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Interleukin (IL)-17A contributes to hypertension in preclinical models. T helper 17 and dendritic cells are activated by NaCl, which could involve the epithelial Na + channel (ENaC). We hypothesized that the ENaC blocker amiloride reduces plasma IL-17A and related cytokines in patients with hypertension. Concentrations of IL-17A, IFN-γ, TNF, IL-6, IL-1β, and IL-10 were determined by immunoassays in plasma from two patient cohorts before and after amiloride treatment: 1 ) patients with type 2 diabetes mellitus (T2DM) and treatment-resistant hypertension ( n = 69, amiloride 5-10 mg/day for 8 wk) and 2 ) patients with hypertension and type 1 diabetes mellitus (T1DM) ( n = 29) on standardized salt intake (amiloride 20-40 mg/day, 2 days). Plasma and tissue from ANG II-hypertensive mice with T1DM treated with amiloride (2 mg/kg/day, 4 days) were analyzed. The effect of amiloride and benzamil on macrophage cytokines was determined in vitro. Plasma cytokines showed higher concentrations (IL-17A ∼40-fold) in patients with T2DM compared with T1DM. In patients with T2DM, amiloride had no effect on IL-17A but lowered TNF and IL-6. In patients with T1DM, amiloride had no effect on IL-17A but increased TNF. In both cohorts, blood pressure decline and plasma K + increase did not relate to plasma cytokine changes. In mice, amiloride exerted no effect on IL-17A in the plasma, kidney, aorta, or left cardiac ventricle but increased TNF in cardiac and kidney tissues. In lipopolysaccharide-stimulated human THP-1 macrophages, amiloride and benzamil (from 1 nmol/L) decreased TNF, IL-6, IL-10, and IL-1β. In conclusion, inhibition of ENaC by amiloride reduces proinflammatory cytokines TNF and IL-6 but not IL-17A in patients with T2DM, potentially by a direct action on macrophages. NEW & NOTEWORTHY ENaC activity may contribute to macrophage-derived cytokine release, since amiloride exerts anti-inflammatory effects by suppression of TNF and IL-6 cytokines in patients with resistant hypertension and type 2 diabetes and in THP-1-derived macrophages in vitro.

Background The aim of this study was to prospectively evaluate the effects of renal artery stenting in consecutive patients with severe atherosclerotic renal artery stenosis and high-risk clinical presentations as defined in a national protocol developed in 2015. Methods and Results Since the protocol was initiated, 102 patients have been referred for revascularization according to the following high-risk criteria: severe renal artery stenosis (≥70%) with true resistant hypertension, rapidly declining kidney function, or recurrent heart failure/sudden pulmonary edema. At baseline, the mean 24-hour ambulatory systolic blood pressure was 166.2 mm Hg (95% CI, 162.0-170.4), the defined daily dose of antihypertensive medication was 6.5 (95% CI, 5.8-7.3), and the estimated glomerular filtration rate was 41.1 mL/min per 1.73m 2 (95% CI, 36.6-45.6). In 96 patients with available 3-month follow-up data, mean 24-hour ambulatory systolic blood pressure decreased by 19.6 mm Hg (95% CI, 15.4-23.8; P< 0.001), the defined daily dose of antihypertensive medication was reduced by 52% (95% CI, 41%-62%; P <0.001), and estimated glomerular filtration rate increased by 7.8 mL/min per 1.73m 2 (95% CI, 4.5-11.1; P <0.001). All changes persisted after 24 month follow-up. Among 17 patients with a history of hospitalization for acute decompensated heart failure, 14 patients had no new episodes after successful revascularization. Conclusions In this prospective cohort study, we observed a reduction in blood pressure and antihypertensive medication, an increase in estimated glomerular filtration rate, and a decrease in new hospital admissions attributable to heart failure/sudden pulmonary edema after renal artery stenting. Registration URL: https://clinicaltrials.gov. Identifier: NCT02770066.

