Long-term Blood Pressure Control Research Articles

Effectiveness of a Pharmacist-Physician Team-Based Collaboration to Improve Long-Term Blood Pressure Control at an Inner-City Safety-Net Clinic.

To evaluate the effectiveness of a pharmacist-physician collaborative practice model (PPCPM) to improve long-term blood pressure (BP) control rates in a primarily African-American underserved urban population. Volunteer physicians established initial diagnoses, whereas pharmacists provided most (more than 70%) of the medication management. During each scheduled visit, the pharmacist reconciled the medication list, completed a clinical interview, conducted a focused physical examination, developed and implemented a treatment plan, and provided documentation in a shared medical record. A retrospective chart review was performed to collect data for a longitudinal cohort of patients managed by the PPCPM from 2010-2013. Of 385 patients with at least two pharmacist visits during 2009, 172 patients received continuous care over the study period. At baseline, the mean age of the cohort was 51.3 years, 62% were female, and 76% were African-American. Approximately 65% were obese (body mass index 30 kg/m(2) or higher), and 39% were cigarette smokers. Mean baseline BP was 156/98 mm Hg, with only 17% of the cohort at their BP goal of lower than 140/90 mm Hg. The BP control rate improved to 66% during the first year and persisted throughout the study period, with 68% of patients at goal in 2013 (p<0.05 compared with baseline). The PPCPM BP control rate ranks in the 90th percentile of National Committee for Quality Assurance benchmarks and was superior even to the 2013 reported mean for commercial insurers. The PPCPM effectively improved hypertension control in an uninsured, primarily African-American, urban population despite significant health barriers. Key elements of this asynchronous care model included access to a common medical record, optimization of distinct interprofessional roles, frequent follow-up with evaluation, and collaborative practice agreement with sufficient scope of practice to implement medication changes at the time of the visit.

Anandamide and its metabolites: what are their roles in the kidney?

Anandamide (AEA) is the N-acyl ethanolamide of arachidonic acid, an agonist of cannabinoid and non-cannabinoid receptors in the body. The kidneys are enriched in AEA and in enzymes that metabolize AEA, but the roles of AEA and its metabolites in the kidney remain poorly understood. This system likely is involved in the regulation of renal blood flow and hemodynamics and of tubular sodium and fluid reabsorption. It may act as a neuromodulator of the renal sympathetic nervous system. AEA and its cyclooxygenase-2 metabolites, the prostamides, in the renal medulla may represent a unique antihypertensive system involved in the long-term control of blood pressure. AEA and its metabolites are also implicated as modulators of inflammation and mediators of signaling in inflammation. AEA and its metabolites may be influential in chronic kidney disease states associated with inflammation and cardiovascular diseases associated with hyperhomocysteinemia. The current knowledge of the roles of AEA and its derivatives highlights the need for further research to define and potentially exploit the role of this endocannabinoid system in the kidney.

The angiotensin converting enzyme (ace) gene polymorphism: Insight study of the renal regulation of the arterial blood pressure

Since the renin-angiotensin-aldosterone system (RAAS) was originally described, it has become one of the best described hormonal systems, especially regarding the fact that it plays an important role in regulating blood volume and systemic vascular resistance, and thus indirectly influencing blood pressure (BP). On the other hand, arterial hypertension is one of the most pertinent disorders which plays an important role, not only in the progression of renal failure, but also represents a risk factor for the occurrence of end stage renal disease. Several epidemiological studies pointed out the fact that genetic predisposition accounts for about 30% of the BP variability. Up to date, there are several RAAS genes that may have effect in long-term BP control, but ACE is the most important and the most thoroughly examined. In this review, we present available data regarding the influence of gene polymorphisms of ACE on its function, within the RAAS related BP regulation. Therefore, by specially describing all its potential physiological roles, it will likely offer a new insight in the renal regulation of the BP, along with its other, not less important, roles.

Role of the kidney in the pathogenesis of hypertension: time for a neo-Guytonian paradigm or a paradigm shift?

