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1.
Hydrochlorothiazide treatment increases the abundance of the NaCl cotransporter in urinary extracellular vesicles of essential hypertensive patients.
Pathare, G, Tutakhel, OAZ, van der Wel, MC, Shelton, LM, Deinum, J, Lenders, JWM, Hoenderop, JGJ, Bindels, RJM
American journal of physiology. Renal physiology. 2017;(6):F1063-F1072
Abstract
The thiazide-sensitive NaCl cotransporter (NCC), located apically in distal convoluted tubule epithelia, regulates the fine-tuning of renal sodium excretion. Three isoforms of NCC are generated through alternative splicing of the transcript, of which the third isoform has been the most extensively investigated in pathophysiological conditions. The aim of this study was to investigate the effect of different anti-hypertensive treatments on the abundance and phosphorylation of all three NCC isoforms in urinary extracellular vesicles (uEVs) of essential hypertensive patients. In uEVs isolated from patients (n = 23) before and after hydrochlorothiazide or valsartan treatment, the abundance and phosphorylation of the NCC isoforms was determined. Additionally, clinical biochemistry and blood pressure of the patients was assessed. Our results show that NCC detected in human uEVs has a glycosylated and oligomeric structure, comparable to NCC present in human kidney membrane fractions. Despite the inhibitory action of hydrochlorothiazide on NCC activity, immunoblot analysis of uEVs showed significantly increased abundance of NCC isoforms 1 and 2 (NCC1/2), total NCC (NCC1-3), and the phosphorylated form of total NCC (pNCC1-3-T55/T60) in essential hypertensive patients treated with hydrochlorothiazide but not with valsartan. This study highlights that NCC1/2, NCC1-3, and pNCC1-3-T55/T60 are upregulated by hydrochlorothiazide, and the increase in NCC abundance in uEVs of essential hypertensive patients correlates with the blood pressure response to hydrochlorothiazide.
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2.
Adding Hydrochlorothiazide to Olmesartan/Amlodipine Increases Efficacy in Patients With Inadequate Blood Pressure Control on Dual-Combination Therapy.
Rump, LC, Ammentorp, B, Laeis, P, Scholze, J
Journal of clinical hypertension (Greenwich, Conn.). 2016;(1):60-9
Abstract
This randomized, parallel-group study in patients inadequately controlled on olmesartan medoxomil/amlodipine (OLM/AML) 40/10 mg assessed the effects of adding hydrochlorothiazide (HCTZ) 12.5 mg and 25 mg, using seated blood pressure (SeBP) measurements and ambulatory blood pressure (BP) monitoring. Enrolled patients were screened and tapered off of therapy if required. All patients received OLM/AML 40/10 mg and those with mean seated BP (SeBP) ≥140/90 mm Hg after 8 weeks (n=808) were randomized (1:1:1) to continue with OLM/AML 40/10 mg or receive OLM/AML/HCTZ 40/10/12.5 or 40/10/25 mg for a further 8 weeks. The primary endpoint was the change in seated diastolic BP (SeDBP) from the start to the end of the randomized treatment period. The addition of HCTZ 25 mg significantly reduced SeDBP (-2.8 mm Hg; P<.0001), lowered seated systolic BP (SeSBP) and ambulatory DBP and SBP, and improved BP goal rates. In patients uncontrolled on OLM/AML 40/10 mg, adding HCTZ led to further BP reductions, particularly in ambulatory BP.
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3.
Angiotensin II receptor blockade and skeletal muscle metabolism in overweight and obese adults with elevated blood pressure.
Boutagy, NE, Marinik, EL, McMillan, RP, Anderson, AS, Frisard, MI, Davy, BM, Rivero, JM, Davy, KP, Hulver, MW
Therapeutic advances in cardiovascular disease. 2015;(2):45-50
Abstract
OBJECTIVES Whether angiotensin II receptor blockade improves skeletal muscle fatty acid oxidation in overweight and obese humans is unknown. The purpose of the study was to test the hypothesis that the angiotensin II receptor blocker, olmesartan, would increase fatty acid oxidation and the activity of enzymes associated with oxidative metabolism in skeletal muscle of overweight and obese humans. METHODS A total of 12 individuals (6 men and 6 women) aged 18-75 and with a body mass index ⩾25 kg/m2 were assigned to olmesartan or placebo for 8 weeks in a crossover fashion. Fatty acid oxidation was measured before and after each intervention by counting the (14)CO2 produced from [1-(14)C] palmitic acid in skeletal muscle homogenates. RESULTS Fatty acid oxidation was not significantly different between treatment periods at baseline and post intervention. In addition, the enzyme activities of citrate synthase and β-hydroxyacyl-coenzyme A dehydrogenase in skeletal muscle homogenates did not differ between treatment periods at baseline or post intervention. CONCLUSIONS Treatment with olmesartan for 8 weeks does not improve fatty acid oxidation or the activity of enzymes associated with oxidative metabolism in skeletal muscle from overweight and obese individuals. Taken together, our results indicate that improvements in skeletal muscle metabolism are not among the additional benefits of olmesartan that extend beyond blood pressure reduction.
