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Majority of patients with hypertension and chronic kidney disease (CKD) undergoing renal denervation (RDN) are maintained on antihypertensive medication. However, RDN may impair compensatory responses to hypotension induced by blood loss. Therefore, continuation of antihypertensive medications in denervated patients may exacerbate hypotensive episodes. This study examined whether antihypertensive medication compromised hemodynamic responses to blood loss in normotensive (control) sheep and in sheep with hypertensive CKD at 30 months after RDN (control-RDN, CKD-RDN) or sham (control-intact, CKD-intact) procedure. CKD-RDN sheep had lower basal blood pressure (BP; ≈9 mm Hg) and higher basal renal blood flow (≈38%) than CKD-intact. Candesartan lowered BP and increased renal blood flow in all groups. 10% loss of blood volume alone caused a modest fall in BP (≈6–8 mm Hg) in all groups but did not affect the recovery of BP. 10% loss of blood volume in the presence of candesartan prolonged the time at trough BP by 9 minutes and attenuated the fall in renal blood flow in the CKD-RDN group compared with CKD-intact. Candesartan in combination with RDN prolonged trough BP and attenuated renal hemodynamic responses to blood loss. To minimize the risk of hypotension-mediated organ damage, patients with RDN maintained on antihypertensive medications may require closer monitoring when undergoing surgery or experiencing traumatic blood loss.

The present paper provides an update of previous recommendations on Home Blood Pressure Monitoring from the European Society of Hypertension (ESH) Working Group on Blood Pressure Monitoring and Cardiovascular Variability sequentially published in years 2000, 2008 and 2010. This update has taken into account new evidence in this field, including a recent statement by the American Heart association, as well as technological developments, which have occurred over the past 20 years. The present document has been developed by the same ESH Working Group with inputs from an international team of experts, and has been endorsed by the ESH. ispartof: JOURNAL OF HYPERTENSION vol:39 issue:9 pages:1742-1767 ispartof: location:Netherlands status: published

Summary: Recent clinical trial data suggest a cardiorenal protective effect of sodium glucose cotransporter 2 (SGLT2) inhibition. We demonstrate that chemical denervation in neurogenic hypertensive Schlager (BPH/2J) mice reduced blood pressure, improved glucose homeostasis, and reduced renal SGLT2 protein expression. Inhibition of SGLT2 prevented weight gain, reduced blood pressure, significantly reduced elevations of tyrosine hydroxylase and norepinephrine, and protects against endothelial dysfunction. These findings provide evidence for significant crosstalk between activation of the sympathetic nervous system and SGLT2 regulation and possible ancillary effects on endothelial function, which may contribute to the observed cardiorenal protective effects of SGLT2 inhibition. Key Words: denervation, heart, hypertension, kidney, SGLT2, sympathetic nervous system

Introduction: We have previously demonstrated that the naturally-occurring anti-inflammatory and pro-resolving protein Annexin-A1 (Anx-A1) limits the acute inflammatory response post myocardial infarction, but its impact on chronic inflammation, such as hypertension, has not been explored. This study aims to investigate the role of Anx-A1 in a preclinical model of hypertension, induced by angiotensin-II (Ang-II). Methods: 15-week-old male C57BL/6 or ANXA1 -/- were anesthetized (isoflurane, 2-4% v/v) and implanted with an osmotic minipump randomly assigned to receive Ang-II (0.7mg/kg/day) or vehicle (saline). Radiotelemetry recordings of blood pressure were taken at 10 intermittent timepoints from baseline to the end of the 29-day infusion period. Animals were euthanized with pentobarbitone (100mg/kg; i.p.) at endpoint and organ weights recorded and normalized to bodyweight. Left ventricle (LV) samples were stained with picrosirius red to assess total LV collagen deposition. Results: Ang II-induced mice at the end of the study had elevated mean arterial pressure (MAP), cardiac hypertrophy and fibrosis compared to normotensive mice (Table). Anx-A1 deficient mice given Ang II had an even greater increase in MAP and cardiac remodeling compared to WT. Interestingly, MAP of Anx-A1 deficient mice at baseline is significantly higher compare to C57BL/6 counterparts (Table). Conclusion: This is the first study to demonstrate that deficiency of Anx-A1 exaggerates cardiac remodeling in AngII-induced hypertension, suggesting that endogenous Anx-A1 might play previously unappreciated physiological role in regulating blood pressure. This supports the development of Anx-A1 based pharmacotherapy against hypertension-induced cardiac damage.