The "Guytonian paradigm" places the direct effect of arterial pressure, on renal excretion of salt and water, at the center of long-term control of blood pressure, and thus the pathogenesis of hypertension. It originated in the sixties and remains influential within the field of hypertension research. However, the concept of one central long-term feedback loop, through which arterial pressure is maintained by its influence on renal function, has been questioned. Furthermore, some concepts in the paradigm are undermined by experimental observations. For example, volume retention and increased cardiac output induced by high salt intake do not necessarily lead to increased arterial pressure. Indeed, in multiple models of salt-sensitive hypertension the major abnormality appears to be failure of the vasodilator response to increased cardiac output, seen in salt-resistant animals, rather than an increase in cardiac output itself. There is also evidence that renal control of extracellular fluid volume is driven chiefly by volume-dependent neurohumoral control mechanisms rather than through direct or indirect effects of changes in arterial pressure, compatible with the concept that renal sodium excretion is controlled by parallel actions of different feedback systems, including hormones, reflexes, and renal arterial pressure. Moreover, we still do not fully understand the sequence of events underlying the phenomenon of "whole body autoregulation." Thus the events by which volume retention may develop to hypertension characterized by increased peripheral resistance remain enigmatic. Finally, by definition, animal models of hypertension are not "essential hypertension;" progress in our understanding of essential hypertension depends on new results on system functions in patients.

Blood Pressure Management After Intracerebral Hemorrhage.

Elevated blood pressure (BP), which presents in approximately 80% of patients with acute intracerebral hemorrhage (ICH), is associated with increased risk of poor outcome. The Second Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT2) study, a multinational, multicenter, randomized controlled trial published in 2013, demonstrated better functional outcomes with no harm for patients with acute spontaneous ICH within 6h of onset who received target-driven, early intensive BP lowering (systolic BP target <140mmHg within 1h, continued for 7days) and suggested that greater and faster reduction in BP might enhance the treatment effect by limiting hematoma growth. The trial resulted in revisions of guidelines for acute management of ICH, in which intensive BP lowering in patients with acute ICH is recommended as safe and effective treatment for improving functional outcome. BP lowering is also the only intervention that is proven to reduce the risk of recurrent ICH. Current evidences from several randomized trials, including PROGRESS and SPS3, indicate that long-term strict BP control in patients with ICH is safe and could offer additional benefits in major reduction in risk of recurrent ICH. The latest American Heart Association/American Stroke Association (AHA/ASA) guidelines recommended a target BP of <130/80mmHg after ICH, but supporting evidence is limited. Randomized controlled trials are needed that focus on strict BP control, initiated early after onset of the disease and continued long-term, to demonstrate effective prevention of recurrent stroke and other major vascular events without additional harms in the ICH population.

A Systematic Review on the Efficacy of Amlodipine in the Treatment of Patients With Hypertension With Concomitant Diabetes Mellitus and/or Renal Dysfunction, When Compared With Other Classes of Antihypertensive Medication.

The long-term cardiovascular (CV) effects of calcium channel blockers, with special focus on amlodipine, were compared with other classes of antihypertensive medications in high-risk hypertensive patient subgroups. A systematic literature review and meta-analysis was undertaken of 38 unique randomized, active-controlled, parallel-group trials comparing amlodipine/calcium channel blockers with diuretics, β-blockers, α-blockers, angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers, with ≥6-month follow-up, and which had included assessment of blood pressure (BP) and CV events [all-cause death, CV death, myocardial infarction (MI), stroke, congestive heart failure (CHF), or major CV events (MACE: MI, CHF, stroke, and CV death)], in hypertensive patients (baseline systolic/diastolic BP ≥140/≥90 mm Hg) with either concomitant diabetes and/or renal dysfunction. In hypertensive patients with diabetes, no difference was found for amlodipine versus comparators with respect to all-cause death, CV death, MACE, and MI; a decrease in stroke risk, and an increase in CHF risk, was seen. In hypertensive patients with renal dysfunction, no difference was found for amlodipine versus comparators with respect to all-cause death, CV death, MACE, MI, and CHF; a decrease in stroke risk was seen. Amlodipine was found to be at least as efficacious as all the other classes of antihypertensive agents in reducing systolic and diastolic BP. Long-term control of BP is critical for avoiding complications of hypertension in high-risk patients, particularly CV and cerebrovascular events such as stroke. This analysis has provided evidence that amlodipine is an appealing therapeutic option in the long-term management of hypertension in both diabetic and renal dysfunction patients.