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4.
Different aspects of sartan + calcium antagonist association compared to the single therapy on inflammation and metabolic parameters in hypertensive patients.
Derosa, G, Cicero, AF, Carbone, A, Querci, F, Fogari, E, D'Angelo, A, Maffioli, P
Inflammation. 2014;(1):154-62
Abstract
This study aims to evaluate the effects of an angiotensin receptor blocker (ARB)/calcium channel blocker combination on blood pressure control, lipid profile, insulin sensitivity, and inflammation markers. We randomized 276 hypertensive patients to olmesartan 20 mg, amlodipine 10 mg, or a single pill containing an olmesartan/amlodipine combination 20/5 mg for 12 months. We evaluated the following: body weight, systolic and diastolic blood pressure, fasting plasma glucose, fasting plasma insulin (FPI), M value, lipid profile, adiponectin (ADN), high sensitivity C-reactive protein (Hs-CRP), monocyte chemoattractant protein-1 (MCP-1), and macrophage migration inhibitory factor-1β (MIP-1β). Olmesartan/amlodipine combination better reduced blood pressure, FPI, homeostasis model assessment index, and increased M value and ADN compared to olmesartan and amlodipine monotherapies. Olmesartan/amlodipine significantly decreased Hs-CRP, MCP-1, and MIP-1β. In this multicenter, randomized, double-blind, clinical study, ARB/calcium antagonist combination resulted to be more effective than single monotherapies in reducing blood pressure, in improving insulin sensitivity, and in reducing inflammation parameters in patients with stage I essential hypertension.
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5.
The effects of telmisartan alone or in combination with hydrochlorothiazide on morning home blood pressure control: the SURGE 2 practice-based study.
Redon, J, Bilo, G, Parati, G, ,
Blood pressure. 2013;(6):377-85
Abstract
SURGE 2, a large-scale, practice-based study in 10 countries, evaluated the effects of telmisartan alone or with hydrochlorothiazide (HCTZ) on morning (06:00-11:59) home blood pressure (HBP) control. Hypertensive patients (clinic blood pressure [BP] ≥ 140/90 mmHg) received telmisartan 40 or 80 mg either alone or in combination with HCTZ 12.5 mg for 8 weeks. Treatment could be adjusted if clinic BP remained ≥ 140/90 mmHg. Clinic BP was measured in the morning prior to medication, and seated HBP monitoring was performed, three times per day, 2 days per week. A total of 25,882 patients were included (71% were previously using antihypertensives). There was a statistically significant (all p < 0.001) reduction in mean morning, lunchtime and evening HBP following treatment with telmisartan/telmisartan plus HCTZ, and morning HBP control increased from 10.6-19.8% to 51.1-64.6%. Similar improvements were observed for lunchtime (from 20.6-26.0% to 57.7-70.5%) and evening (from 21.3-31.4% to 59.0-68.8%). The morning HBP response ranged from 62.6-67.5% (systolic BP) and from 81.4-87.0% (diastolic BP). Adverse events were reported by 1.2% of patients. Telmisartan alone or with HCTZ improved morning HBP control and maintained a smooth HBP profile throughout the day in a real-life setting.
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6.
Combination therapy of angiotensin II receptor blocker and calcium channel blocker exerts pleiotropic therapeutic effects in addition to blood pressure lowering: amlodipine and candesartan trial in Yokohama (ACTY).