We examined whether renal denervation (RDN) reduced blood pressure (BP), improved glomerular filtration rate, albuminuria, and left ventricular mass in sheep with hypertensive chronic kidney disease (CKD). To examine whether renal nerve function returned in the long term, we examined vascular contraction to nerve stimulation in renal arteries and determined nerve regrowth by assessing renal TH (tyrosine hydroxylase), CGRP (calcitonin gene-related peptide), and norepinephrine levels in kidneys at 30 months after RDN. RDN normalized BP in hypertensive CKD sheep such that BP was similar to that of the normotensive sheep with intact nerves. Glomerular filtration rate decreased by ≈22% in CKD sheep with intact nerves but increased ≈26% in hypertensive CKD-RDN sheep by 30 months. At 30 months, urinary albumin was ≈127% and left ventricular mass was ≈41% greater in CKD sheep with intact nerves than control. However, urinary albumin was ≈60% less and left ventricular mass was ≈40% less in the CKD sheep that underwent RDN compared with intact counterpart. At 30 months in CKD-RDN sheep, neurovascular contraction (≈56%), renal proportion of TH (≈50%), CGRP (≈67%), and norepinephrine content (≈49%) were all less than CKD-intact; all these variables were similar between normotensive-intact and normotensive-RDN groups. RDN caused a sustained reduction in BP and improvements in renal function. Regrowth of renal nerves and return of function were observed in hypertensive CKD-RDN sheep, but levels were only partially restored to levels of intact. These suggest that RDN lowers BP in the long term and is renoprotective and cardioprotective as a result of lesser nerve regrowth in CKD.

MicroRNA miR-181a is down-regulated in the kidneys of hypertensive patients and hypertensive mice. In vitro, miR-181a is a posttranslational inhibitor of renin expression, but pleiotropic mechanisms by which miR-181a may influence blood pressure (BP) are unknown. Here we determined whether deletion of miR-181a/b-1 in vivo changes BP and the molecular mechanisms involved at the single-cell level. We developed a knockout mouse model lacking miR-181a/b-1 genes using CRISPR/Cas9 technology. Radio-telemetry probes were implanted in twelve-week-old C57BL/6J wild-type and miR-181a/b-1 knockout mice. Systolic and diastolic BP were 4-5mmHg higher in knockout compared with wild-type mice over 24-hours (P.01). Compared with wild-type mice, renal renin was higher in the juxtaglomerular cells of knockout mice. BP was similar in wild-type mice on a high (3.1%) versus low (0.3%) sodium diet (+0.4±0.8mmHg) but knockout mice showed salt sensitivity (+3.3±0.8mmHg, P.001). Since microRNAs can target several mRNAs simultaneously, we performed single-nuclei RNA-sequencing in 6,699 renal cells. We identified 12 distinct types of renal cells, all of which had genes that were dysregulated. This included genes involved in renal fibrosis and inflammation such as Stat4, Col4a1, Cd81, Flt3l, Cxcl16, Smad4. We observed up-regulation of pathways related to the immune system, inflammatory response, reactive oxygen species and nerve development, consistent with higher tyrosine hydroxylase. In conclusion, downregulation of the miR-181a gene led to increased BP and salt sensitivity in mice. This is likely due to an increase in renin expression in juxtaglomerular cells, as well as microRNA-driven pleiotropic effects impacting renal pathways associated with hypertension.

Overactivity of renal sympathetic nerves and nitric oxide (NO) deficiency occur in hypertensive chronic kidney disease (CKD). In sheep with hypertensive CKD and NO deficiency, renal denervation (RDN) reduces blood pressure and improves kidney function (glomerular filtration rate). We hypothesized that this improvement in glomerular filtration rate after RDN is associated with increased NO bioavailability. In this study, glomerular filtration rate response to systemic inhibition of NOS (NO synthase) was examined in healthy and CKD sheep at 2 and 30 months after a sham (intact nerves) or RDN procedure. Basal urinary total nitrate (nitrate+nitrite) excretion was examined at 2 and 30 months, and kidney protein expression of endothelial and neuronal NOS was assessed at 30 months. Urinary nitrate+nitrite in CKD-RDN and healthy sheep was ≈50% to 70% greater than in CKD-intact. During NOS inhibition, the fall in glomerular filtration rate in CKD-RDN sheep was ≈20% greater than in CKD-intact. These effects in CKD-RDN sheep were similar to those in healthy sheep. Endothelial NOS protein expression was lower in CKD-intact sheep compared with healthy sheep and compared with CKD-RDN. In summary, RDN normalizes NO bioavailability and restores contribution of NO to renal hemodynamics in CKD. These changes may promote improvements in kidney function and sustained blood pressure lowering after RDN in hypertensive CKD.

Background: Inflammation can play an important role in the progression of hypertension and end organ damage, yet anti-inflammatory drugs remain relatively underexplored as antihypertensive therapeutic options. Formyl peptide receptors (FPR) are integral to the regulation and resolution of inflammation and may be an attractive target for the treatment of hypertension-induced end organ damage, especially given our previous observation that a small molecule FPR prototype molecule reduced cardiac inflammation and fibrosis in a model of myocardial infarction and exhibited vasodilator effects in isolated blood vessels. Objective: The aim of the present study is to determine whether Cmpd17b has antihypertensive and antifibrotic effects in a mouse model of spontaneous hypertension. Methods: Hypertensive BPH/2J (n=14) and normotensive BPN/3J mice (n=12) were treated daily with Cmpd17b (50mg/kg/day, i.p.) or vehicle (8% tween80 and 10% dimethyl sulfoxide in saline, i.p.) for 4 weeks. Mean arterial pressure (MAP) was measured via pre-implanted radiotelemetry probes at baseline and throughout the treatment period. Sirius red staining of left ventricle tissue was used as a marker of cardiac fibrosis. Results: MAP in BPH/2J mice was markedly greater than BPN/3J mice at baseline (126±2 vs 106±1mmHg respectively, P P P =0.533) and vehicle treated BPH/2J mice (1±1mmHg, P =0.316). Collagen content in the left ventricle (%LV) was greater in vehicle treated BPH/2J compared with BPN/3J mice ( P P Conclusion: These findings suggest that targeting FPR with the agonist Cmpd17b, has both antihypertensive and antifibrotic effects in hypertensive mice, thus supporting further assessment of FPR based therapeutics for the treatment of hypertension and end organ damage.

