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Objective Nonadherence to medication is present in at least 50% of patients with apparent treatment-resistant hypertension. We examined the factors associated with nonadherence as detected by a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based urine antihypertensive drug assay. Methods All urine antihypertensive test results, carried out for uncontrolled hypertension (BP persistently >140/90 mmHg) between January 2015 and December 2016 at a single toxicology laboratory were analysed. Drugs detected were compared with the antihypertensive drugs prescribed. Patients were classified as adherent (all drugs detected), partially nonadherent (at least one prescribed drug detected) or completely nonadherent (no drugs detected). Demographic and clinical parameters were compared between the adherent and nonadherent groups. Binary logistic regression analysis was performed to determine association between nonadherence and demographic and clinical factors. Results Data on 300 patients from nine hypertension centres across the United Kingdom were analysed. The median age was 59 years, 47% women, 71% Caucasian, median clinic BP was 176/95 mmHg and the median number of antihypertensive drugs prescribed was four. One hundred and sixty-six (55%) were nonadherent to prescribed medication with 20% of these being completely nonadherent. Nonadherence to antihypertensive medication was independently associated with younger age, female sex, number of antihypertensive drugs prescribed, total number of all medications prescribed (total pill burden) and prescription of a calcium channel blocker. Conclusion This LC-MS/MS urine analysis-based study suggests the majority of patients with apparent treatment-resistant hypertension are nonadherent to prescribed treatment. Factors that are associated with nonadherence, particularly pill burden, should be taken into account while treating these patients.

Kidney damage is a common consequence of arterial hypertension, but is also a cause of atherogenesis. Dysfunction and/or harm of the endothelium in glomeruli and tubular interstitium damage the function of these structures and translates into dynamic changes of filtration fraction, with progressive reduction in glomerular filtration rate, expansion of extracellular fluid volume, abnormal ion balance, and hypoxia, ultimately leading to chronic kidney disease. Considering the key role played by endothelial dysfunction in chronic kidney disease, the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension and the Japanese Society of Hypertension have critically reviewed available knowledge on the mechanisms underlying endothelial cell injury. This resulted into two articles: in the first, we herein examine the mechanisms by which endothelial factors induce vascular remodeling and the role of different players, including endothelin-1, the renin-angiotensin-aldosterone system and their interactions, and of oxidative stress; in the second, we discuss the role of endothelial dysfunction in the major disease conditions that affect the kidney.

After examining in Part I the general mechanisms of endothelial cell injury in the kidney, the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension and the Japanese Society of Hypertension will herein review current knowledge on the role of endothelial dysfunction in multiple disease conditions that affect the kidney, including diabetes mellitus, preeclampsia, solid organ transplantation, hyperhomocysteinemia and antiangiogenic therapy in cancer. The few available randomized controlled clinical trials specifically designed to evaluate strategies for correcting endothelial dysfunction in patients with hypertension and/or chronic kidney disease are also discussed alongside their cardiovascular and renal outcomes.

OBJECTIVE Increased arterial stiffness, as measured by pulse wave velocity (PWV), is associated with increased cardiovascular risk in the general population. Few studies have examined factors associated with increased PWV in people with Type 2 diabetes. The aim of this study was to determine whether there was a link between PWV and clinical variables associated with central obesity, in men and women with Type 2 diabetes. RESEARCH DESIGNS AND METHODS Eight hundred and sixty individuals [mean age (±SD) 69 (±4) years] from the Edinburgh Type 2 Diabetes Study, underwent applanation tonometry using a high-fidelity micromanometer. PWV was measured by sequentially recording electrocardiogram-gated carotid and femoral artery waveforms. RESULTS Waist circumference (β = 0.10, P

