Hydrochlorothiazide Treatment Research Articles

Ablation of the Cl-/HCO3- Exchanger Pendrin Enhances Hydrochlorothiazide-Induced Diuresis

Background/Aims: The Cl^-/HCO₃^- exchanger pendrin and the thiazide-sensitive Na-Cl cotransporter NCC are expressed in the kidney distal nephron and mediate salt absorption. We hypothesized that deletion of pendrin leaves NCC as the major salt absorbing transporter in the distal nephron and therefore enhances salt excretion by hydrochlorothiazide (HCTZ). Methods: Metabolic cage studies were performed in wild type, pendrin KO and NCC KO mice at baseline and following HCTZ treatment. In parallel studies, systemic blood pressure was measured in mice treated with HCTZ with the tail cuff method. Results: Urine output, salt excretion and water intake were comparable in all groups under baseline condition. Urine output and water intake increased significantly only in pendrin KO mice in response to HCTZ, but not in WT or NCC KO mice. Sodium and chloride excretion increased in HCTZ-treated pendrin KO mice, but they remained unchanged in WT or NCC KO mice. Pendrin KO mice treated with HCTZ developed volume depletion, as determined by increased expression of renin mRNA and protein. The expression of ENaC and pendrin increased in HCTZ-treated WT mice. HCTZ treatment did not significantly modify blood pressure in any of the experimental group. Conclusion: The ablation of the Cl^-/HCO₃^- exchanger Pendrin enhances the magnitude of salt wasting by HCTZ.

Targeted Knockin of Constitutively Active SPAK (CA‐SPAK) in the Early Distal Convoluted Tubule (DCT1) Causes Hyperkalemic Hypertension

Familial Hyperkalemic Hypertension (FHHt) is caused by aberrant gain in WNK function, leading to elevate blood pressure via hyperactivation of the thiazide‐sensitive sodium chloride co‐transporter (NCC) in DCT. Altered potassium homeostasis (hyperkalemia) is also observed in FHHt and attributed to reduced ROMK mediated potassium secretion. Two mechanisms are thought to contribute to attenuated kaliuresis in FHHt: 1) Increased phospho‐activation of NCC via the WNK‐SPAK signaling cascade results in limited sodium availability for electrogenic potassium secretion in the connecting tubule and cortical collecting duct (CNT and CCD); 2) increased ROMK endocytosis induced via the WNK‐Erk5‐ARH pathway in the CNT and CCD. The relative contribution of these two pathways in limiting potassium secretion is unclear. Here, we explore if constitutive activation of SPAK (CA‐SPAK) in the DCT1 is sufficient to drive hyperphosphorylation of NCC, can phenocopy FHHt (hypertension and hyperkalemia). Knockin‐CA‐SPAK (CA‐SPAK KI) lox/lox mice were created by inserting a SPAK phosphomimetic mutant (T243E and S383D) between LoxP sites in the first exon of the SPAK gene. To drive DCT1‐specific expression of CA‐SPAK in the kidney, mice expressing Cre‐recombinase under the parvalbumin promoter were crossed with the CA‐SPAK KI lox/lox mice. The phenotypes of DCT‐specific CA‐SPAK KI were compared to matched wild‐type (WT) controls. As observed by immunofluorescent confocal microscopy, CA‐SPAK is specifically targeted to parvalbumin positive tubules in CA‐SPAK KI, consistent with DCT1‐specific expression. CA‐SPAK KI display significantly more total and phosphorylated NCC (T58) than WT even though the abundance of CA‐SPAK protein was slightly less than SPAK in WT, verifying the constitutively active nature of the knockin. Telemetric blood pressure (BP) measurements revealed CA‐SPAK KI are hypertensive despite low renin activity. The BP of KI mice is further elevated by a high salt diet, but is normalized to WT levels by hydrochlorothiazide (HCTZ). CA‐SPAK KI display metabolic acidosis, hyperkalemia, and a diminished capacity to secret potassium, which are all remediated by HCTZ. These results suggest increasing sodium delivery to the CNT and CCD is sufficient to ameliorate hyperkalemia. However, further investigation via confocal microscopy in conjunction with morphometric analysis indicates CA‐SPAK KI mice have a structural contraction in the CNT that is matched by an expansion of the DCT1, consistent with other FHHt animal models. Additionally, significant down‐regulation of ROMK is observed via western blot analysis in CA‐SPAK KI, which is nearly normalized to WT levels following 3 days of HCTZ. In summary: 1) DCT1 expression of CA‐SPAK KI phenocopies FHHt, underscoring the chief role NCC activation plays in the pathogenesis of the disease; 2) Normalization of ROMK expression and plasma potassium levels in CA‐SPAK KI following HCTZ treatment suggests an anti‐kaliuretic process may be activated in FHHt, but is inhibited during HCTZ treatment.Support or Funding InformationDK093501, DK063049, DK54231

Hydrochlorothiazide Potentiates Contractile Activity of Mouse Cavernosal Smooth Muscle.

