Hydrochlorothiazide Treatment Research Articles

Renal upregulation of NCC counteracts empagliflozin-mediated NHE3 inhibition in normotensive but not in hypertensive male rat.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce blood pressure (BP) in patients with hypertension, yet the precise molecular mechanisms remain elusive. SGLT2i inhibits proximal tubule (PT) NHE3-mediated sodium reabsorption in normotensive rodents, yet no hypotensive effect is observed under this scenario. This study examined the effect of empagliflozin (EMPA) on renal tubular sodium transport in normotensive and spontaneously hypertensive rats (SHRs). It also tested the hypothesis that EMPA-mediated PT NHE3 inhibition in normotensive rats is associated with upregulation of distal nephron apical sodium transporters. EMPA administration for 14 days reduced BP in 12-wk-old SHRs but not in age-matched Wistar rats. PT NHE3 activity was inhibited by EMPA treatment in both Wistar and SHRs. In Wistar rats, EMPA increased NCC activity, mRNA expression, protein abundance, and phosphorylation levels, but not in SHRs. SHRs showed higher NKCC2 activity and an abundance of cleaved ENaC α and γ subunits compared with Wistar rats, none of which were affected by EMPA. Another set of male Wistar rats was treated with EMPA, the NCC inhibitor hydrochlorothiazide (HCTZ), and EMPA combined with HCTZ or vehicle for 14 days. In these rats, BP reduction was observed only with combined EMPA and HCTZ treatment, not with either drug alone. These findings suggest that NCC upregulation counteracts EMPA-mediated inhibition of PT NHE3 in male normotensive rats, maintaining their baseline BP. Moreover, the reduction of NHE3 activity without further upregulation of major apical sodium transporters beyond the PT may contribute to the BP-lowering effect of SGLT2i in experimental models and patients with hypertension.NEW & NOTEWORTHY This study suggests that reduced NHE3-mediated sodium reabsorption in the renal proximal tubule may account, at least in part, for the BP-lowering effect of SGLT2 inhibitors in the setting of hypertension. It also demonstrates that chronic treatment with SGLT2 inhibitors upregulates NCC activity, phosphorylation, and expression in the distal tubule of normotensive but not hypertensive rats. SGLT2 inhibitor-mediated upregulation of NCC seems crucial to counteract proximal tubule natriuresis in subjects with normal BP.

Association of hydrochlorothiazide treatment compared to alternative diuretics with overall and skin cancer risk: a propensity-matched cohort study

Abstract Introduction Hydrochlorothiazide (HCT) has been suggested to induce photosensitivity, thereby increasing the incidence of skin cancers. After a pharmacovigilance alert, HCT was frequently withdrawn or substituted by other diuretics. The aim of this study was to compare the association of exposure to HCT with cancer risk versus alternative diuretics. Methods A retrospective cohort study was conducted based on data from the AOK PLUS, a large German statutory health insurance fund. Patients with HCT treatment were propensity score matched (PSM) to patients using non-HCT diuretics. Incidence of cancer of any kind and, specifically, skin cancer was assessed in both groups. Time to incident cancer diagnosis was evaluated and compared between the groups. Results A total of 199,708 patients were included in the final analysis (n=76,855 in the HCT-group; n=122,853 in the non-HCT-diuretics group). After PSM, 122,554 patients remained in the sample (n=61,277 for both groups, of which >96% had hypertension, mean age 73 years, 61% female). HCT treatment was associated with a lower incidence of cancer of any kind, compared with non-HCT diuretics (Incidence rate ratio (IRR) per 100 patient years 0.84 95% Confidence interval (CI): 0.82-0.87). HCT treatment was associated with a small albeit significantly higher IRR of skin cancer (1.14 95% CI: 1.06-1.24) with significant variances over time. Although numerically higher, the difference accounts to only 0.05 more skin cancer diagnoses in 100 patient years. Conclusions HCT treatment compared to alternative diuretics was associated with a lower all-cancer risk and was not associated with a meaningful increase in skin cancer risk in a large German population. Nevertheless, advice for skin protection is warranted in all patients taking thiazide or thiazide-like diuretics.HR of overall and skin cancerTime to cancer diagnosis - time to event

A randomized, placebo-controlled, trial to assess the photosensitizing, phototoxic and carcinogenic potential of hydrochlorothiazide in healthy volunteers.