Abstract P082: Mitochondrial Gene Expression is Decreased in Renal Inner Medulla of Non-human Primates with Spontaneous Hypertension

Mitochondrial gene expression may influence renal function and consequently, long-term blood pressure control. The African Green Monkey (Chlorocebus aethiops sabaeus; AGM) exhibits heritable, spontaneous hypertension and thus is a translational model for the study of human essential hypertension. We hypothesized that renal mitochondrial gene expression in hypertensive AGMs is decreased and may contribute to renal mitochondrial dysfunction in specific kidney regions. AGMs were phenotyped as normotensive (NT, systolic blood pressure; SBP &lt;120 mmHg) or hypertensive (HT, SBP &gt; 140 mmHg) by forearm plethysmography. Gene expression was determined using qRT-PCR with RNA extracted from renal cortex, outer medulla (OM), inner medulla (IM), and liver of 18 HT (mean SBP 166±7 mmHg) and 18 NT (mean SBP 98±3 mmHg) animals. In renal cortical and OM tissue of HT vervets, COX 3 (Complex IV), Cyt B (Complex III), NADH4 (Complex I) and ATP8 (Complex V) expression were similar in NT and HT AGMs. In IM of HT AGMs, COX3, NADH4, ATP8, and CYTB were downregulated by 4.7-fold (p=0.007), 4-fold (p=0.002), 4.1-fold (p=0.006), and 3-fold (p=0.018), respectively. In the liver, COX 3 expression was decreased 1.9-fold (p=0.04), 1.6-fold for ATP8 (p=0.03), and 2.0-fold for CYTB (p=0.01). Expression of SDH (Complex II) and COX4 (Complex IV), nuclear encoded subunits of the OXPHOS chain, was also assessed. SDH expression was up-regulated 8-fold in renal OM (p=0.005) but unchanged in liver, IM, and cortex. COX4 expression however, was down-regulated in OM by 8-fold (p=0.05), in IM by 5-fold (p=0.011) but unchanged in cortex and liver. Gene expression of the mitochondrial transcription factor TFAM was downregulated by 4-fold in renal OM, and unchanged in renal cortex and liver. Citrate synthase activity showed no difference in mitochondrial number between NT and HT AGMs (p=0.73). We suggest that reduced expression of mitochondrially encoded OXPHOS subunits in the renal IM may contribute to the development of hypertension in the AGM. Mitochondrial gene down-regulation in the liver may be a consequence of the systemic hypertension. We conclude that altered mitochondrial gene expression may be a cellular response to increased oxidative stress in the renal inner medulla of HT AGM.

Monotherapy versus dual therapy for the initial treatment of hypertension (PATHWAY-1): a randomised double-blind controlled trial

IntroductionPrevious studies have suggested that more intensive initial therapy for hypertension results in better long-term blood pressure (BP) control. We test this hypothesis comparing initial monotherapy with dual therapy in...

Electrical carotid sinus stimulation: chances and challenges in the management of treatment resistant arterial hypertension.

Treatment resistant arterial hypertension is associated with excess cardiovascular morbidity and mortality. Electrical carotid sinus stimulators engaging baroreflex afferent activity have been developed for such patients. Indeed, baroreflex mechanisms contribute to long-term blood pressure control by governing efferent sympathetic and parasympathetic activity. The first-generation carotid sinus stimulator applying bilateral bipolar stimulation reduced blood pressure in a controlled clinical trial but nevertheless failed to meet the primary efficacy endpoint. The second-generation device utilizes smaller unilateral unipolar electrodes, thus decreasing invasiveness of the implantation while saving battery. An uncontrolled clinical study suggested improvement in blood pressure with the second-generation device. We hope that these findings as well as preliminary observations suggesting cardiovascular and renal organ protection with electrical carotid sinus stimulation will be confirmed in properly controlled clinical trials. Meanwhile, we should find ways to better identify patients who are most likely to benefit from electrical carotid sinus stimulation.

