RESUMEN
The Na+-Cl- cotransporter (NCC) drives salt reabsorption in the kidney and plays a decisive role in balancing electrolytes and blood pressure. Thiazide and thiazide-like diuretics inhibit NCC-mediated renal salt retention and have been cornerstones for treating hypertension and edema since the 1950s. Here we determine NCC co-structures individually complexed with the thiazide drug hydrochlorothiazide, and two thiazide-like drugs chlorthalidone and indapamide, revealing that they fit into an orthosteric site and occlude the NCC ion translocation pathway. Aberrant NCC activation by the WNKs-SPAK kinase cascade underlies Familial Hyperkalemic Hypertension, but it remains unknown whether/how phosphorylation transforms the NCC structure to accelerate ion translocation. We show that an intracellular amino-terminal motif of NCC, once phosphorylated, associates with the carboxyl-terminal domain, and together, they interact with the transmembrane domain. These interactions suggest a phosphorylation-dependent allosteric network that directly influences NCC ion translocation.
Asunto(s)
Hidroclorotiazida , Inhibidores de los Simportadores del Cloruro de Sodio , Miembro 3 de la Familia de Transportadores de Soluto 12 , Fosforilación , Miembro 3 de la Familia de Transportadores de Soluto 12/metabolismo , Miembro 3 de la Familia de Transportadores de Soluto 12/química , Humanos , Hidroclorotiazida/farmacología , Hidroclorotiazida/química , Inhibidores de los Simportadores del Cloruro de Sodio/farmacología , Animales , Clortalidona/metabolismo , Clortalidona/química , Clortalidona/farmacología , Proteínas Quinasas/metabolismo , Proteínas Quinasas/química , Diuréticos/farmacología , Diuréticos/química , Diuréticos/metabolismo , Tiazidas/farmacología , Tiazidas/química , Tiazidas/metabolismo , Células HEK293 , Modelos Moleculares , Proteínas Serina-Treonina QuinasasRESUMEN
Diuretics have been used for decades in the treatment of hypertension. Its efficacy has been demonstrated in numerous clinical trials. It is well known that the reduction in cardiovascular risk is a consequence of the reduction in blood pressure levels regardless of the drug used, but thiazide diuretics continue to be first-line drugs, especially in low doses and combined with other drugs. The debate on the advantages of using chlorthalidone or hydrochlorothiazide continues, however hydrochlorothiazide is drug most used and for which there is greater availability. The association with potassium-sparing diuretics increases the effectiveness and reduces the adverse reactions of thiazides. A new group of drugs, close to potassium-sparing diuretics, that antagonise aldosterone synthase are showing promising results as antihypertensives. There are no significant differences between men and women regarding the antihypertensive effect of thiazide diuretics.
Asunto(s)
Antihipertensivos , Diuréticos , Hipertensión , Humanos , Hipertensión/tratamiento farmacológico , Diuréticos/efectos adversos , Diuréticos/administración & dosificación , Diuréticos/uso terapéutico , Diuréticos/farmacología , Antihipertensivos/efectos adversos , Antihipertensivos/administración & dosificación , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Inhibidores de los Simportadores del Cloruro de Sodio/efectos adversos , Inhibidores de los Simportadores del Cloruro de Sodio/uso terapéutico , Inhibidores de los Simportadores del Cloruro de Sodio/administración & dosificación , Inhibidores de los Simportadores del Cloruro de Sodio/farmacología , Hidroclorotiazida/efectos adversos , Hidroclorotiazida/administración & dosificación , Hidroclorotiazida/uso terapéutico , Clortalidona/administración & dosificación , Clortalidona/uso terapéutico , Clortalidona/efectos adversos , Femenino , Masculino , Quimioterapia CombinadaRESUMEN
Chronic angiotensin II (ANG II) infusion is an experimental model that induces hypertension in rodents. The natriuresis, diuresis, and blood pressure responses differ between males and females. This is perhaps not unexpected, given the rodent kidney, which plays a key role in blood pressure regulation, exhibits marked sex differences. Under normotensive conditions, compared with males, the female rat nephron exhibits lower Na+/H+ exchanger 3 (NHE3) activity along the proximal tubule but higher Na+ transporter activities along the distal segments. ANG II infusion-induced hypertension induces a pressure natriuretic response that reduces NHE3 activity and shifts Na+ transport capacity downstream. The goals of this study were to apply a computational model of epithelial transport along a rat nephron 1) to understand how a 14-day ANG II infusion impacts segmental electrolyte transport in male and female rat nephrons and 2) to