Background: Orexin is a neuropeptide which can influence a wide range of physiological functions including blood pressure, sympathetic nervous system activity and arousal. Orexinergic signalling is suggested to contribute to the neurogenic hypertension in BPH/2J mice, based on the hypotensive response to the dual orexin receptor (OxR) antagonist, Almorexant, which was not observed in normotensive BPN/3J controls. Orexin is also known to influence the cardiovascular response to certain stressors. Thus, it is possible that orexin may also contribute to the exaggerated pressor response to stress that is reported in BPH/2J mice. Objective: To determine the contribution of orexin to the hypertension and exaggerated stress reactivity in BPH/2J wild type mice by comparing with BPH/2J Orexin homozygous knock out (BPH OxKO) mice. Methods: BPH OxKO (n=9) and BPH wild type (BPH WT) mice (n=6) were implanted with radiotelemetry probes to measure blood pressure (BP), heart rate (HR) and locomotor activity across the 24hr period and in response to restraint and dirty cage swap stressors. The BP responses to ganglion blocker pentolinium (5mg/kg, i.p.), was also measured. Results: There was no difference in average mean arterial pressure (MAP) over the 24hr period in BPH OxKO mice (131±1 vs 133±1mmHg, P =0.351), but there was a modest elevation in systolic AP (+4.5mmHg) exclusively during light period in BPH OxKO compared with BPH WT mice (145±2 vs 141±2mmHg, P P =0.160) and locomotor activity tended to be lower in BPH OxKO compared with BPH WT mice during the dark period (1.1±0.2 vs 1.7±0.3 units respectively, P =0.051). The pressor response to dirty cage swap stress was lower in BPH OxKO compared with BPH WT mice (22±1 vs 28±1mmHg respectively, P P P =0.255). Conclusion: The present findings suggest that whilst orexin does not contribute to sympathetically mediated hypertension, it may play a role in the exaggerated cardiovascular response to stress and hyperactivity in BPH/2J mice.

Hypertension is a major, independent risk factor for atherosclerotic cardiovascular disease. However, this pathology can arise through multiple pathways, which could influence vascular disease through distinct mechanisms. An overactive sympathetic nervous system is a dominant pathway that can precipitate in elevated blood pressure. We aimed to determine how the sympathetic nervous system directly promotes atherosclerosis in the setting of hypertension. We used a mouse model of sympathetic nervous system-driven hypertension on the atherosclerotic-prone apolipoprotein E-deficient background. When mice were placed on a western type diet for 16 weeks, we showed the evolution of unstable atherosclerotic lesions. Fortuitously, the changes in lesion composition were independent of endothelial dysfunction, allowing for the discovery of alternative mechanisms. With the use of flow cytometry and bone marrow imaging, we found that sympathetic activation caused deterioration of the hematopoietic stem and progenitor cell niche in the bone marrow, promoting the liberation of these cells into the circulation and extramedullary hematopoiesis in the spleen. Specifically, sympathetic activation reduced the abundance of key hematopoietic stem and progenitor cell niche cells, sinusoidal endothelial cells and osteoblasts. Additionally, sympathetic bone marrow activity prompted neutrophils to secrete proteases to cleave the hematopoietic stem and progenitor cell surface receptor CXCR4. All these effects could be reversed using the β-blocker propranolol during the feeding period. These findings suggest that elevated blood pressure driven by the sympathetic nervous system can influence mechanisms that modulate the hematopoietic system to promote atherosclerosis and contribute to cardiovascular events.

Self-measurement of blood pressure at home by patients with hypertension is being widely used for several decades in many countries. Statements and guidelines for using home blood pressure monitoring for hypertension management have been published in the last three decades in the USA, Canada, Europe, Australia, and Japan. Initially there was some caution by several organizations in using home blood pressure measurements for decision-making in hypertension. However, in the last two decades the publication of outcome studies showing superiority of home measurements in predicting risk compared to the conventional office measurements has supported a major role for home blood pressure monitoring in decision-making in hypertension. Several organizations recommend ambulatory blood pressure monitoring as the primary method for hypertension diagnosis, with home monitoring proposed as a useful alterative. However, home blood pressure monitoring is much more widely available than ambulatory monitoring, it is preferred by most patients, and has been shown to improve patients’ long-term compliance with treatment and thereby hypertension control rates. Thus, home blood pressure monitoring is currently recommended for wide clinical application in subjects with suspected or treated hypertension, as it offers a pragmatic approach for out-of-office blood pressure evaluation for clinical practice. Efforts to implement the wide use of home blood pressure monitoring would likely enhance the diagnosis and control of hypertension across communities.