IntroductionHydrochlorothiazide has a negative influence on penile erection but little is known about the mechanism(s) involved.AimsTo characterize the effects of this diuretic on mouse corpus cavernosum (CC) smooth muscle in vitro and ex vivo.MethodsCC strips of C57BL/6 mice (12–16 weeks old) were mounted in organ baths containing Krebs-Henseleit solution and tissue reactivity was evaluated. Expression of genes encoding diuretic targets and enzymes involved in penile erection were evaluated by polymerase chain reaction.Main Outcome MeasuresStimulation-response curves to phenylephrine (10 nmol/L–100 μmol/L) or to electrical field stimulation (1–32 Hz) were constructed, with or without hydrochlorothiazide. Strips of CC from mice after long-term hydrochlorothiazide treatment (6 mg/kg/day for 4 weeks) with or without amiloride (0.6 mg/kg/day for 4 weeks) in vivo also were studied. Nitric oxide and Rho-kinase pathways were evaluated.ResultsHydrochlorothiazide (100 μmol/L) increased the maximum response to phenylephrine by 64% in vitro. This effect was unaffected by the addition of indomethacin (5 μmol/L) but was abolished by N(ω)-nitro-L-arginine methyl ester (100 μmol/L). Hydrochlorothiazide (100 μmol/L) potentiated electrical field stimulation-induced contraction in vitro, but not ex vivo. Long-term treatment with hydrochlorothiazide increased the maximum response to phenylephrine by 60% and resulted in a plasma concentration of 500 ± 180 nmol/L. Amiloride (100μmol/L) caused rightward shifts in concentration-response curves to phenylephrine in vitro. Long-term treatment with hydrochlorothiazide plus amiloride did not significantly increase the maximum response to phenylephrine (+13%). Reverse transcriptase polymerase chain reaction did not detect the NaCl cotransporter in mouse CC. Hydrochlorothiazide did not change Rho-kinase activity, whereas amiloride decreased it in vitro and ex vivo (approximately 18% and 24% respectively). A 40% decrease in Rock1 expression also was observed after long-term treatment with hydrochlorothiazide plus amiloride.ConclusionHydrochlorothiazide potentiates contraction of smooth muscle from mouse CC. These findings could explain why diuretics such as hydrochlorothiazide are associated with erectile dysfunction.

Urine Calcium and Bone Mineral Density in Calcium Stone-Forming Patients Treated with Alendronate and Hydrochlorothiazide

Introduction: The objective was to evaluate the effect of hydrochlorothiazide and alendronate on urine calcium and bone mineral density in calcium stone-forming patients. Material and Methods: A prospective, non-randomized, non-observational comparative study was performed; this study included 111 patients with recurrent calcium stones, divided into 3 groups according to the treatment received. Group 1: 36 patients were treated with alendronate, 70 mg/week; Group 2: 34 patients were treated with alendronate, 70 mg/week + hydrochlorothiazide, 50 mg/day; Group 3: 41 patients were treated with hydrochlorothiazide, 50 mg/day. All patients received recommendations on diet and fluid intake. Other variables of bone mineral density were studied and analyzed, including bone remodeling markers and urinary calcium before and after 2 years of treatment. The statistical analysis was performed using the SPSS 17.0 program, with a statistical significance of p < 0.05. Results: After 2 years of treatment, a significant difference was observed in the β-crosslaps and a bone mineral density improvement in Group 1, along with a decrease in urinary calcium. In Group 3, a statistically significant difference was found in urinary calcium and fasting calcium/creatinine ratio, as well as an improvement in bone mineral density after 2 years of medical treatment. In Group 2 patients treated with the combination, there was an improvement in bone mineral density and a decrease in the β-crosslaps marker similar to patients in Group 1, and a decrease in urinary calcium similar to those in Group 3. Conclusion: Combined alendronate + hydrochlorothiazide treatment offers the best results along with the improvement in bone mineral density and decrease in urine calcium in patients with recurrent calcium stones.

Pharmacogenomic Genome-Wide Meta-Analysis of Blood Pressure Response to β-Blockers in Hypertensive African Americans.