OBJECTIVES Peripheral exercise blood pressure and resting central blood pressure are considered more relevant to cardiovascular health than resting peripheral blood pressure. Central exercise blood pressure may well be an even more useful measure, but there is no simple non-invasive means of determining it. The aim of the present study was to establish whether the estimation of central blood pressure from peripheral blood pressure using a transfer function derived at rest, would hold after aerobic exercise. METHODS Thirty healthy young men were studied before and immediately (< 1 min) and 10 min after 15 min bicycle exercise at 65-70% of maximum heart rate. Simultaneous carotid and radial artery waveforms were recorded, and radial-to-carotid generalized transfer functions (GTF) were calculated using Fourier analysis for rest and immediately postexercise. Central systolic blood pressure (SBP) and augmentation index (AIx) were calculated for measured and derived waves. RESULTS The resting GTF underestimated central SBP and AIx immediately (-5.8 +/- 2.1 mmHg, P = 0.01; -8.3 +/- 2.9%, P = 0.008) and 10 min after (-2.0 +/- 0.7 mmHg, P = 0.008; -7.0 +/- 2.1%, P = 0.003) exercise. No significant bias was found between measured and derived (using resting GTF) carotid values at rest. The use of an exercise-specific GTF resulted in no specific bias immediately or 10 min after exercise, although it overestimated blood pressure and AIx at rest (2.5 +/- 1.0 mmHg, P = 0.02; 11.3 +/- 3.0%, P = 0.001). CONCLUSION A peripheral-to-central arterial GTF derived at rest significantly underestimates key measures of central arterial pressure immediately after exercise, and pressure estimations may be improved by the use of an exercise-specific GTF.

Dysfunction of the vascular endothelium is a hallmark of most conditions that are associated with atherosclerosis and is therefore held to be an early feature in atherogenesis. However, the mechanisms by which endothelial dysfunction occurs in smoking, dyslipidaemia, hyperhomocysteinaemia, diabetes mellitus, arterial hypertension, cerebrovascular diseases, coronary artery disease and heart failure are complex and heterogeneous. Recent data indicate that endothelial dysfunction is often associated with erectile dysfunction, which can precede and predict cardiovascular disease in men. This paper will provide a concise overview of the mechanisms causing endothelial dysfunction in the different cardiovascular risk factors and disease conditions, and of the impact of the intervention measures and treatments.

An enormous number of studies in the last two decades have been devoted to investigating the role of the endothelium in cardiovascular diseases. Nonetheless, the optimal methodology for investigating the multifaceted aspects of endothelial dysfunction is still under debate. Biochemical markers, molecular genetic tests and invasive and non-invasive tools with and without pharmacological and physiological stimuli have been introduced. Furthermore newer pharmacological tools have been proposed. However, the application of these methodologies should fulfil a number of requirements in order to provide conclusive answers in this area of research. Thus, the most relevant methodological issues in the research on endothelial function and dysfunction are summarized in this paper.

Objective The aim of this study was to determine the reproducibility of pulse wave velocity (PWV) and augmentation index (Alx) measured using pulse wave analysis (PWA), prior to its use in large-scale clinical trials. Methods Arterial pressure waveforms were recorded and analysed using an established technique (Sphygmocor). Subjects with and without a range of recognized cardiovascular risk factors were studied to provide a wide range of values. Measurements were made after a brief introduction to the technique in a clinical setting. Two observers recorded aortic and brachial PWV in 24 subjects, each on two occasions, in a random order. In a separate study, two different observers used PWA to determine Alx in 33 subjects, each on two occasions, in a random order. Data were analysed using Bland-Altman plots and presented as mean ± SD. Results Brachial PWV was 8.65 ± 1.58 m/s (range 6.16-10.95 m/s) and aortic PWV was 8.15 ± 3.01 m/s (5.01-17.97 m/s). Within-observer variability was 0.14 ± 0.82 m/s for brachial PWV and 0.07 ± 1.17 m/s for aortic PWV. Corresponding between-observer values were -0.44 ± 1.09 m/s and -0.30 ± 1.25 m/s. Alx ranged from -15.0 to +45.0%, with a group mean of +19.6 ± 12.0%. The within-observer difference was 0.49 ± 5.37% and between-observer difference 0.23 ± 3.80%. Conclusion PWA is a simple and reproducible technique with which to measure PWV and Alx. Reproducibility accords with that reported by other workers using different methodologies. PWA may, therefore, be suitable for large-scale population and intervention studies investigating the clinical relevance of vascular stiffness.