The European Society of Hypertension (ESH) Working Group on Blood Pressure (BP) Monitoring and Cardiovascular Variability organized a Teaching Course on 'Blood Pressure Monitoring: Theory and Practice' during the 2017 ESH Meeting in Milan, Italy. This course performed by 11 international BP monitoring experts covered key topics of BP monitoring, including office BP measurement, ambulatory BP monitoring, home BP monitoring, ambulatory versus home BP, white-coat and masked hypertension, cuff use, and BP variability. This article presents a summary of the proceedings of the ESH BP Monitoring Teaching Course, including essential information, practical issues, and recommendations on the clinical application of BP monitoring methods, aiming to the optimal management of patients with suspected or diagnosed hypertension.

A brake assembly piston rod from a RAAF aircraft had fractured as a result of tensile fatigue that had initiated within a relatively pronounced machining mark at the change in section from a stress relief groove to piston rod body. While cracking could be detected under Scanning Electron Microscope (SEM) examination, crack width was such that high sensitivity fluorescent dye penetrant inspection methods did not highlight cracking and ultra-high sensitivity fluorescent dye penetrant indicated the presence of cracking but not its full length. At the time of writing the OEM recommendations are for high sensitivity fluorescent dye penetration inspection to determine the presence of cracking within the stress relief groove. Approximately 360 similar aircraft (which includes a number of different variants), were understood to be in service, operating in fourteen (14) countries around the world. The risk to the aircraft and crew should a piston rod with an undetected or undetectable crack fail during an aborted take-off or during landing is potentially catastrophic.

Objective:Patients with increased short term blood pressure (BP) variability have a poorer prognosis. In the Ohasama population study, standard deviation (SD) of BP has been shown to be a BP independent risk factor for cardiovascular death in an 8.5 year follow up. However, SD doesn’t distinguish be

Feeding a high-fat diet (HFD) to rabbits results in increased blood pressure and renal sympathetic nerve activity (RSNA) and marked increases in plasma leptin and insulin. We determined the contribution of insulin and leptin signaling in the central nervous system to the increased blood pressure and RSNA during a HFD using specific antagonists. New Zealand White rabbits were implanted with an intracerebroventricular (ICV) catheter and RSNA electrode and placed on a normal or 13.5% HFD for 1 or 3 weeks. Blood pressure, heart rate, and RSNA were recorded before and for 90 minutes after ICV administration of a leptin antagonist (100 µg), insulin antagonist (0.5 U), or vehicle (50 µL) on separate days. Rabbits had higher blood pressure (+8%, +17%) and RSNA (+55%, +71%), at 1 and 3 weeks, respectively, of HFD compared with controls (n=7–11). ICV leptin antagonist reduced blood pressure by 9% and RSNA by 17% ( P P

BACKGROUND Dyslipidemia is one the most well-established risk factors for cardiovascular disease development. Moreover, hypercholesterolemia and plasma cholesterol level in the high to normal range are established triggers for impairment in endothelial function. Evidence indicates that endothelial function is closely linked with sympathetic nervous activity in healthy individuals. We therefore investigated whether both endothelial and sympathetic functions may be impaired in young females with abnormal plasma cholesterol levels. METHODS Baseline endothelial function (digital pulse amplitude) and muscle sympathetic nervous activity (microneurography) were retrospectively analyzed in 14 young healthy females with dyslipidemia as indicated by total cholesterol ≥197mg/dL, high-density lipoprotein ≤39mg/dL, or low-density lipoprotein >116mg/dL, and in 13 females with lipids in the healthy range. RESULTS Subjects with dyslipidemia had significantly impaired endothelial function compared to those with a normal cholesterol profile (reactive hyperemia index; 1.61±0.10 vs. 2.32±0.14, P < 0.001), increased muscle sympathetic nervous activity (after adjusting for body mass and age, 36±3 vs. 27±3 bursts per 100 heartbeats, P = 0.049) and elevated high-sensitivity C-reactive protein (4.13±0.77 vs. 1.92±0.61mg/L, P = 0.03). DISCUSSION Our results indicate that young healthy females with dyslipidemia present with a strong impairment of endothelial function and increased sympathetic drive. The sympathetic activation observed in the subjects with an elevated cholesterol profile may play a role in the development of cardiovascular disease development.

Schlager inbred hypertensive mice (BPH/2J) have been suggested to have high blood pressure (BP) due to an overactive sympathetic nervous system (SNS). The brain nuclei associated with the hypertension are also those involved in the integration of the cardiovascular responses to stress. Therefore, in the present study, we hypothesize that BPH/2J mice likely have a greater response to stress that is associated with greater neuronal activation in the limbic system, hypothalamus and medulla in regions known to regulate sympathetic activity. Male hypertensive BPH/2J and normotensive BPN/3J mice were implanted with telemetry devices and exposed to dirty cage-switch, an acute model of aversive stress. Stress exposure caused a 60% greater pressor response in BPH/2J compared with BPN/3J mice and an increase in activity, by contrast the level of tachycardia was less in BPH/2J mice. Stress-induced cardiovascular responses were also associated with greater neuronal activation, as detected by c-Fos expression, in BPH/2J compared with BPN/3J mice in the medial nucleus of the amygdala (MeAm), dorsomedial hypothalamus (DMH) (P

