasma 8-isoprostane levels and negatively with plasma FRAP levels in the vitamins C+E- and placebo-treated groups. In conclusion, the present study supports the view that oxidative stress is involved in the pathogenesis of EH, and that enhancement of antioxidant status by supplementation with vitamins C and E in patients with EH is associated with lower BP. This suggests intervention with antioxidants as an adjunct therapy for hypertension.

To date, the main cardiovascular application of TDI (tissue Doppler imaging) has been in myocardial evaluation. In the present study, we investigated the feasibility and reproducibility of assessing arterial elasticity using the DC (distensibility coefficient) measured by TDI, the correlation of this with the DC obtained by other methods and the DC in patients with various degrees of cardiovascular risk. We studied 450 subjects (256 men; age, 51±10 years) with and without risk factors of cardiovascular disease. Arterial displacement was measured from TDI, and B-mode and M-mode images of the common carotid artery in the longitudinal plane, and the DC with each method was compared. Linear regression showed a good correlation between all three methods. The results for TDI and B-mode were comparable [(21±10) compared with (21±10)×10 −3 /kPa respectively; P =not significant], but there were significant differences between TDI and M-mode [(21±10) compared with (31±13)×10 −3 /kPa respectively; P <0.0001] and between B-mode and M-mode [(21±10) compared with (31±13)×10 −3 /kPa respectively; P <0.0001]. Similarly, Bland–Altman analysis showed the least variability in the DC between TDI and B-mode, and there were no significant differences between the average measurements. The TDI DC also had the lowest paired difference for inter-observer variability [(−0.1±1.1)×10 −3 /kPa; P =not significant]. In conclusion, the results of the present study suggest that TDI of the carotid arteries is feasible, comparable with B-mode measurements, more robust than M-mode and less variable than the other methods.

There have been only a few reports on the sympathoadrenal and renin–angiotensin systems in children of small gestational age. The purpose of the present study was to investigate plasma levels of ACE (angiotensin-converting enzyme) activity, angiotensin and catecholamines in 8- to 13-year-old children and to determine whether there are correlations between the components of these systems with both birthweight and BP (blood pressure) levels. This clinical study included 66 children (35 boys and 31 girls) in two groups: those born at term with an appropriate birthweight [AGA (appropriate-for-gestational age) group, n =31] and those born at term but with a small birthweight for gestational age [SGA (small-for-gestational age) group, n =35]. Concentrations of angiotensin, catecholamines and ACE activity were determined in plasma. Circulating noradrenaline levels were significantly elevated in SGA girls compared with AGA girls ( P =0.036). In addition, angiotensin II and ACE activity were higher in SGA boys ( P =0.024 and P =0.050 respectively). There was a significant association of the circulating levels of both angiotensin II and ACE activity with BP levels in our study population. Although the underlying mechanisms that link restricted fetal growth with later cardiovascular events are not fully understood, the findings in the present study support the link between low birthweight and overactivity of both sympathoadrenal and renin–angiotensin systems into later childhood.

Clinical and experimental studies indicate that the progression of renal disease is faster in males than females. These observations are corroborated by a sexual dimorphism observed in the polygenetic MWF (Munich Wistar Frömter) rat model. The age-dependent spontaneous progression of increased UAE (urinary albumin excretion) in male MWF rats is influenced by multiple QTLs (quantitative trait loci). In contrast, female MWF rats only develop a slight increase in UAE, while the role of genetic factors for this phenotype is unknown. In the present study, we show that, compared with resistant SHRs (spontaneously hypertensive rats), both male and female MWF rats develop a significant increase in UAE at 24 weeks of age ( P <0.0001), although blood pressures were lower compared with SHRs ( P <0.0001). UAE was significantly higher in male (7-fold) compared with female MWF rats (162.6±15.9 compared with 24.0±5.5 mg/24 h respectively; P <0.0001), and only male MWF rats developed significant glomerulosclerosis and tubulointerstitial damage in the kidney ( P <0.0001). To test the role of genetic factors in the development of low grade albuminuria in female MWF rats, we analysed the role of a major UAE QTL on rat chromosome 6. To this end, we analysed a consomic MWF-6 SHR strain in which chromosome 6 from SHRs was introgressed into the MWF rat background. Time course analysis of UAE in females indicated that the small increase in UAE in MWF rats was fully suppressed by exchange of rat chromosome 6. Thus, taken together with previous studies in males, we show that RNO6 protects against the increase in albuminuria with age in both female and male MWF rats.