Pharmacovigilance reports, associating hydrochlorothiazide (HCT) with skin cancer, resulted in a significant decrease of HCT prescriptions for hypertension and heart failure. Whether HCT exhibits phototoxic properties thereby causing skin cancer remains unknown. This study aimed to examine the photosensitizing, phototoxic and carcinogenic potential of HCT in a randomized, placebo-controlled, double-blind trial in vivo and also in vitro . The trial assigned 30 healthy, normotensive adult volunteers in a 2:1 ratio to either HCT 25 mg/day or placebo for 15 days. Photosensitivity of the skin with and without the effect of HCT treatment were assessed. Following whole-body ultraviolet A (UVA) and B (UVB, 311 nm) irradiation, phototoxic and carcinogenic reactions by measuring urinary excretion of pyrimidine dimers were evaluated. For the in-vitro studies, human keratinocytes (HaCaT) were incubated with HCT, irradiated with UVB, and analysed for markers of inflammation, apoptosis and carcinogenesis. Skin photosensitivity following exposure to UVA and UVB remained unchanged from baseline to 15-day follow-up in both groups (UVA change HCT 0.0 J/cm 2 vs. placebo 0.0 J/cm 2 ; P = 0.99; UVB change HCT 0.0 J/cm 2 vs. placebo -0.2 J/cm 2 ; P = 0.06). Pyrimidine dimers were not detected in either group. In vitro , combination of HCT and UVB irradiation did not induce the expression of oxidative stress marker proteins, inflammatory proteins, apoptotic proteins or activation of oncoproteins. HCT did not increase photosensitivity for UVA or UVB in healthy volunteers compared with placebo, and was not associated with phototoxic or carcinogenic reactions. In vitro , HCT was also not associated with phototoxicity or carcinogenesis (NCT04654312).

Comparison of the Effect of Hydroalcholic Extract of Alhagi maurorum and Hydrochlorothiazide on Excretion of 4-10 mm Kidney and Ureteral Stones in Adults: A Randomized Prospective Study.

The prevalence of kidney stones and their complications is high. The review of the literature showed the therapeutic effects of Alhagi maurorum extract on urinary tract stones. This study reviewed the Alhagi plant's hydroalcholic extract's effect on eliminating kidney and ureteral stones compared to hydrochlorothiazide. In this randomized prospective study, from March 2019 to September 2021, 80 patients over 18 years of age with kidney stones in the upper ureter with a size of 4-10 mm were divided into two groups based on the block random allocation method. The first group received hydrochlorothiazide tablets (50 mg), and the second group received 1 gram/day of the hydroalcholic areal extract of Alhagi maurorum in a two-divided capsule. The mean size and number of stones, renal function tests, and side effects were checked and compared in both groups before and after the study. Mean age, sex, serum urea level (P=0.351), serum creatinine (P=0.393), stone size (P=0178), and the number of stones (P=0.052) before intervention were similar. After intervention, the size and number of stones diminished, up to 70% in both groups. However, there was not a statistically significant difference between the two groups. The study showed that Alhagi maurorum is as effective as hydrochlorothiazide in treatment of kidney and ureteral stones with no significant complications and is promising.

Chronic Use of Hydrochlorothiazide and Risk of Skin Cancer in Caucasian Adults: A PharmLines Initiative Inception Cohort Study.

Photosensitizing properties of hydrochlorothiazide may increase skin cancer risk. To date, study findings on the association between hydrochlorothiazide use and skin cancer risk are inconsistent, notably regarding confounding and dose-response. The aim of this study was to investigate the association between hydrochlorothiazide use and incidence of skin cancer in a cohort of unselected Caucasian adults, taking dosing into account. As part of the PharmLines Initiative, which links data from the Lifelines Cohort Study and prescription database IADB.nl, patients aged ≥ 40 years were included from Lifelines, a prospective population-based cohort study in the north of the Netherlands. Skin cancer incidence was compared between subjects starting hydrochlorothiazide treatment (n = 608), subjects starting treatment with other antihypertensives (n = 508), and non-antihypertensive long-term medication users (n = 1,710). Cox regression analyses were performed to obtain hazard ratios, adjusted for potential confounders. The risk of any skin cancer, keratinocyte carcinoma, basal cell carcinoma and squamous cell carcinoma was not significantly increased in general hydrochlorothiazide users. A clear association was observed between high cumulative hydrochlorothiazide use (≥ 5,000 defined daily dose; ≥ 125,000 mg) and the risk of any skin cancer (adjusted hazard ratio 5.32, 95% confidence interval (95% CI) 2.40-11.81), keratinocyte carcinoma (adjusted hazard ratio 7.31, 95% CI 3.12-17.13), basal cell carcinoma (adjusted hazard ratio 7.72, 95% CI 3.11-19.16) and squamous cell carcinoma (adjusted hazard ratio 19.63, 95% CI 3.12-123.56). These findings should lead to awareness with high use of hydrochlorothiazide in Caucasian adults.