Background: The mineralocorticoid receptor antagonist spironolactone lowers blood pressure in patients with resistant hypertension despite antihypertensive treatment with angiotensin-converting inhibitors (ACEi) and angiotensin-II receptor blockers (ARB). In preclinical studies, spironolactone suppresses pro-hypertensive interleukin 17A (IL-17A)., Objectives: Plasma samples were analysed from a randomized, double-blind placebo-controlled trial with spironolactone given to patients with type 2 diabetes mellitus (T2DM) and resistant hypertension on three antihypertensive drugs. We tested the hypothesis that spironolactone-induced antihypertensive effects are associated with suppression of IL-17A and related cytokines., Methods: Interferon-γ (IFN-γ), IL-17A, tumor necrosis factor-α (TNF-α), IL-6, IL-1β and IL-10 were assessed in plasma with immunoassay in samples before and after 16 weeks of treatment with placebo or spironolactone (12.5-25-50 mg/day)., Results: Spironolactone significantly reduced plasma IFN-γ and IL-6 while IL-17A, TNF-α, IL-1β and IL-10 were unchanged. IL-6 was more sensitive to higher doses of spironolactone. At baseline, serum aldosterone correlated positively with diastolic night blood pressure. Urine albumin/creatinine-ratios correlated positively with plasma IL-6 at baseline. There were no relations between aldosterone and cytokine concentrations at baseline; between cytokine concentration and blood pressure at baseline; and between cytokine concentration decrease and blood pressure decrease, except for IFN-γ, after treatment. The spironolactone-induced elevation in plasma potassium related inversely to blood pressure but not to changes in cytokines. In macrophages in vitro, spironolactone suppressed lipopolysaccharide (LPS)-induced TNF-α, IL-6, IL-1β and IL-10 levels., Conclusion: The antihypertensive action of spironolactone in resistant hypertensive patients is associated with suppressed IFN-γ and IL-6 and not IL-17A. Spironolactone exerts anti-inflammatory actions in vivo on macrophages and T-cells., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The mineralocorticoid receptor antagonist spironolactone significantly reduces albuminuria in subjects with diabetic kidney disease, albeit with a large variability between individuals. Identifying novel biomarkers that predict response to therapy may help to tailor spironolactone therapy. We aimed to identify a set of metabolites for prediction of albuminuria response to spironolactone in subjects with type 2 diabetes. Systems biology molecular process analysis was performed a priori to identify metabolites linked to molecular disease processes and drug mechanism of action. Individual subject data and urine samples were used from 2 randomized placebo controlled double blind clinical trials (NCT01062763, NCT00381134). A urinary metabolite score was developed to predict albuminuria response to spironolactone therapy using penalized ridge regression with leave-one-out cross validation. Bioinformatic analysis identified a set of 18 metabolites linked to a diabetic kidney disease molecular model and potentially affected by spironolactone mechanism of action. Spironolactone reduced UACR relative to placebo by median -42% (25th to 75% percentile -65 to 6) and -29% (25th to 75% percentile -37 to -1) in the test and replication cohorts, respectively. In the test cohort, UACR reduction was higher in the lowest tertile of the baseline urinary metabolite score compared with middle and upper tertiles -58% (25th to 75% percentile -78 to 33), -28% (25th to 75% percentile -46 to 8), -40% (25th to 75% percentile -52% to 31), respectively, P = 0.001 for trend). In the replication cohort, UACR reduction was -54% (25th to 75% percentile -65 to -50), -41 (25th to 75% percentile -46% to 30), and -17% (25th to 75% percentile -36 to 5), respectively, P = 0.010 for trend). We identified a set of 18 urinary metabolites through systems biology to predict albuminuria response to spironolactone in type 2 diabetes. These data suggest that urinary metabolites may be used as a tool to tailor optimal therapy and move in the direction of personalized medicine., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aims: The epithelial sodium channel (ENaC) is expressed in cultured endothelial cells and inhibitory coupling to eNOS activity has been proposed. The present study tested the hypothesis that ENaC blockers increase systemic NO-products and lower blood pressure in patients and mice, depending on eNOS., Methods: NO-products and cGMP were measured in diabetes patient urine and plasma samples before and after amiloride treatment (20-40 mg for two days, plasma n = 22, urine n = 12 and 5-10 mg for eight weeks, plasma n = 52, urine n = 55). Indwelling catheters were implanted in the femoral artery and vein in mice for continuous arterial blood pressure and heart rate recordings and infusion., Results: Treatment with amiloride for two days increased plasma and urine NO-products, while plasma cGMP decreased and urinary cGMP was unchanged in patient samples. Eight weeks of treatment with amiloride did not alter NO-products and cGMP. In mice, amiloride boli of 5, 50, and 500 µg/kg lowered heart rate and arterial blood pressure significantly and acutely. Benzamil had no effect on pressure and raised heart rate. In hypertensive eNOS -/- and L-NAME-treated mice, amiloride lowered blood pressure significantly. L-NAME infusion significantly decreased NO-products in plasma; amiloride and eNOS-deletion had no effect. An acetylcholine bolus resulted in acute blood pressure drop that was attenuated in eNOS -/- and L-NAME mice. ENaC subunit expressions were not detected consistently in human and mouse arteries and endothelial cells., Conclusion: Amiloride has an acute hypotensive action not dependent on ENaC and eNOS and likely related to the heart., (© 2018 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Background: The mineralocorticoid receptor antagonist spironolactone significantly reduces albuminuria in patients with diabetes. Prior studies have shown large between-patient variability in albuminuria treatment response. We previously developed and validated a urinary proteomic classifier that predicts onset and progression of chronic kidney disease. Here, we tested whether the proteomic classifier based on 273 urinary peptides (CKD273) predicts albuminuria response to spironolactone treatment., Methods: We performed a post hoc analysis in a double-blind randomized clinical trial with allocation to either spironolactone 12.5-50 mg/day (n = 57) or placebo (n = 54) for 16 weeks. Patients were diagnosed with type 2 diabetes and resistant hypertension. Treatment was an adjunct to renin-angiotensin system inhibition. Primary endpoint was the percentage change in urine albumin to creatinine ratio (UACR). Capillary electrophoresis mass spectrometry was used to quantify urinary peptides at baseline. The previously validated combination of 273 known urinary peptides was used as proteomic classifier., Results: Spironolactone reduced UACR relative to placebo by 50%, although with a large between-patient variability in UACR response (5th to 95th percentile, 7 to 312%). An interaction was detected between CKD273 and treatment assignment (β = -1.09, P = 0.026). Higher values of CKD273 at baseline were associated with a larger reduction in UACR in the spironolactone group (β = -0.70, P = 0.049), but not in the placebo group (β = 0.39, P = 0.25). Stratified in tertiles of baseline CKD273, reduction in UACR was greater in the highest tertile, 63% (95% confidence interval: 35-79%), as compared with the two other tertiles combined, 16% (-17 to 40%) (P = 0.011)., Conclusions: A urinary proteomics classifier can be used to identify individuals with type 2 diabetes who are more likely to show an albuminuria-lowering response to spironolactone treatment. These results suggest that urinary proteomics may be a valuable tool to tailor therapy, but confirmation in a larger clinical trial is required., (© The Authors 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

