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Ian P. Hall - One of the best experts on this subject based on the ideXlab platform.
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Urinary Extracellular Vesicle Protein Profiling and Endogenous Lithium Clearance Support Excessive Renal Sodium Wasting and Water Reabsorption in Thiazide-Induced Hyponatremia
Elsevier, 2019Co-Authors: Sarath K. Channavajjhala, Wenjing Jia, Ian P. Hall, Roger Bramley, Theresa Peltz, Wilna Oosthuyzen, Sue Kinnear, Barry Sampson, Nick Martin, Matthew A. BaileyAbstract:Introduction: Thiazide diuretics are among the most widely used antihypertensive medications worldwide. Thiazide-induced hyponatremia (TIH) is 1 of their most clinically significant adverse effects. A priori TIH must result from excessive saliuresis and/or water reabsorption. We hypothesized that pathways regulating the Thiazide-sensitive sodium-chloride cotransporter NCC and the water channel aquaporin-2 (AQP2) may be involved. Our aim was to assess whether patients with TIH would show evidence of altered NCC and AQP2 expression in urinary extracellular vesicles (UEVs), and also whether abnormalities of renal sodium reabsorption would be evident using endogenous lithium clearance (ELC). Methods: Blood and urine samples were donated by patients admitted to hospital with acute symptomatic TIH, after recovery to normonatremia, and also from normonatremic controls on and off Thiazides. Urinary extracellular vesicles were isolated and target proteins evaluated by western blotting and by nanoparticle tracking analysis. Endogenous lithium clearance was assessed by inductively coupled plasma mass spectrometry. Results: Analysis of UEVs by western blotting showed that patients with acute TIH displayed reduced total NCC and increased phospho-NCC and AQP2 relative to appropriate control groups; smaller differences in NCC and AQP2 expression persisted after recovery from TIH. These findings were confirmed by nanoparticle tracking analysis. Renal ELC was lower in acute TIH compared to that in controls and convalescent case patients. Conclusion: Reduced NCC expression and increased AQP2 expression would be expected to result in saliuresis and water reabsorption in TIH patients. This study raises the possibility that UEV analysis may be of diagnostic utility in less clear-cut cases of Thiazide-associated hyponatremia, and may help to identify patients at risk for TIH before Thiazide initiation. Keywords: diuretic, hypertension, hyponatremia, sodium, Thiazide, urinary extracellular vesicle
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urinary extracellular vesicle protein profiling and endogenous lithium clearance support excessive renal sodium wasting and water reabsorption in Thiazide induced hyponatremia
Kidney International Reports, 2019Co-Authors: Sarath Kiran Channavajjhala, Wenjing Jia, Ian P. Hall, Roger Bramley, Theresa Peltz, Wilna Oosthuyzen, Sue Kinnear, Barry Sampson, Nicholas G Martin, Matthew A. BaileyAbstract:Introduction Thiazide diuretics are among the most widely used antihypertensive medications worldwide. Thiazide-induced hyponatremia (TIH) is 1 of their most clinically significant adverse effects. A priori TIH must result from excessive saliuresis and/or water reabsorption. We hypothesized that pathways regulating the Thiazide-sensitive sodium-chloride cotransporter NCC and the water channel aquaporin-2 (AQP2) may be involved. Our aim was to assess whether patients with TIH would show evidence of altered NCC and AQP2 expression in urinary extracellular vesicles (UEVs), and also whether abnormalities of renal sodium reabsorption would be evident using endogenous lithium clearance (ELC). Methods Blood and urine samples were donated by patients admitted to hospital with acute symptomatic TIH, after recovery to normonatremia, and also from normonatremic controls on and off Thiazides. Urinary extracellular vesicles were isolated and target proteins evaluated by western blotting and by nanoparticle tracking analysis. Endogenous lithium clearance was assessed by inductively coupled plasma mass spectrometry. Results Analysis of UEVs by western blotting showed that patients with acute TIH displayed reduced total NCC and increased phospho-NCC and AQP2 relative to appropriate control groups; smaller differences in NCC and AQP2 expression persisted after recovery from TIH. These findings were confirmed by nanoparticle tracking analysis. Renal ELC was lower in acute TIH compared to that in controls and convalescent case patients. Conclusion Reduced NCC expression and increased AQP2 expression would be expected to result in saliuresis and water reabsorption in TIH patients. This study raises the possibility that UEV analysis may be of diagnostic utility in less clear-cut cases of Thiazide-associated hyponatremia, and may help to identify patients at risk for TIH before Thiazide initiation.