Cardiovascular-related diseases are the leading cause of death in the world in both men and women. In addition to the environmental and genetic factors, early life conditions are now also considered important contributing elements to these pathologies. The concept of ‘fetal’ or ‘developmental’ origins of adult diseases has received increased recognition over the last decade, yet the mechanism by which altered perinatal environment can lead to dysfunction mostly apparent in the adult are incompletely understood. This review will focus on the mechanisms and pathways that epidemiological studies and experimental models have revealed underlying the adult cardiovascular phenotype dictated by the perinatal experience, as well as the probable key causal or triggering elements. Programmed elevated blood pressure in the adult human or animal is characterized by vascular dysfunction and microvascular rarefaction. Developmental mechanisms that have been more extensively studied include glucocorticoid exposure, the role of the kidneys and the renin–angiotensin system. Other pathophysiological pathways have been explored, such as the role of the brain and the sympathetic nervous system, oxidative stress and epigenetic changes. As with many complex diseases, a unifying hypothesis linking the perinatal environment to elevated blood pressure and vascular dysfunction in later life cannot be presumed, and a better understanding of those mechanisms is critical before clinical trials of preventive or ‘deprogramming’ measures can be designed.

IOH (initial orthostatic hypotension) comprises symptoms of cerebral hypoperfusion caused by an abnormally large transient MAP (mean arterial pressure) decrease 5–15 s after arising from a supine, sitting or squatting position. Few treatment options are available. In the present study, we set out to test the hypothesis that LBMT (lower body muscle tensing) attenuates IOH after rising from squatting and its symptoms in daily life. A total of 13 IOH patients (nine men; median age, 27 years) rose from squatting twice, once with LBMT and once without. In addition, seven healthy volunteers (five men; median age, 27 years) were studied in a cross-over study design. They stood up from the squatting position three times, once combined with LBMT. Blood pressure (Finometer) was measured continuously, and CO (cardiac output) by Modelflow and TPR (total peripheral resistance) were computed. MAP, CO and TPR were compared without and with LBMT. Using a questionnaire, the perceived effectiveness of LBMT in the patients' daily lives was evaluated. With LBMT, the minimal MAP after standing up was higher in both groups (19 mmHg in patients and 13 mmHg in healthy subjects). In healthy subjects, the underlying mechanism was a blunted TPR decrease (to 47% compared with 60%; P <0.05), whereas in the patients no clear CO or TPR pattern was discernible. During follow-up, eight out of ten patients using LBMT reported fewer IOH symptoms. In conclusion, LBMT is a new intervention to attenuate the transient blood pressure decrease after standing up from squatting, and IOH patients should be advised about the use of this manoeuvre.

NTG (nitroglycerine) is used in routine tilt testing to elicit a vasovagal response. In the present study we hypothesized that with increasing age NTG triggers a more gradual BP (blood pressure) decline due to a diminished baroreflex-buffering capacity. The purpose of the present study was to examine the effect of NTG on baroreflex control of BP in patients with distinct age-related vasovagal collapse patterns. The study groups consisted of 29 patients (16–71 years old, 17 females) with clinically suspected VVS (vasovagal syncope) and a positive tilt test. Mean FAP (finger arterial pressure) was monitored continuously (Finapres). Left ventricular SV (stroke volume), CO (cardiac output) and SVR (systemic vascular resistance) were computed from the pressure pulsations (Modelflow). BRS (baroreflex sensitivity) was estimated in the time domain. In the first 3 min after NTG administration, BP was well-maintained in all patients. This implied an adequate arterial resistance response to compensate for steeper reductions in SV and CO with increasing age. HR (heart rate) increased and the BRS decreased after NTG administration. The rate of mean FAP fall leading to presyncope was inversely related to age ( r =0.51, P =0.005). Accordingly, patients with a mean FAP fall >1.44 mmHg/s (median) were generally younger compared with patients with a slower mean FAP-fall (30±10 years compared with 51±17 years; P =0.001). The main determinant of the rate of BP fall on approach of presyncope was the rate of fall in HR ( r =0.75, P <0.001). It was concluded that, in older patients, sublingual NTG provokes a more gradual BP decline compared with younger patients. This gradual decline cannot be ascribed to failure of the baroreflex-buffering capacity with increasing age. Age-related differences in the laboratory presentation of a vasovagal episode depend on the magnitude of the underlying bradycardic response.