African Americans suffer a higher prevalence of hypertension compared with other racial/ethnic groups. In this study, we performed a pharmacogenomic genome-wide association study of blood pressure (BP) response to β-blockers in African Americans with uncomplicated hypertension. Genome-wide meta-analysis was performed in 318 African American hypertensive participants in the 2 Pharmacogenomic Evaluation of Antihypertensive Responses studies: 150 treated with atenolol monotherapy and 168 treated with metoprolol monotherapy. The analysis adjusted for age, sex, baseline BP and principal components for ancestry. Genome-wide significant variants with P<5×10(-8) and suggestive variants with P<5×10(-7) were evaluated in an additional cohort of 141 African Americans treated with the addition of atenolol to hydrochlorothiazide treatment. The validated variants were then meta-analyzed in these 3 groups of African Americans. Two variants discovered in the monotherapy meta-analysis were validated in the add-on therapy. African American participants heterozygous for SLC25A31 rs201279313 deletion versus wild-type genotype had better diastolic BP response to atenolol monotherapy, metoprolol monotherapy, and atenolol add-on therapy: -9.3 versus -4.6, -9.6 versus -4.8, and -9.7 versus -6.4 mm Hg, respectively (3-group meta-analysis P=2.5×10(-8), β=-4.42 mm Hg per variant allele). Similarly, LRRC15 rs11313667 was validated for systolic BP response to β-blocker therapy with 3-group meta-analysis P=7.2×10(-8) and β=-3.65 mm Hg per variant allele. In this first pharmacogenomic genome-wide meta-analysis of BP response to β-blockers in African Americans, we identified novel variants that may provide valuable information for personalized antihypertensive treatment in this group.

Hypertension subtypes modify metabolic response to thiazide diuretics.

Blood pressure (BP) and metabolic response to thiazide diuretics might be varied in patients with different hypertension subtypes and ethnicities. This study aimed to investigate the response of BP and metabolic profiles to short-term thiazide treatment in an Asian cohort with different hypertension subtypes. Serial ethnic Chinese nondiabetic subjects with hypertension were evaluated. After diet instruction and lifestyle modification for 2 weeks, patients who still had elevated systolic BP (SBP≥140 mmHg) and/or diastolic BP (DBP≥90 mmHg) were given 50 mg of hydrochlorothiazide daily for 2 weeks. The responses of BP and metabolic profiles were evaluated before and after treatment according to the patient's baseline BP subtype - isolated systolic hypertension (ISH), systo-diastolic hypertension (SDH) and isolated diastolic hypertension (IDH). Hydrochlorothiazide treatment significantly reduced the BP in all 92 patients (62 males, aged 45·7 ± 9·6 years), irrespective of their baseline BP subtypes. In patients with SDH (n = 39) or IDH (n = 40), hydrochlorothiazide treatment significantly increased serum adiponectin (P = 0·001 and 0·007, respectively) and reduced asymmetric dimethylarginine levels (P < 0·001, in both groups). Serum cholesterol (P = 0·027) and fasting blood sugar levels (P = 0·044) were significantly improved only in the IDH patients. Furthermore, IDH was independently associated with changes in fasting blood sugar (β = -11·178, P = 0·022) and cholesterol (β = -22·654, P = 0·027). The characteristics of the Asian hypertensive patients with diastolic hypertension can present a favourable metabolic response to the short-term hydrochlorothiazide treatment. The potential positive effect on cardiovascular risk should be validated in long-term studies in this diastolic type of hypertension.

Pharmacometabolomic Assessments of Atenolol and Hydrochlorothiazide Treatment Reveal Novel Drug Response Phenotypes.

Achieving hypertension (HTN) control and mitigating the adverse health effects associated with HTN continues to be a global challenge. Some individuals respond poorly to current HTN therapies, and mechanisms for response variation remain poorly understood. We used a nontargeted metabolomics approach (gas chromatography time-of-flight/mass spectrometry gas chromatography time-of-flight/mass spectrometry) measuring 489 metabolites to characterize metabolite signatures associated with treatment response to anti-HTN drugs, atenolol (ATEN), and hydrochlorothiazide (HCTZ), in white and black participants with uncomplicated HTN enrolled in the Pharmacogenomic Evaluation of Antihypertensive Responses study. Metabolite profiles were significantly different between races, and metabolite responses associated with home diastolic blood pressure (HDBP) response were identified. Metabolite pathway analyses identified gluconeogenesis, plasmalogen synthesis, and tryptophan metabolism increases in white participants treated with HCTZ (P < 0.05). Furthermore, we developed predictive models from metabolite signatures of HDBP treatment response (P < 1 × 10(-5)). As part of a quantitative systems pharmacology approach, the metabolites identified herein may serve as biomarkers for improving treatment decisions and elucidating mechanisms driving HTN treatment responses.

Effects of hydrochlorothiazide on oxidative stress and pulse pressure in hypertensive patients with chronic stroke: the EMINENT study.