The proteinase prostasin is a candidate mediator for aldosterone-driven proteolytic activation of the epithelial sodium channel (ENaC). It was hypothesized that the aldosterone-mineralocorticoid receptor (MR) pathway stimulates prostasin abundance in kidney and urine. Prostasin was measured in plasma and urine from type 2 diabetic patients with resistant hypertension (n = 112) randomized to spironolactone/placebo in a clinical trial. Prostasin protein level was assessed by immunoblotting in (1) human and rat urines with/without nephrotic syndrome, (2) human nephrectomy tissue, (3) urine and kidney from aldosterone synthase-deficient (AS -/- ) mice and ANGII- and aldosterone-infused mice, and in (4) kidney from adrenalectomized rats. Serum aldosterone concentration related to prostasin concentration in urine but not in plasma. Plasma prostasin concentration increased significantly after spironolactone compared to control. Urinary prostasin and albumin related directly and were reduced by spironolactone. In patients with nephrotic syndrome, urinary prostasin protein was elevated compared to controls. In rat nephrosis, proteinuria coincided with increased urinary prostasin, unchanged kidney tissue prostasin, and decreased plasma prostasin while plasma aldosterone was suppressed. Prostasin protein abundance in human nephrectomy tissue was similar across gender and ANGII inhibition regimens. Prostasin urine abundance was not different in AS -/- and aldosterone-infused mice. Prostasin kidney level was not different from control in adrenalectomized rats and AS -/- mice. We found no evidence for a direct relationship between mineralocorticoid receptor signaling and kidney and urine prostasin abundance. The reduction of urinary prostasin in spironolactone-treated patients is most likely the result of an improved glomerular filtration barrier function and generally reduced proteinuria.

Diabetic patients with hypertension are at particularly high risk of vascular damage and consequently cardiovascular and renal disease. Fibulin-1, an extracellular matrix glycoprotein, is increased in arterial tissue and plasma from individuals with type 2 diabetes. This study aimed to evaluate whether antihypertensive treatment with spironolactone changes plasma fibulin-1 levels. In a multicenter, double-blind, randomized, placebo-controlled study, 119 patients with type 2 diabetes and resistant hypertension were included. A dose of spironolactone 25 mg or matching placebo was added to previous treatment at randomization. Blood pressure (BP) and plasma fibulin-1 were measured at baseline and at 16 weeks follow-up. Overall, 112 patients completed the study. All measures of BP were reduced in the spironolactone group at follow-up. Plasma fibulin-1 was significantly reduced after spironolactone treatment (P=0.009), but increased after placebo (P=0.017). Baseline plasma fibulin-1 correlated with BP and estimated glomerular filtration rate. Increased levels of plasma fibulin-1 (P=0.004) were observed in diabetic participants reporting erectile dysfunction as compared with participants who did not. Treatment with low-dose spironolactone reduced plasma fibulin-1 levels in patients with type 2 diabetes and resistant hypertension. This supports the hypothesis that the antihypertensive effect of the mineralocorticoid receptor blocker in part may be due to regression of vascular remodeling.

