Long-term Blood Pressure Control Research Articles

The Kidneys and Aldosterone/Mineralocorticoid Receptor System in Salt-Sensitive Hypertension

Strong evidence supports the ability of the aldosterone/mineralocorticoid receptor (MR) system to dominate long-term blood pressure control. It is also increasingly recognized as an important mediator of cardiovascular and renal diseases, particularly in the presence of excessive salt intake. In a subgroup of individuals with metabolic syndrome, adipocyte-derived aldosterone-releasing factors cause inappropriate secretion of aldosterone in the adrenal glands during salt loading, resulting in the development of salt-induced hypertension and cardiac and renal damage. On the other hand, emerging data reveal that aldosterone is not a sole regulator of MR activity. We have identified the signaling crosstalk between MR and small GTPase Rac1 as a novel pathway to facilitate MR signaling. Such a local control system for MR can also be relevant to the pathogenesis of salt-sensitive hypertension, and future studies will clarify the detailed mechanism for the intricate regulation of the aldosterone/MR cascade.

Long-Term Blood Pressure Control: What Can We Do?

There are unique problems associated with the long-term control of blood pressure (BP) in patients with hypertension. Many of these problems warrant specific discussion for the primary care physician. Up to one-third of high-risk patients are estimated to have uncontrolled hypertension. Although long-term control is essential to avoid complications of cardiovascular disease, such as myocardial infarction, stroke, heart failure, and kidney disease, it can become troublesome because of challenges with patient compliance and adherence to medication regimens. This may be due to low tolerability profiles, complicated regimens, or prohibitive costs. Trials have shown that a combination approach may reduce side effects with complementary therapies such as a calcium channel blocker (CCB)/angiotensin receptor blocker (ARB) combination. Combination therapy can be used in any patient group not responsive to monotherapy, or who remain 20 mm Hg higher than their BP goal. This method may achieve the goal of reaching target BP sooner as a first-line approach and, in a fixed-dose combination, may be a more economic choice as well as a simpler regimen for the patient. Together with supportive measures, CCB/ARB combinations are a compelling alternative for the long-term treatment of hypertension.

Blood pressure reduction in secondary stroke prevention.

: Risk factor modification plays an important role in recurrent stroke prevention. These modifiable risk factors tend to cluster in stroke patients, but for a significant subgroup the only identifiable risk factor is high blood pressure or chronic hypertension. This article reviews the current evidence for management of blood pressure in secondary stroke prevention. : Over the years, data from primary prevention trials have shown that antihypertensive drug treatment reduces the risk of first stroke by 32%. Similarly, various secondary prevention studies have shown a relative risk reduction in recurrent strokes of up to 30%. These trials have also shown that the impact of blood pressure reduction in stroke prevention is similar in patients with hypertension and patients without hypertension, and larger reductions in systolic blood pressure were associated with greater reduction in risk of recurrent stroke. : Although it is clear from the current evidence that long-term blood pressure control is one of the most important interventions for secondary stroke prevention, the optimal management of blood pressure in the immediate poststroke period is not well defined.

Comments on Point:Counterpoint: The dominant contributor to systemic hypertension: Chronic activation of the sympathetic nervous system vs. Activation of the intrarenal renin-angiotensin system

Comments on Point:Counterpoint: The dominant contributor to systemic hypertension: Chronic activation of the sympathetic nervous system vs. Activation of the intrarenal renin-angiotensin system

Dopamine Receptors

Essential hypertension, which affects 25% of the middle-aged adult population, constitutes a major risk factor for stroke, myocardial infarction, and heart and kidney failure.1 The kidney, vasculature, and nervous system govern the long-term control of blood pressure by regulating sodium homeostasis and peripheral resistance; they, in turn, are influenced by numerous hormones and neural and humoral factors. These hormones and neural and humoral factors can be divided into 2 groups based on their effects on sodium excretion and vascular smooth muscle contractility. One group leads to natriuresis and vasodilation whereas the other causes sodium retention and vasoconstriction. The balance between those 2 groups keeps the blood pressure within the normal range. Hypertension may be caused not only by increased activity of prohypertensive systems (for example, the renin-angiotensin system [RAS] and sympathetic nervous system) but also by defects in antihypertensive systems that serve as counterregulatory mechanisms. Aberrations in these counterregulatory pathways, which include the dopaminergic pathway, may be involved in the pathogenesis of essential hypertension. Dopamine has been shown to be an important regulator of renal and hormonal function and, ultimately, blood pressure, through an independent, nonneural dopaminergic system.2 There is a difference in the synthesis and metabolism of dopamine in neural and nonneural cells (see following paragraphs). For example, dopamine synthesized in renal proximal tubule (RPT) cells is not converted into norepinephrine and epinephrine; it is transported across the basolateral and apical membranes and into the peritubular space and tubular lumen, respectively, where it acts on its receptors locally and in more distal nephron segments. Dopamine, by occupation of its specific receptors as well by direct or indirect interaction with other G protein–coupled receptors (for example, adenosine, angiotensin, endothelin, insulin, oxytocin, and vasopressin) and interaction with other hormones/humoral agents (for example, aldosterone, angiotensins, atrial natriuretic peptide, eicosanoids, insulin, …