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Clinical and Molecular Features of Thiazide-Induced Hyponatremia
Current Hypertension Reports, 2018Co-Authors: Jodie Nadal, Jenny Clayton, Sarath K. Channavajjhala, Wenjing Jia, Ian P. Hall, Mark GloverAbstract:Purpose of Review Hypertension affects more than 30% of the world’s adult population and Thiazide (and Thiazide-like) diuretics are amongst the most widely used, effective, and least costly treatments available, with all-cause mortality benefits equivalent to angiotensin-converting enzyme inhibitors or calcium channel antagonists. A minority of patients develop Thiazide-induced hyponatremia (TIH) and this is largely unpredictable at the point of Thiazide prescription. In some cases, TIH can cause debilitating symptoms and require hospital admission. Although TIH affects only a minority of patients exposed to Thiazides, the high prevalence of hypertension leads to TIH being the most common cause of drug-induced hyponatremia requiring hospital admission in the UK. This review examines current clinical and scientific understanding of TIH. Consideration is given to demographic associations, limitations of current electrolyte monitoring regimens, clinical presentation, the phenotype evident on routine clinical blood and urine tests as well as more extensive analyses of blood and urine in research settings, recent genetic associations with TIH, and thoughts on management of the condition. Recent Findings Recent genetic and phenotyping analysis has suggested that prostaglandin E2 pathways in the collecting duct may have a role in the development of TIH in a subgroup of patients. Greater understanding of the molecular pathophysiology of TIH raises the prospect of pre-prescription TIH risk profiling and may offer novel insights into how TIH may be avoided, prevented and treated. Summary The rising prevalence of hypertension and the widespread use of Thiazides mean that further understanding of TIH will continue to be a pressing issue for patients, physicians, and scientists alike for the foreseeable future.
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Thiazide diuretic prescription and electrolyte abnormalities in primary care
British Journal of Clinical Pharmacology, 2006Co-Authors: J A Clayton, S Rodgers, J Blakey, Anthony J Avery, Ian P. HallAbstract:Aims Thiazide diuretics have a number of well-documented metabolic adverse effects. The aim of this study was to estimate the frequency of hyponatraemia and hypokalaemia amongst patients taking a Thiazide diuretic in primary care. Methods A computerized search of the electronic prescribing and laboratory records of six UK general practices was performed. Of the 32 218 adult patients identified, 3773 had received at least one prescription for a Thiazide between the years 1990 and 2002. Results Detailed prescribing data were available for 2942 patients of whom 951 (32.3%) had a recorded check of their electrolytes. One hundred and ninety-six (20.6%) had a sodium and/or potassium concentration below the normal range. The sodium distribution had a negative skew (−1.8) and in 130 (13.7%) patients was within the hyponatraemic range. Hypokalaemia was less common, occurring in 79 (8.5%) patients. Hyponatraemia was significantly associated with increased age; the odds ratio for developing hyponatraemia in patients over 70 years was 3.87 compared with those of ≤ 70 years. Hypokalaemia was significantly associated with increased Thiazide dose. Conclusions Prescription of a Thiazide diuretic in primary care is associated with a high frequency of hyponatraemia and hypokalaemia. Thiazides should be prescribed at low dose and the risk of hyponatraemia, especially in the elderly, should be considered and monitored for when prescribing these agents.
Matthew A. Bailey - One of the best experts on this subject based on the ideXlab platform.