In conditions with albuminuria, plasminogen is aberrantly filtered across the glomerular barrier and activated along the tubular system to plasmin. In the collecting duct, plasmin activates epithelial sodium channels (ENaC) proteolytically. Hyperactivity of ENaC could link microalbuminuria/proteinuria to resistant hypertension. Amiloride, an ENaC inhibitor, inhibits urokinase-type plasminogen activator. We hypothesized that amiloride (1) reduces blood pressure (BP); (2) attenuates plasminogen-to-plasmin activation; and (3) inhibits urine urokinase-type plasminogen activator in patients with resistant hypertension and type 2 diabetes mellitus (T2DM).In an open-label, non-randomized, 8-week intervention study, a cohort (n = 80) of patients with resistant hypertension and T2DM were included. Amiloride (5 mg/d) was added to previous triple antihypertensive treatment (including a diuretic and an inhibitor of the renin-angiotensin-aldosterone system) and increased to 10 mg if BP control was not achieved at 4 weeks. Complete dataset for urine analysis was available in 60 patients. Systolic and diastolic BP measured by ambulatory BP monitoring and office monitoring were significantly reduced. Average daytime BP was reduced by 6.3/3.0 mm Hg. Seven of 80 cases (9%) discontinued amiloride due to hyperkalemia >5.5 mol/L, the most frequent adverse event. Urinary plasmin(ogen) and albumin excretions were significantly reduced after amiloride treatment (P < .0001). Urokinase activity was detectable in macroalbuminuric urine, with a tendency toward reduction in activity after amiloride treatment. Amiloride lowers BP, urine plasminogen excretion and activation, and albumin/creatinine ratio, and is a relevant add-on medication for the treatment of resistant hypertension in patients with T2DM and microalbuminuria., (Copyright © 2014 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Aim: In essential hypertension (EH), the regulation of renal sodium excretion is aberrant. We hypothesized that in mild EH, (i) abnormal dynamics of plasma renin concentration (PRC) and atrial natriuretic peptide (ANP) are responsible for the exaggerated natriuresis, and (ii) exosomic protein patterns reflect the renal tubular abnormality involved in the dysregulation of sodium excretion., Methods: After 2-week drug washout and 4-day diet, systemic and renal hemodynamics, cardio-renal hormones, glomerular filtration and renal excretion were studied in male patients during saline loading (SL). Excretion rates of exosome-related urinary proteins including apical membrane transporters were determined by proteomics-based methods., Results: In patients, baseline renal vascular conductance was reduced (-44%, P < 0.001), but non-renal vascular conductances were normal while PRC was reduced and ANP elevated (both P < 0.01). SL induced exaggerated natriuresis and reduced PRC (P < 0.01), at normal suppression rate. SL increased arterial pressure in patients (+11 mmHg, P < 0.001), but not in controls; however, during time control, patients showed identical increases (+10 mmHg, P < 0.005) apparently dissociating arterial pressure from natriuresis. At baseline, excretion rates of 438 proteins ranged from 0.07 to 49.8 pmol (mmol creatinine)(-1); 12 proteins were found in all subjects, and 21 proteins were found in two or more patients, but not in controls. In patients, the excretion rate of retinoic acid-induced gene 2 protein was reduced, and excretion rates of other proteins showed increased variances compatible with pathophysiological and clinical applicability., Conclusion: Essential hypertension patients exhibit selective renal vasoconstriction and individually varying excretion rates of several exosome-related proteins. Hormonal changes, rather than arterial pressure, seem to cause exaggeration of natriuresis., (© 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Background: Aberrant filtration of plasminogen from plasma and subsequent activation to plasmin in the urinary space may activate proteolytically the epithelial sodium channel, ENaC. In conditions with chronic albuminuria, this may cause hypertension. It was hypothesized that patients with type 2 diabetes mellitus (T2DM) and treatment-resistant hypertension excrete plasmin(ogen) in urine in proportion to albumin and that plasmin confers to urine the ability to activate ENaC., Method: Patients (n = 113) with T2DM and resistant hypertension, defined as systolic blood pressure (SBP) more than 130 mmHg and/or diastolic blood pressure (DBP) more than 80 mmHg despite use of at least three drugs with one diuretic and one renin-angiotensin system inhibitor, were included. Urine was analyzed for albumin, creatinine, plasmin(ogen), protease activity, and ability to activate inward current in single collecting duct cells., Results: Mean ambulatory SBP/DBP was 143 ± 1/77 ± 0.7 mmHg; HbA1c 7.35%; and eGFR 81.0 ml/min per 1.73 m (geometric means). Patients with microalbuminuria (39%) and macroalbuminuria (13%) displayed significantly elevated levels of urinary plasmin(ogen) normalized to urine creatinine compared with patients with normal excretion of albumin (48%). Urinary plasminogen correlated significantly to urine albumin. Western immunoblotting and gelatine zymography confirmed active plasmin in urine samples from patients with microalbuminuria and macroalbuminuria. Single collecting duct cells displayed significantly increased, amiloride-sensitive, inward current when superfused with urine from albuminuric patients compared with patients with normal albumin excretion. Urinary plasminogen/creatinine ratio correlated significantly with 24-h ambulatory blood pressure., Conclusion: Aberrant presence of plasmin in preurine may inappropriately activate ENaC in patients with type 2 diabetes and microalbuminuria. This may contribute to treatment-resistant hypertension.

Background: The increased risk of cardiovascular morbidity and mortality associated with arterial hypertension is particularly pronounced in patients with type 2 diabetes mellitus. Blood pressure control is, therefore, decisively important but often not sufficiently achieved., Objective: The primary objective of this study was to evaluate the antihypertensive effect of low dose spironolactone added to triple therapy for resistant hypertension in patients with type 2 diabetes measured by ambulatory monitoring. Secondary objectives were to evaluate the effects on glycaemic control and urinary albumin excretion as well as adverse effects., Methods: In a multicentre, double-blind, randomized, placebo-controlled study 119 patients with blood pressure at or above 130/80 mmHg despite triple antihypertensive therapy were included. One tablet of 25 mg spironolactone or placebo was added to previous treatment and increased to two if blood pressure below 130/80 mmHg was not achieved after 4 weeks. Blood pressure was measured by ambulatory monitoring at baseline and after 16 weeks., Results: The study was completed by 112 patients, 57 randomized to spironolactone and 55 to placebo. Average daytime placebo-corrected blood pressure was reduced by 8.9 (4.7-13.2)/3.7 (1.5-5.8) mmHg. Also office blood pressure, night-time, 24-h and pulse pressures were reduced significantly. Urinary albumin/creatinine ratio was significantly reduced in the spironolactone group. Glycaemic control remained unchanged. Hyperkalemia was the most frequent adverse event leading to dose reduction in three cases and discontinuation in one, whereas gynaecomastia was not reported., Conclusion: Low dose spironolactone exerts significant BP and urinary albumin creatinine ratio lowering effects in high-risk patients with resistant hypertension and type 2 diabetes mellitus.