A Cluster-Randomized Effectiveness Trial of a Physician-Pharmacist Collaborative Model to Improve Blood Pressure Control

Numerous studies have demonstrated the value of team-based care to improve blood pressure (BP) control, but there is limited information on whether these models would be adopted in diverse populations. The purpose of this study was to evaluate whether a collaborative model between physicians and pharmacists can improve BP control in multiple primary care medical offices with diverse geographic and patient characteristics and whether long-term BP control can be sustained. This study is a randomized prospective trial in 27 primary care offices first stratified by the percentage of underrepresented minorities and the level of clinical pharmacy services within the office. Each office is then randomized to either a 9- or 24-month intervention or a control group. Patients will be enrolled in this study until 2012. The results of this study should provide information on whether this model can be implemented in large numbers of diverse offices, if it is effective in diverse populations, and whether BP control can be sustained long term. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00935077.

Blood Pressure and Medication During Long-Term Antihypertensive Therapy Based on Morning Home SBP in Hypertensive Patients: Hypertension Control Based On Home Systolic Pressure (HOSP) Substudy

We examined blood pressure (BP) and medication over 5 years in 80 hypertensive patients who participated in the Hypertension Control Based on home systolic pressure (HOSP) study that compares effects of strict and mild control of morning home systolic blood pressure (SBP) as well as amlodipine- and losartan-based regimens. Average morning home SBP after 5 years was 126 mmHg in the strict control group and 135 mmHg in the mild control group. The strict control group and the losartan group required more combination therapy than the other groups. These results show that long-term strict control of morning BP is feasible. Amlodipine appears to be more effective in controlling morning BP than losartan when the medication is administered alone in the morning.

EARLY BLOOD PRESSURE CONTROL BY THE NIFEDIPINE GITS/TELMISARTAN COMBINATION: PP.33.314

Background: Guidelines recommend combination treatment to be used as initial step in hypertensive patients at high cardiovascular (CV) risk because in this condition the earlier blood pressure (BP) control (and CV protection) achievable by two vs. one antihypertensive drug administration may be desirable. Goals: To determine whether initial treatment with telmisartan plus nifedipine GITS provides an earlier office and ambulatory BP control compared to initial treatment with the combination components in monotherapy and to verify whether initiating treatment with a combination allows a better long-term BP control, compared to use of combination treatment after initial monotherapy. Methods: 405 subjects with office systolic BP at inclusion >=135mmHg and with a high CV risk because of diabetes, metabolic syndrome and/or organ damage were randomized to initial administration of telmisartan plus nifedipine GITS (80 mg and 20 mg daily, respectively), to telmisartan alone or nifedipine GITS alone in a 2:1:1 ratio. Treatment was continued for 24 weeks shifting the monotherapy groups to combination treatment after 8 weeks. Office and ambulatory blood pressure were measured respectively after 2, 8, 16 and 24 and after 8, 16 and 24 weeks of treatment. Results: The main results for the per-protocol population (N = 327) are shown in the Table. Table. Systolic (S) and diastolic (D) office and ambulatory BP (least square means ± SE; mmHg) in the three study groups: Telmisartan 80 mg (N = 74), Nifedipine GITS 20 mg (N = 89); combination (N=164). All subjects were on combination therapy starting from week 8. No significant baseline differences were found between groups.Conclusion: Combination and monotherapy treatments all lowered systolic and diastolic BP substantially, the 24 h data showing that the effect was long lasting. Compared to the monotherapy, initiating treatment with the calcium antagonist/angiotensin receptor blocker combination allowed BP reduction and control to be achieved earlier, this being the case both for office and for ambulatory BP. Longer term BP control, on the other hand, was similar irrespective of the initial (combination or monotherapy) treatment strategy.