Association of hydrochlorothiazide treatment compared with alternative diuretics with overall and skin cancer risk: a propensity-matched cohort study.

Hydrochlorothiazide (HCT) has been suggested to induce photosensitivity, thereby increasing the incidence of skin cancers. After a pharmacovigilance alert, HCT was frequently withdrawn or substituted by other diuretics. The aim of this study was to compare the association of exposure to HCT with cancer risk versus alternative diuretics. A retrospective cohort study was conducted based on data from the AOK PLUS, a large German statutory health insurance fund. Patients with HCT treatment were propensity score matching to patients using non-HCT diuretics. Incidence of cancer of any kind and, specifically, skin cancer was assessed in both groups. Time-to-incident cancer diagnosis was evaluated and compared between the groups. A total of 199 708 patients were included in the final analysis ( n = 76 855 in the HCT group; n = 122 853 in the non-HCT-diuretics group). After propensity score matching, 122 554 patients remained in the sample ( n = 61 277 for both groups, of which >96% had hypertension, mean age 73 years, 61% female). HCT treatment was associated with a lower incidence of cancer of any kind compared with non-HCT diuretics (incidence rate ratio per 100 patient years 0.84 95% confidence interval: 0.82-0.87). HCT treatment was associated with a small albeit significantly higher incidence rate ratio of skin cancer (1.15 95% confidence interval: 1.06-1.24) with significant variances over time. Although numerically higher, the difference accounts to only 0.05 more skin cancer diagnoses in 100 patient-years. HCT treatment compared with alternative diuretics was associated with a lower all-cancer risk and a numerically small increased skin cancer risk in a large German population. Risk-benefit evaluation should be executed in patients with increased skin cancer risk and treatment with HCT. Furthermore, advice for skin protection is warranted in all patients taking thiazide or thiazide-like diuretics.

Diagnostic Pitfalls of a Newborn with Congenital Nephrogenic Diabetes Insipidus.

Congenital nephrogenic diabetes insipidus (NDI) is a rare cause of hypernatremia in newborns. Central diabetes insipidus (CDI) is the main differential diagnosis of NDI. NDI responds poorly to desmopressin acetate (DDAVP) treatment while this is the mainstay of CDI management. Therefore, an early and correct diagnosis of NDI is crucial to avoid the complications of inappropriate therapy. Here, we report a newborn with hypernatremia and hypotonic polyuria. The patient was initially responsive but subsequently unresponsive to intranasal DDAVP treatment in regard to urine output and serum sodium levels. A novel hemizygous missense mutation (c.632T>C, p.L211P) in the AVPR2 gene was found both in the baby and his mother, and the diagnosis of congenital NDI was established. After hydrochlorothiazide treatment and hypo-osmolar formula were given, urine volume was decreased, and serum sodium levels were normalized. Early recognition and appropriate management of NDI can prevent complications of hypernatremic dehydration in young infants.

PS-BPB01-8: IMPACT OF DIFFERENT DIURETIC TYPES ON ARTERIAL STIFFNESS AND CALCIFICATION IN A RAT MODEL OF CHRONIC KIDNEY DISEASE

Introduction: We reported that antihypertensive therapy with a hydrochlorothiazide (HCTZ)-based regimen aggravates arterial stiffness and vascular calcification in a rat model of chronic kidney disease (CKD) with mineral and bone disorder (MBD). In this study, we investigated whether the aggravation of arterial stiffness and vascular calcification in CKD-MBD rats is induced by HCTZ and whether these abnormalities could also occur with other types of diuretic currently used in clinic. Methods: In rats with renal mass ablation-induced CKD, MBD was generated by a Ca/P-rich diet and calcitriol supplementation. The animals were divided into 4 groups; 1) CKD-MBD control; 2) CKD-MBD + HCTZ (thiazide diuretic, 5 mg/kg/d); 3) CKD-MBD + Chlorthalidone (thiazide-like diuretic, 5 mg/kg/d), and; 4) CKD-MBD + Furosemide (loop diuretics, 10 mg/kg/d). At week 6, hemodynamic parameters including systolic and mean blood pressure (SBP and MBP), pulse pressure (PP) and pulse wave velocity (PWV) were determined. The thoracic aorta was harvested to assess vascular calcification. Results: SBP was reduced by all types of diuretic in CKD-MBD rats. Contrary to chlortalidone nor furosemide, HCTZ treatment led to a reduction of MBP, but an increase in PP and PWV in CKD-MBD rats (p < 0.05). As expected from these hemodynamic changes, medial calcification in the thoracic aorta was significantly greater in CKD-MBD rats treated with HCTZ as compared to all the other groups of rats (p < 0.05). Conclusion: In rats with CKD-MBD, antihypertensive therapy with the thiazide diuretic HCTZ, but not other types of diuretic, exacerbated arterial stiffness and vascular calcification despite a reduction in SBP. The deleterious effect of HCTZ in CKD-MBD rats may have major clinical impact as this diuretic is widely use in patients with CKD that often develop MBD.