Background: Patients with hypertension are primarily treated in general practice. However, major studies of patients with hypertension are rarely based on populations from primary care. Knowledge of blood pressure (BP) control rates in patients with diabetes and/or cardiovascular diseases (CVDs), who have additional comorbidities, is lacking. We aimed to investigate the association of comorbidities with BP control using a large cohort of hypertensive patients from primary care practices., Methods and Results: Using the Danish General Practice Database, we included 37 651 patients with hypertension from 231 general practices in Denmark. Recommended BP control was defined as BP <140/90 mm Hg in general and <130/80 mm Hg in patients with diabetes. The overall control rate was 33.2% (95% CI: 32.7 to 33.7). Only 16.5% (95% CI: 15.8 to 17.3) of patients with diabetes achieved BP control, whereas control rates ranged from 42.9% to 51.4% for patients with ischemic heart diseases or cerebrovascular or peripheral vascular diseases. A diagnosis of cardiac heart failure in addition to diabetes and/or CVD was associated with higher BP control rates, compared with men and women having only diabetes and/or CVD. A diagnosis of asthma in addition to diabetes and CVD was associated with higher BP control rates in men., Conclusion: In Danish general practice, only 1 of 3 patients diagnosed with hypertension had a BP below target. BP control rates differ substantially within comorbidities. Other serious comorbidities in addition to diabetes and/or CVD were not associated with lower BP control rates; on the contrary, in some cases the BP control rates were higher when the patient was diagnosed with other serious comorbidities in addition to diabetes and/or CVD.

Background: Auscultatory measurement using a sphygmomanometer has been the predominant method for clinical estimation of blood pressure, but it is now rapidly being replaced by oscillometric measurement., Objective: To compare blood pressure by auscultatory and oscillometric measurements in patients ≥ 80 years., Method: 100 patients had blood pressure measured by auscultation with a sphygmomanometer and by an electronic device using the oscillometric method. For each patient the mean of two blood pressures with each method measured within 15 min were compared., Results: The mean age of participants was 85.8 years; 55.8% were women. The correlation coefficient for systolic blood pressure was 0.88 and for diastolic 0.79. Differences between auscultatory and oscillometric values were less than 10 mmHg in 70.6% of systolic blood pressures and in 83.2% for diastolic. Arrhythmia and hypertension did not influence the results, and there was no correlation between the magnitude of the differences and the level of blood pressure., Conclusion: Agreement between oscillometric and auscultatory measurements of blood pressure in octogenarians was found to be less than required by validation protocols. However, semi-automatic equipment, which is observer-independent, may be used even in the very elderly, particularly if multiple readings are performed.

Our objective was to estimate the effect of addition of low-dose spironolactone to previous antihypertensive therapy in patients with resistant hypertension. Patients had 25 to 50 mg of spironolactone once daily added to the treatment of hypertension that was uncontrolled despite previous treatment with three classes of antihypertensive drugs. The effect on blood pressure was estimated by office measurements together with serum potassium and adverse effects. The data were analyzed retrospectively. A total of 544 patients were identified; 200 were excluded because of secondary hypertension, other indications for spironolactone than hypertension, previous antihypertensive therapy with less than three drugs unless demonstrated intolerance to a third drug, insufficient compliance, and lack of follow-up data. Thus, 344 cases were included in the analysis. The population was 62.1 ± 12.8 years old, 45.1% were males, and 43% had cardiovascular comorbidity. Mean blood pressure before the addition of spironolactone was 169/88 mm Hg. At 1, 3, and 6 months after the addition, blood pressure was decreased by an average of 16.6/7.0, 23.9/9.7, and 26.0/10.7 mm Hg (all P < .001). Serum potassium increased from an average of 3.7 mmol/L to 4.1 mmol/L (P < .001). Spironolactone was discontinued because of hyperkalemia in 4.1% of the cases. A total of 18% of all patients had adverse effects, which in 9.9% led to discontinuation of the drug. A total of 5.2% of the males developed gynecomastia. In conclusion, low-dose spironolactone is highly effective when added to previous treatment of patients with resistant hypertension., (2010 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Hypertension is the most important modifiable risk factor for cardiovascular disease. However, less than half of all hypertensives have their blood pressure reduced to relevant goals. The prevalence of hypertension in Denmark was found to be between 26% and 40% of the adult population. Just over half were aware of the diagnosis, but less than half were in treatment. Blood pressure control in patients who are undergoing treatment has improved during recent years, but there is still a gap to achievable control rates.

Hypertension is an important modifiable risk factor for cardiovascular disease. Risk is reduced by reduction of blood pressure (BP). The present survey estimated the prevalence of hypertension, awareness, treatment, and BP control in Denmark. BP was measured three times on one occasion in a representative sample (n = 7,767) of the Danish population ages 20 to 89 years. Persons with screening BP >/=140/90 mm Hg also measured BP at home. Participants with home BP >/=135/85 mm Hg in general and >/=125/75 mm Hg for patients with diabetes or renal disease were categorized as hypertensive together with those already on antihypertensive treatment. Awareness was registered by questionnaire. Treated patients with BP below relevant limits were categorized as controlled. Age-adjusted prevalence of hypertension was on the basis of screening BP 25.7% and by home BP 22.3%. Seventy-two percent of patients found hypertensive by home BP were aware of it, 64% were treated, and 57% of those treated were controlled by office BP and 68% by home BP. One-fifth of the adult Danish population was found to be hypertensive, Awareness and control of hypertension was better than in most previous reports. Control rates similar to those of clinical trials are achievable in clinical practice.