Longitudinal Blood Pressure Control, Long-Term Mortality, and Predictive Utility of Serum Liver Enzymes and Bilirubin in Hypertensive Patients.

There is accruing evidence from general population studies that serum bilirubin and liver enzymes affect blood pressure (BP) and cardiovascular risk, but it is unclear whether these have an impact on hypertensive patients in terms of long-term survival or BP control. We analyzed 12 000 treated hypertensive individuals attending a tertiary care clinic followed up for 35 years for association between baseline liver function tests and cause-specific mortality after adjustment for conventional cardiovascular covariates. Generalized estimating equations were used to study the association of liver tests and follow-up BP. The total time at risk was 173 806 person years with median survival 32.3 years. Follow-up systolic BP over 5 years changed by -0.4 (alanine transaminase and bilirubin), +2.1(alkaline phosphatase), +0.9(γ-glutamyl transpeptidase) mm Hg for each standard deviation increase. Serum total bilirubin and alanine transaminase showed a significant negative association with all-cause and cardiovascular mortality, whereas alkaline phosphatase and γ-glutamyl transpeptidase showed a positive association and aspartate transaminase showed a U-shapedassociation. Serum bilirubin showed an incremental improvement of continuous net reclassification improvement by 8% to 26% for 25 year and 35 year cardiovascular mortality, whereas all liver markers together improved continuous net reclassification improvement by 19% to 47% compared with reference model. In hypertensive patients, serum liver enzymes and bilirubin within 4 standard deviations of the mean show independent effects on mortality and BP control. Our findings would support further studies to elucidate the mechanisms by which liver enzymes and bilirubin may exert an effect on BP and cardiovascular risk, but there is little support for using them in risk stratification.

The role of renal nerves in cardiovascular and renal function in normal and pathophysiological states.