Does systemic hydrochlorothiazide increase the risk of developing ultraviolet radiation-induced skin tumours in hairless mice?

Hydrochlorothiazide (HCTZ) is a frequently prescribed diuretic that exhibits photosensitizing properties. It is used to treat hypertension and edema. Dermato-epidemiological studies in various populations have linked HCTZ treatment with increased risk of particular types of skin cancer, including malignant melanoma (lentigo subtype), and both basal cell carcinoma and squamous cell carcinoma (SCC). This study investigated whether either of two different doses of HCTZ increased the risk of SCC development in mice exposed to ultraviolet radiation (UVR). A total of three groups of hairless mice were used in this study (total, N= 71). One group received a low dose (0.26 mg/mouse/day) and another group received a high dose (0.52 mg/mouse/day) of HCTZ in their drinking water; a third UVR control group received only tap water. All three groups were irradiated with UVR until the mice developed three tumours that were 4 mm in size. The times to SCC tumour development were recorded. In the low-dose group, the median time to develop an SCC tumour was 170 days; in both the high-dose group and the control group, the median time to develop anexd SCC tumour was 163 days (p≥ 0.331). In our hairless mouse model, we found that mice treated with UVR plus HCTZ did not develop SCCs more rapidly than mice treated with UVR but not HCTZ.

Abstract 13023: Exercise Training Potentiates Diuretic Benefits on Mechanism of Arterial Pressure Control in Hypertensive Postmenopausal Rats: Role of Inflammatory and Redox Balance

Introduction: Thiazide diuretic is a classic drug used to treat elevated arterial pressure (AP). However, their neuroinflammatory effects are limited when compared with other therapies. Objective: To compare the effect of hydrochlorothiazide (HCTZ) alone or combined with concurrent exercise training (aerobic+resistance, CET) on mechanisms of AP control and on inflammatory and redox balance in hypertensive postmenopausal rats. Methods: Female spontaneously hypertensive rats were distributed into sedentary (S) and ovariectomized groups: sedentary (OS), sedentary treated with HCTZ (OSH), trained (OT) and trained treated with HCTZ (OTH). HCTZ treatment (30 mg/kg) and CET (40-60% maximal capacity, 3 days/wk) were conducted for 8wks. AP was directly recorded at rest and after vasopressor system blockade (vasopressin antagonist, losartan and hexamethonium). Inflammation and oxidative stress were evaluated in cardiac tissue. Results: Trained groups presented higher exercise tests performance. Systolic (OT:178±18 and OTH:178±17 vs. OS:205±15) and mean AP (mmHg) (OTH:153±17 vs. OS:176±16) were reduced in trained groups. CET promoted an increase in both bradycardic and tachycardic responses of baroreflex sensitivity and a reduction in AP variability indexes in relation to OS group. After sympathetic blockade, AP (mmHg) reduction was higher in OS group (-75.7±19.2 vs. S:-53.2±12.6 and OTH:-49.8±12.4). In addition, IL-10 (OTH vs. OS and OSH) and IL-10/TNF-alpha ratio (OTH vs. S, OS, OSH and OT) were higher in OTH group. OS group showed increased NAPDHoxidase and reduced catalase (vs. S); however, these changes were not observed in OTH group. Negative correlation was observed between sympathetic vascular modulation and IL/TNF-alpha ratio (p<0.001, r:-0.6). Conclusions: We concluded that CET alone or combined with HCTZ are more efficient approaches than HCTZ to reduce AP and improve AP control of circulation. Specifically, the combination HCTZ plus CET induces additional positive adaptations on physical, autonomic, inflammatory and redox balance. These results highlight the key role of exercise in the management of HTN, probably impacting on the quality of life and reducing the residual risk in post menopause. Grants: FAPESP (2019/06277-0).