The result of treatment of renovascular hypertension by renal angioplasty over a period of 13 years was analysed. Patients with a positive diagnostic work-up with renography or renal vein renin measurement had renal angiography performed and in cases of renal artery stenosis, transluminal angioplasty. A total of 124 patients were treated; 31% were normotensive immediately after angioplasty, 59% had improved blood pressure control and 10% had unchanged hypertension. The corresponding figures after six months and at the latest follow-up were 13, 72 and 15%.

Objective: The study is a follow-up on treatment of renovascular hypertension (RVH) with percutaneous transluminal renal angioplasty (PTRA)., Methods: Patients were screened on the basis of clinical criteria of increased probability of RVH with renography and in selected cases with renal vein renin measurements. A positive work-up suggesting a functionally important renal artery stenosis led to renal angiography and PTRA if stenosis was confirmed; in 59%, an intravascular stent was inserted., Results: Outcome of treatment was classified as follows - group I: normotensive without medication; group II: with improved control of blood pressure; group III: unchanged blood pressure control. Grouping was performed immediately after treatment, at 1 month, 6 months and at the latest follow-up. One hundred-and-twenty-two patients (124 atherosclerotic and 12 fibromuscular lesions) were treated during 13 years. Immediately after PTRA the patients were grouped as follows - I: 31%, II: 59%, III: 10%. At 1 month, I: 13%, II: 72%, III: 15%; at 6 months, I: 11%, II: 74%, III: 15%, and at the latest follow-up, I: 11%, II: 78%, III: 11%. There were few significant complications, and renal function remained on average stable., Conclusion: PTRA is an effective treatment of RVH in patients selected by signs of a flow-restricting stenosis. Twelve percent were normotensive after angioplasty and a further 77% had better controlled hypertension. Few complications were seen and renal function was on average unchanged as measured by serum creatinine.

A case of severe amlodipine overdose with only mild symptoms is described. Plasma concentrations of amlodipine were measured in serial samples by gas chromatography. There was no concomitant overdose. The present case is compared with previous reported cases of amlodipine overdose where patients all developed severe symptoms. We conclude that amlodipine overdose does not always cause severe symptoms.

The pharmacokinetics of amlodipine 5 mg and felodipine ER (extended release) 5 mg o.d. after single and 2 weeks of repeated oral doses, were compared in 28 essential hypertensive patients using a crossover design. As a secondary parameter the effects of the drugs on blood pressure were assessed. Significant differences were found between all principal pharmacokinetic variables, when comparing the 2 treatments after both single and repeated dosing. The coefficients of variation of maximal drug concentration and AUC after single dosing and at steady-state were significantly higher for felodipine ER than for amlodipine. After repeated dosing the peak-to-trough plasma concentration ratio were 1.58 and 4.43 (p < 0.001) for amlodipine and felodipine ER, respectively. Both drugs lowered systolic and diastolic blood pressure to the same extent after 2 weeks of repeated dosing. No significant differences between the blood pressure lowering vs time profile of the 2 drugs were encountered. In conclusion, the interpatient drug concentration variability and the peak-to-trough plasma concentration ratio were more favorable for amlodipine compared to felodipine ER. It remains to be established whether these characteristics are also reflected in a more smooth and consistent blood pressure control.

The Danish Medical Association and the scientific societies have initiated three studies to evaluate the use of questionnaires for continuous medical education. One study was a questionnaire in anaesthesiology with 30 questions with answers yes/no/no answer, which was sent to 600 specialists in anaesthesiology. One study was in cardiology with a multiple choice questionnaire, sent to 300 general practitioners and 75 specialists in internal medicine outside cardiology. One study concerned the educational value of State-of-the-Art articles about neurology in Ugeskrift for Laeger (Journal of the Danish Medical Association) sent to 500 doctors outside neurology. All questionnaires were sent anonymously, with one general reminder. For the anaesthesiology study 234 questionnaires were returned (40.5%). In the cardiology study 195 questionnaires were returned (52%). For the study on neurology 278 answered (56%). Only about half of the questionnaires were returned for the three studies, and a lot of effort and resources were put into the studies. An extension from these small pilot studies to a general systematic continuous methodology with updated questionnaires in the postgraduate medical education seems troublesome. An optional self-registration for medical education such as The Canadian "Mocomp concept" might be a more realistic suggestion.

Angiotensin converting enzyme (ACE) inhibitors are generally well tolerated. Worldwide, only few reports have been published associating pancreatitis with ACE inhibitor therapy. We report a case in whom there was no other likely explanation for the acute pancreatitis than enalapril therapy, which was temporally associated with the symptoms. Possible mechanisms underlying the induction of pancreatitis by ACE inhibitors are discussed. With the increasing use of ACE inhibitors, the incidence of rare adverse effects such as potentially lethal pancreatitis is likely to increase. Clinicians need to be aware of this association.