Video slideshow introduction to the Symposium by Symposium Speaker Clive May can be found here. The notion that increased sympathetic nervous system activity is important to trigger and maintain hypertension has been under consideration for decades. It is well known that an increase in renal sympathetic nerve activity (RSNA) stimulates renin secretion, which leads to renal vasoconstriction and increases sodium reabsorption (DiBona & Kopp, 1997), indicating that excessive RSNA will contribute to hypertension. Historically, surgical sympathectomy has been used to improve blood pressure control (Smithwick, 1940; Grimson, 1941). Nevertheless, this procedure was abandoned because of its high operative morbidity and mortality. Recently, however, catheter-based interventional strategies that interrupt the RSNA have shown promising results in providing a better long-term blood pressure control in patients with resistant arterial hypertension (Esler, 2010; Esler et al. 2010). These studies have raised enormous interest in understanding the role of renal nerves in the control of cardiovascular and renal functions. Nevertheless, the mechanisms underlying the initiation and maintenance of sympathoexcitation in pathophysiological conditions and how the renal denervation leads to a long-term reduction of blood pressure are not well understood. The symposium entitled ‘The Role of renal nerves in cardiovascular and renal function in normal and pathophysiological states’, which was held at The First Pan-American Congress of Physiological Sciences, Iguassu Falls, Brazil, 2–6 August 2014, focused on the new advances regarding the importance of efferent and afferent renal fibres on sodium homeostasis and the effects of renal denervation and reinnervation on cardiovascular and kidney functions. Regarding the mechanisms underlying sympathoexcitation in hypertension, the importance of increased oxidative stress in the paraventricular nucleus of hypothalamus and the rostral ventrolateral medulla for the autonomic dysfunction associated with renovascular hypertension was discussed (Campos et al. 2015). The effect of interaction between the sympathetic nervous system and angiotensin II on sodium reabsorption is a well-known classical mechanism for the maintenance of extracellular volume homeostasis; however, the underlying molecular signalling is not clearly understood. Recent data were presented in this symposium to demonstrate that renal nerve stimulation increases intrarenal angiotensin II and activates angiotensin II type 1 receptors, triggering a signalling cascade that leads to elevation of Na+–H+ exchanger isoform 3-mediated tubular transport. The findings enhance our understanding in relation to the interaction and synergism between the sympathetic nervous system and intrarenal angiotensin II actions in normal conditions (Bergamaschi et al. 2015). Additionally, the interaction between the brain and the kidneys to maintain homeostasis is still a matter of debate and was discussed in this symposium. Recent evidences suggest that increased RSNA and renal afferent nerve activity to the brain may contribute to the outcome to the disease, such as hypertension or heart failure (Nishi et al. 2014). During renovascular hypertension, increased afferent signalling from the ischaemic kidney may contribute to the increase in blood pressure. Indeed, in renovascular hypertensive rats submitted to treatment with bone marrow-derived mesenchymal stem cells, an improvement was found in the kidney tissue and function. This was accompanied by a reduction of sympathetic vasomotor activity to the kidneys and a reduction of blood pressure, probably as a consequence of reduced afferents from the diseased kidney (Oliveira-Sales et al. 2015). In another interesting recent study, the time course of the effects of renal denervation was investigated in sheep. In this study, 11 months after catheter-based radiofrequency renal denervation, functional and anatomical evidence of afferent and efferent renal nerve reinnervation were found. Therefore, the mechanism by which catheter-based renal denervation causes a prolonged decrease in blood pressure is not well understood. Further studies are required to address this important issue (Booth et al. 2015). In conclusion, the present symposium discussed new ideas about the mechanisms by which the brain and kidneys communicate and how they interact to maintain cardiovascular and renal homeostasis. Understanding the mechanisms of crosstalk between these two important organs (brain and kidneys) related to the control of blood pressure will probably increase the possibility of finding new strategies for the treatment of cardiovascular and renal diseases. Disclaimer: Supporting information has been peer-reviewed but not copyedited. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

G protein-coupled receptor kinase 4: role in hypertension.

The kidney plays an important role in the long-term control of blood pressure and is the major organ involved in the regulation of sodium homeostasis.1 The inappropriate sodium retention in hypertension results from enhanced renal sodium transport per se or a failure to respond appropriately to signals that decrease renal sodium transport in the face of increased sodium intake. Humans with polygenic essential hypertension have increased renal sodium transport that is not properly regulated by natriuretic and antinatriuretic hormones and humoral factors, including dopamine and angiotensin II (Ang II). Dopamine and Ang II exert their effects via G protein-coupled receptors (GPCRs).1–3 GPCRs constitute by far the largest receptor family in mammals, which are encoded by >800 genes in the human genome and play a vital role in the regulation of most cellular and physiological functions in the body.4 On ligand binding, GPCRs regulate and modulate a variety of cell functions by coupling to heterotrimeric G proteins and regulating downstream effectors, such as adenylyl cyclases, phospholipases, protein kinases, and ion channels.5 Activation of renal GPCRs, including dopamine and Ang II receptors, leads to either natriuresis (sodium excretion) or antinatriuresis (sodium retention), keeping a normal sodium balance, resulting in the maintenance of a normal blood pressure.2,3 GPCR kinases (GRKs) constitute a family of 7 serine/threonine protein kinases characterized by their ability to specifically recognize and phosphorylate agonist-activated GPCRs.6 GRK-mediated receptor phosphorylation is one of the well-characterized mechanisms for GPCR desensitization. In the process of GPCR desensitization, GRKs phosphorylate agonist-bound receptors, leading to the translocation and binding of arrestins to the receptors and inhibition of subsequent receptor activation by blocking GPCR-G protein coupling. In particular, GRK4 seems to play a vital role in regulating dopamine-mediated natriuresis and renin–angiotensin system (RAS)–mediated antinatriuresis.7 Increasing …

Cluster-randomized trial of a physician/pharmacist collaborative model to improve blood pressure control.