Maeda, A, Tamura, K, Kanaoka, T, Ohsawa, M, Haku, S, Azushima, K, Dejima, T, Wakui, H, Yanagi, M, Okano, Y, et al
Clinical and experimental hypertension (New York, N.Y. : 1993). 2012;(4):249-57
Abstract
Recent guidelines recommend combination antihypertensive therapy to achieve the target blood pressure (BP) and to suppress target organ damage. This study aimed to examine the beneficial effects of combination therapy with candesartan and amlodipine on BP control and markers of target organ function in Japanese essential hypertensive patients (N = 20) who did not achieve the target BP level during the monotherapy period with either candesartan or amlodipine. After the monotherapy period, for patients already being treated with amlodipine, a once-daily 8 mg dose of candesartan was added on during the combination therapy period (angiotensin II receptor blocker [ARB] add-on group, N = 10), and a once-daily 5 mg dose of amlodipine was added on for those already being treated with candesartan (calcium channel blocker [CCB] add-on group, N = 10). Combination therapy with candesartan and amlodipine for 12 weeks significantly decreased clinic and home systolic blood pressure (SBP) and diastolic blood pressure (DBP). In addition, the combination therapy was able to significantly reduce urine albumin excretion without decrease in estimated glomerular filtration ratio and resulted in significant improvements in brachial-ankle pulse wave velocity, central SBP, and insulin sensitivity. Furthermore, the CCB add-on group showed a significantly greater decrease in clinic and home DBP than the ARB add-on group. The calcium channel blocker add-on group also exhibited better improvements in vascular functional parameters than the ARB add-on group. These results suggest that combination therapy with candesartan and amlodipine is an efficient therapeutic strategy for hypertension with pleiotropic benefits.
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7.
Antihypertensive efficacy of the losartan/hydrochlorothiazide combination and its effect on plasma B-type natriuretic peptide in hypertensive patients uncontrolled by angiotensin II type 1 receptor antagonist-based therapy: a multicentre prospective observational study.
Meno, H, Inou, T, Tanaka, M, Tsuchiya, Y, Shiga, Y, Kobayashi, K, Nakamura, Y, Ota, T, Kubara, I
Clinical drug investigation. 2012;(3):171-8
Abstract
BACKGROUND AND OBJECTIVES Although strict blood pressure (BP) control is effective in the prevention of cardiovascular events, it is often insufficient in many hypertensive patients. B-type natriuretic peptide (BNP) has been shown to be associated with cardiovascular events. We investigated the effects of the losartan/hydrochlorothiazide combination on BP and plasma BNP in hypertensive patients uncontrolled by an angiotensin II type 1 receptor antagonist (angiotensin receptor blocker [ARB])-based therapy. METHODS In a multicentre prospective observational study, we enrolled 185 patients aged 36-79 years (mean age 63.8 years) with essential hypertension but without symptoms of heart failure who received an ARB-based therapy for ≥3 months but failed to achieve a target BP recommended by the Japanese Society of Hypertension (JSH). ARBs were switched to losartan (LOS) 50 mg/hydrochlorothiazide (HCTZ) 12.5 mg. The antihypertensive efficacy, safety, and effects of this combination on blood biochemical parameters and plasma BNP were evaluated for 12 months. RESULTS Mean ± SD systolic and diastolic BP decreased from 152 ± 13/87 ± 10 mmHg to 128 ± 14/74 ± 10 mmHg, respectively, after 12 months (p < 0.001). Mean ± SD plasma BNP levels decreased significantly from 46.0 ± 83.0 pg/mL to 40.8 ± 68.0 pg/mL (p < 0.05). The percentage of patients who achieved the JSH 2004 target BP was 51% after 12 months; the percentage was 63% in elderly patients aged ≥65 years without complications, and 43% in patients with concomitant diabetes mellitus or chronic kidney disease. No association was found between a decrease in plasma BNP levels and BP, age, body mass index or estimated glomerular filtration rate. There was a significant increase in serum uric acid and a decrease in serum potassium, but both were within the range of normal values. Adverse events were observed in 8.6% of the patients. CONCLUSION Antihypertensive treatment using two types of drugs (LOS/HCTZ) with different mechanisms yielded potent antihypertensive efficacy with safety and decreased plasma BNP levels.
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8.
High doses of irbesartan offer long-term kidney protection in cases of established diabetic nephropathy.