identify and explain any sex differences in the effects of loop diuretics, thiazide diuretics, and K+-sparing diuretics. Model simulations suggest that the NHE3 downregulation in the proximal tubule is a major contributor to natriuresis and diuresis in hypertension, with the effects stronger in males. All three diuretics are predicted to induce stronger natriuretic and diuretic effects under hypertension compared with normotension, with relative increases in sodium excretion higher in hypertensive females than in males. The stronger natriuretic responses can be explained by the downstream shift of Na+ transport load in hypertension and by the larger distal transport load in females, both of which limit the ability of the distal segments to further elevate their Na+ transport.NEW & NOTEWORTHY Sex differences in the prevalence of hypertension are found in human and animal models. The kidney, which regulates blood pressure, exhibits sex differences in morphology, hemodynamics, and membrane transporter distributions. This computational modeling study provides insights into how the sexually dimorphic responses to a 14-day angiotensin II infusion differentially impact segmental electrolyte transport in rats. Simulations of diuretic administration explain how the natriuretic and diuretic effects differ between normotension and hypertension and between the sexes.
Asunto(s)
Angiotensina II , Hipertensión , Natriuresis , Intercambiador 3 de Sodio-Hidrógeno , Animales , Hipertensión/inducido químicamente , Hipertensión/metabolismo , Hipertensión/fisiopatología , Masculino , Femenino , Intercambiador 3 de Sodio-Hidrógeno/metabolismo , Natriuresis/efectos de los fármacos , Diuréticos/farmacología , Presión Sanguínea/efectos de los fármacos , Factores Sexuales , Simulación por Computador , Sodio/metabolismo , Ratas , Inhibidores de los Simportadores del Cloruro de Sodio/farmacología , Caracteres Sexuales , Modelos Animales de Enfermedad , Diuresis/efectos de los fármacos , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico/farmacología , Riñón/metabolismo , Riñón/efectos de los fármacos , Riñón/fisiopatologíaRESUMEN
BACKGROUND: The magnitude of blood pressure (BP)-lowering effects and decrease of the adverse effects of thiazide diuretics provided by potassium-sparing diuretics remain uncertain. The aim of this study was to compare the BP-lowering efficacy and the incidence of adverse effects of high (T+) and low-dose (T-) thiazide diuretics, alone or combined with high (PS+) or low-dose (PS-) potassium-sparing diuretics in patients with primary hypertension. METHODS: A systematic literature search was performed in PubMed/MEDLINE, the Cochrane Central Register of Controlled Trials, Embase, Web of Science, Scopus and LILACS. Randomized double-blind placebo or active-controlled trials (RCT) with 3 weeks to 1 year of follow-up were included. Sample size, mean and standard deviation from baseline, follow-up and change from baseline values were extracted by two independent reviewers. Pairwise random effect models and Bayesian network meta-analysis models were used to compare the effects of treatments. The risk of bias in individual studies was assessed using the Rob 1.0 tool. The primary outcome was the mean difference in office SBP. Secondary outcomes were the mean difference in biochemical parameters and the incidence of nonmelanoma skin cancer. RESULTS: Two hundred and seventy-six double-blind RCTs involving 58â807 participants (mean age: 55âyears; 45% women) were included. All treatment groups were more effective than placebo in lowering BP, with mean differences (MDs) of change from baseline ranging from -7.66âmmHg [95% credible interval (95% CrI), -8.53 to -6.79] for T- to -12.77âmmHg (95% CrI, -15.22 to -10.31) for T+PS-. T+ alone or combined with potassium-sparing was more effective in reducing BP than T-. The surface under the cumulative ranking curve (SUCRA) estimated ranking showed that the best effectiveness in lowering SBP was found for T+PS- (0.69), T+PS+ (0.65) and T+ (0.54). Compared with placebo, all treatments (except T-PS-) were associated with more potassium reduction and T+ compared with all other treatments and T- when compared with T-PS-. Compared with placebo, all active treatments (except T+PS+) showed higher elevations of uric acid. The increase of plasma glucose promoted by thiazides alone was reduced by potassium-sparing agents. CONCLUSION: Thiazides with potassium-sparing diuretics are associated with increased BP-lowering efficacy compared with thiazides alone while minimizing hypokalaemia and hyperglycaemia. These findings demonstrate that thiazide and potassium-sparing diuretic combination is preferable to thiazide alone in treating hypertension.