ANTILITHIASIS EFFECTIVENESS TEST OF ETHANOL EXTRACT OF ALANG-ALANG (Imperata cylindrica (L.) Beauv) ON WHITE RATS (Rattus novergicus)

The purpose of this study was to determine the antilithiation effectiveness of alang-alang extract in white rats by looking at the histology of the rat kidney. The study design, the treatment group was divided into 5 groups. Control group (P0), ethylene glycol group (P1), Hydrochlorothiazide treatment group (P2), alang-alang extract group at a dose of 100 mg/kgBW (P3), and alang-lang extract group at a dose of 200 mg/kgBW (P4). The results showed that alang-alang extract had activity in repairing the kidneys of white rats with urolithiasis. And the alang-alang extract dose of 200 mg/kgBW has better effectiveness.

DIURETIC ASSOCIATED WITH CONCURRENT EXERCISE PROMOTES ADDITIONAL PHYSICAL, AUTONOMIC AND INFLAMMATORY ADAPTATIONS IN HYPERTENSIVE RATS SUBMITTED TO OVARIAN HORMONE PRIVATION

Objective: To evaluate the effects of hydrochlorothiazide (HCTZ) combined or not with concurrent exercise training on physical capacity and neurohumoral mechanism of blood pressure (BP) control in a model of hypertension and menopause. Design and method: Female spontaneously hypertensive rats were allocated into sedentary (S) and ovariectomized groups: sedentary (OS), sedentary treated with HCTZ (OSH) and trained treated with HCTZ (OTH). Ovariectomy procedure was performed at initial of protocol. HCTZ (30 mg/kg) was administrated orally in drinking water. Aerobic and resistance exercises (40–60% maximal capacity) were conducted 3 days/wk for 8 weeks. BP, heart rate and its variabilities were nalysed using signals of direct recording of BP. Vasopressin receptor antagonist, losartan and hexamethonium were sequentially injected to evaluate vasopressor system. Inflammatory profile was evaluated. Results: Systolic and mean BP (mmHg) were lower in OTH (178 ± 17 and 153 ± 17, respectively) compared with OS group (205 ± 15 and 176 ± 16, respectively). Treadmill (OTH vs. OSH) and ladder physical test performance (OTH vs. OS, OS and OSH) were higher in OTH group. Baroreflex sensitivity (bpm/mmHg) was lower in OS group (vs. S) and both bradycardic (OTH:- 1.6 ± 0.3 vs. OS:-0.6 ± 0.3) and tachycardic response (OSH:-2.2 ± 0.7 and OTH:-2.4 ± 0.8 vs. OS:- 1.3 ± 0.4) were improved after HCTZ treatment. OTH showed higher (high-frequency band: OTH:77.8 ± 4.9 vs. OS:69.8 ± 4.0nu) and lower cardiac sympathetic modulation (low-frequency band: OTH:22.2 ± 4.9 vs. OS:30.2 ± 4.0nu) and LF/HF ratio (OTH:0.30 ± 0.08 vs. OS:0.45 ± 0.09). In addition, reduced variance (OTH:30.3 ± 10.5 vs. OS:60.1 ± 13.1) and low-frequency band of systolic BP (mmHg2) (OTH:6.2 ± 5.2 vs. S:16.3 ± 6.7, OS:18.8 ± 6.1 and OSH:15.8 ± 5.5) was observed in trained group. Drop in BP (mmHg) after hexamethonium was higher in OS group (- 75.7 ± 19.2 vs. S:-53.2 ± 12.6, OSH:-54.9 ± 9.0 and OTH:-49.8 ± 12.4). IL-10 (OTH:78.1 ± 17.3 vs. OS:52.8 ± 23.2 and OSH:45.1 ± 10.6) and IL-10/TNF-a ratio (OTH:1.99 ± 0.07 vs. S:1.32 ± 0.21, OS: 1.18 ± 0.12 and OSH:1.18 ± 0.27) was higher in trained group. Conclusions: We concluded that HCTZ combined with exercise training is more efficient than HCTZ alone to improve BP control, probably due to a better adjustment on autonomic modulation and inflammation profile, in addition to induce cardiofunctional benefits. This data reinforces the key role of exercise in the attenuation of hypertension-induced damage in menopaused rats. Grants: FAPESP (2019/06277–0).