Treatment-resistant hypertension (TRH) is defined as the failure to achieve an office BP target of 10%, these levels may be inflated by white-coat hypertension and poor adherence. Indeed, PATHWAY-2 (Williams et al., Lancet 2016) and SYMPLICITY HNT-3 (Bhatt et al., NEJM 2014) suggest that true TRH is rarer than generally thought. Risk factors for TRH (which themselves increase cardiovascular risk) include obesity, older age, African ethnicity, CKD and diabetes. Although not fully addressed, evidence suggests that prolonged poorly controlled BP in TRH has a poor outcome. Before diagnosing TRH, pseudo-resistant HT must be excluded. Poor adherence to treatment – which may be caused by side-effects, complicated dosing schedules, pill burden, poor doctor-patient relationship, poor understanding or acceptance of the need for treatment, and medication cost –is common, with up to 40% of newly diagnosed hypertensive patients discontinuing medications within a year. Directly observed therapy and urine drug screens can be very helpful in its detection. Poor office BP measurement technique is another common problem. Sufficient rest, use of the right cuff, and repeated automated measurement in a quiet setting, is critical. ABPM (or at least home BP measurement) is crucial to excluding ‘white coat’ HT. In those diagnosed with true TRH, modifiable causes must be excluded, including diet, drugs, secondary endocrine and renal causes, and sleep apnoea. In most cases, however, the aetiology of TRH is multifactorial and treatment aimed at multiple targets. Treatment of TRH includes appropriate life-style change (focused on diet, salt intake, exercise, weight), withdrawal or minimization of offending drugs (including alcohol), and the use of effective multi-drug regimens. Pre-existing drug treatment should ideally combine a thiazide-like diuretic (TLD), calcium channel blocker, and ACE inhibitor/ARB. Optimising diuretic use appears very important, so use of a long-acting TLD, such as chlortalidone or indapamide, may help. Loop diuretics should be considered in CKD patients. Low-dose spironolactone (25 mg, increased to 50 mg, once daily) or eplerenone (both mineralocorticoid receptor antagonists) are now guideline approved as suitable 4th line agents in patients with TRH. Their success may be accounted for by the elevated aldosterone levels frequently found in TRH, either through undetected primary hyperaldosteronism or because aldosterone secretion escapes renin-angiotensin system blockade. Vital new evidence for the effectiveness of spironolactone in TRH comes from PATHWAY-2 (Williams et al., Lancet 2016). This randomised double-blind crossover trial involved sequential treatment with spironolactone (n = 285), an α1 blocker doxazosin (n = 282), β blocker bisoprolol (n = 285) and placebo (n = 274), each for 12 weeks. Spironolactone led to significantly greater mean reductions in systolic blood pressure than placebo (−10 [−11.7 to −8.74] mmHg, p An alternative promising approach is the use of endothelin (ET) receptor antagonists. These drugs, which block the vasoconstrictor, inflammatory and pro-atherogenic actions of ET-1, also reduce BP and proteinuria in CKD (Davenport et al., Pharmacol Rev 2016). Clinical trials have shown their efficacy in TRH (Weber et al., Lancet 2009), and phase 3 trials are currently ongoing in patients with diabetic nephropathy. Other drugs, such as b-blockers, a-blockers, centrally acting agents such as moxonidine or potent vasodilators, including hydralazine or minoxidil, may be considered in a multi-drug approach, depending on the clinical circumstances. The only combination that cannot be recommended is the addition of a second agent to block the renin-angiotensin system, with evidence of increased renal failure with the combination of ACE-I + ARB or ARB + renin inhibitor. Two promising non-pharmacological therapies have been under evaluation for the treatment of TRH – renal denervation (RDN) and baroreflex activation therapy (BAT). These are attractive targeted interventional options, with considerable underpinning evidence that sympathetic overactivity contributes to raised BP. However, when the first blinded and randomised study with RDN was performed, SYMPLICITY HNT-3 (Bhatt et al., NEJM 2014), it did no better than the sham procedure. Technically, it will be significantly easier to do randomised and blinded studies with BAT. However, currently, given their potential for adverse effects, and the lack of evidence of efficacy, RDN and BAT should only be used in the context of ongoing clinical research. This is an exciting time in the management of TRH. Spironolactone shows clear superiority to other standard treatments, and supports the case for excess sodium as a component of TRH. Other agents, such as ET antagonists, show promise. The results of SPRINT (The SPRINT Research Group, NEJM 2015) suggest we may need new lower targets for BP control, so TRH will become an increasing challenge. We also need good research on the risks of TRH, and what target blood pressures provide optimal outcomes.