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Urinary Extracellular Vesicle Protein Profiling and Endogenous Lithium Clearance Support Excessive Renal Sodium Wasting and Water Reabsorption in Thiazide-Induced Hyponatremia
Elsevier, 2019Co-Authors: Sarath K. Channavajjhala, Wenjing Jia, Ian P. Hall, Roger Bramley, Theresa Peltz, Wilna Oosthuyzen, Sue Kinnear, Barry Sampson, Nick Martin, Matthew A. BaileyAbstract:Introduction: Thiazide diuretics are among the most widely used antihypertensive medications worldwide. Thiazide-induced hyponatremia (TIH) is 1 of their most clinically significant adverse effects. A priori TIH must result from excessive saliuresis and/or water reabsorption. We hypothesized that pathways regulating the Thiazide-sensitive sodium-chloride cotransporter NCC and the water channel aquaporin-2 (AQP2) may be involved. Our aim was to assess whether patients with TIH would show evidence of altered NCC and AQP2 expression in urinary extracellular vesicles (UEVs), and also whether abnormalities of renal sodium reabsorption would be evident using endogenous lithium clearance (ELC). Methods: Blood and urine samples were donated by patients admitted to hospital with acute symptomatic TIH, after recovery to normonatremia, and also from normonatremic controls on and off Thiazides. Urinary extracellular vesicles were isolated and target proteins evaluated by western blotting and by nanoparticle tracking analysis. Endogenous lithium clearance was assessed by inductively coupled plasma mass spectrometry. Results: Analysis of UEVs by western blotting showed that patients with acute TIH displayed reduced total NCC and increased phospho-NCC and AQP2 relative to appropriate control groups; smaller differences in NCC and AQP2 expression persisted after recovery from TIH. These findings were confirmed by nanoparticle tracking analysis. Renal ELC was lower in acute TIH compared to that in controls and convalescent case patients. Conclusion: Reduced NCC expression and increased AQP2 expression would be expected to result in saliuresis and water reabsorption in TIH patients. This study raises the possibility that UEV analysis may be of diagnostic utility in less clear-cut cases of Thiazide-associated hyponatremia, and may help to identify patients at risk for TIH before Thiazide initiation. Keywords: diuretic, hypertension, hyponatremia, sodium, Thiazide, urinary extracellular vesicle
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urinary extracellular vesicle protein profiling and endogenous lithium clearance support excessive renal sodium wasting and water reabsorption in Thiazide induced hyponatremia
Kidney International Reports, 2019Co-Authors: Sarath Kiran Channavajjhala, Wenjing Jia, Ian P. Hall, Roger Bramley, Theresa Peltz, Wilna Oosthuyzen, Sue Kinnear, Barry Sampson, Nicholas G Martin, Matthew A. BaileyAbstract:Introduction Thiazide diuretics are among the most widely used antihypertensive medications worldwide. Thiazide-induced hyponatremia (TIH) is 1 of their most clinically significant adverse effects. A priori TIH must result from excessive saliuresis and/or water reabsorption. We hypothesized that pathways regulating the Thiazide-sensitive sodium-chloride cotransporter NCC and the water channel aquaporin-2 (AQP2) may be involved. Our aim was to assess whether patients with TIH would show evidence of altered NCC and AQP2 expression in urinary extracellular vesicles (UEVs), and also whether abnormalities of renal sodium reabsorption would be evident using endogenous lithium clearance (ELC). Methods Blood and urine samples were donated by patients admitted to hospital with acute symptomatic TIH, after recovery to normonatremia, and also from normonatremic controls on and off Thiazides. Urinary extracellular vesicles were isolated and target proteins evaluated by western blotting and by nanoparticle tracking analysis. Endogenous lithium clearance was assessed by inductively coupled plasma mass spectrometry. Results Analysis of UEVs by western blotting showed that patients with acute TIH displayed reduced total NCC and increased phospho-NCC and AQP2 relative to appropriate control groups; smaller differences in NCC and AQP2 expression persisted after recovery from TIH. These findings were confirmed by nanoparticle tracking analysis. Renal ELC was lower in acute TIH compared to that in controls and convalescent case patients. Conclusion Reduced NCC expression and increased AQP2 expression would be expected to result in saliuresis and water reabsorption in TIH patients. This study raises the possibility that UEV analysis may be of diagnostic utility in less clear-cut cases of Thiazide-associated hyponatremia, and may help to identify patients at risk for TIH before Thiazide initiation.
Wenjing Jia - One of the best experts on this subject based on the ideXlab platform.