An organ preservation solution has been developed by combining some features of the hypertonic citrate formulation of Ross, Marshall, and Escott (RME) with some features of UW solution. Specifically the solution (HP16) contains a balance of cations similar to that in RME and the same concentration of citrate, but sulfate is replaced by chloride and mannitol by a starch hydrolysis product (SHP). A gelatin-derived polypeptide (Haemaccel) is included to provide colloid osmotic pressure. The objective was to increase the effectiveness of RME by using a higher-molecular-weight osmoticum than mannitol, but avoiding the expense of raffinose; reducing the osmolality to a more physiological level; and including a colloid to make the solution suitable for continuous perfusion. The effectiveness of the solution was tested by 48-hr hypothermic preservation of rabbit kidneys. The results were compared with those obtained using RME or UW. It was shown that simple hypothermic storage was more effective than continuous perfusion, and that HP16 was more effective than RME and as effective as UW. The improvement over RME was ascribed to the isotonic osmolality and the inclusion of a higher-molecular-weight osmoticum (the SHP), possibly supplemented by the colloid (Haemaccel). Two SHP preparations, both with dextrose-equivalent values of approximately 35, were equally effective. These materials contain a standardized mixture of dextrose, maltose, and tri- and oligosaccharides, and have the osmotic properties of a trisaccharide. The results provide a new, inexpensive preservation solution that is as effective as any so far tested with this model, and they support the importance of appropriate osmotic properties for solutions to be used in organ preservation.

2,3-dimercaptosuccinic acid (DMSA) mobilizes lead from superficial depots. In comparison with other chelating agents, DMSA has a high therapeutic index and has the additional advantage that it can be administered orally. We have used DMSA for treatment of chronic occupational lead poisoning in a 54-year old male with signs of neurotoxic effects. The treatment resulted in a rapid decrease in the blood-lead concentration, followed by a slow increase after the treatment and subsequent stabilization at a blood-lead level lower than prior to treatment. During the first course of treatment, almost 100 mumols lead was excreted in the urine. As a result of successive courses of treatments, the patient's condition was improved. However, during the third course of treatment, he developed a mucocutaneous rash which faded again after withdrawal of DMSA; this reaction was subsequently provoked by sub-therapeutic doses, and continued treatment was therefore cancelled. Only minor, reversible side effects of DMSA have hitherto been reported, and DMSA must therefore be regarded a promising agent for long-term, out-patient chelation treatment of chronic lead poisoning.

A 54-year-old male with chronic lead poisoning was treated with 2.3-dimercaptosuccinic acid (DMSA). A daily dosage of 30 mg/kg body weight for three days and 20 mg/kg for four days resulted in a decrease of the blood-lead concentration (B-Pb) from 3.7 to 0.7 mumol/l; the total amount of lead excreted in the urine during the first seven 24 hr periods was 75 mumol. After the treatment, B-Pb slowly increased to 3.3 mumol/l. A second treatment was then initiated and resulted in similar changes in B-Pb. However, during the third treatment, the patient developed a mucocutaneous vesicular flare; the eruptions faded after cessation of the chelation therapy, but could be provoked by DMSA doses of 10 mg/kg and above. Despite the small number of treatment courses, the patient showed obvious mental improvement and reported less headache and improved memory. Thus, DMSA is an efficient chelator that results in a rapid, though temporary decrease in B-Pb. Although oral treatment with this chelator may be supervised from the out-patient clinic, careful monitoring for potential side effects is recommended.

Microwaves offer the prospect of rapid and uniform heating of frozen organs. This is significant in the context of cryopreservation, and particularly of vitrification, because microwave heating may help to avoid crystallization or recrystallization of ice during warming, minimize any effects of high cell density, and reduce thermal-mechanical stresses. Previous work has established a rationale for reducing the ionic strength of solutions used to prepare tissues for microwave heating, since this permits the use of lower frequencies, which makes heating more uniform, without increasing the risk of thermal runaway (T. P. Marsland, S. Evans, and D. E. Pegg, Cryobiology 24, 311-323, 1987). In this paper we report a study of two possible low ionic strength perfusates, in rabbit kidneys, using 48 hr of hypothermic storage and autotransplantation as the test system. This model was chosen because there is a great deal of basic information about it. Both a single-pass "flush" preservation solution and a solution designed for continuous perfusion gave excellent results. The continuous perfusion system, which would be the more suitable for introducing cryoprotectants, gave five of five surviving animals with peak serum creatinine levels of 353-555 mumol/liter normal histology in three cases, and only very minor damage in the other two. There would therefore seem to be no obstacle to the use of perfusates having a low ionic strength in renal cryopreservations studies.

Acute chloroquine poisoning is life threatening with risk of death from apnoea and cardiac arrhythmia within a few hours of ingestion. Mechanical ventilation, infusion of pressor agents and large doses of diazepam seem to provide effective treatment. This treatment was introduced by Riou et alii (N Engl J Med 1988; 318; 1-6), and we used it successfully in a case of severe chloroquine poisoning. Intensive treatment was given during the first two days of intoxication, when the whole blood chloroquine phosphate concentration was high (more than 10 mumol/kg), corresponding to absorption from the gut and distribution to the organs. Hereafter the whole blood chloroquine phosphate concentration decreased increasingly slowly, probably due to equilibrium with tissue stores.