Excess weight is established as a major risk factor for cardiovascular diseases, particularly in young individuals. To get a better understanding of the pathophysiology underlying increased cardiovascular disease risk, we evaluated early signs of organ damage and their possible relationship to sympathetic nervous activity. Eighteen lean (body mass index 2 ) and 25 overweight or obese (body mass index >25 kg/m 2 ) healthy university students were included in the study. We comprehensively assessed subclinical target organ damage, including the following: (1) assessment of renal function; (2) left ventricular structure and systolic and diastolic function; and (3) endothelial function. Muscle sympathetic nervous activity was assessed by microneurography. Participants with excess weight had decreased endothelial function ( P P P P P P R 2 =0.244; P R 2 =0.318, P R 2 =0.312, P

Background and purpose: We determined if chronic sympatho-inhibition with rilmenidine has functional significance for the kidney by altering responses of renal blood flow (RBF) and plasma renin activity (PRA) to stress and acute hypotension in rabbits with renovascular hypertension. Experimental approach: RBF to each kidney and renal sympathetic nerve activity (RSNA) to the left kidney were measured in rabbits in which a renal artery clip induced hypertension (2K1C) and in sham-operated rabbits. After 2 weeks, a subcutaneous minipump was implanted to deliver rilmenidine (2.5 mg·kg−1·day−1) to 2K1C rabbits for 3 weeks. Key results: After 5 weeks of renal artery stenosis, mean arterial pressure (MAP) was 23% higher and PRA 3-fold greater than in sham-operated rabbits. Blood flow and renal vascular conductance in the stenosed kidney were lower (−75% and −80%) compared with sham, and higher in the non-clipped kidney (68% and 39%). Responses of RBF and PRA to hypotension were similar in 2K1C and sham rabbits. Airjet stress evoked a greater increase in MAP in 2K1C rabbits than sham controls. Chronic rilmenidine normalized MAP, reduced RSNA and PRA, and did not reduce RBF in the stenosed kidney. Responses of RBF (clipped and non-clipped kidney), RSNA and PRA to hypotension and airjet were little affected by rilmenidine. Conclusions and implications: Our observations suggest that chronic sympatho-inhibition is an effective antihypertensive therapy in renovascular hypertension. It normalizes MAP and reduces basal PRA without compromising blood flow in the stenosed kidney or altering responses of MAP, haemodynamics and PRA to acute hypotension and stress.

Objective We examined whether renal sympathetic nerve activity (RSNA) and heart rate (HR) baroreflexes in conscious rabbits were altered by exposure to a combination of stress and hypertension and determined how this was modified by acute and chronic treatment with the sympathoinhibitory agent rilmenidine. Methods Rabbits were made hypertensive with a renal-artery clip and a renal nerve recording electrode was implanted 4-5 weeks later. After recovery, baroreflexes were measured before and during airjet stress and again after receiving rilmenidine (either acutely or by infusion for 3 weeks). Results Renal clipping increased mean arterial pressure (MAP) and shifted baroreflex RSNA and HR curves rightward. The HR and RSNA upper plateaus were similar to those of normotensive animals but HR baroreflex sensitivity was reduced in the hypertensive group. Airjet stress lowered HR baroreflex sensitivity in sham but not in hypertensive rabbits. By contrast, stress increased the baroreflex-induced maximum RSNA in hypertensive animals but not in normotensive rabbits. MAP variability was greater in the hypertensive group but was unaffected by airjet stress. Acute and chronic rilmenidine lowered MAP to close to normotensive levels, markedly reduced MAP variability and RSNA but did not prevent the RSNA baroreflex facilitation produced by airjet stress. Conclusion Baroreflex control of HR was diminished by either hypertension or acute airjet stress but the effects were not additive. Although the baroreflex-induced RSNA maximum was increased by stress only in hypertensive animals, rilmenidine was effective in minimizing the reflex autonomic disturbances produced by hypertension and stress.

A low nephron endowment is a strong predictor for future risk of hypertension, kidney and cardiovascular disease. Previously, we have shown that fetal uninephrectomy (uni-x) results in elevated arterial pressure, reduced renal function and low plasma renin activity in adulthood in sheep. However, the mechanisms via which a reduction in renal mass in early life contributes to the development of hypertension and renal disease are not well understood. Nitric oxide (NO) plays an important role in driving the fall in renal vascular resistance (RVR) and rise in glomerular filtration rate (GFR) that characterizes the normal postnatal maturation of renal function in the newborn. We hypothesized that the early onset of renal dysfunction in individuals with a congenital reduction in renal mass is due to a reduced renal contribution of NO. Fetal uni-x (n=9) or sham operation (n=7) was performed at 100d of gestation (term=150 days). In conscious female lambs at 6 months of age, mean arterial pressure (MAP) was measured via an indwelling carotid arterial catheter and GFR and renal blood flow (RBF) were measured via clearance methods before and after nitric oxide synthase inhibition (L-NAME; 20mg/kg/h iv). Basal MAP was elevated in uni-x as compared to the sham sheep (sham: 80 ± 2 mmHg, uni-x: 86 ± 1 mmHg; P < 0.01). In response to systemic administration of L-NAME MAP increased similarly in both groups (sham: 13 ± 3 mmHg, uni-x: 13 ± 4 mmHg). Basal RBF (sham: 933 ± 29 ml/kg/h; uni-x 757 ± 43 ml/kg/h; P