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urinary extracellular vesicle protein profiling and endogenous lithium clearance support excessive renal sodium wasting and water reabsorption in Thiazide induced hyponatremia
Kidney International Reports, 2019Co-Authors: Sarath Kiran Channavajjhala, Wenjing Jia, Ian P. Hall, Roger Bramley, Theresa Peltz, Wilna Oosthuyzen, Sue Kinnear, Barry Sampson, Nicholas G Martin, Matthew A. BaileyAbstract:Introduction Thiazide diuretics are among the most widely used antihypertensive medications worldwide. Thiazide-induced hyponatremia (TIH) is 1 of their most clinically significant adverse effects. A priori TIH must result from excessive saliuresis and/or water reabsorption. We hypothesized that pathways regulating the Thiazide-sensitive sodium-chloride cotransporter NCC and the water channel aquaporin-2 (AQP2) may be involved. Our aim was to assess whether patients with TIH would show evidence of altered NCC and AQP2 expression in urinary extracellular vesicles (UEVs), and also whether abnormalities of renal sodium reabsorption would be evident using endogenous lithium clearance (ELC). Methods Blood and urine samples were donated by patients admitted to hospital with acute symptomatic TIH, after recovery to normonatremia, and also from normonatremic controls on and off Thiazides. Urinary extracellular vesicles were isolated and target proteins evaluated by western blotting and by nanoparticle tracking analysis. Endogenous lithium clearance was assessed by inductively coupled plasma mass spectrometry. Results Analysis of UEVs by western blotting showed that patients with acute TIH displayed reduced total NCC and increased phospho-NCC and AQP2 relative to appropriate control groups; smaller differences in NCC and AQP2 expression persisted after recovery from TIH. These findings were confirmed by nanoparticle tracking analysis. Renal ELC was lower in acute TIH compared to that in controls and convalescent case patients. Conclusion Reduced NCC expression and increased AQP2 expression would be expected to result in saliuresis and water reabsorption in TIH patients. This study raises the possibility that UEV analysis may be of diagnostic utility in less clear-cut cases of Thiazide-associated hyponatremia, and may help to identify patients at risk for TIH before Thiazide initiation.
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Urinary Extracellular Vesicle Protein Profiling and Endogenous Lithium Clearance Support Excessive Renal Sodium Wasting and Water Reabsorption in Thiazide-Induced Hyponatremia
Elsevier, 2019Co-Authors: Sarath K. Channavajjhala, Wenjing Jia, Ian P. Hall, Roger Bramley, Theresa Peltz, Wilna Oosthuyzen, Sue Kinnear, Barry Sampson, Nick Martin, Matthew A. BaileyAbstract:Introduction: Thiazide diuretics are among the most widely used antihypertensive medications worldwide. Thiazide-induced hyponatremia (TIH) is 1 of their most clinically significant adverse effects. A priori TIH must result from excessive saliuresis and/or water reabsorption. We hypothesized that pathways regulating the Thiazide-sensitive sodium-chloride cotransporter NCC and the water channel aquaporin-2 (AQP2) may be involved. Our aim was to assess whether patients with TIH would show evidence of altered NCC and AQP2 expression in urinary extracellular vesicles (UEVs), and also whether abnormalities of renal sodium reabsorption would be evident using endogenous lithium clearance (ELC). Methods: Blood and urine samples were donated by patients admitted to hospital with acute symptomatic TIH, after recovery to normonatremia, and also from normonatremic controls on and off Thiazides. Urinary extracellular vesicles were isolated and target proteins evaluated by western blotting and by nanoparticle tracking analysis. Endogenous lithium clearance was assessed by inductively coupled plasma mass spectrometry. Results: Analysis of UEVs by western blotting showed that patients with acute TIH displayed reduced total NCC and increased phospho-NCC and AQP2 relative to appropriate control groups; smaller differences in NCC and AQP2 expression persisted after recovery from TIH. These findings were confirmed by nanoparticle tracking analysis. Renal ELC was lower in acute TIH compared to that in controls and convalescent case patients. Conclusion: Reduced NCC expression and increased AQP2 expression would be expected to result in saliuresis and water reabsorption in TIH patients. This study raises the possibility that UEV analysis may be of diagnostic utility in less clear-cut cases of Thiazide-associated hyponatremia, and may help to identify patients at risk for TIH before Thiazide initiation. Keywords: diuretic, hypertension, hyponatremia, sodium, Thiazide, urinary extracellular vesicle
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Clinical and Molecular Features of Thiazide-Induced Hyponatremia
Current Hypertension Reports, 2018Co-Authors: Jodie Nadal, Jenny Clayton, Sarath K. Channavajjhala, Wenjing Jia, Ian P. Hall, Mark GloverAbstract:Purpose of Review Hypertension affects more than 30% of the world’s adult population and Thiazide (and Thiazide-like) diuretics are amongst the most widely used, effective, and least costly treatments available, with all-cause mortality benefits equivalent to angiotensin-converting enzyme inhibitors or calcium channel antagonists. A minority of patients develop Thiazide-induced hyponatremia (TIH) and this is largely unpredictable at the point of Thiazide prescription. In some cases, TIH can cause debilitating symptoms and require hospital admission. Although TIH affects only a minority of patients exposed to Thiazides, the high prevalence of hypertension leads to TIH being the most common cause of drug-induced hyponatremia requiring hospital admission in the UK. This review examines current clinical and scientific understanding of TIH. Consideration is given to demographic associations, limitations of current electrolyte monitoring regimens, clinical presentation, the phenotype evident on routine clinical blood and urine tests as well as more extensive analyses of blood and urine in research settings, recent genetic associations with TIH, and thoughts on management of the condition. Recent Findings Recent genetic and phenotyping analysis has suggested that prostaglandin E2 pathways in the collecting duct may have a role in the development of TIH in a subgroup of patients. Greater understanding of the molecular pathophysiology of TIH raises the prospect of pre-prescription TIH risk profiling and may offer novel insights into how TIH may be avoided, prevented and treated. Summary The rising prevalence of hypertension and the widespread use of Thiazides mean that further understanding of TIH will continue to be a pressing issue for patients, physicians, and scientists alike for the foreseeable future.