The purpose of this study was to evaluate if a physician/pharmacist collaborative model would be implemented as determined by improved blood pressure (BP) control in primary care medical offices with diverse geographic and patient characteristics and whether long-term BP control could be sustained. Prospective, cluster-randomized trial of 32 primary care offices stratified and randomized to control, 9-month intervention (brief), and 24-month intervention (sustained). We enrolled 625 subjects with uncontrolled hypertension; 54% from racial/ethnic minority groups and 50% with diabetes mellitus or chronic kidney disease. The primary outcome of BP control at 9 months was 43% in intervention offices (n=401) compared with 34% in the control group (n=224; adjusted odds ratio, 1.57 [95% confidence interval, 0.99-2.50]; P=0.059). The adjusted difference in mean systolic/diastolic BP between the intervention and control groups for all subjects at 9 months was -6.1/-2.9 mm Hg (P=0.002 and P=0.005, respectively), and it was -6.4/-2.9 mm Hg (P=0.009 and P=0.044, respectively) in subjects from racial or ethnic minorities. BP control and mean BP were significantly improved in subjects from racial minorities in intervention offices at 18 and 24 months (P=0.048 to P<0.001) compared with the control group. Although the results of the primary outcome (BP control) were negative, the key secondary end point (mean BP) was significantly improved in the intervention group. Thus, the findings for secondary end points suggest that team-based care using clinical pharmacists was implemented in diverse primary care offices and BP was reduced in subjects from racial minority groups. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00935077.

Role of antihypertensive drugs in the treatment of migraine

The treatment of migraine depends on the frequency, severity and concomitant diseases. There are several specific drugs developed for migraine prevention in addition to the additive antimigraine effects of some other non-specific drugs. The aim of this literature-based review is to summarize the possible antimigraine properties of different antihypertensive agents (beta-blockers, calcium channel blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, etc.) focusing on the possible side effects (avoidance of beta blockers in the absence of heart disease, possible antiparkinson effect of calcium channel blockers, additive effect of drugs modifying the renin-angiotensin system activity, etc.). Current evidence supports the use of angiotensin converting enzyme inhibitors (mainly lisinopril) and angiotensin receptor blockers (mainly candesartan) for long-term migraine prevention and blood pressure control. Long-term beta-blocker treatment should be avoided in the absence of ischemic heart disease due to possible unfavourable cardiovascular effects.

The effect of regular primary care utilization on long-term glycemic and blood pressure control in adults with diabetes.

Complications of diabetes mellitus (DM) can be reduced with regular preventive care and guidance on self-management. We investigated whether regular primary care utilization could improve glycemic control and blood pressure control among American Indian/Alaska Native people with DM. Patient characteristics, risk factors, and health outcomes were identified from electronic health records of a cohort of 2138 adults with DM who received care between 1995 and 2010 from Southcentral Foundation, a tribal provider. Bivariate probit regression models estimated the probability of glycemic control and blood pressure control as functions of regular primary care, risk factors, and access factors, while taking into account potential bias arising from voluntarily choosing to seek primary care services. Regular primary care was associated with an 89% increased likelihood of blood pressure control (95% confidence interval [CI], 59-118%) and 177% increased likelihood of glycemic control (95% CI, 123-222%). Increasing the distance by 10 miles to primary care services reduced the likelihood of regular primary care by 3.7% (95% CI, -2.9% to -4.6%). Regular primary care utilization over 16 years was associated with higher rates of blood pressure control and glycemic control for adults with DM. People living closer to primary care services had a better chance of improved outcomes.

