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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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Parathyroid Hormone and the Use of Diuretics and Calcium-Channel Blockers: The Multi-Ethnic Study of Atherosclerosis.
Zaheer, S, de Boer, I, Allison, M, Brown, JM, Psaty, BM, Robinson-Cohen, C, Ix, JH, Kestenbaum, B, Siscovick, D, Vaidya, A
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2016;(6):1137-45
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Abstract
Thiazide diuretic (TZ) use is associated with higher bone mineral density, whereas loop diuretic (LD) use is associated with lower bone density and incident fracture. Dihydropyridine-sensitive calcium channels are expressed on parathyroid cells and may play a role in parathyroid hormone (PTH) regulation. The potential for diuretics and calcium-channel blockers (CCBs) to modulate PTH and calcium homeostasis may represent a mechanism by which they influence skeletal outcomes. We hypothesized that the use of LD and dihydropyridine CCBs is associated with higher PTH, and TZ use is associated with lower PTH. We conducted cross-sectional analyses of participants treated for hypertension in the Multi-Ethnic Study of Atherosclerosis who did not have primary hyperparathyroidism or chronic kidney disease (n = 1888). We used adjusted regression models to evaluate the independent association between TZ, LD, and CCB medication classes and PTH. TZ use was associated with lower PTH when compared with non-TZ use (44.4 versus 46.9 pg/mL, p = 0.02), whereas the use of LD and CCBs was associated with higher PTH when compared with non-users of each medication class (LD: 60.7 versus 45.5 pg/mL, p < 0.0001; CCB: 49.5 versus. 44.4 pg/mL, p < 0.0001). Adjusted regression models confirmed independent associations between TZ use and lower PTH (β = -3.2 pg/mL, p = 0.0007), and LD or CCB use and higher PTH (LD: β = +12.0 pg/mL, p < 0.0001; CCB: +3.7 pg/mL, p < 0.0001). Among CCB users, the use of dihydropyridines was independently associated with higher PTH (β = +5.0 pg/mL, p < 0.0001), whereas non-dihydropyridine use was not (β = +0.58 pg/mL, p = 0.68). We conclude that in a large community-based cohort with normal kidney function, TZ use is associated with lower PTH, whereas LD and dihydropyridine CCB use is associated with higher PTH. These associations may provide a mechanistic explanation linking use of these medications to the development of skeletal outcomes. © 2016 American Society for Bone and Mineral Research.
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The Combined Effect of High Ambient Temperature and Antihypertensive Treatment on Renal Function in Hospitalized Elderly Patients.
Sagy, I, Vodonos, A, Novack, V, Rogachev, B, Haviv, YS, Barski, L
PloS one. 2016;(12):e0168504
Abstract
BACKGROUND The aging kidney manifests structural, functional as well as pharmacological changes, rendering elderly patients more susceptible to adverse environmental influences on their health, dehydration in particular. HYPOTHESIS Higher temperature is associated with renal function impairment in patients 65 years and older who routinely take thiazide and/or ACE-inhibitors/ARBs. METHODS We obtained health data of patients older than 65 who were admitted to a large tertiary center during the years 2006-2011, with a previous diagnosis of hypertension, and treated with thiazide, ACE-inhibitors/ARBs or both. We collected environmental data of daily temperature, available from collaborative public and governmental institutions. In order to estimate the effect of daily temperature on renal function we performed linear mixed models, separately for each treatment group and creatinine change during hospital admission. RESULTS We identified 26,286 admissions for 14, 268 patients with a mean age of 75.6 (±6.9) years, of whom 53.6% were men. Increment in daily temperature on admission of 5°C had significant effect on creatinine increase in the no treatment (baseline creatinine adjusted 0.824 mg/dL, % change 1.212, % change 95% C.I 0.082-2.354) and dual treatment groups (baseline creatinine adjusted 1.032mg/dL, % change 3.440, % change 95% C.I 1.227-5.700). Sub-analysis stratified by advanced age, chronic kidney disease and primary diagnosis on hospital admission, revealed a significant association within patients admitted due to acute infection and treated with dual therapy. CONCLUSION Whereas previous studies analyzed sporadic climate effects during heat waves and/or excluded older population taking anti-hypertensive medications, the present study is novel by showing a durable association of temperature and decreased renal function specifically in elderly patients taking anti-hypertensive medications.
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Long-term effects of incident diabetes mellitus on cardiovascular outcomes in people treated for hypertension: the ALLHAT Diabetes Extension Study.