Renal denervation (RDN) has been shown to reduce blood pressure (BP), muscle sympathetic nerve activity (MSNA) and target organ damage in patients with resistant hypertension (RH) and bilateral single renal arteries. The safety and efficacy of RDN in patients with multiple renal arteries remains unclear.We measured office and 24-hour BP at baseline, 3 and 6 months following RDN in 91 patients with RH, including 65 patients with single renal arteries bilaterally (group 1), 16 patients with dual renal arteries on either one or both sides (group 2) and 10 patients with other anatomical constellations or structural abnormalities (group 3). Thirty nine out of 91 patients completed MSNA at baseline and follow-up.RDN significantly reduced office and daytime SBP in group 1 at both 3 and 6 months follow-up (P0.001) but not in groups 2 and 3. Similarly, a significant reduction in resting baseline MSNA was only observed in group 1 (P0.05). There was no deterioration in kidney function in any group.While RDN can be performed safely irrespective of the underlying renal anatomy, the presence of single renal arteries with or without structural abnormalities is associated with a more pronounced BP and MSNA lowering effect than the presence of dual renal arteries in patients with RH. However, when patients with dual renal arteries received renal nerve ablation in all arteries there was trend towards a greater BP reduction. Insufficient renal sympathetic nerve ablation may account for these differences.

The 16-kDa polypeptide hormone, leptin along with the neurotransmitters noradrenaline and serotonin (5-HT) have important physiological roles in the regulation of a number of neuroendocrine actions particularly feeding. Leptin receptor mRNA and immunoreactivity has been reported in various brain regions, while recent studies suggest that leptin is released from the human brain. This study investigated the interactions between leptinergic and neurotransmitter systems of the rat brain in vitro. Techniques were established to simultaneously monitor the release of endogenous noradrenaline and its metabolite 3,4 dihydroxyphenylglycol (DHPG), and 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) from the rat brain. The neuromodulatory action of leptin (0.2 and 3 nM) on the overflow of noradrenaline and DHPG from the medulla and hypothalamus was examined. The effect of leptin on 5-HT and 5-HIAA overflow from the hypothalamus was also investigated. Administration of 0.2 and 3 nM leptin significantly increased medullary noradrenaline overflow to 172% and 174% of basal levels, respectively. Leptin had no significant effect on hypothalamic noradrenaline overflow, while leptin perfusion induced a significant increase in 5-HIAA overflow from the hypothalamus. This study lends support to the notion of a complex interaction of the leptinergic and brain neurotransmitters involved in the control of feeding and energy metabolism.

Background Numerous studies have shown sex differences in the onset and severity of hypertension. Despite these sex-differences the majority of animal studies are carried out in males. This study investigated expression changes in both male and female hypertensive mouse kidneys to identify common mechanisms that may be involved in the development of hypertension. Methods The Schlager hypertensive mouse model (BPH/2J) and its normotensive control (BPN/3J) were used in this study. Radiotelemetry was performed on 12 to 13 week old BPH/2J and BPN/3J male and female animals. Affymetrix GeneChip Mouse Gene 1.0 ST Arrays were performed in kidney tissue from 12 week old BPH/2J and BPN/3J male and female mice (n = 6/group). Genes that were differentially expressed in both male and female datasets were validated using qPCR. Results Systolic arterial pressure and heart rate was significantly higher in BPH/2J mice compared with BPN/3J mice in both males and females. Microarray analysis identified 153 differentially expressed genes that were common between males and females (70 upregulated and 83 downregulated). We validated 15 genes by qPCR. Genes involved in sympathetic activity (Hdc, Cndp2), vascular ageing (Edn3), and telomere maintenance (Mcm6) were identified as being differentially expressed between BPH/2J and BPN/3J comparisons. Many of these genes also exhibited expression differences between males and females within a strain. Conclusions This study utilised data from both male and female animals to identify a number of genes that may be involved in the development of hypertension. We show that female data can be used to refine candidate genes and pathways, as well as highlight potential mechanisms to explain the differences in prevalence and severity of disease between men and women. Electronic supplementary material The online version of this article (doi:10.1186/s12881-014-0101-x) contains supplementary material, which is available to authorized users.

BackgroundWe determined clinical predictors of the rate of rise (RoR) in blood pressure in the morning as well as a novel measure of the power of the BP surge (BP(power)) derived from ambulatory blood pressure recordings.MethodsBP(power) and RoR were calculated from 409 ambulatory blood pressure (ABP) recordings from subjects attending a cardiovascular risk clinic. Anthropometric data, blood biochemistry, and history were recorded. The 409 subjects were 20-82 years old (average 57, SD = 13), 46% male, 9% with hypertension but not on medication and 34% on antihypertensive medication.ResultsAverage RoR was 11.1 mmHg/hour (SD = 8) and BP(power) was 273 mmHg(2)/hour (SD = 235). Only cholesterol, low density lipoprotein and body mass index (BMI) were associated with higher BP(power) and RoR (PConclusionsCholesterol is an independent predictor of a greater and more rapid rise in morning BP as well as of further increases over several years. Reduction of cholesterol with statin therapy is very effective in reducing the morning blood pressure surge.