Thiazide diuretics are reported to have antioxidant effects and reduce pulse pressure (PP). The aim of this study was to elucidate whether hydrochlorothiazide additionally exerts such effects in stroke patients under treatment with losartan. This study was an open-label, randomized, multicenter study. Patients with a history of chronic stroke and treatment with angiotensin receptor blockers or angiotensin-converting enzyme inhibitors for essential hypertension were enrolled. Fifty-five hypertensive patients were randomly assigned to two groups: those further treated with hydrochlorothiazide and those further treated with non-diuretic antihypertensive drugs. Both groups showed a significant decrease in PP over six months (hydrochlorothiazide group: 67±12 mmHg to 58±12, p<0.001; non-diuretic group: 72±12 to 61±12, p<0.001), although no significant differences were observed between the two groups. The malondialdehyde-modified low-density lipoprotein levels did not change significantly after treatment in either group. In this study, hydrochlorothiazide treatment did not provide any additional benefits over non-diuretic antihypertensive drugs in terms of antioxidant effects or reducing PP.

The Sonographic Appearance of Podagra in Gout

©2014 Turkish League Against Rheumatism. All rights reserved. A 49-year-old man was admitted to our clinic with pain, acute-onset swelling, and local erythema in his right big toe. He was under valsartan hydrochlorothiazide treatment for hypertension. The medical history was non-specific. He did have no constitutional symptoms such as morning stiffness, fatigue and fever. Physical examination revealed swelling, local erythema (Figure 1a) and pain on palpation of the right big toe. Serum C-reactive protein level was 14.6 mg/L (normal range: <10), and uric acid level was 10.1 mg/dl (normal range: 3.5-7.2). Complete blood count, erythrocyte sedimentation rate, blood urea nitrogen and creatinine levels were within normal limits. While foot radiograph was unremarkable (Figure 1b), ultrasonography showed sugar cluster appearance and effusion with increased power Doppler activity (Figure 1c, d). Monosodium urate crystals were detected in synovial fluid aspiration, and the patient was diagnosed with gout. Oral colchicine 1 mg/d and diclofenac sodium 150 mg/d were commenced. Valsartan hydrochlorothiazide was changed to valsartan, and amlodipine was added for hypertension treatment. Uric acid poor diet and hydration were also recommended. Uric acid levels were 9.1 and 7.1 mg/dl at the first and sixth month controls, respectively. A significant improvement in the swelling was detected on physical examination (Figure 2a). On the other hand, ultrasonography showed erosion of the proximal phalanx (Figure 2b).

CLINICAL EFFICIENCY AND INFLUENCE OF COMBINED ANTIHYPERTENSIVE THERAPY UPON CYTOKINE PROFILE IN THE PATIENTS WITH ARTERIAL HYPERTENSION

Abstract. We have evaluated effects of combined anti-hypertensive therapy upon the indexes of proinflammatory cytokines and clinical aspects of chronic heart failure among the patients suffering from essential hypertension (stages II-III, high and very high risk groups). The first group (n = 45) was treated with Enalapril + Hydrochlorothiazide, while the second group (n = 41) received Enalapril + Indapamide. Before starting the therapy, a pro-inflammatory cytokinemia was revealed, followed by a significant decrease of IL-6 and TNFαα levels in patients of the first group (p < 0,01), after two weeks of hospital treatment. During combined therapy, showed a sufficient decrease in systolic, diastolic and mean blood pressure levels for the both groups. A more pronounced regression of the mean blood pressure level was detected under Enalapril + Hydrochlorothiazide treatment (p < 0.002), accompanied by clinical improvement of chronic heart failure according to the clinical conditions rating scale (p < 0,001). Due to the correction of the systolic blood pressure level, all the patients showed a decrease in fatal risk of cardiovascular complications: they have left a high-risk group (5 to 10% SCORE) for a low risk group (< 5 % SCORE).

Efficacy of Hydrochlorothiazide and low renal solute feed in Neonatal Central Diabetes Insipidus with transition to Oral Desmopressin in early infancy.

BackgroundThe treatment of central diabetes insipidus (DI) with desmopressin in the neonatal period is challenging because of the significant risk of hyponatremia with this agent. The fixed anti-diuresis action of desmopressin and the obligate high fluid intake with milk feeds lead to considerable risk of water intoxication and hyponatremia. To reduce this risk, thiazide diuretics, part of the treatment of nephrogenic DI, were used in conjunction with low renal solute feed and were effective in a single case series of neonatal central DI.Aim We evaluated the efficacy of early treatment of neonatal central DI with hydrochlorothiazide with low solute feed and investigated the clinical indicators for transition to desmopressin during infancy.MethodsA retrospective chart review was conducted at Princess Margaret Hospital, Perth of neonates diagnosed with central DI and treated with hydrochlorothiazide, between 2007 and 2013. Four newborns were identified. Mean sNa and mean change in sNa with desmopressin and hydrochlorothiazide treatment were recorded along with episodes of hyponatremia and hypernatremia. Length and weight trajectories during the first 12 months were assessed.ResultsThe mean change in sNa per day with hydrochlorothiazide and low renal solute feed was 2.5 - 3 mmol/L; on desmopressin treatment, the mean change in sNa was 6.8-7.9 mmol/L. There was one episode of symptomatic hyponatremia with intranasal desmopressin with no episodes of hyponatremia or hypernatremia during treatment with hydrochlorothiazide or following transition to oral desmopressin. Transition to oral desmopressin between 3 to 12 months of age was associated with good control of DI. Following introduction of solids, sNa remained stable but weight gain was slow. This improved following transition to desmopressin in one infant.ConclusionsHydrochlorothiazide with low renal solute feed is a safe and effective treatment option in neonatal central DI. However, transition to desmopressin should be considered early in infancy following initiation of solids to facilitate growth.