EARLY BLOOD PRESSURE CONTROL BY THE NIFEDIPINE GITS/TELMISARTAN COMBINATION: HT.1.01

Background: Guidelines recommend combination treatment to be used as initial step in hypertensive patients at high cardiovascular(CV) risk because in this condition the earlier blood pressure (BP) control (and CV protection) achievable by two vs. one antihypertensive drug administration may be desirable. Goals: To determine whether initial treatment with telmisartan plus nifedipine GITS provides an earlier office and ambulatory BP control compared to initial treatment with the combination components in monotherapy and to verify whether initiating treatment with a combination allows a better long-term BP control, compared to use of combination treatment after initial monotherapy. Methods: 405 subjects with office systolic BP at inclusion ≥ 135 mmHg and with a high CV risk because of diabetes, metabolic syndrome and/or organ damage were randomized to initial administration of telmisartan plus nifedipine GITS (80 mg and 20 mg daily, respectively), to telmisartan alone or nifedipine GITS alone in a 2:1:1 ratio. Treatment was continued for 24 weeks shifting the monotherapy groups to combination treatment after 8 weeks. Office and ambulatory blood pressure were measured respectively after 2, 8, 16 and 24 and after 8, 16 and 24 weeks of treatment. Results: The main results for the per-protocol population (N = 327) are shown in the Table.Table. Systolic (S) and diastolic (D) office and ambulatory BP (least square means±SE; mmHg) in the three study groups: Telmisartan 80 mg (N = 74), Nifedipine GITS 20 mg (N = 89); their combination (N = 164). All subjects were on combination therapy starting from week 8. No significant differences were found between groups at baseline. Conclusion: Combination and monotherapy treatments all lowered systolic and diastolic BP substantially, the 24 h data showing that the effect was long lasting. Compared to the monotherapy, initiating treatment with the calcium antagonist/angiotensin receptor blocker combination allowed BP reduction and control to be achieved earlier, this being the case both for office and for ambulatory BP. Longer term BP control, on the other hand, was similar irrespective of the initial (combination or monotherapy) treatment strategy.

Depression in Relation to Long-term Control of Glycemia, Blood Pressure, and Lipids in Patients with Diabetes

Little information is available about the association of depression with long-term control of glycemia, blood pressure, or lipid levels in patients with diabetes. To determine whether minor and major depression at study enrollment compared with no depression are associated with higher average HbA(1c), systolic blood pressure (SBP) and LDL cholesterol over the long term in patients with an indication for or receiving drug treatment. Cohort study. A total of 3,762 patients with type 2 diabetes mellitus enrolled in the Pathways Epidemiologic Study in 2001-2002 and followed for 5 years. Depression was assessed at study enrollment using the Patient Health Questionnaire-9 (PHQ-9). SBP and information on cardiovascular co-morbidity were abstracted from medical records, and LDL cholesterol and HbA(1c) measured during clinical care were obtained from computerized laboratory data during a median of 4.8 years' follow-up. Among those with an indication for or receiving drug treatment, after adjustment for demographic and clinical characteristics, average long-term HbA(1c), SBP, and LDL cholesterol did not differ in patients with comorbid diabetes and minor or major depression compared with those with diabetes alone. The adverse effect of depression on outcomes in patients with diabetes may not be mediated in large part by poorer glycemic, blood pressure, or lipid control. Further study is needed of the biologic effects of depression on patients with diabetes and their relation to adverse outcomes.

Adrenal corticosteroid effects in the central nervous system on long-term control of blood pressure

Adrenal corticosteroid effects in the central nervous system on long-term control of blood pressure

The epithelial sodium channel (ENaC): Mediator of the aldosterone response in the vascular endothelium?