Aims The nucleus of the solitary tract (NTS) is important for cardiovascular regulation and contains angiotensin type 1A (AT1A) receptors. To assess its function, we examined the effect of expressing in AT1A receptors in the NTS of mice lacking these receptors. Methods and results Bilateral microinjections of lentivirus expressing AT1A receptors (AT1Av mice, n = 6) or green fluorescent protein (GFPv, n = 8, control) under the control of the PRSx8 promotor were made into the NTS of AT1A receptors null mice (AT1A−/−). Telemetry devices recorded blood pressure (BP), heart rate (HR), and locomotor activity. Expression of AT1A receptors in the NTS increased BP by 11.2 ± 4 mmHg ( P < 0.05) at 2 and 3 weeks, whereas GFPv mice remained at pre-injection BP. Ganglion blockade reduced BP to similar levels pre- and post-transfection in GFPv and AT1Av mice. Greater pressor responses to cage-switch stress were observed following AT1A receptors expression (+18 ± 2 mmHg pre- to +24 ± 2 mmHg post-virus, P < 0.05) with similar stress-induced pressor responses pre- and post-virus in GFPv mice. Pressor responses to restraint stress pre- and post-virus were similar in AT1Av but were 20% less post-GFPv ( P < 0.001). The lack of attenuation in BP to restraint was associated with four-fold greater Fos-expression in AT1A receptors mice. AT1A receptors expression in the NTS did not alter baroreflex gain differently between groups. Conclusion The results suggest that transfection of AT1A receptors on neurons in the NTS elevates BP independent of the SNS and pressor responses to aversive stimuli are associated with greater Fos-expression in forebrain regions. This study suggests a novel mechanism by which the NTS may modulate MAP in the long-term via AT1A receptors.

Aim: Oxidative stress may play an important role in the pathogenesis of hypertension. The aim of our study is to examine whether increased expression of the predominant endothelial L-arginine transporter, cationic amino acid transporter-1 (CAT1), can prevent oxidative stress-induced hypertension. Methods: Wild-type mice (WT; n = 9) and endothelial CAT1 overexpressing (CAT+ )m ice (n = 6) had telemetry probes implanted for the measurement of mean arterial pressure (MAP), heart rate (HR) and locomotor activity. Minipumps were implanted for infusion of the superoxide dismutase inhibitor diethyldithiocarbamic acid (DETCA; 30 mg kg 1 day 1 ; 14 days) or its saline vehicle. Baseline levels of MAP, HR and locomotor activity were determined before and during chronic DETCA administration. Mice were then killed, and their plasma and kidneys collected for analysis of F2-isoprostane levels. Results: Basal MAP was less in CAT+ (92 2 mmHg; n = 6) than in WT (98 2 mmHg; n = 9; P< 0.001). During DETCA infusion, MAP was increased in WT (by 4.2 0.5%; P < 0.001) but not in CAT+, when compared to appropriate controls (PDETCA*genotype = 0.006). DETCA infusion increased total plasma F2-isoprostane levels (by 67 11%; P = 0.05) in WT but not in CAT+. Total renal F2-isoprostane levels were greater during DETCA infusion in WT (by 72%; P < 0.001), but not in CAT+, compared to appropriate controls. Conclusion: Augmented endothelial L-arginine transport attenuated the prohypertensive effects of systemic and renal oxidative stress, suggesting that manipulation of endothelial CAT1 may provide a new therapeutic approach for the treatment of cardiovascular disease associated with oxidative stress.

With animal models, death as an intentional end point is ethically unacceptable. However, in the study of septic shock, death is still considered the only relevant end point. We defined eight humane end points into four stages of severity (from healthy to moribund) and used to design a clinically relevant scoring tool, termed "the mouse clinical assessment score for sepsis" (M-CASS). The M-CASS was used to enable a consistent approach to the assessment of disease severity. This allowed an ethical and objective assessment of disease after which euthanasia was performed, instead of worsening suffering. The M-CASS displayed a high internal consistency (Cronbach α = 0.97) with a high level of agreement and an intraclass correlation coefficient equal to 0.91. The plasma levels of cytokines and markers of oxidative stress were all associated with the M-CASS score (Kruskal-Wallis test, P < 0.05). The M-CASS allows tracking of disease progression and animal welfare requirements.

A morning blood pressure surge (MBPS) may be either a mechanism for, or a marker of, increased cardiovascular events. This study has examined factors which may influence the morning surge: age, gender, metabolic factors, sympathetic function, blood pressure and arterial stiffness. Four measures of the MBPS were examined--sleep-trough surge, pre-awake surge, rate of blood pressure rise and a Power function. Subjects underwent ambulatory blood pressure monitoring, glucose tolerance test, central pulse wave velocity, sympathetic autonomic function tests (mental stress and sustained handgrip). MBPS was associated with age, hypertension, blood pressure variability and serum lipids. After adjustment for age and waist circumference, all four measures of MBPS remained positively associated with low-density lipoprotein (LDL) cholesterol. The novel finding of a significant relationship between measures of MBPS and LDL-cholesterol is an intriguing link between two major cardiovascular risk factors.