The α-adducin Gly460Trp polymorphism alters renal sodium transport and is associated with hypertension. Despite the immediate sodium- and volume-depleting effects of aerobic exercise, the influence of the α-adducin Gly460Trp polymorphism on PEH (postexercise hypotension) has not been studied. In the present study we examined the effects of the α-adducin Gly460Trp polymorphism on PEH among 48 men (42.6±1.6 years; mean±S.E.M.) with high BP (blood pressure; 144.0±1.7/84.7±1.1 mmHg). Subjects completed three experiments: non-exercise control and two cycle exercise sessions at 40% (light exercise) and 60% (moderate exercise) of maximal oxygen consumption. Subjects left the laboratory wearing an ambulatory BP monitor. PCR and restriction enzyme digestion determined the genotypes. No subjects had the Trp460Trp genotype due to the low frequency of 5% in the population. Repeated measure ANCOVA tested whether BP differed over time between experimental conditions and genotypes (Gly460Gly, n =36; Gly460Trp, n =12). Among Gly460Gly genotypes, SBP (systolic BP) was reduced by 5.2±1.4 mmHg after moderate exercise compared with non-exercise controls over 9 h ( P <0.01). Among Gly460Trp genotypes, SBP was lowered by 7.8±2.3 mmHg; after light exercise compared with non-exercise controls over 9 h ( P <0.05). The SBP reductions after light exercise (0.6±1.3 compared with 7.8±2.3 mmHg; P <0.05) but not moderate exercise (5.2±1.4 compared with 3.8±2.4 mmHg; P ≥0.05) differed between the Gly460Gly and Gly460Trp genotypes respectively. Men with Gly460Gly had a reduced SBP after moderate exercise, whereas men with Gly460Trp had a reduced SBP after light exercise. However, only the SBP reductions after light exercise differed between genotypes. Our findings indicate that the α-adducin Gly460Trp genotype may be useful in identifying men who have a reduced BP after lower intensity aerobic exercise.

The relationships of cortisol with elevated blood pressure and insulin resistance are likely to be the result of a complex interplay of different mechanisms. We hypothesize that cortisol is associated with impaired microvascular function and that this contributes to cortisol-associated high blood pressure and insulin resistance. We examined 24 h urinary free cortisol excretion in 56 healthy adults (26 women). Blood pressure was assessed by 24 h ambulatory measurements. Insulin sensitivity was determined using the hyperinsulinaemic euglycaemic clamp technique. Skin capillary recruitment after arterial occlusion was visualized with videomicroscopy and endothelium-(in)dependent vasodilation was evaluated with iontophoresis of acetylcholine and sodium nitroprusside combined with laser Doppler fluxmetry. Men were characterized by higher urinary cortisol excretion [median (interquartile range), 162 (130–194) compared with 118 (99–156) nmol/24 h, P <0.05]. In women, but not in men, urinary cortisol excretion was associated with impaired capillary recruitment ( r =−0.66, P <0.001), higher systolic blood pressure ( r =0.64, P <0.001) and lower insulin sensitivity ( r =−0.43, P <0.05). Urinary cortisol excretion was not associated with endothelium-(in)dependent vasodilation in men or women. Regression analysis demonstrated that capillary recruitment statistically explained 37% of the association between urinary cortisol and blood pressure in women. Capillary recruitment did not explain part of the association between urinary cortisol and insulin sensitivity. In conclusion, urinary cortisol excretion is inversely associated with capillary recruitment in women, but not in men, and capillary recruitment explains part of the cortisol–blood pressure relationship. These data suggest that, in women, impairment of capillary function mediates some of the adverse effects of cortisol and thus may provide a target to prevent such adverse effects.

Dopamine plays an important role in the pathogenesis of hypertension by regulating epithelial sodium transport, vascular smooth muscle contractility and production of reactive oxygen species and by interacting with the renin–angiotensin and sympathetic nervous systems. Dopamine receptors are classified into D 1 -like (D 1 and D 5 ) and D 2 -like (D 2 , D 3 and D 4 ) subtypes based on their structure and pharmacology. Each of the dopamine receptor subtypes participates in the regulation of blood pressure by mechanisms specific for the subtype. Some receptors regulate blood pressure by influencing the central and/or peripheral nervous system; others influence epithelial transport and regulate the secretion and receptors of several humoral agents. This review summarizes the physiology of the different dopamine receptors in the regulation of blood pressure, and the relationship between dopamine receptor subtypes and hypertension.