In the kidney the epithelial sodium channel (ENaC) is regulated by the mineralocorticoid hormone aldosterone, which is essential for long-term blood pressure control. Evidence has accumulated showing that ENaC is expressed in endothelial cells. Moreover, its activity modifies the biomechanical properties of the endothelium. Therefore, the vascular system is also an important target for aldosterone and responds to the hormone with an increase in cell volume, surface area, and mechanical stiffness. These changes occur in a concerted fashion from minutes to hours and can be prevented by the specific sodium channel blocker amiloride and the mineralocorticoid receptor (MR) blocker spironolactone. Aldosterone acts on cells of the vascular system via genomic and non-genomic pathways. There is evidence that the classical cytosolic MR could mediate both types of response. Using a nanosensor covalently linked to aldosterone, binding sites at the plasma membrane were identified by atomic force microscopy. The interaction of aldosterone and this newly identified surface receptor could precede the slow classic genomic aldosterone response resulting in fast activation of endothelial ENaC. Recent data suggest that aldosterone-induced ENaC activation initiates a sequence of cellular events leading to a reduced release of vasodilating nitric oxide. We propose a model in which ENaC is the key mediator of aldosterone-dependent blood pressure control in the vascular endothelium.

Arterial hypertension defeated? Attacked from another angle

the cumulative sodium retention. Furthermore, this renal denervation was shown to prevent, markedly attenuate or delay the development of hypertension in a diverse number of models of elevated blood pressure. 4 These promising experimental results of renal sympathetic nerve denervation for the treatment of hypertension prompted the establishment of the first clinical trial of this approach as a proof-of-principle study. 3 In brief, in 45 patients with resistant hypertension a catheter connected to a radiofrequency generator was introduced into renal arteries via femoral access and up to six discrete radiofrequency ablations were delivered within each renal artery. The major aims of this study were to assess firstly the efficacy of blood pressure lowering and s econdly the safety of this procedure. The initial blood pressure in these patients who had been treated with four to seven anti-hypertensive medications was 177/101 mmHg. The highly significant average reduction in office measured systolic/diastolic blood pressure at 1 month after the renal sympathetic denervation procedure was 14/10 mmHg. Blood pressure was further reduced at 3 months by 22/10 mmHg, with this effect persisting on s ubsequent assessments with the reduction 12 months after the procedure being 27/17 mmHg. Only six out of 45 patients did not benefit from this treatment, defined as a s ystolic blood pressure reduction of less than 10 mmHg. In 12 patients, 24 hour ambulatory blood pressure monitoring was performed before and after the denervation procedure. The change in office systolic blood pressure correlated closely with the change in mean ambulatory blood pressure (r 2 50.62, p50.002). Furthermore, renal sympathetic denervation was associated with an increase in the number of n octurnal dippers in the group of patients that had responded to this treatment. The effectiveness of the radiofrequency method in achieving efferent renal denervation was assessed in a subgroup of patients (n 51 0) by measuring renal Arterial hypertension is a major risk factor for an array of cardiovascular diseases, particularly in the context of concomitant diabetes. Furthermore, elevated blood pressure is at least twice as prevalent in type 2 diabetes as in the g eneral population. Clinical data suggest that lower blood pressure may induce even greater cardiovascular benefits in diabetic subjects than in individuals without diabetes. With respect to renal disease, recent data from the Action in Diabetes and Vascular Disease (ADVANCE) study indicate that there is no lower threshold for blood pressure reduction when one is aiming to reduce the burden of renal disease. 1 So far, the major therapeutic strategy for arterial hypertension has focused on pharmacological treatments. Despite the abundance of available antihypertensive drugs, arterial hypertension remains undertreated, in particular in diabetes and specifically in the setting of associated chronic kidney disease. Clinical trials involving patients with diabetes or renal impairment have demonstrated that achieving lower blood pressure goals requires treatment with on average at least three different antihypertensive agents. 2 Moreover, it has been shown that with current standard antihypertensive therapies only one of out seven patients with type 2 diabetes can achieve a target blood pressure of less than 130/80 mmHg. Recently, a multi-centre prospective cohort study has demonstrated the efficacy of a non-pharmacological, minimally invasive percutaneous radiofrequency catheter-based treatment to disrupt renal sympathetic nerves in the management of patients with resistant hypertension, which included a significant subgroup with type 2 diabetes. 3 The rationale for renal sympathetic nerves denervation as a treatment strategy for systemic hypertension lies in the hypothesis that abnormal excretory function is crucial for the initiation, p rogression and maintenance of primary hypertension with sodium and water balance considered to be of central importance in the long-term control of systemic blood pressure. In addition, in animal models it has been confirmed that renal sympathetic nerve stimulation results in a substantial increase in the renin secretion rate and promotes antinatriuresis without affecting glomerular filtration rate and renal plasma flow. Moreover, in animal models renal sympathetic denervation has been used to demonstrate that renal sympathetic nerve activity is responsible for approximately 40% of