Ros-Ruiz, S, Aranda-Lara, P, Fernández, JC, Martínez-Esteban, MD, Jironda, C, Hidalgo, P, Hernández-Marrero, D
Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia. 2012;(2):187-96
Abstract
BACKGROUND Hypothetically, the greater the blockade of angiotensin AT1 receptors from ultra-high doses of angiotensin receptors blockers (ARB), the greater the expected renoprotection effects. The aim of our study was to evaluate the effects of ultra-high doses of irbesartan on proteinuria and renal function in diabetics with established or overt diabetic nephropathy (ODN). MATERIAL AND METHOD Ours was a prospective, non-randomised 3-year follow-up study, using a multifactorial therapeutic approach based on irbesartan 600mg daily. Demographic variables, anthropometric data, and biochemical parameters were comparatively analysed at the beginning and end of the study. Forty patients (75% with type 2 diabetes) were included, average age 57.1 +/- 10, 29 male (72.5%). RESULTS SBP (157.6 +/- 27mm Hg vs 130.1 +/- 14mm Hg) and DBP (88.8 +/- 10mm Hg vs 76.2 +/- 8mm Hg) decreased significantly at the end of follow-up (P<.001). Serum creatinine increased by only 0.17mg/dl, although this was a statistically significant difference (P<.05). Proteinuria markedly decreased from 2.64 +/- 1.99 to 0.98 +/- 1.18 (P<.0001), i.e. 59.2%. Twenty-five percent of patients had normal albuminuria at the end of the follow-up period. Lipid profiles significantly improved. No patients withdrew from the study due to side effects, and serum potassium did not change significantly over the course of the study. Except for BMI and HbA1c, all other therapeutic targets set out by ADA recommendations improved significantly. CONCLUSIONS The treatment of ODN with ultra-high doses of irbesartan was highly effective and safe in reducing proteinuria and slowing the progressive course to ESRD.
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9.
Olmesartan reduces arterial stiffness and serum adipocyte fatty acid-binding protein in hypertensive patients.
Miyoshi, T, Doi, M, Hirohata, S, Kamikawa, S, Usui, S, Ogawa, H, Sakane, K, Izumi, R, Ninomiya, Y, Kusachi, S
Heart and vessels. 2011;(4):408-13
Abstract
Adipocyte fatty acid binding protein (A-FABP) has been reported to be involved in insulin resistance, lipid metabolism, and atherosclerosis; however, little is known about the effect of medication on the change in circulating A-FABP in human subjects. We evaluated the effects of angiotensin II type 1 receptor blocker (ARB) on arterial stiffness and its association with serum A-FABP in patients with hypertension. Thirty patients newly diagnosed with essential hypertension were treated with olmesartan (20 mg/day), an ARB, for 6 months. Serum levels of A-FABP and high-sensitivity C-reactive protein (hsCRP) were examined and the cardio-ankle vascular index (CAVI), which is a marker of arterial stiffness, was also determined. Serum A-FABP at baseline was significantly correlated with the body mass index (r = 0.45, P = 0.01), homeostasis model assessment as a marker of insulin resistance (r = 0.53, P < 0.01), and systolic blood pressure (r = 0.37, P = 0.047), and tended to be correlated with low-density lipoprotein cholesterol, triglyceride, and CAVI. Olmesartan treatment resulted in a significant decrease in CAVI, serum A-FABP levels, and hsCRP, besides a significant reduction of blood pressure. Multiple regression analysis revealed that the change in CAVI was independently correlated with the change in serum A-FABP. Olmesartan ameliorated arterial stiffness in patients with hypertension, which may be involved in the reduction of serum A-FABP.
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10.
Switching therapy from variable-dose multiple pill to fixed-dose single-pill combinations of angiotensin II receptor blockers and thiazides for hypertension.
Sakima, A, Ohshiro, K, Nakada, S, Yamazato, M, Kohagura, K, Nakamoto, M, Tana, T, Ohya, Y
Clinical and experimental hypertension (New York, N.Y. : 1993). 2011;(5):309-15
Abstract
The efficacy and tolerability of switching therapy from free combinations of angiotensin II receptor blocker (ARB) and thiazide (A/T) to a fixed-dose of losartan and hydrochlorothiazide (L/H) has not been evaluated in Japan. We examined effects of switching therapy from variable-dose multiple-pill A/T to a fixed-dose L/H on blood pressure (BP) along with medication adherence and the degree of satisfaction in 91 hypertensive outpatients (mean age, 65.2 ± 9.6 years). After 6 months, a significant BP reduction (132 ± 9/76 ± 10 vs. 126 ± 12/72 ± 11 mm Hg), along with an improvement of attaining target BP (44.0 vs. 61.5%) and that of adherence, were observed. The magnitude of BP reduction in the participants increased their degree of satisfaction more significantly than in the participants who worsened their degree of satisfaction. The estimated glomerular filtration rate and the serum uric acid (UA) level decreased slightly but significantly. The hemoglobin A1c of participants with diabetes mellitus increased slightly but significantly. In conclusion, a switch in therapy from variable-dose, multiple-pill A/T combinations to a fixed-dose, single-pill L/H was effective in decreasing BP and serum UA in Japanese clinical practice. Metabolic side effects of L/H in patients with diabetes mellitus remain to be investigated.