Effects of Hydrochlorothiazide on the Pharmacokinetics, Pharmacodynamics, and Tolerability of Canagliflozin, a Sodium Glucose Co-transporter 2 Inhibitor, in Healthy Participants

BackgroundMany patients with type 2 diabetes mellitus (T2DM) also have hypertension, which is commonly treated with thiazide diuretics, including hydrochlorothiazide (HCTZ). Canagliflozin, a sodium glucose cotransporter 2 inhibitor developed for the treatment of T2DM, lowers plasma glucose by inhibiting renal glucose reabsorption, thereby increasing urinary glucose excretion and mild osmotic diuresis. Because patients with T2DM are likely to receive concurrent canagliflozin and HCTZ, potential interactions were evaluated. ObjectiveThis study evaluated the effects of HCTZ on the pharmacokinetic and pharmacodynamic properties and tolerability of canagliflozin in healthy participants. MethodsThis Phase I, single-center, open-label, fixed-sequence, 2-period study was conducted in healthy participants. During period 1, participants received canagliflozin 300 mg once daily for 7 days, followed by a 14-day washout period. During period 2, participants received HCTZ 25 mg once daily for 28 days, followed by canagliflozin 300 mg + HCTZ 25 mg once daily for 7 days. Blood samples were taken before and several times after administration on day 7 of period 1 and on days 28 and 35 of period 2 for canagliflozin and HCTZ pharmacokinetic analyses using LC-MS/MS. Blood and urine samples were collected for up to 24 hours after canagliflozin administration on day 1 of period 1 and day 35 of period 2 for pharmacodynamic glucose assessment. Tolerability was also evaluated. ResultsThirty participants were enrolled (16 men, 14 women; all white; mean age, 43.7 years). Canagliflozin AUC during a dosing interval (T) at steady state (AUCτ,ss) and Cmax at steady state (Cmax,ss) were increased when canagliflozin was coadministered with HCTZ, with geometric mean ratios (90% CI) of 1.12 (1.08–1.17) and 1.15 (1.06–1.25), respectively. AUCτ,ss and Cmax,ss for HCTZ were similar with and without canagliflozin coadministration. The 24-hour mean renal threshold for glucose and mean plasma glucose were comparable for canagliflozin alone and coadministered with HCTZ. The change in 24-hour urine volume from baseline was −0.1 L with canagliflozin alone and 0.4 L with HCTZ alone and with canagliflozin + HCTZ. The overall incidence of adverse events (AEs) was higher with canagliflozin + HCTZ (69%) than with canagliflozin (47%) or HCTZ (50%) alone; most AEs were of mild severity. Overall, minimal changes in serum electrolytes (eg, sodium, potassium) were observed after coadministration of canagliflozin + HCTZ compared with individual treatments. ConclusionsAdding canagliflozin treatment to healthy participants on HCTZ treatment had no notable pharmacokinetic or pharmacodynamic effects; canagliflozin coadministered with HCTZ was generally well tolerated, with no unexpected tolerability concerns. ClinicalTrials.gov identifier: NCT01294631.

Genetic predictors of thiazide-induced serum potassium changes in nondiabetic hypertensive patients

Thiazide diuretics are associated with an increased risk of hypokalemia. However, pharmacogenetic markers of thiazide-induced changes in serum potassium are not well studied. The aim of this study was to investigate possible predictors of serum potassium changes after thiazide treatment. Nondiabetic hypertensive patients with a systolic blood pressure of ⩾140 or a diastolic blood pressure of ⩾90 mm Hg were enrolled in our study. After 2 weeks of lifestyle modification and diet instruction, patients with persistently elevated blood pressure were given 50 mg of hydrochlorothiazide every morning for 2 weeks. Twenty single-nucleotide polymorphism (SNP) markers were selected from two candidate genes, SLC12A3 and WNK1. Serum potassium levels were checked before and after hydrochlorothiazide treatment. A total of 75 patients eventually qualified for enrollment in our study. They received 50 mg of hydrochlorothiazide every morning for 2 weeks. Six SNPs in WNK1 (rs11064524, rs4980973, rs12581940, rs880054, rs953361, and rs10849582) were correlated with decreases in serum potassium. None of the SLC12A3 polymorphisms were correlated with decreases in serum potassium. After Bonferroni's correction, only rs4980973 was correlated with decreases in serum potassium (corrected P=0.014). Multivariate stepwise linear regression analysis revealed that the changes in serum potassium levels were independently associated with the baseline potassium level (β=-0.587, 95% confidence interval=-0.875--0.299, P=0.0001) and WNK1 rs4980973 (A/A and A/G vs. G/G, β=-0.418, 95% confidence interval=-0.598--0.237, P=0.00002). In conclusion, the baseline potassium level and the WNK1 rs4980973 polymorphism were independent predictors of decreases in serum potassium after short-term hydrochlorothiazide treatment in nondiabetic hypertensive patients.