Barzilay, JI, Davis, BR, Pressel, SL, Cutler, JA, Einhorn, PT, Black, HR, Cushman, WC, Ford, CE, Margolis, KL, Moloo, J, et al
Circulation. Cardiovascular quality and outcomes. 2012;(2):153-62
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Abstract
BACKGROUND Thiazide-type diuretics are associated with an increased incidence of diabetes compared with other antihypertensive medications. In this study, we determined the long-term cardiovascular disease (CVD) consequences of incident diuretic-associated diabetes compared with the effects of incident diabetes associated with calcium channel blocker and angiotensin-converting enzyme inhibitor use. METHODS AND RESULTS A total of 22 418 participants from the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) with baseline diabetes, incident diabetes (7.5% with chlorthalidone, 5.6% with amlodipine, and 4.3% with lisinopril), or no diabetes at 2 years of in-trial follow-up were followed for a mean total of 6.9 years (2.9 years in-trial and 4 additional years posttrial) through the use of national databases. The primary outcome was CVD mortality (death from coronary heart disease [CHD], stroke, heart failure, or other CVD). Among other outcomes were all-cause mortality, non-CVD mortality, and CHD (nonfatal myocardial infarction or fatal CHD). Participants on chlorthalidone with incident diabetes versus no diabetes had consistently lower, nonsignificant risk for CVD mortality (hazard ratio [HR], 1.04; 95% CI, 0.74-1.47), all-cause mortality (HR, 1.04; 95% CI, 0.82-1.30), and non-CVD mortality (HR, 1.05; 95% CI, 0.77-1.42) than participants on amlodipine or lisinopril with incident diabetes (HR range, 1.22-1.53). Participants with incident diabetes had elevated CHD risk compared with those with no diabetes (HR, 1.46; 95% CI, 1.09-1.96), but those on chlorthalidone had significantly lower risk than those on lisinopril (HR, 1.18 versus 2.57; P=0.04 for interaction). CONCLUSIONS The findings suggest that thiazide-related incident diabetes has less adverse long-term CVD impact than incident diabetes that develops while on other antihypertensive medications.
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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.
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Left ventricular (LV) geometry and dipping state are determinants of LV mass reduction with angiotensin-converting enzyme inhibitor antihypertensive treatment.
Aznaouridis, KA, Vyssoulis, GP, Karpanou, EA, Marinakis, AG, Barbetseas, JD, Zervoudaki, AI, Cokkinos, DV, Stefanadis, CI
Blood pressure monitoring. 2007;(2):87-94
Abstract
OBJECTIVES Left ventricular hypertrophy is a major risk predictor in hypertensive patients and its regression is beneficial in terms of prognosis. The aim of this observational, open-labeled study was to investigate the effect of left ventricular geometry and dipping pattern on left ventricular mass reduction after chronic treatment with angiotensin-converting enzyme inhibitors, in a large population of hypertensive patients. METHODS We evaluated untreated patients with mild to moderate essential hypertension, before and 6 months after treatment with angiotensin-converting enzyme inhibitor monotherapy or angiotensin-converting enzyme inhibitor-low-dose thiazide combination. Left ventricular mass index, relative wall thickness and geometry pattern were derived from echocardiography. Dipping state was determined with 24-h ambulatory blood pressure monitoring at enrollment. RESULTS Overall, left ventricular mass index decrease in the 1400 patients (mean age 52.5 years) who completed the study was 12.9% of baseline value (P<0.00001). After adjusting for pretreatment value, left ventricular mass index reduction was similar with all angiotensin-converting enzyme inhibitors used [P= NS (not significant)], but it was higher in nondippers than dippers (14.1 vs. 12.3%, P<0.0001) and in patients with than without baseline left ventricular hypertrophy (14.6 vs. 11.3%, P<0.0001). We observed a stepwise augmentation of left ventricular mass index decrease with worsening left ventricular geometry (P<0.001). In multivariable analysis, impaired left ventricular geometry and blunted nocturnal blood pressure fall before treatment were independent predictors of a high left ventricular mass index reduction after treatment, independent of blood pressure fall, pretreatment left ventricular mass index, and other potential confounders. CONCLUSION In essential hypertension, left ventricular geometry and dipping state are independent determinants of left ventricular mass reduction with angiotensin-converting enzyme inhibitor treatment. All angiotensin-converting enzyme inhibitors are efficient in decreasing left ventricular mass.
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Thiazide diuretics enhance nocturnal blood pressure fall and reduce proteinuria in immunoglobulin A nephropathy treated with angiotensin II modulators.
Uzu, T, Harada, T, Namba, T, Yamamoto, R, Takahara, K, Yamauchi, A, Kimura, G
Journal of hypertension. 2005;(4):861-5
Abstract
OBJECTIVE We examined whether thiazide diuretics could restore nocturnal blood pressure (BP) decline and reduce urinary protein excretion in patients with glomerulopathy treated with angiotensin II modulators (angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers). METHODS Twenty-five Japanese outpatients (11 men, 14 women; mean age 43 +/- 12 years) with biopsy-proven immunoglobulin (Ig)A nephropathy, preserved renal function (serum creatinine concentration ≤1.2 mg/dl), stable non-nephrotic proteinuria (0.5-3 g daily), and treatment with angiotensin II modulators were studied. The patients received a diuretic, trichlormethiazide (2 mg daily) for 4 weeks after a baseline period lasting for 4 weeks. RESULTS Diuretic therapy significantly reduced conventional, 24-h, daytime and night-time blood pressures. Nocturnal blood pressure fall was significantly enhanced by diuretic therapy and a significant interaction existed between diuretic therapy and nocturnal fall in mean arterial pressure, which indicated that the degree of nocturnal blood pressure fall was affected by diuretic therapy. The urinary protein excretion rate was significantly reduced from 1.10 +/- 0.62 to 0.63 +/- 0.39 g/day by diuretic therapy. Diuretic/baseline ratio of urinary protein excretion rate was not correlated with diuretic/baseline ratio of conventional, 24-h and daytime mean arterial pressures, but with diuretic/baseline ratio of night-time mean arterial pressure (r = 0.54, P = 0.006). CONCLUSIONS Diuretics enhanced nocturnal BP decline and reduced urinary protein excretion in patients with IgA nephropathy treated with angiotensin II modulators. The combination of angiotensin II modulators and diuretics may have additional therapeutic advantages in relieving the renal and cardiovascular risks by reducing nocturnal high blood pressure.