Rene J M Bindels - One of the best experts on this subject based on the ideXlab platform.
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Thiazide induced hypocalciuria is accompanied by a decreased expression of ca2 transport proteins in kidney
Kidney International, 2003Co-Authors: Tom Nijenhuis, Joost G J Hoenderop, Johannes Loffing, Annemiete W C M Van Der Kemp, Rene J M BindelsAbstract:INTRODUCTION: Thiazide diuretics have the unique characteristic of increasing renal Na+ excretion, while decreasing Ca2+ excretion. However, the molecular mechanism responsible for this Thiazide-induced hypocalciuria remains unclear. The present study investigates the effect of Thiazides on the expression of the proteins involved in active Ca2+ transport as well as the role of extracellular volume (ECV) status. METHODS: HydrochloroThiazide (HCTZ), 12 mg/24 hours, was administered during 7 days to Wistar rats by osmotic minipumps. In addition, ECV contraction was either prevented by Na+ repletion or induced by a low-salt diet. Expression levels of the proteins involved in active Ca2+ transport [i.e., epithelial Ca2+ channel (TRPV5/ECaC1), calbindin-D28K, Na+/Ca2+ exchanger (NCX1)], as well as the Thiazide-sensitive Na+ Cl- cotransporter (NCC) were determined by real-time quantitative polymerase chain reaction (PCR) and semiquantitative immunohistochemistry. RESULTS: HCTZ significantly reduced urinary Ca2+ excretion (22%+/- 5% relative to controls). Hematocrit was significantly increased, confirming ECV contraction. In addition, Na+ depletion virtually abolished Ca2+ excretion (8%+/- 1%), while Na+ repletion during HCTZ treatment prevented both ECV contraction and hypocalciuria. HCTZ significantly decreased mRNA expression of TRPV5 (71%+/- 6%), calbindin-D28K (53%+/- 6%), NCX1 (51%+/- 8%) and NCC (50%+/- 11%), regardless of ECV status or calciuresis. Immunohistochemistry revealed reduced TRPV5 (43%+/- 2%), calbindin-D28K (59%+/- 1%) and NCC (56%+/- 4%) abundance. Furthermore, during HCTZ treatment, the subset of tubules coexpressing NCC and calbindin-D28K was significantly reduced (43%+/- 5%) and a disturbed cellular localization of NCC was observed. CONCLUSION: These data suggest that ECV contraction is a critical determinant of the Thiazide-induced hypocalciuria, which is accompanied by a decreased expression of Ca2+ transport proteins.