Improving Outcomes in Hypertensive Patients: Focus on Adherence and Persistence With Antihypertensive Therapy

Although effective control of blood pressure (BP) reduces the risk of cardiovascular events in patients with hypertension, BP control rates among treated patients in actual clinical practice are less than optimal. Although the costs of medicines and medical care (which are difficult to estimate both in clinical trials and general clinical practice) are important, medication-taking behavior--adherence and persistence with antihypertensive regimens--influences BP control rates. Many factors affect adherence and persistence with medications, including efficacy and tolerability of drugs prescribed, such that rates vary greatly among antihypertensive classes. In general, medications with fewer adverse effects (in registration trials or large outcomes studies) are associated with increased adherence and lower discontinuation rates. More widespread use of such agents, particularly those available in generic formulations or in low-cost formularies, may lead to better long-term BP control and fewer cardiovascular events.

Favorable cardiac and aortic remodeling in olmesartan-treated spontaneously hypertensive rats

Cardiovascular remodeling contributes to the progression of cardiovascular disease. Thus, our aim was to evaluate the action of long-term treatment with olmesartan on cardiac and aortic adverse remodeling and its relationship with blood pressure (BP) and tensile forces acting on the aortic wall. Five-month-old male rats were divided in: WKY group (n = 6), SHR group (n = 6), and SHRs treated with hydralazine 30 mg/kg/day (SHR-H, n = 8) or olmesartan 10 mg/kg/day (SHR-O, n = 8). Medications were administered for 16 weeks. The SHR group showed hypertension (189 +/- 4 mmHg), cardiomyocyte hypertrophy (+107%), interstitial fibrosis (5.7% vs 1.9% in WKY), and reduced intramyocardial vascularization (9.1% vs 22.8% in WKY). In aorta, the SHRs showed outward hypertrophic remodeling, increased elastic fibers content (+36%), and increased circumferential wall tension (CWT, 2.79 x 10(4) dyne/cm) and tensile stress (TS, 261.4 x 10(4) dyne/cm(2)). Hydralazine and olmesartan decreased BP (-45% approximately) and likewise CWT and TS (-45% and -35% approximately). Both medications prevented left ventricle remodeling, but olmesartan improved cardiomyocyte hypertrophy better than hydralazine. Hydralazine did not alter media hypertrophy, but it enlarged lumen diameter and increased elastic fibers. It is unlikely that olmesartan prevented all aortic alterations. Taken together, long-term control of BP alone is not sufficient to prevent aortic remodeling due to hypertension, but in myocardium it seems to be enough, except for cardiomyocyte hypertrophy. The differential action of olmesartan suggests that it is essential to block growth stimulation by angiotensin II in cardiomyocytes and vascular smooth muscle cells in order to better prevent cardiovascular adverse remodeling due to arterial hypertension.

Renal medullary effects of transient prehypertensive treatment in young spontaneously hypertensive rats

Transient angiotensin II receptor blockade (ARB) leads to prolonged blood pressure (BP) lowering, but the underlying mechanism remains uncertain. Long-term BP control is regulated by the medullary microcirculation with the pericyte as contractile cell. We hypothesize that the prolonged BP effect is caused by increased medullary blood flow (MBF) associated with structural alterations based on reduced medullary pericyte number. Four-week-old spontaneously hypertensive rats (SHR) were treated for 4 weeks with losartan (SHR-Los: 20 mg kg(-1) day(-1)), hydralazine (SHR-Hyd: 15 mg kg(-1) day(-1)), losartan and pan-caspase inhibitor zVAD (SHR-Los + 1 mg kg(-1) day(-1) zVAD), losartan and glycogen synthase kinase-3beta (GSK) inhibitor valproate (SHR-Los + 10 mg kg(-1) day(-1) Val) or placebo. BP, MBF and pericyte number were determined under and after treatment (8 and 12 weeks). Apoptotic pericytes were determined with alpha-actin and TUNEL double staining. Sodium concentration was determined in renal medulla and urine. Antihypertensive treatment equipotently reduced BP at 8 weeks of age. After drug withdrawal (12 weeks of age) BP reduction was restricted to SHR-Los (SHR-Los: 153 +/- 5, SHR-Hyd: 177 +/- 2, SHR: 184 +/- 3 mmHg). Simultaneously, MBF was increased and pericyte number reduced, while medullary and urinary sodium concentration increased. Transient ARB in combination with zVAD or valproate resulted in more medullary pericytes and higher BP (SHR-Los/zVAD: 164 +/- 7; SHR-Los/Val: 168 +/- 6 mmHg) compared with transient ARB alone. After drug withdrawal, transient ARB leads to increased MBF and is associated with a reduction in medullary pericytes. This may be associated with pericyte apoptosis as anti-apoptosis during transient ARB increases pericyte number and BP.