181-OR: Sympathetic Activity in Patients with Type 2 Diabetes Mellitus Treated with Empagliflozin or Hydrochlorothiazide

Changes in sympathetic nervous system activity may contribute to beneficial effects of sodium glucose transporter (SGLT2) inhibition on cardiovascular outcomes. We hypothesized that SGLT inhibition with empagliflozin lowers sympathetic activity compared with hydrochlorothiazide (HCT) to discern SGLT2-specific actions from non-specific responses to increased natriuresis. In this double-blind, randomized study patients with type 2 diabetes mellitus on metformin monotherapy received either 25 mg/day empagliflozin (n=20) or 25 mg/day HCT (n=21) for 6 weeks. Muscle sympathetic nerve activity (MSNA) , blood pressure, cardiovascular, and metabolic biomarkers were assessed at baseline and end of treatment. Empagliflozin significantly increased urinary glucose excretion (difference in change from baseline 47.4 mmol/l vs. HCT) , reduced fasting plasma glucose (-1.91 mmol/l) , HbA1c (-0.58%) , and body weight (-1.23 kg, all p<0.05) . Office systolic blood pressure decreased with both treatments. MSNA (burst frequency -1.95 [95% confidence interval -8.67; 4.78] bursts/min) , baroreflex heart rate control (0.84 [-1.18; 2.87] ms/mmHg) and plasma catecholamines did not change significantly with either treatment. MSNA increased with higher body weight loss with both treatments, but more pronounced and significant only with HCT (p=0.0015) . In conclusion, neither empagliflozin nor HCT treatment led to clinically relevant changes in sympathetic activity. Given the important role of the sympathetic nervous system in the progression of cardiovascular disease, mechanisms attenuating sympathetic activity in the face of increased sodium excretion deserve further attention. Disclosure K.Heusser: None. J.Tank: None. A.Fischer: None. T.Heise: Advisory Panel; Novo Nordisk A/S, Research Support; ADOCIA, AstraZeneca, Biocon, Boehringer Ingelheim International GmbH, Crinetics Pharmaceuticals, Inc., Eli Lilly and Company, Gan & Lee Pharmaceuticals, Genova, Nestlé, Neuraly Inc., Novo Nordisk A/S, Sanofi, Zealand Pharma A/S, Speaker's Bureau; Eli Lilly and Company, Gan & Lee Pharmaceuticals, Novo Nordisk A/S. J.Jordan: Consultant; Novo Nordisk, Other Relationship; Eternygen, Research Support; Boehringer Ingelheim International GmbH.

Enalapril associated with combined training is more effective in reducing SBP and improve baroreflex sensitivity than drug therapies alone in hypertensive rats

High blood pressure is the leading risk factor to development of cardiovascular disease worldwide. Diuretic and angiotensin‐converting enzyme blockers treatment is widely used for its efficiency in reducing blood pressure (BP). Combined physical training (aerobic + resistance) is recommended for hypertensive patients; however, it is not yet clear whether the combination of antihypertensive treatment with this training modality results in additional benefits. Therefore, the aim of this study was to compare the effects of combined training with different drug treatments on systolic BP (SBP) and baroreflex sensitivity (BRS) of spontaneously hypertensive rats (SHR). Twenty‐eight males SHR rats were divided into four groups (n=7/group): HS (sedentary hydrochlorothiazide), HT (trained hydrochlorothiazide), ES (sedentary enalapril) and ET (trained enalapril). Drugs were administered in drinking water (enalapril 3 mg/kg/day and hydrochlorothiazide 30 mg/kg/day). All groups underwent exercise testing before and after 2 months. The trained groups performed combined training 3 times a week, being aerobic and resistance at same session, moderate intensity. The SBP was analyzed by caudal plethysmography before starting the drugs and 24h after the last training session. BRS was analyzed by response to phenylephrine and sodium nitroprusside. Both trained groups increased maximal aerobic exercise test (p<0.0001) and resistance exercise test (HT vs. HS, p=0.02; ET vs. ES, p<0.0001) versus the sedentary groups at the end of the protocol. There was no difference in the initial SBP between the groups (HS 176 ± 4.3, HT 175 ± 3, ES 173 ± 1.4 and ET 183 ± 3 mmHg). There were reductions in SBP in the HT (161 ± 1.3 mmHg), ES (159 ± 4.4 mmHg) and ET groups (147 ± 3.3 mmHg) at the end of the protocol. In addition, the trained group associated with enalapril treatment further reduced SBP when compared to the trained hydrochlorothiazide group (ET vs. HT, p = 0.02). Regarding BRS, there was no difference in tachycardic response between groups; however, ET group (‐2.8 ± 0.5 bpm/mmHg) showed increased bradycardic responses comparing with ES group (‐1.8 ± 0.1 bpm/mmHg). Therefore, the data support that the association of combined exercise training with enalapril treatment and is more effective in reducing SBP and improving BRS than the combination with hydrochlorothiazide treatment. It is noteworthy that the training proposed in this study was performed only three times a week, getting closer to clinical recommendations, and being enough for induce additional benefits to classical drug therapies in functional capacity and blood pressure control in an experimental model of hypertension.