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Thiazide induced hypocalciuria is accompanied by a decreased expression of ca2 transport proteins in kidney
Kidney International, 2003Co-Authors: Tom Nijenhuis, Joost G J Hoenderop, Johannes Loffing, Annemiete W C M Van Der Kemp, Carel H Van Os, Rene J M BindelsAbstract:Thiazide-induced hypocalciuria is accompanied by a decreased expression of Ca 2+ transport proteins in kidney. Introduction Thiazide diuretics have the unique characteristic of increasing renal Na + excretion, while decreasing Ca 2+ excretion. However, the molecular mechanism responsible for this Thiazide-induced hypocalciuria remains unclear. The present study investigates the effect of Thiazides on the expression of the proteins involved in active Ca 2+ transport as well as the role of extracellular volume (ECV) status. Methods HydrochloroThiazide (HCTZ), 12mg/24hours, was administered during 7days to Wistar rats by osmotic minipumps. In addition, ECV contraction was either prevented by Na + repletion or induced by a low-salt diet. Expression levels of the proteins involved in active Ca 2+ transport [i.e., epithelial Ca 2+ channel (TRPV5/ECaC1), calbindin-D 28K , Na + /Ca 2+ exchanger (NCX1)], as well as the Thiazide-sensitive Na + Cl - cotransporter (NCC) were determined by real-time quantitative polymerase chain reaction (PCR) and semiquantitative immunohistochemistry. Results HCTZ significantly reduced urinary Ca 2+ excretion (22%± 5% relative to controls). Hematocrit was significantly increased, confirming ECV contraction. In addition, Na + depletion virtually abolished Ca 2+ excretion (8%± 1%), while Na + repletion during HCTZ treatment prevented both ECV contraction and hypocalciuria. HCTZ significantly decreased mRNA expression of TRPV5 (71%± 6%), calbindin-D 28K (53%± 6%), NCX1 (51%± 8%) and NCC (50%± 11%), regardless of ECV status or calciuresis. Immunohistochemistry revealed reduced TRPV5 (43%± 2%), calbindin-D 28K (59%± 1%) and NCC (56%± 4%) abundance. Furthermore, during HCTZ treatment, the subset of tubules coexpressing NCC and calbindin-D 28K was significantly reduced (43%± 5%) and a disturbed cellular localization of NCC was observed. Conclusion These data suggest that ECV contraction is a critical determinant of the Thiazide-induced hypocalciuria, which is accompanied by a decreased expression of Ca 2+ transport proteins.
Johannes Loffing - One of the best experts on this subject based on the ideXlab platform.
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Thiazide effects and adverse effects insights from molecular genetics
Hypertension, 2009Co-Authors: David H. Ellison, Johannes LoffingAbstract:One of the longest-running debates in clinical medicine shows no sign of disappearing; just when it seems that Thiazides have reassumed their role as front-line drugs to treat hypertension,1 new concerns emerge,2–4 leading some to question their role once again.5 Thiazides are effective antihypertensives with long track records and low cost. The major concerns about their use arise from their tendency to cause hypokalemia, impair glucose tolerance, increase serum cholesterol, and increase serum uric acid. Few medical controversies have generated as much heat, with well-established camps staking out positions that appear resistant to change.6–9 The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, the largest study of antihypertensive monotherapy ever performed,10 was intended to identify the best first-line treatment for high-risk hypertensive individuals; however, despite its size and the numerous resulting publications, its implications and authority continue to be disputed. The goal of this review is not take sides in this debate but rather to inject a distinct, and sometimes neglected, perspective; during the past 15 years, remarkable developments in molecular biology and human genetics have provided substantial insights into the pathogenesis of hypertension and mechanisms and adverse effects of diuretics. Diuretic proponents and antagonists alike often neglect these developments when addressing the topic; it is the purpose of this Brief Review to integrate these developments into the debate with the goal of generating questions that can be addressed scientifically. Thiazide diuretics were developed during the 1950s, when chemists and physiologists at Merck Sharpe and Dohme tested derivatives of sulfonamide-based carbonic anhydrase inhibitors, with the goal of discovering drugs that enhance the excretion of sodium with chloride rather than sodium bicarbonate.* Although these drugs lower arterial pressure effectively, the mechanisms have long perplexed investigators.11 Thiazides reduce cardiac output acutely by reducing extracellular …