Effects of sodium restriction and hydrochlorothiazide on RAAS blockade efficacy in diabetic nephropathy: a randomised clinical trial

Reduction of dietary sodium intake or diuretic treatment increases renin-angiotensin-aldosterone system (RAAS) blockade efficacy in non-diabetic nephropathy. We aimed to investigate the effect of sodium restriction and the diuretic hydrochlorothiazide, separately and in combination, added to RAAS blockade on residual albuminuria in patients with type 2 diabetic nephropathy. In this multicentre, double-blind, placebo-controlled, crossover randomised trial, we included patients with type 2 diabetic nephropathy. Main entry criteria were microalbuminaria or macroalbuminuria, and creatinine clearance of 30 mL/min or higher with less than 6 mL/min decline in the previous year. We tested the separate and combined effects of sodium restriction (dietary counselling in the outpatient setting) and hydrochlorothiazide (50 mg daily), added to standardised maximal angiotensin-converting enzyme (ACE) inhibition (lisinopril 40 mg daily), on albuminuria (primary endpoint). Patients were given hydrochlorothiazide (50 mg per day) or placebo during four treatment periods of 6 weeks. Both treatments were combined with regular sodium diet or sodium restriction (target sodium intake 50 mmol Na(+) per day). The 6-week treatment periods were done consecutively in a random order. Patients were randomised in blocks of two patients. The trial was analysed by intention to treat. The trial is registered with TrialRegister.nl, number 2366. Of 89 eligible patients, 45 were included in the study. Both sodium restriction and hydrochlorothiazide significantly reduced albuminuria, irrespective of treatment sequence. Residual geometric mean albuminuria with baseline treatment was 711 mg per day (95% CI 485-1043); it was significantly reduced by sodium restriction (393 mg per day [258-599], p=0·0002), by hydrochlorothiazide (434 mg per day [306-618], p=0·0003), and to the greatest extent by their combination (306 mg per day [203-461], p<0·0001). Orthostatic complaints were present in two patients (4%) during baseline treatment, five (11%) during addition of sodium restriction, five (11%) during hydrochlorothiazide treatment, and 12 (27%) during combination treatment. No serious adverse events occurred. We conclude that sodium restriction is an effective non-pharmacological intervention to increase RAAS blockade efficacy in type 2 diabetic nephropathy. None.

Treatment with telmisartan/rosuvastatin combination has a beneficial synergistic effect on ameliorating Th17/Treg functional imbalance in hypertensive patients with carotid atherosclerosis

ObjectivesTo explore synergistic effect between angiotensin II receptor blockers (ARBs) and statins on Th17/Treg functional imbalance in hypertensive patients with carotid atherosclerosis. MethodsThis study was a 2×2 factorial randomized, prospective, double-blind, placebo-controlled trial. One hundred and fifty nine hypertensive patients with carotid atherosclerosis were randomized to the administration of control group, telmisartan group, rosuvastatin group, and combination group (telmisartan plus rosuvastatin) base on hydrochlorothiazide treatment. Carotid ultrasonography, parameters of Th17/Treg functional axis, interleukin (IL)-1β, IL-2, interferon (IFN)-γ, hypersensitive C-reactive protein (hsCRP), monocyte chemotactic protein (MCP)-1 were evaluated. ResultsBlood pressure level markedly reduced in four groups. There was significantly synergistic effect of combination of telmisartan with rosuvastatin on reducing carotid imtima-media thickness (IMT), Th17 cells frequency, IL-17, IL-6, IL-23, tumor necrosis factor (TNF)-α, expression of retinoic acid receptor-related orphan receptor (ROR)γt mRNA, Th17/Treg ratio, IL-1β, IL-2, IFN-γ, hsCRP, and MCP-1, and increasing Treg cells frequency, IL-10, transforming growth factor(TGF)-β1, and expression of forkhead/winged helix transcription factor (Foxp3) mRNA (all P<0.05). Change rate of IMT statistical positively related to descent rates of Th17 cells frequency, IL-17, IL-6, IL-23, TNF-α, expression of RORγt mRNA, Th17/Treg ratio, IL-1β, IL-2, IFN-γ, hsCRP, and MCP-1, and negatively related to increased rates of Treg frequency, IL-10, TGF-β1, and expression of Foxp3 mRNA, respectively (all P<0.05). ConclusionThere is a synergistic effect of combination of telmisartan with rosuvastatin on ameliorating Th17/Treg functional imbalance in hypertensive patients with carotid atherosclerosis.