Long-term blood pressure control in patients undergoing adrenalectomy for primary hyperaldosteronism

Data on long-term blood pressure (BP) control after adrenalectomy for primary hyperaldosteronism are limited. We analyzed long-term outcomes to identify factors predictive of cure. We performed a retrospective cohort study of patients undergoing adrenalectomy for primary hyperaldosteronism (1997-2013). BP and antihypertensive medications were assessed at long-term follow-up (≥ 12 months). Primary outcome was cure, defined as normotension off antihypertensives. Of 85 patients, 15.3% (n = 13) were cured, 54.1% (n = 46) were normotensive while remaining on anti-hypertensives, and 30.6% (n = 26) were hypertensive. Younger age (P = .011), female sex (P < .001), lesser body mass index (P = .018), shorter duration of hypertension (P = .002), lower creatinine (P = .001), and fewer preoperative antihypertensive medications (P < .001) were associated with cure. Female sex, body mass index ≤ 25 kg/m(2), hypertension <5 years, creatinine ≤ 0.8 mg/dL, and <2 antihypertensives were incorporated into a scoring system. For a score of 0-1 (n = 61) the cure rate was 3%; 100% of patients with a score of 4-5 (n = 3) were cured. This scoring system performed comparably to the Aldosterone Resolution Score, which has been used to evaluate short-term postoperative outcomes. This is the largest study to identify factors associated with long-term BP control after adrenalectomy and incorporate these into a scoring system. These data provide a potential tool to guide preoperative patient counseling.

Reactive oxygen species as important determinants of medullary flow, sodium excretion, and hypertension.

The physiological evidence linking the production of superoxide, hydrogen peroxide, and nitric oxide in the renal medullary thick ascending limb of Henle (mTAL) to regulation of medullary blood flow, sodium homeostasis, and long-term control of blood pressure is summarized in this review. Data obtained largely from rats indicate that experimentally induced elevations of either superoxide or hydrogen peroxide in the renal medulla result in reduction of medullary blood flow, enhanced Na(+) reabsorption, and hypertension. A shift in the redox balance between nitric oxide and reactive oxygen species (ROS) is found to occur naturally in the Dahl salt-sensitive (SS) rat model, where selective reduction of ROS production in the renal medulla reduces salt-induced hypertension. Excess medullary production of ROS in SS rats emanates from the medullary thick ascending limbs of Henle [from both the mitochondria and membrane NAD(P)H oxidases] in response to increased delivery and reabsorption of excess sodium and water. There is evidence that ROS and perhaps other mediators such as ATP diffuse from the mTAL to surrounding vasa recta capillaries, resulting in medullary ischemia, which thereby contributes to hypertension.

Rebuttal from Markus P. Schlaich, Yusuke Sata and Murray D. Esler.

Extreme positions are rarely useful and almost invariably hinder rather than facilitate progress in clinical science. Dr Jordan (Jordan, 2014) and Dr Paton (Ratcliffe et al. 2014) and their colleagues seem to share this view and, while making a strong case for each of their points, have provided a reasonably balanced appraisal of the evidence surrounding the interventional approaches for resistant hypertension under debate. Importantly, we seem to share common ground in the view that resistant hypertension is a relevant clinical problem, that non-adherence to prescribed medication is common, that alternative and perhaps device-based therapeutic approaches are needed, and that sympathetic overactivity is a major contributor to the pathophysiology of resistant hypertension thereby providing a logical therapeutic target. Our views differ in how this is best achieved. Dr Jordan elegantly reviews the role of baroreflex circuits in long-term blood pressure (BP) control and how electrical carotid sinus stimulation (CCS) may ameliorate resistant hypertension. While highlighting potential advantages of CCS such as the ability of stimulation adjustment, it becomes clear from his pathophysiological considerations that sympathetic inhibition, specifically suppression of efferent renal sympathetic nerve activity, is an important mediator of CCS-induced depressor responses (Iliescu et al. 2012). Why not target the renal nerves directly when this can be achieved safely with catheter-based approaches (Esler et al. 2010; Bhatt et al. 2014)? Carotid body (CB) denervation is the least developed and investigated approach, which does not negate the physiological relevance of chemoreceptor activation and its role in modulation of both sympathetic nerve activity and blood pressure. Dr Paton promotes the concept of CB tonicity driving sympathetic vasomotor activity chronically, particularly in the scenario of hypertension (Paton et al. 2013). Surgical resection of the CB has been performed to alleviate dyspnoea in patients with obstructive airway disease and coincidentally, a BP reduction was observed in a subgroup of hypertensive patients (Nakayama, 1961). Clearly, recent experimental data is more convincing (McBryde et al. 2013). Nevertheless, evidence for a pivotal role of CB-related mechanisms in human resistant hypertension is weak and the concept far from proven. Major concerns that need to be addressed relate to the potential attenuation or loss of hypoxic ventilatory drive and the potentially serious procedural complications. In keeping with the hypothetical ideals for an interventional approach brought forward by Dr Paton, we would argue that renal denervation remains the most promising therapeutic approach despite the recent setback from a suboptimally conducted clinical trial (Bhatt et al. 2014).