More than 80% of patients with type 2 diabetes mellitus develop hypertension, and approx. 20% of patients with hypertension develop diabetes. This combination of cardiovascular risk factors will account for a large proportion of cardiovascular morbidity and mortality. Lowering elevated blood pressure in diabetic hypertensive individuals decreases cardiovascular events. In patients with hypertension and diabetes, the pathophysiology of cardiovascular disease is multifactorial, but recent evidence points toward the presence of an important component dependent on a low-grade inflammatory process. Angiotensin II may be to a large degree responsible for triggering vascular inflammation by inducing oxidative stress, resulting in up-regulation of pro-inflammatory transcription factors such as NF-κB (nuclear factor κB). These, in turn, regulate the generation of inflammatory mediators that lead to endothelial dysfunction and vascular injury. Inflammatory markers (e.g. C-reactive protein, chemokines and adhesion molecules) are increased in patients with hypertension and metabolic disorders, and predict the development of cardiovascular disease. Lifestyle modification and pharmacological approaches (such as drugs that target the renin–angiotensin system) may reduce blood pressure and inflammation in patients with hypertension and metabolic disorders, which will reduce cardiovascular risk, development of diabetes and cardiovascular morbidity and mortality.

Isometric HG (handgrip) training lowers resting arterial BP (blood pressure), yet the mechanisms are elusive. In the present study, we investigated improved systemic endothelial function as a mechanism of arterial BP modification following isometric HG training in normotensive individuals. This study employed a within-subject repeated measures design primarily to assess improvements in BA FMD (brachial artery flow-mediated dilation; an index of endothelium-dependent vasodilation), with the non-exercising limb acting as an internal control. Eleven subjects performed four 2-min unilateral isometric HG contractions at 30% of maximal effort, three times per week for 8 weeks. Pre-, mid- and post-training resting ABP and BA FMD (exercised arm and non-exercised arm) were measured via automated brachial oscillometry and ultrasound respectively. BA FMD (normalized to the peak shear rate experienced in response to the reactive hyperaemic stimulus) remained unchanged [exercised arm, 0.029±0.003 to 0.026±0.003 to 0.029±0.004%/s −1 (pre- to mid- to post-training respectively); non-exercised arm, 0.023±0.003 to 0.023±0.003 to 0.024±0.003%/s −1 (pre- to mid- to post-training respectively); P =0.22]. In conclusion, improved systemic endothelial function is unlikely to be responsible for lowering arterial BP in this population.

Low BP (blood pressure) is a recognized risk factor for some patients with NPG (normal pressure glaucoma). We have shown previously that patients with orthostasis have impaired circadian renal handling of sodium, which may contribute to the low BP. Therefore the aim of the present study was to examine the renal handling of sodium, the circadian variations in BP and the neurohormonal response to an orthostatic test in a selected subpopulation of 18 patients with NPG with vasospastic and orthostatic symptoms, and in 24 healthy control subjects. The variations in BP and renal tubular sodium handling were evaluated using 24 h ambulatory BP recordings, 24 h urine collections and determination of endogenous lithium clearance as a marker of proximal sodium reabsorption. The neurohormonal and BP responses to changes in posture were also determined in a 30 min orthostatic test. This selected group of patients with NPG had lower 24 h ambulatory BPs ( P <0.001), and a more pronounced fall in BP when assuming an upright position ( P <0.001) compared with controls. FE Li (fractional excretion of lithium) was higher in patients with NPG than controls during the day (36.6±21.8 compared with 20.4±8.7% respectively; P <0.01; values are means±S.D.) as well as during the night (38.8±41.9 compared with 19.7±10.8% respectively; P <0.02), suggesting a reduced reabsorption of sodium in the proximal tubule. This was compensated for by an increased distal reabsorption of sodium in patients with NPG ( P <0.01). These data demonstrate that patients with vasospastic NPG have a high excretion of lithium, suggesting reduced sodium reabsorption in the proximal tubule, in spite of a low BP. The abnormal renal sodium handling might contribute to the maintenance of arterial hypotension and progression of the optic nerve damage in these patients.