Pharmacokinetic properties and bioequivalence of olmesartan medoxomil/hydrochlorothiazide in healthy Korean male subjects

Olmesartan medoxomil inhibits the vasoconstrictor effects of angiotensin II. Hydrochlorothiazide (HCTZ) promotes sodium excretion, resulting in a reduction of plasma volume and peripheral resistance. A combination of these agents is known to have a greater effect for the treatment of hypertension than monotherapy with either one of these components. To assess bioequivalence between fixed-dose combination of olmesartan medoxomil and hydrochlorothiazide (HCTZ) in healthy Korean subjects. 40 healthy Korean volunteers were randomized into two groups. After administration of a single dose of investigational products, blood samples were collected before study drug administration (baseline) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, and 36 hours after study drug administration. The plasma concentrations of olmesartan and HCTZ were measured by LC-MS/MS. The pharmacokinetic parameters were calculated, and the 90% confidence intervals (CIs) of the geometric mean ratio (test/reference) of the parameters were obtained by analysis of variance (ANOVA) on logarithmically transformed data. The corresponding 90% CIs for the geometric mean ratio of the test to reference drugs were 0.93 - 1.04, 0.93 - 1.04, and 0.95 - 1.10. For HCTZ treatments, the 90% CIs for the geometric mean ratio of test to reference drugs were 0.95 - 1.03 for AUClast, 0.96 - 1.03 for AUC∞, and 0.89 - 1.04 for Cmax. This study demonstrated that the test and reference products met the regulatory criteria assuming bioequivalence. Both formulations were safe and well tolerated, and there were no noteworthy differences in the safety profiles of the test and reference drugs.

Hydrochlorothiazide attenuates lithium-induced nephrogenic diabetes insipidus independently of the sodium-chloride cotransporter

Lithium is the most common cause of nephrogenic diabetes insipidus (Li-NDI). Hydrochlorothiazide (HCTZ) combined with amiloride is the mainstay treatment in Li-NDI. The paradoxical antidiuretic action of HCTZ in Li-NDI is generally attributed to increased sodium and water uptake in proximal tubules as a compensation for increased volume loss due to HCTZ inhibition of the Na-Cl cotransporter (NCC), but alternative actions for HCTZ have been suggested. Here, we investigated whether HCTZ exerted an NCC-independent effect in Li-NDI. In polarized mouse cortical collecting duct (mpkCCD) cells, HCTZ treatment attenuated the Li-induced downregulation of aquaporin-2 (AQP2) water channel abundance. In these cells, amiloride reduces cellular Li influx through the epithelial sodium channel (ENaC). HCTZ also reduced Li influx, but to a lower extent. HCTZ increased AQP2 abundance on top of that of amiloride and did not affect the ENaC-mediated transcellular voltage. MpkCCD cells did not express NCC mRNA or protein. These data indicated that in mpkCCD cells, HCTZ attenuated lithium-induced downregulation of AQP2 independently of NCC and ENaC. Treatment of Li-NDI NCC knockout mice with HCTZ revealed a significantly reduced urine volume, unchanged urine osmolality, and increased cortical AQP2 abundance compared with Li-treated NCC knockout mice. HCTZ treatment further resulted in reduced blood Li levels, creatinine clearance, and alkalinized urinary pH. Our in vitro and in vivo data indicate that part of the antidiuretic effect of HCTZ in Li-NDI is NCC independent and may involve a tubuloglomerular feedback response-mediated reduction in glomerular filtration rate due to proximal tubular carbonic anhydrase inhibition.

Impact of TCF7L2 single nucleotide polymorphisms on hydrochlorothiazide-induced diabetes