Objective Established hypertension is characterized byincreased peripheral vascular resistance and endothelialdysfunction, features that may underlie the reducedexercise-induced vasodilatation seen in hypertensivepatients. Sildenafil citrate is a phosphodiesterase type 5(PDE5) inhibitor used clinically for the treatment of maleerectile dysfunction. Its vasodilating properties are due tothe inhibition of cyclic guanosine monophosphate (cGMP)breakdown and prolongation of the signalling actions of thenitric oxide (NO)–cGMP pathway in vascular smoothmuscle cells. Sildenafil has beneficial effects on endothelialfunction and exercise tolerance in congestive heart failureand pulmonary hypertension, and we hypothesized that itwould improve exercise-induced vasodilatation inhypertensive patients.Methods and results Ten hypertensive patients and tenmatched normotensive subjects were studied in a three-way, randomized, single-blind and placebo-controlledstudy. On each study day, forearm blood flow (FBF)responses to handgrip exercise were assessed before andafter intra-arterial (brachial) infusion of sildenafil, verapamil(a control, cGMP-independent vasodilator), and saline(placebo). Preinfusion exercise-induced vasodilatation wassignificantly reduced in hypertensive patients compared tonormotensive controls. Sildenafil and verapamil infusionsboth caused a similar increase in baseline FBF. However,while verapamil did not affect the vasodilator response tohandgrip exercise in either group, sildenafil substantiallyenhanced this response in hypertensive patients, but not innormotensive subjects.Conclusions Our data suggest that sildenafil, through anincreaseincGMPlevels inthevasculature,substantiallyandselectively improves the vasodilator response to handgripexercise in hypertensive patients. These findings representan essential first step in support of further studies exploringthe potentially beneficial effects of PDE5 inhibition onexercise capacity in hypertension. J Hypertens 25:000–000Q 2007 Wolters Kluwer Health | Lippincott Williams &Wilkins.

The endothelins are a family of endothelium-derived peptides that possess characteristically sustained vasoconstrictor properties. Endothelin-1 appears to be the predominant member of the family generated by vascular endothelial cells. In addition to its direct vascular effects, endothelin-1 has inotropic and mitogenic properties, influences homeostasis of salt and water, alters central and peripheral sympathetic activity and stimulates the renin-angiotensin-aldosterone system. Studies with endothelin receptor antagonists have indicated that endothelin-1 probably has complex opposing vascular effects mediated through vascular smooth muscle and endothelial ET(A) and ET(B)receptors. Endogenous generation of endothelin-1 appears to contribute to maintenance of basal vascular tone and blood pressure through activation of vascular smooth muscle ET(A)receptors. At the same time, endogenous endothelin-1 acts through endothelial ET(B) receptors to stimulate formation of nitric oxide tonically and to oppose vasoconstriction. In view of the multiple cardiovascular actions of endothelin-1, there has been much interest in its contribution to the pathophysiology of hypertension. Results of most studies suggest that generation of, or sensitivity to, endothelin-1 is no greater in hypertensive than it is in normotensive subjects. Nonetheless, the deleterious vascular effects of endogenous endothelin-1 may be accentuated by reduced generation of nitric oxide caused by hypertensive endothelial dysfunction. It also appears likely that endothelin participates in the adverse cardiac and vascular remodelling of hypertension, as well as in hypertensive renal damage. Irrespective of whether vascular endothelin activity is increased in hypertension, anti-endothelin agents do produce vasodilatation and lower blood pressure in hypertensive humans. There is more persuasive evidence for increased endothelin-1 activity in secondary forms of hypertension, including pre-eclampsia and renal hypertension. Endothelin-1 also appears to play an important role in pulmonary hypertension, both primary and secondary to diseases such as chronic heart failure. The hypotensive effects of endothelin converting enzyme inhibitors and endothelin receptor antagonists should be useful in the treatment of hypertension and related diseases. Development of such agents will increase knowledge of the physiological and pathological roles of the endothelins, and should generate drugs with novel benefits.

Objective : To elucidate the sequential mechanisms underlying cyclosporin-induced hypertension and nephrotoxicity. Design : A study of healthy males over the first 9 days of drug ingestion to permit the detection of serial changes in renal function and blood pressure in a situation free from the confounding variables of concomitant disease or drugs. Methods : Double-blind, placebo-controlled, randomized crossover study with cyclosporin (5 mg/kg twice a day) or placebo. Blood pressure and urinary sodium excretion were measured each day, and glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured on days 1, 4, 7 and 9. Cholesterol, lipoprotein (a) and endothelin were measured on days 1 and 9. Results : GFR decreased by 9% with cyclosporin and was significantly lower than with placebo on day 4 of therapy. ERPF fell by 24%. The fall in GFR correlated significantly with suppressed plasma renin activity (P