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Thiazide induced hypocalciuria is accompanied by a decreased expression of ca2 transport proteins in kidney
Kidney International, 2003Co-Authors: Tom Nijenhuis, Joost G J Hoenderop, Johannes Loffing, Annemiete W C M Van Der Kemp, Rene J M BindelsAbstract:INTRODUCTION: Thiazide diuretics have the unique characteristic of increasing renal Na+ excretion, while decreasing Ca2+ excretion. However, the molecular mechanism responsible for this Thiazide-induced hypocalciuria remains unclear. The present study investigates the effect of Thiazides on the expression of the proteins involved in active Ca2+ transport as well as the role of extracellular volume (ECV) status. METHODS: HydrochloroThiazide (HCTZ), 12 mg/24 hours, was administered during 7 days to Wistar rats by osmotic minipumps. In addition, ECV contraction was either prevented by Na+ repletion or induced by a low-salt diet. Expression levels of the proteins involved in active Ca2+ transport [i.e., epithelial Ca2+ channel (TRPV5/ECaC1), calbindin-D28K, Na+/Ca2+ exchanger (NCX1)], as well as the Thiazide-sensitive Na+ Cl- cotransporter (NCC) were determined by real-time quantitative polymerase chain reaction (PCR) and semiquantitative immunohistochemistry. RESULTS: HCTZ significantly reduced urinary Ca2+ excretion (22%+/- 5% relative to controls). Hematocrit was significantly increased, confirming ECV contraction. In addition, Na+ depletion virtually abolished Ca2+ excretion (8%+/- 1%), while Na+ repletion during HCTZ treatment prevented both ECV contraction and hypocalciuria. HCTZ significantly decreased mRNA expression of TRPV5 (71%+/- 6%), calbindin-D28K (53%+/- 6%), NCX1 (51%+/- 8%) and NCC (50%+/- 11%), regardless of ECV status or calciuresis. Immunohistochemistry revealed reduced TRPV5 (43%+/- 2%), calbindin-D28K (59%+/- 1%) and NCC (56%+/- 4%) abundance. Furthermore, during HCTZ treatment, the subset of tubules coexpressing NCC and calbindin-D28K was significantly reduced (43%+/- 5%) and a disturbed cellular localization of NCC was observed. CONCLUSION: These data suggest that ECV contraction is a critical determinant of the Thiazide-induced hypocalciuria, which is accompanied by a decreased expression of Ca2+ transport proteins.
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Thiazide induced hypocalciuria is accompanied by a decreased expression of ca2 transport proteins in kidney
Kidney International, 2003Co-Authors: Tom Nijenhuis, Joost G J Hoenderop, Johannes Loffing, Annemiete W C M Van Der Kemp, Carel H Van Os, Rene J M BindelsAbstract:Thiazide-induced hypocalciuria is accompanied by a decreased expression of Ca 2+ transport proteins in kidney. Introduction Thiazide diuretics have the unique characteristic of increasing renal Na + excretion, while decreasing Ca 2+ excretion. However, the molecular mechanism responsible for this Thiazide-induced hypocalciuria remains unclear. The present study investigates the effect of Thiazides on the expression of the proteins involved in active Ca 2+ transport as well as the role of extracellular volume (ECV) status. Methods HydrochloroThiazide (HCTZ), 12mg/24hours, was administered during 7days to Wistar rats by osmotic minipumps. In addition, ECV contraction was either prevented by Na + repletion or induced by a low-salt diet. Expression levels of the proteins involved in active Ca 2+ transport [i.e., epithelial Ca 2+ channel (TRPV5/ECaC1), calbindin-D 28K , Na + /Ca 2+ exchanger (NCX1)], as well as the Thiazide-sensitive Na + Cl - cotransporter (NCC) were determined by real-time quantitative polymerase chain reaction (PCR) and semiquantitative immunohistochemistry. Results HCTZ significantly reduced urinary Ca 2+ excretion (22%± 5% relative to controls). Hematocrit was significantly increased, confirming ECV contraction. In addition, Na + depletion virtually abolished Ca 2+ excretion (8%± 1%), while Na + repletion during HCTZ treatment prevented both ECV contraction and hypocalciuria. HCTZ significantly decreased mRNA expression of TRPV5 (71%± 6%), calbindin-D 28K (53%± 6%), NCX1 (51%± 8%) and NCC (50%± 11%), regardless of ECV status or calciuresis. Immunohistochemistry revealed reduced TRPV5 (43%± 2%), calbindin-D 28K (59%± 1%) and NCC (56%± 4%) abundance. Furthermore, during HCTZ treatment, the subset of tubules coexpressing NCC and calbindin-D 28K was significantly reduced (43%± 5%) and a disturbed cellular localization of NCC was observed. Conclusion These data suggest that ECV contraction is a critical determinant of the Thiazide-induced hypocalciuria, which is accompanied by a decreased expression of Ca 2+ transport proteins.