Effects of Hydrochlorothiazide and Metformin on Aquaresis and Nephroprotection by a Vasopressin V2 Receptor Antagonist in ADPKD: A Randomized Crossover Trial.

The vasopressin V2 receptor antagonist tolvaptan is the only drug that has been proven to be nephroprotective in autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan also causes polyuria, limiting tolerability. We hypothesized that cotreatment with hydrochlorothiazide or metformin may ameliorate this side effect. We performed a clinical study and an animal study. In a randomized, controlled, double-blind, crossover trial, we included 13 tolvaptan-treated patients with ADPKD. Patients were treated for three 2-week periods with hydrochlorothiazide, metformin, or placebo in random order. Primary outcome was change in 24-hour urine volume. We also measured GFR and a range of metabolic and kidney injury markers. Patients (age 45±8 years, 54% women, measured GFR of 55±11 ml/min per 1.73 m2) had a baseline urine volume on tolvaptan of 6.9±1.4 L/24 h. Urine volume decreased to 5.1 L/24 h (P<0.001) with hydrochlorothiazide and to 5.4 L/24 h (P<0.001) on metformin. During hydrochlorothiazide treatment, plasma copeptin (surrogate for vasopressin) decreased, quality of life improved, and several markers of kidney damage and glucose metabolism improved. Metformin did not induce changes in these markers or in quality of life. Given these results, the effect of adding hydrochlorothiazide to tolvaptan was investigated on long-term kidney outcome in an animal experiment. Water intake in tolvaptan-hydrochlorothiazide cotreated mice was 35% lower than in mice treated with tolvaptan only. Combination treatment was superior to "no treatment" on markers of disease progression (kidney weight, P=0.003 and cystic index, P=0.04) and superior or equal to tolvaptan alone. Both metformin and hydrochlorothiazide reduced tolvaptan-caused polyuria in a short-term study. Hydrochlorothiazide also reduced polyuria in a long-term animal model without negatively affecting nephroprotection. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_03_21_CJN11260821.mp3.

Plasma metabolomic profiles associated with hypertension and blood pressure in response to thiazide diuretics.

This study aimed to identify the metabolomic alterations associated with hypertension (HTN) and the response of blood pressure (BP) to thiazide diuretics. A total of 50 participants previously untreated for HTN were prospectively recruited. After a 2-week lifestyle adjustment, 30 participants with systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg were classified into the HTN group and prescribed hydrochlorothiazide (HCTZ) at 50 mg per day for 2 weeks. The remaining 20 participants, who had relatively normal BP, were assigned to the normotension group. Metabolomic profiles related to the response of BP to thiazide diuretics were analyzed. A total of 73 differential metabolites were found to be associated with HTN, and 27 metabolites were significantly changed upon HCTZ treatment (HCTZ-sensitive metabolites). Among the identified metabolites, 7 (aspartate, histidine, C5-DC, C5-M-DC, C14:1, phosphatidylcholine ae C34:1, and phosphatidylcholine ae C34:3) were positively associated with HTN and decreased in abundance upon HCTZ treatment (HCTZ-reduced/HTN-associated metabolites). Moreover, multivariate analysis of 20 metabolites whose baseline levels were associated with the response of BP revealed that aspartate, glutamate, lysophosphatidylcholine C16:0, lysophosphatidylcholine C20:3, and sphingomyelin C24:1 were independently related to systolic BP reduction, and lysophosphatidylcholine C20:3 was independently associated with diastolic BP reduction. In conclusion, we identified 5 metabolites independently related to BP changes with HCTZ treatment. An advanced biomarker profile of thiazide-induced metabolomic changes may provide a clue with which to further explore the complex and mixed effects of thiazide treatment in a clinical setting.

Race-Specific Comparisons of Antihypertensive and Metabolic Effects of Hydrochlorothiazide and Chlorthalidone