Transplantation is necessary for evaluation of kidney preservation procedures, and a model using a small laboratory animal is desirable. The rabbit was found to be a suitable animal for this purpose. Even long periods of anaesthesia without artificial respiration were safely achieved. Hydration and serum electrolytes could be maintained within normal ranges with intravenous injections of isotonic saline and dextrose during and after the operation. The kidneys were implanted by anastomosing the artery and vein end-to-side to the abdominal aorta and the posterior vena cava respectively. The ureter was implanted into the bladder over a nylon stent. In a recent 100 transplantations the incidence of vascular thrombosis was low (4%), but rather more (10%) mainly late ureteral complications were encountered. Transplanted kidneys showed good function with mean peak serum creatinines of 285 mumol/l and normal macroscopic and histological appearance at autopsy.

Propane-1,2-diol (propylene glycol, PG) permeates more rapidly than glycerol, has a strong glass-forming tendency, and appears to have a low toxicity. It is therefore attractive as a potential cryoprotectant for renal preservation. In this paper we compared the effect on subsequent function, of exposing rabbit renal cortical slices to 1 M PG or glycerol in a range of vehicle solutions and we demonstrated a remarkably low toxicity of PG at this concentration. Rabbit kidneys were then perfused with solutions containing PG up to a maximum concentration of 3 M, after which the cryoprotectant was removed and the function of cortical slices prepared from the perfused kidneys was assessed. Marked differences in perfusion characteristics were found between PG and glycerol and between different vehicle solutions for PG, but the two most suitable perfusates, both containing about 100 mM mannitol, permitted normal function in slices prepared after removal of PG. These results indicate that, with an appropriate vehicle perfusate, exposure to PG up to a concentration of 3 mol/liter has remarkably little effect upon vascular resistance and the renal cortical functions measured.

There is good evidence that blood should be removed from kidneys as completely as possible before they are transplanted. Rabbit kidneys, either freshly isolated or after one hour of warm ischaemia, were perfused with a solution of osmolality 400 mOsm/kg which contained high concentrations of Mg++ (72 mEq) and glucose (167 mM). The rate and completeness of blood removal were measured by collecting effluent fractions until 100 ml had been perfused, and then assaying the haemoglobin in each effluent fraction and the residual haemoglobin in the kidney. A pressure of 60 mmHg was found to be sufficient for effective perfusion. The addition of 5% dextran 40 (Rheomacrodex) to the perfusate greatly improved the completeness of blood removal from kidneys subjected to one hour of warm ischaemia. Rabbit kidneys washed out with this solution functioned excellently after transplantation.

Survival or renal xenografts from rabbit to cat has been prolonged by several hours by injection of antibodies against cat serum into the recipient. In control experiments the transplanted rabbit kidney was rejected by the cat in a few minutes.

Cooling and warming rates are known to be important determinants of viability for cryopreserved cells, but optimal rates have not previously been determined for any whole organ. In this study, rabbit kidneys, permeated with 2 M glycerol were cooled to -80 degrees C at four rates varying from 1 degrees C/hr to 3.1 degrees C/min and then rewarmed at four rates from 1 degrees C/hr to 4.2 degrees C/min, giving 16 experimental treatments. After gradual deglycerolization at 10 degrees C, each kidney was autografted and observed for 30 min. Assessment was by measurement of vascular resistance, immediate post-thaw lactate dehydrogenase (LDH) release, gross appearance, light- and electron microscopy, and tissue K+/Na+ ratio 30 min after transplantation. The best results were obtained after cooling at 1 degrees C/hr; warming rate had little apparent influence on the criteria used to assess function with the exception of LDH release, which indicated a preferred warming rate around 1 degrees C/min. Histological studies revealed extensive vascular damage, notably to the glomerular capillaries, that was minimized by very slow cooling. Freeze substitution, carried out on samples removed at -80 degrees C, demonstrated extensive ice formation in the interstitial space and, at the faster cooling rates, in the glomerular capillaries. Intracapillary ice formation was reduced in the kidneys cooled at 1 degrees C/hr.

The measurement of lactate dehydrogenase (LDH) release into perfusates after hypothermic storage was found to be a reliable index of ischemic injury of rabbit kidneys. Kidneys were exposed to warm and cold ischemia for varying periods. Each kidney was perfused before and after storage at simple hypothermia with 25 ml of a modified Collins solution. The venous effuent was collected in 5 ml fractions. Total LDH activity was measured in the first fraction after storage and used as a measure of ischemic tissue damage. It was confirmed that increasing the period of cold ischemia result in significant increases in LDH activity. The release of LDH into perfusates was then used to compare kidney damage after preservation with various fluids. With this method, it was not possible to demonstrate any difference in the extent of tissue damage after preservation with sodium-rich vs. potassium-rich perfusion fluid. Addition of steroids, vitamins and essential amino acids did not prevent or reduce tissue damage, estimated in this way. The effects of adding cryoprotectants to the perfusion fluid varied; LDH release following addition of 5% DMSO was significantly greater, and after addition of 5% glycerol smaller than the release after perfusion with a modified Collins solution alone. Stepwise addition of DMSO up to 20% resulted in serious tissue damage with a large LDH release into the perfusate.

Five rabbit kidneys were perfused with human blood and another five with their own blood in a re-circulating oxygenated system at 37 degrees C. The flow decreased to 2 ml/min. within 30 min. in all xenoperfusions, while none of the autoperfused had decreased to this level by 60 min. Endothelial damage, exudation, and IgG deposits along the basement membrane of the glomerular capillaries were the discriminative features of the xenoperfusion. In these experiments, we were unable to demonstrate any major role of platelets in the process leading to decreased blood flow.