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[The treatment of coronary heart disease by beta-adrenoblockers or tiazide diuretics preparation in combination with vegetarian diet].
Medkova, IL, Ieromuzo, AA, Ivanov, AN, Mosiakina, LI, Biriukova, LS
Voprosy pitaniia. 2005;(3):39-41
Abstract
Work make on 84 patients with coronare heart diseases were divided into two groups, equal quantity. The first groups were given athenolol (50 mg daily), the second--hypotiazide (25 mg daily). In every groupspart patients received an antiatherogenic lactoovovegetetarian diet, part--an standard antiatherogenic diet 10c. Time observation--24 daily. By the end of the treatment period with athenolol in backoground the vegetarian diet the level of total cholesterol decreased by 16%, low-density lipoproteins cholesterol decreased by 18%. In groups patients received an standard antiatherogenic diet these parameters practically did'nt change. In the vegetarian group the atherogenic coefficient (KA) decreased by 31%., while in the patients on standard antiatherogenic diet KA showed only a tendency for decreasing. By the end to the treatment period with hypotiazide the slight decrease in total cholesterol, KA levels and a slight increase in HDL cholesterol were observed only the vegetarian group.
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Efficacy of tadalafil in the treatment of erectile dysfunction in hypertensive men on concomitant thiazide diuretic therapy.
Kloner, RA, Sadovsky, R, Johnson, EG, Mo, D, Ahuja, S
International journal of impotence research. 2005;(5):450-4
Abstract
Many men with erectile dysfunction (ED) have hypertension as a comorbid condition. Recent guidelines recommend thiazide diuretics as first-line therapy for hypertension. We analyzed data from 14 randomized, double-blind, placebo-controlled trials (N=2501) to evaluate the efficacy of tadalafil 20 mg for the treatment of ED in men on thiazides. Of the 2501 patients, 163 were on concomitant thiazides (116 tadalafil/47 placebo) and 159 (98%) were reported to have hypertension. The primary efficacy measures were mean change from baseline in the international index of erectile function (IIEF) erectile function (EF) domain and the proportion of 'yes' responses to sexual encounter profile (SEP) Questions 2 and 3. The tadalafil group showed a significantly (P<0.001) greater mean baseline to endpoint improvement on all efficacy outcome measures compared to placebo-treated patients regardless of concomitant thiazide use. More importantly, the responses to tadalafil were similar regardless of concomitant thiazide use. Additionally, responses to tadalafil were comparable between thiazide and nonthiazide users regardless of baseline ED severity (P>0.05).
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Comparison of effects of exercise and diuretic on left ventricular geometry, mass, and insulin resistance in older hypertensive adults.
Rinder, MR, Spina, RJ, Peterson, LR, Koenig, CJ, Florence, CR, Ehsani, AA
American journal of physiology. Regulatory, integrative and comparative physiology. 2004;(2):R360-8
Abstract
To compare the effects of exercise training and hydrochlorothiazide on left ventricular (LV) geometry and mass, blood pressure (BP), and hyperinsulinemia in older hypertensive adults, we studied 28 patients randomized either to a group (age 66.4 +/- 1.3 yr; n = 16) that exercised or to a group (age 65.3 +/- 1.2 yr; n = 12) that received hydrochlorothiazide for 6 mo. Endurance exercise training induced a 15% increase in peak aerobic power. The reduction in systolic BP was twofold greater with thiazide than with exercise (26.6 +/- 12.2 vs. 11.5 +/- 10.9 mmHg). Exercise and thiazide reduced LV wall thickness, LV mass index (14% in each group), and the LV wall thickness-to-radius ratio (h/r) similarly (exercise: before 0.48 +/- 0.2, after 0.42 +/- 0.01; thiazide: before 0.47 +/- 0.04, after 0.40 +/- 0.04; P = 0.017). The reductions in systolic BP and h/r were correlated in the exercise group (r = 0.70, P = 0.005) but not in the thiazide group. Exercise training reduced glucose-stimulated hyperinsulinemia (before: 13.65 +/- 2.6 vs. 9.84 +/- 1.5 mU.ml(-1).min; P = 0.04) and insulin resistance. Thiazide did not affect plasma insulin levels. The results suggest that although exercise is less effective in reducing systolic BP than thiazide, it can induce regression of LV hypertrophy similar in magnitude to thiazide. Unlike hydrochlorothiazide, exercise training can improve insulin resistance and aerobic capacity in older hypertensive people.