Onset of hypertension during pregnancy is associated with long-term worse blood pressure control and adverse cardiac remodeling

Up to 20% of women with hypertensive pregnancy disorders might persist with chronic hypertension. This study compared clinical and echocardiographic features between women whose hypertension began as hypertensive pregnancy disorders (PH group) and women whose diagnosis of hypertension did not occur during pregnancy (NPH group). Fifty PH and 100 NPH women were cross–sectionally evaluated by clinical, laboratory, and echocardiography analysis, and the groups were matched by duration of hypertension. PH exhibited lower age (46.6 ± 1.4 vs. 65.3 ± 1.1 years; P < .001), but higher systolic (159.8 ± 3.9 vs. 148.0 ± 2.5 mm Hg; P = .009) and diastolic (97.1 ± 2.4 vs. 80.9 ± 1.3 mm Hg; P < .001) blood pressure than NPH, although used more antihypertensive classes (3.4 ± 0.2 vs. 2.6 ± 0.1; P < .001). Furthermore, PH showed higher left ventricular wall thickness and increased prevalence of concentric hypertrophy than NPH after adjusting for age and blood pressure. In conclusion, this study showed that PH may exhibit worse blood pressure control and adverse left ventricular remodeling compared with NPH.

Systemic and renal oxidative stress in the pathogenesis of hypertension: modulation of long-term control of arterial blood pressure by resveratrol.

Hypertension affects over 25% of the global population and is associated with grave and often fatal complications that affect many organ systems. Although great advancements have been made in the clinical assessment and treatment of hypertension, the cause of hypertension in over 90% of these patients is unknown, which hampers the development of targeted and more effective treatment. The etiology of hypertension involves multiple pathological processes and organ systems, however one unifying feature of all of these contributing factors is oxidative stress. Once the body's natural anti-oxidant defense mechanisms are overwhelmed, reactive oxygen species (ROS) begin to accumulate in the tissues. ROS play important roles in normal regulation of many physiological processes, however in excess they are detrimental and cause widespread cell and tissue damage as well as derangements in many physiological processes. Thus, control of oxidative stress has become an attractive target for pharmacotherapy to prevent and manage hypertension. Resveratrol (trans-3,5,4′-Trihydroxystilbene) is a naturally occurring polyphenol which has anti-oxidant effects in vivo. Many studies have shown anti-hypertensive effects of resveratrol in different pre-clinical models of hypertension, via a multitude of mechanisms that include its function as an anti-oxidant. However, results have been mixed and in some cases resveratrol has no effect on blood pressure. This may be due to the heavy emphasis on peripheral vasodilator effects of resveratrol and virtually no investigation of its potential renal effects. This is particularly troubling in the arena of hypertension, where it is well known and accepted that the kidney plays an essential role in the long term regulation of arterial pressure and a vital role in the initiation, development and maintenance of chronic hypertension. It is thus the focus of this review to discuss the potential of resveratrol as an anti-hypertensive treatment via amelioration of oxidative stress within the framework of the fundamental physiological principles of long term regulation of arterial blood pressure.