Overexpression of a HIF prolyl‐4‐hydroxylase Transgene in the Renal Medulla Increases the Salt Sensitivity of Arterial Blood Pressure

We have demonstrated that HIF prolyl‐4‐hydroxylase domain‐containing proteins (PHDs), a family of enzymes that promote HIF‐1α degradation, are abundantly present in the renal medulla and regulate sodium excretion through regulation of HIF‐1 α and its targeted genes, such as nitric oxide synthase, cyclooxygenase and heme oxygenase. The present study was designed to test the hypothesis that overexpression a PHD transgene in the renal medulla increases the salt sensitivity of blood pressure. Plasmids expressing PHD2, the predominant isoform of PHDs in the kidneys, were transfected into the renal medulla in uninephretomized rats. Three weeks after PHD2 transfection, the mRNA levels of PHD2 was increased by two folds in the renal medulla. Mean arterial pressure measured by a telemetry system was significantly raised in PHD2 transfected rats after high salt challenge compared with control animals (131.3 ± 6.7 vs. 110.7 ± 4.2 mmHg). There was no blood pressure change in PHD2 transfected rats that were maintained on the normal salt diet. Urinary sodium excretion in response to acute sodium loading or elevation of renal perfusion pressure were blunted by 30% and 50%, respectively, in PHD2 transfected animals. In conclusion, PHD2 in the renal medulla importantly participates in the regulation of renal medullary function and in the long‐term control of arterial blood pressure. (Supported by NIH grant DK54927 and HL89563)

Editorial comment: MontaniversusOsborn exchange of views

The long-term control of blood pressure has been recognized as a complex mixture of neural, hormonal and intrinsic factors involving the brain, heart, vasculature and especially the kidney. While computational modelling approaches to organ function have offered much promise recently (Hunter & Borg, 2003; Hunter et al. 2003), allowing researchers to test hypotheses or simulate stimuli difficult to assess experimentally, their application to blood pressure control has been somewhat limited. In 1972, Guyton and Coleman published a model which attempted to provide the basis for long-term blood pressure control (Guyton et al. 1972). This model, composed of hundreds of equations, has both baffled and intrigued legions of physiologists. The model has been somewhat updated to reflect recent advances (Guyton, 1990), although the role of the central nervous system is predominantly lacking. The central feature of the model is the linkage between blood pressure and sodium balance, where any imbalance between salt intake and excretion leads to a progressive alteration in the filling of the vascular system and thus changes in blood pressure. This in turn alters sodium excretion, a feature defined as the pressure–natriuresis relationship. A key aspect in this concept is that it puts the kidney at the very centre of long-term blood pressure control. This means that any chronic change in blood pressure must have been accompanied by an alteration in the pressure–natriuresis relationship. One effect of this model and concept has been to focus much research in hypertension on the kidney. More recently, this fundamental role of the kidney has become a source of renewed debate (Osborn, 2005; Osborn et al. 2005; Korner, 2007). The question has arisen as to whether the Guyton–Coleman model is still valid and can therefore form the basis of an updated model or whether it should be moved aside and a new structure built from the ground up. There is little doubt that the area has held itself back to some extent through the use of propriority modelling platforms and a failure to make the underlying code accessible. However, newer modelling tools, such as CMISS (http://www.cmiss.org) or Simulink in Matlab (http://www.mathworks.com), offer the prospect of providing an open-source platform for future modelling endeavours. This could allow multiple research groups to test and refine sections of the model in a collaborative nature. In this issue of Experimental Physiology, two opposing views are presented. Montani and Van Vliet (2009a,b) argue that the structure of the Guyton–Coleman model is fundamentally sound. Osborn and co-workers (2009a,b) argue that in light of the evidence for a major role of the sympathetic nervous system in long-term control of arterial pressure and the pathogenesis of hypertension, new mathematical models for long-term control of arterial pressure may be necessary. They argue that renal control of total blood volume is not the only factor that affects the long-term level of arterial pressure, that the Guyton–Coleman model overestimates the importance of renal control of body fluids and total blood volume in blood pressure regulation and that an alternative model can be developed in which sympathetic nervous system activity plays an important role in long-term control of arterial pressure independent of its effects on total blood volume. The aim in publishing these ‘Exchange of Views’ articles is to stimulate debate and encourage further research in this area. At the first cardiovascular control conference, held 4 years ago in Jaipur, India, it was proposed (Evans et al. 2005) that computational modelling held much promise for the area of long-term blood pressure control but it was also one with few research groups active. At the second meeting, held in December 2008 in Mamallapuram, India, the need for computational approaches was again emphasized and it was suggested that the area would lend itself well to a consortium of engineers and physiologists.