BackgroundChlorthalidone is recommended over hydrochlorothiazide (HCTZ) as the preferred thiazide, but the supporting evidence is not robust at routinely used doses, or in whites vs blacks, in whom differences in response to thiazides are well known. We compare the efficacy and safety of HCTZ and chlorthalidone as first-line therapies for white and black hypertensive patients. MethodsWe compared treatment-related outcomes between the HCTZ arm (12.5 mg for 2-3 weeks; 25 mg for additional 6 weeks) of the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR, n = 376) and chlorthalidone arm (15 mg for 2 weeks; 25 mg for additional 6 weeks) of PEAR-2 (n = 326) clinical trials, in 17–65-year-old mild-moderate uncomplicated hypertensive whites and blacks. ResultsMean systolic/diastolic blood pressure (SBP/DBP) reduction with HCTZ vs chlorthalidone: 8 ± 8/4 ± 5 vs 12 ± 9/7 ± 5 mm Hg in whites (P < 10−6 SBP and DBP); 12 ± 10/7 ± 6 vs 15 ± 10/9 ± 6 in blacks (P = .008 SBP, P = .054 DBP). Treatment with HCTZ vs chlorthalidone in whites resulted in significantly fewer patients achieving target BP (<140/90 mm Hg) (44% vs 57%, P = .018) and clinical response rate (≥10 mm Hg DBP reduction); and significantly higher nonresponse rate (<6 mm Hg DBP reduction); but no significant differences in rates among blacks (eg, target-BP rate: 56% vs 63%, P = .31). HCTZ treatment led to significantly lower rates of hypokalemia and hyperuricemia in whites and blacks, vs chlorthalidone, and significantly lower odds of requiring potassium supplementation among blacks (odds ratio 0.16; 95% confidence interval, 0.07-0.37; P = 3.4e−7). ConclusionCompared with HCTZ, chlorthalidone showed greater blood pressure lowering and adverse metabolic effects in whites, but similar blood pressure lowering and greater adverse effects in blacks; suggesting that the recent guideline recommendations to choose chlorthalidone over HCTZ may not be warranted in blacks.

A Randomized, Double-Blind, Placebo-Controlled Trial Assessing Efficacy of Standard and Low-Dose Hydrochlorothiazide Treatment for Prevention of Recurrent Calcareous Nephrolithiasis (NOSTONE Trial)

A Randomized, Double-Blind, Placebo-Controlled Trial Assessing Efficacy of Standard and Low-Dose Hydrochlorothiazide Treatment for Prevention of Recurrent Calcareous Nephrolithiasis (NOSTONE Trial)

Risk of squamous cell carcinoma of the lip and cutaneous melanoma in older Australians using hydrochlorothiazide: A population-based case-control study.

Recent European and US studies reported increased risks of skin cancers associated with hydrochlorothiazide (HCTZ) treatment. Our study aimed to determine the risk of lip cancer and malignant melanoma among Australians prescribed HCTZ. We conducted a case-control study nested within a population of veterans residing in New South Wales in 2004-2015, using Australian Department of Veterans' Affairs data linked with cancer registrations, hospitalisation and prescription dispensings. Among DVA healthcare card holders 65years and older, we identified incident cases of squamous cell carcinoma of the lip and of cutaneous melanoma, each matched with up to 20 controls through risk-set sampling. We estimated odds ratios (ORs) associating HCTZ use with each cancer using conditional logistic regression, adjusting for predefined confounders. For lip cancer (45 cases), ever-use of HCTZ yielded an OR of 2.6 (95% CI: 1.4-5.0) and high HCTZ use (≥25000mg) an OR of 4.7 (95% CI: 1.6-13.7). For cutaneous melanoma (659 cases), ever-use of HCTZ resulted in an OR of 1.2 (95% CI 1.0-1.5) and high HCTZ use in an OR of 1.2 (95% CI: 0.8-1.8). Our findings align with risk estimates from previous studies and provide further evidence that HCTZ's photosensitising properties may promote carcinogenesis in sun-exposed tissues.

Formulation and Characterisation of a Combination Captopril and Hydrochlorothiazide Microparticulate Dosage Form.

Cardiovascular diseases such as hypertension and cardiac failure in South African children and adolescents are effectively managed long term, using a combination treatment of captopril and hydrochlorothiazide. The majority of commercially available pharmaceutical products are designed for adult patients and require extemporaneous manipulation, prior to administration to paediatric patients. There is a need to develop an age appropriate microparticulate dosing technology that is easy to swallow, dose and alter doses whilst overcoming the pharmacokinetic challenges of short half-life and biphasic pharmacokinetic disposition exhibited by hydrochlorothiazide and captopril. An emulsion solvent evaporation approach using different combinations of polymers was used to manufacture captopril and hydrochlorothiazide microparticles. Design of experiments was used to develop and analyse experimental data, and identifyoptimum formulation and process conditions for the preparation of the microparticles. Characterisation studies to establish encapsulation efficiency, in vitro release, shape, size and morphology of the microparticles were undertaken. The microparticles produced were in the micrometre size range, with an encapsulation efficiency >75% for both hydrochlorothiazide and captopril. The microparticulate technology is able to offer potential resolution to the half-life mediated dosing frequency of captopril as sustained release of the molecule was observed over a 12-h period. The release of hydrochlorothiazide of >80% suggests an improvement in solubility limited dissolution.