The influence of atrial natriuretic peptide (ANP) on the blood pressure (BP)-heart rate (HR) baroreflex was studied in conscious chronically instrumented dogs and rats. In both species, sigmoid steady-state baroreflex curves were constructed from the baroreflex changes in HR to alternating slow injections of vasopressor and vasodepressor drugs. When this method was used in dogs, ANP caused a small but significant (P < 0.05) enhancement of the sensitivity (22 +/- 10%) and curvature (26 +/- 10%) of the baroreflex, which was without a change in HR range. In rats, ANP had no significant effect on any baroreflex parameter derived from steady-state curves. By contrast, in the same rats, fast reflex HR responses to rapid increases in BP (ramp) exposed a substantial (81 +/- 21%) ANP-induced enhancement of baroreflex sensitivity. Contribution from arterial vs. nonarterial afferents to the baroreflex is not uniform between these two techniques (steady state reflects largely arterial baroreceptor input, ramp evokes a greater proportion of cardiopulmonary afferent activation). The present study demonstrated that baroreceptor HR reflex responses to ANP depend on the baroreflex techniques employed and probably exposed a selectivity by ANP for nonarterial baroreflex pathways.

Background Twenty-four hour ambulatory blood pressure thresholds have been defined for the diagnosis of mild hypertension but not for its treatment or for other blood pressure thresholds used in the diagnosis of moderate to severe hypertension. We aimed to derive age and sex related ambulatory blood pressure equivalents to clinic blood pressure thresholds for diagnosis and treatment of hypertension. Methods We collated 24 hour ambulatory blood pressure data, recorded with validated devices, from 11 centres across six Australian states (n=8575). We used least product regression to assess the relation between these measurements and clinic blood pressure measured by trained staff and in a smaller cohort by doctors (n=1693). Results Mean age of participants was 56 years (SD 15)with mean body mass index 28.9 (5.5) and mean clinic systolic/diastolic blood pressure 142/82 mm Hg (19/12);4626 (54%) were women. Average clinic measurements by trained staff were 6/3 mm Hg higher than daytime ambulatory blood pressure and 10/5 mm Hg higher than 24 hour blood pressure, but 9/7 mm Hg lower than clinic values measured by doctors. Daytime ambulatory equivalents derived from trained staff clinic measurements were 4/3 mm Hg less than the 140/90 mm Hg clinic threshold (lower limit of grade 1 hypertension),2/2 mm Hg less than the 130/80 mm Hg threshold (target upper limit for patients with associated conditions), and 1/1 mm Hg less than the 125/75 mm Hg threshold.Equivalents were 1/2 mm Hg lower for women and 3/1 mm Hg lower in older people compared with the combined group. Conclusions Our study provides daytime ambulatory blood pressure thresholds that are slightly lower than equivalent clinic values. Clinic blood pressure measurements taken by doctors were considerably higher than those taken by trained staff and therefore gave inappropriate estimates of ambulatory thresholds. These results provide a framework for the diagnosis and management of hypertension using ambulatory blood pressure values. Refereed/Peer-reviewed

Objective:Hypertensive Schlager mice (BPH) are hypertensive due to an exaggerated contribution of the sympathetic nervous system (SNS) and renin angiotensin system (RAS). The latter was associated with reduced expression of the renin regulatory micro RNA-181a. We therefore determined the effect of b

The paper deals with hypertension phenotypes defined by office and ambulatory blood pressure in 9,153 subjects referred to hypertension clinics in four continents: the Artemis International Registry

Background: Although Type 2 diabetes (T2DM) is associated with retinal vascular disease, the underlying pathophysiological mechanisms are unclear. Reduced retinal arteriolar diameter has been linked to high clinic blood pressure (BP) but the role of more sensitive measures of BP control have never been assessed. This study aimed to determine the relationship between retinal arteriolar diameter and 24 hour ambulatory BP (including BP variability) in people with and without T2DM. Methods: Digitized retinal photographs were analysed to quantify retinal arteriolar diameters in 37 non-diabetic (aged 53±10 years; 48.2% male) and 29 T2DM (aged 60±9 years; 48.6% male) participants. Daytime rate of systolic BP variation (BPV) was derived from 24 hour ambulatory BP as the 3-hour moving average for the slope of the change in systolic BP between each systolic BP reading over time. Results: There was a non-significant trend for patients with T2DM to have greater BPV compared with non-diabetics (35.9±7.1 versus 32.6±6.6; p=0.08). BPV was significantly and negatively associated with retinal arteriolar diameter in non-diabetics alone (β=−0.006, p=0.03), but not in people with T2DM (β=0.004, p=0.402), even after adjusting for age, body mass index and ambulatory systolic BP (either night time, day time or 24 hour systolic BP). Conclusions: BPV was inversely related to retinal arteriolar diameter only in people without T2DM. This suggests that mechanisms underlying retinal vascular disease may differ between people with and without T2DM, with the rate of BP variation possibly being an important factor.