The inhibitor of human renin, H142, was studied in nine male volunteers. On three occasions, in random order, volunteers were infused with 5% dextrose or with H142 at 1.0 or 2.5 mg/kg per h for 30 min while supine and thereafter with dextrose for 1 1/2 h. There was a marked reduction in plasma active renin concentration as assayed by an enzyme-kinetic method, with parallel falls in the circulating concentrations of angiotensins (ANG) I and II, all of which rebounded transiently to values above basal after the H142 infusion was stopped. In contrast, total renin concentration as measured by radio-immunoassay rose while ANG I and II fell, subsiding when H142 was discontinued. There was a slight but significant increase in plasma noradrenaline as renin became inhibited; plasma adrenaline was unchanged. H142 produced a slight fall in systolic blood pressure (SBP) and a clearer, highly significant, dose-related fall in diastolic blood pressure (DBP). There was a modest but significant increase in the heart rate. These studies confirm H142 as an effective inhibitor of human renin in vivo.

It is reported that dietary deprivation of sodium in young rats produces changes of sodium balance and aldosterone excretion which persist when normal sodium intake is restored. To test this further, sodium intake was reduced 10-fold in rats. In the first experiment sodium intake was reduced for 5 weeks in rats aged 3 weeks. Systolic blood pressure, heart rate and plasma renin concentration increased and growth rate was reduced. Sodium intake was then increased for 10 weeks. Blood pressure, heart rate and plasma renin concentration fell and growth rate increased but body weight did not regain control values. As compared with controls, plasma concentrations of aldosterone and corticosterone did not increase after the 10-week period. Thus, sodium depletion did not produce an irreversible change in aldosterone but it did raise arterial pressure. Further experiments confirmed the pressor effect in young and adult rats. Blood pressure was measured in the tail in these experiments but the increase in pressure was not a technical artifact as measurements made in the tail correlated well with measurements made simultaneously by intra-arterial catheter. Catheters were inserted under general anaesthetic for this comparison of pressure and rats previously deprived of sodium showed a significantly higher mortality rate due to the anaesthesia and surgery involved. Thus, a 10-fold reduction of dietary sodium raises blood pressure in young and adult rats and it may increase mortality from a minor surgical procedure. It does not produce irreversible changes in aldosterone.

Investigations were performed in 26 patients with essential hypertension and 24 with unilateral renal artery stenosis. In each patient blood was drawn simultaneously and in triplicate, from both renal veins and aorta, for measurement of plasma concentrations of active and inactive renin and of angiotensin II. In 19 patients estimates of individual renal plasma flow were obtained in order to calculate secretion rates for active and inactive renin, and to assess the contribution of renin secretion rate and of renal plasma flow to the renal vein renin ratio. In patients with essential hypertension there was evidence that the kidney secreted active renin (18% mean increase in renal vein concentration above that of arterial plasma; P less than 0.001), but no evidence of secretion of inactive renin (4% mean increase; NS). There was a tendency for the kidney to extract angiotensin II (8% mean decrease in renal vein concentration below that of arterial plasma; P = 0.07). The affected kidney in patients with renal artery stenosis showed marked secretion of active renin (364% mean increase; P less than 0.001) and also secreted inactive renin (80% mean increase; P less than 0.05) with net generation of angiotensin II across the renal circulation (100% mean increase; P less than 0.05). The contralateral kidney exhibited suppressed secretion of active renin (3% mean increase; NS) with no evidence of secretion of inactive renin (2% mean increase; NS), and marked extraction of angiotensin II (50% mean decrease; P less than 0.001). The correlation between combined secretion rate of active renin by both kidneys and the arterial concentration of active renin in patients with essential and renovascular hypertension taken together was strongly positive (r = 0.82; P less than 0.01). The same correlation for inactive renin was weak (r = 0.32; NS). The correlation between the combined secretion rates of active renin by both kidneys and the circulating plasma concentration of angiotensin II (r = +0.60; P less than 0.05) was both significant and positive. By contrast, the total 'secretion' rate of angiotensin II by both kidneys was inversely related to arterial plasma angiotensin II (r = -0.92; P less than 0.001). This latter relationship suggests an important role for the kidney in clearing angiotensin II from the circulation, this being more marked the higher the arterial angiotensin II concentration.(ABSTRACT TRUNCATED AT 400 WORDS)