Thiazide diuretics have been associated with increased risk for new onset diabetes (NOD), but pharmacogenetic markers of thiazide-induced NOD are not well studied. Single nucleotide polymorphisms (SNPs) in the transcription factor 7-like 2 gene (TCF7L2) represent the strongest and most reproducible genetic associations with diabetes. We investigated the association of tag SNPs in TCF7L2 with thiazide-induced NOD. We identified cases that developed NOD and age, sex, and race/ethnicity-matched controls from the INternational VErapamil SR-Trandolapril STudy (INVEST). INVEST compared cardiovascular outcomes between two antihypertensive treatment strategies in ethnically diverse patients with hypertension and coronary artery disease. We genotyped 101 TCF7L2 tag SNPs and used logistic regression to test for pharmacogenetic (SNP×hydrochlorothiazide treatment) interactions. Permuted interaction P values were corrected with the PACT test and adjusted for diabetes-related variables. In INVEST whites, we observed three TCF7L2 SNPs with significant SNP×treatment interactions for NOD. The strongest pharmacogenetic interaction was observed for rs7917983 [synergy index 3.37 (95% CI 1.72-6.59), P=5.0×10, PACT=0.03], which was associated with increased NOD risk in hydrochlorothiazide-treated patients [odds ratio 1.53 (1.04-2.25), P=0.03] and decreased NOD risk in non hydrochlorothiazide-treated patients [odds ratio 0.48 (0.27-0.86), P=0.02]. The TCF7L2 SNP rs4506565, previously associated with diabetes, showed a similar, significant pharmacogenetic association. Our results suggest that hydrochlorothiazide treatment is an environmental risk factor that increases diabetes risk beyond that attributed to TCF7L2 variation in white, hypertensive patients. Further study and replication of our results is needed to confirm pharmacogenetic influences of TCF7L2 SNPs on thiazide-induced NOD.

Chronic renin inhibition lowers blood pressure and reduces upright muscle sympathetic nerve activity in hypertensive seniors

Cardiovascular risk remains high in patients with hypertension even with adequate blood pressure (BP) control. One possible mechanism may be sympathetic activation via the baroreflex. We tested the hypothesis that chronic inhibition of renin reduces BP without sympathetic activation, but diuresis augments sympathetic activity in elderly hypertensives. Fourteen patients with stage-I hypertension (66 ± 5 (SD) years) were treated with a direct renin inhibitor, aliskiren (n = 7), or a diuretic, hydrochlorothiazide (n = 7), for 6 months. Muscle sympathetic nerve activity (MSNA), BP, direct renin and aldosterone were measured during supine and a graded head-up tilt (HUT; 5 min 30° and 20 min 60°), before and after treatment. Sympathetic baroreflex sensitivity (BRS) was assessed. Both groups had similar BP reductions after treatment (all P < 0.01), while MSNA responses were different between hydrochlorothiazide and aliskiren (P = 0.006 pre/post × drug). Both supine and upright MSNA became greater after hydrochlorothiazide treatment (supine, 72 ± 18 post vs. 64 ± 15 bursts (100 beats)(-1) pre; 60° HUT, 83 ± 10 vs. 78 ± 13 bursts (100 beats)(-1); P = 0.002). After aliskiren treatment, supine MSNA remained unchanged (69 ± 13 vs. 64 ± 8 bursts (100 beats)(-1)), but upright MSNA was lower (74 ± 15 vs. 85 ± 10 bursts (100 beats)(-1); P = 0.012 for pre/post × posture). Direct renin was greater after both treatments (both P < 0.05), while upright aldosterone was greater after hydrochlorothiazide only (P = 0.002). The change in upright MSNA by the treatment was correlated with the change of aldosterone (r = 0.74, P = 0.002). Upright sympathetic BRS remained unchanged after either treatment. Thus, chronic renin inhibition may reduce upright MSNA through suppressed renin activity, while diuresis may evoke sympathetic activation via the upregulated renin-angiotensin-aldosterone system, without changing intrinsic sympathetic baroreflex function in elderly hypertensive patients.

Low salt intake and changes in serum sodium levels in the combination therapy of low-dose hydrochlorothiazide and angiotensin II receptor blocker

Background: Although a low salt intake and angiotensin II blockade may act to reduce serum sodium (srNa) levels during low-dose diuretic treatment, the effects of these factors on srNa level have not yet been fully clarified. The present study was conducted to examine the association of dietary salt intake with the changes in srNa levels when angiotensin II receptor blocker (ARB) treatment is changed to the combination of ARB plus a low-dose diuretic, Hydrochlorothiazide (HCTZ). Methods: In 88 patients (age 70±12 years old), ARB treatment was switched to the combination drug (the same dosage ARB plus 12.5 mg/day HCTZ). srNa level was measured before and 6 months after administration of this combination drug. The daily salt intake was estimated by the Kawasaki formula using second morning urine. Results: The study subjects were divided into quintile ranges according to the daily salt intake. The reduction in srNa levels by switching to the ARB plus HCTZ treatment was significant in subjects in the lowest quintile Q5 (7.22 g/day or less salt intake), but not in those in Q1-4 (17.78-7.25 g/day salt intake). Increases in serum creatinine and uric acid levels, however, were significantly larger in the former group than in the latter group. ![Figure][1] Conclusions: In the strict low salt intake condition (< 7.2 g/day), the addition of a low-dose diuretic (12.5 mg HCTZ) to ARB treatment causes significant reductions in srNa levels, which might affect blood osmolarity. [1]: pending:yes