Several studies have shown that standing up is a frequent (3–10%) trigger of loss of consciousness both in young and old subjects. An exaggerated transient BP (blood pressure) fall upon standing is the underlying cause. IOH (initial orthostatic hypotension) is defined as a transient BP decrease within 15 s after standing, >40 mmHg SBP (systolic BP) and/or >20 mmHg DBP (diastolic BP) with symptoms of cerebral hypoperfusion. It differs distinctly from typical orthostatic hypotension (i.e. BP decrease >20 mmHg SBP and/or >10 mmHg DBP after 3 min of standing) as the BP decrease is transient. Only continuous beat-to-beat BP measurement during an active standing-up manoeuvre can document this condition. As IOH is only associated with active rising, passive tilting is of no diagnostic value. The pathophysiology of IOH is thought to be a temporal mismatch between cardiac output and vascular resistance. The marked decrease of vascular resistance during rising is similar to that observed at the onset of leg exercise and is absent during head-up tilting. It is attributed to vasodilatation in the working muscle through local mechanisms. Standing up causes an initial increase in venous return through the effects of contraction of leg and abdominal muscles. The consequent sudden increase in right atrial pressure may contribute to the fall in systemic vascular resistance through a reflex effect. This review alerts clinicians and clinician scientists to a common, yet often neglected, condition that occurs only upon an active change of posture and discusses its epidemiology, pathophysiology and management.

A polymorphism in the cytochrome P450 3A CYP3A5 enzyme has been implicated in BP (blood pressure) control and arterial hypertension. Carriers of the CYP3A5 * 1 allele had high, whereas homozygous carriers of the CYP3A5 * 3 allele exhibit low, CYP3A5 expression in the kidney, where CYP3A5 represents the major CYP3A enzyme. The aim of the present study was to investigate the association of the CYP3A5 * 1 allele with BP, arterial hypertension, LVM [(left ventricular) mass] and LV geometry in a large Caucasian-population-based cohort. We compared BP, LVM and the prevalence of hypertension between carriers ( CYP3A5 * 1 /* 1 and CYP3A5 * 1 /* 3 genotypes) and non-carriers ( CYP3A5 * 3 /* 3 genotype) of the CYP3A5 * 1 allele in the echocardiographic substudy of the third MONICA (MONItoring trends and determinants in CArdiovascular disease) Augsburg survey. After exclusion of 269 individuals who were taking antihypertensive medication, 530 women and 554 men were available for analysis, revealing allele frequencies of 5.8 and 94.2% for the CYP3A5 * 1 and CYP3A5 * 3 alleles respectively. Overall, the presence of the CYP3A5 * 1 allele exhibited no effect on systolic or diastolic BP in either gender. One-third of the individuals in this cohort were hypertensive (BP ≥140/90 mmHg), and the genotype distribution between normotensive and hypertensive individuals revealed no association between CYP3A5 * 1 and hypertension after adjustment for age, BMI and gender (odds ratio, 1.02; P =0.92). Moreover, no effect of CYP3A5 * 1 on LVM, thickness of the septal and posterior wall and LV end-diastolic diameter was found. We conclude that CYP3A5 * 1 exhibits no significant effect on BP, LVM and LV geometry in the KORA/MONICA echocardiographic substudy.

EH (essential hypertension) is a major public health problem in many countries due to its high prevalence and its association with coronary heart disease, stroke, renal disease, peripheral vascular disease and other disorders. Epidemiological studies have demonstrated that EH is heritable. Owing to the fact that blood pressure is controlled by cardiac output and total peripheral resistance, many molecular pathways are believed to be involved in the disease. In this review, recent genetic studies investigating the molecular basis of EH, including different molecular pathways, will be highlighted.