Regulated sodium transport in the renal connecting tubule (CNT) via the epithelial sodium channel (ENaC)

The aldosterone-sensitive distal nephron (ASDN) includes the late distal convoluted tubule 2, the connecting tubule (CNT) and the collecting duct. The appropriate regulation of sodium (Na(+)) absorption in the ASDN is essential to precisely match urinary Na(+) excretion to dietary Na(+) intake whilst taking extra-renal Na(+) losses into account. There is increasing evidence that Na(+) transport in the CNT is of particular importance for the maintenance of body Na(+) balance and for the long-term control of extra-cellular fluid volume and arterial blood pressure. Na(+) transport in the CNT critically depends on the activity and abundance of the amiloride-sensitive epithelial sodium channel (ENaC) in the luminal membrane of the CNT cells. As a rate-limiting step for transepithelial Na(+) transport, ENaC is the main target of hormones (e.g. aldosterone, angiotensin II, vasopressin and insulin/insulin-like growth factor 1) to adjust transepithelial Na(+) transport in this tubular segment. In this review, we highlight the structural and functional properties of the CNT that contribute to the high Na(+) transport capacity of this segment. Moreover, we discuss some aspects of the complex pathways and molecular mechanisms involved in ENaC regulation by hormones, kinases, proteases and associated proteins that control its function. Whilst cultured cells and heterologous expression systems have greatly advanced our knowledge about some of these regulatory mechanisms, future studies will have to determine the relative importance of the various pathways in the native tubule and in particular in the CNT.

Dry-Weight Reduction in Hypertensive Hemodialysis Patients (DRIP)

Volume excess is thought to be important in the pathogenesis of hypertension among hemodialysis patients. To determine whether additional volume reduction will result in improvement in blood pressure (BP) among hypertensive patients on hemodialysis and to evaluate the time course of this response, we randomly assigned long-term hypertensive hemodialysis patients to ultrafiltration or control groups. The additional ultrafiltration group (n=100) had the dry weight probed without increasing time or duration of dialysis, whereas the control group (n=50) only had physician visits. The primary outcome was change in systolic interdialytic ambulatory BP. Postdialysis weight was reduced by 0.9 kg at 4 weeks and resulted in -6.9 mm Hg (95% CI: -12.4 to -1.3 mm Hg; P=0.016) change in systolic BP and -3.1 mm Hg (95% CI: -6.2 to -0.02 mm Hg; P=0.048) change in diastolic BP. At 8 weeks, dry weight was reduced 1 kg, systolic BP changed -6.6 mm Hg (95% CI: -12.2 to -1.0 mm Hg; P=0.021), and diastolic BP changed -3.3 mm Hg (95% CI: -6.4 to -0.2 mm Hg; P=0.037) from baseline. The Mantel-Hanzel combined odds ratio for systolic BP reduction of > or =10 mm Hg was 2.24 (95% CI: 1.32 to 3.81; P=0.003). There was no deterioration seen in any domain of the kidney disease quality of life health survey despite an increase in intradialytic signs and symptoms of hypotension. The reduction of dry weight is a simple, efficacious, and well-tolerated maneuver to improve BP control in hypertensive hemodialysis patients. Long-term control of BP will depend on continued assessment and maintenance of dry weight.