Cardiovascular regulation by the sympathetic nervous system is mediated by activation of one or more of the nine known subtypes of the adrenergic receptor family; α 1A -, α 1B -, α 1D -, α 2A -, α 2B -, α 2C -, β 1 -, β 2 - and β 3 -ARs (adrenoceptors). The role of the α 2 -AR family has long been known to include presynaptic inhibition of neurotransmitter release, diminished sympathetic efferent traffic, vasodilation and vasoconstriction. This complex response is mediated by one of three subtypes which all uniquely affect blood pressure and blood flow. All three subtypes are present in the brain, kidney, heart and vasculature. However, each differentially influences blood pressure and sympathetic transmission. Activation of α 2A -ARs in cardiovascular control centres of the brain lowers blood pressure and decreases plasma noradrenaline (norepinephrine), activation of peripheral α 2B -ARs causes sodium retention and vasoconstriction, whereas activation of peripheral α 2C -ARs causes cold-induced vasoconstriction. In addition, non-selective agonists elicit endothelium-dependent vasodilation and presynaptic inhibition of noradrenaline release. The evidence that each of these receptor subtypes uniquely participates in cardiovascular control is discussed in this review.

The present study was designed to investigate the effects of low-dose ketanserin on BPV (blood pressure variability), BRS (baroreflex sensitivity) and organ damage in SHR (spontaneously hypertensive rats). Ketanserin was mixed in rat chow at an estimated dose of 0.1 mg·kg −1 of body weight·day −1 . SHR were treated for 4 months. BP (blood pressure) was then recorded continuously for 24 h in a conscious state. After determination of BRS, rats were killed for organ damage evaluation. It was found that long-term treatment with low-dose ketanserin did not lower BP levels, but significantly decreased BPV, enhanced BRS and reduced organ damage in SHR. Multiple regression analysis showed that the decrease in left ventricular hypertrophy was most closely correlated (or associated) with the increase in BRS, whereas the decrease in aortic hypertrophy was most closely associated with the decrease in diastolic BPV and the amelioration in renal lesion, with the increase in BRS and the decrease in diastolic BPV. In conclusion, low-dose ketanserin produces organ protection independently of its BP-lowering action in SHR, and this organ protection was importantly attributable to the enhancement of BRS and decrease in BPV.

Since its discovery by Erspamer in the 1930s and identification by Page in the 1950s, 5-HT (5-hydroxytryptamine; serotonin) has been an elusive candidate as a substance that plays a role in the disease of high blood pressure, also known as hypertension. In both animal and human hypertension, arterial contraction to 5-HT is profoundly enhanced. Additionally, 5-HT is a vascular smooth muscle cell mitogen. Because both increased arterial contractility and smooth muscle growth contribute to the disease of hypertension, it is logical to believe that 5-HT is a potential cause of disease, and thus a foe. However, decades of research have produced conflicting results as to the potential role of 5-HT in hypertension. This review will discuss historical findings which both support and refute the involvement of 5-HT in hypertension, and pose some new questions that may reveal novel ways for 5-HT to modify vascular control of blood pressure.

Transfer function techniques are increasingly used for non-invasive estimation of central aortic waveform characteristics. Non-invasive radial waveforms must be calibrated for this purpose. Most validation studies have used invasive pressures for calibration, with little data on the impact of non-invasive calibration on transfer-function-derived aortic waveform characteristics. In the present study, simultaneous invasive central aortic (Millar Mikro-tip® catheter transducer) and non-invasive radial (Millar® Mikro-tip® tonometer) pressure waveforms and non-invasive brachial pressures (Dinamap®) were measured in 42 subjects. In this cohort, radial waveforms were calibrated to both invasive and non-invasive mean and diastolic pressures. From each of these, central waveforms were reconstructed using a generalized transfer function obtained by us from a previous cohort [Hope, Tay, Meredith and Cameron (2002) Am. J. Physiol. Heart Circ. Physiol. 283 , H1150–H1156]. Waveforms were analysed for parameters of potential clinical interest. For calibrated radial and reconstructed central waveforms, different methods of calibration were associated with differences in pressure ( P <0.001), but not time parameters or augmentation index. Whereas invasive calibration resulted in little error in transfer function estimation of central systolic pressure (difference −1±8 mmHg; P =not significant), non-invasive calibration resulted in significant underestimation (7±12 mmHg; P <0.001). Errors in estimated aortic parameters differed with non-invasively calibrated untransformed radial and transfer-function-derived aortic waveforms (all P <0.01), with smaller absolute errors with untransformed radial waveforms for most pressure parameters [systolic pressure, 5±16 and 7±12 mmHg; pulse pressure, 0±16 and 4±12 mmHg (radial and derived aortic respectively)]. When only non-invasive pressures are accessible, analysis of untransformed radial waveforms apparently produces smaller errors in the estimation of central aortic systolic pressure, and other waveform parameters, than using a generalized transfer function.