Asunto(s)
Hipertensión , Inhibidores de los Simportadores del Cloruro de Sodio , Humanos , Femenino , Persona de Mediana Edad , Masculino , Inhibidores de los Simportadores del Cloruro de Sodio/uso terapéutico , Inhibidores de los Simportadores del Cloruro de Sodio/farmacología , Antihipertensivos/uso terapéutico , Metaanálisis en Red , Teorema de Bayes , Ensayos Clínicos Controlados Aleatorios como Asunto , Hipertensión/tratamiento farmacológico , Hipertensión/inducido químicamente , Presión Sanguínea , Diuréticos Conservadores de Potasio/uso terapéutico , Tiazidas/uso terapéutico , Potasio/farmacología , Diuréticos/uso terapéuticoRESUMEN
Sodium chloride cotransporter (NCC) plays a crucial role in regulating blood pressure through Na+ reabsorption. Recently, in Nature, Fan et al. determined the structure of human NCC and revealed the mechanism of action of thiazide diuretics, establishing the groundwork for future drug development.1.
Asunto(s)
Natriuresis , Sodio , Humanos , Sodio/metabolismo , Simportadores del Cloruro de Sodio , Inhibidores de los Simportadores del Cloruro de Sodio/farmacología , BiologíaRESUMEN
SIGNIFICANCE STATEMENT: Thiazide diuretics (thiazides) are among the most widely prescribed drugs worldwide, but their use is associated with glucose intolerance and new-onset diabetes mellitus. The molecular mechanisms remain elusive. Our study reveals that thiazides attenuate insulin secretion through inhibition of the mitochondrial carbonic anhydrase isoform 5b (CA5b) in pancreatic ß cells. We furthermore discovered that pancreatic ß cells express only one functional carbonic anhydrase isoform, CA5b, which is critical in replenishing oxaloacetate in the mitochondrial tricarboxylic acid (TCA) cycle (anaplerosis). These findings explain the mechanism for thiazide-induced glucose intolerance and reveal a fundamental role of CA5b in TCA cycle anaplerosis and insulin secretion in ß cells. BACKGROUND: Thiazide diuretics are associated with glucose intolerance and new-onset diabetes mellitus. Previous studies demonstrated that thiazides attenuate insulin secretion, but the molecular mechanisms remain elusive. We hypothesized that thiazides attenuate insulin secretion via one of the known molecular thiazide targets in ß cells. METHODS: We performed static insulin secretion experiments with islets of wild-type, Sodium/chloride co-transporter (NCC) (SLC12A3), and sodium-driven chloride/bicarbonate exchanger (NDCBE) (SLC4A8) knock-out (KO) mice and with murine Min6 cells with individual knockdown of carbonic anhydrase (CA) isoforms to identify the molecular target of thiazides in ß cells. CA isoform 5b (CA5b) KO mice were then used to assess the role of the putative thiazide target CA5b in ß -cell function and in mediating thiazide sensitivity in vitro and in vivo . RESULTS: Thiazides inhibited glucose- and sulfonylurea-stimulated insulin secretion in islets and Min6 cells at pharmacologically relevant concentrations. Inhibition of insulin secretion by thiazides was CO 2 /HCO 3- -dependent, not additive to unselective CA inhibition with acetazolamide, and independent of extracellular potassium. By contrast, insulin secretion was unaltered in islets of mice lacking the known molecular thiazide targets NCC or NDCBE. CA expression profiling with subsequent knockdown of individual CA isoforms suggested mitochondrial CA5b as a molecular target. In support of these findings, thiazides significantly attenuated Krebs cycle anaplerosis through reduction of mitochondrial oxaloacetate synthesis. CA5b KO mice were resistant to thiazide-induced glucose intolerance, and thiazides did not alter insulin secretion in CA5b KO islets. CONCLUSIONS: Thiazides attenuate insulin secretion via inhibition of the mitochondrial CA5b isoform in ß cells of mice.
Asunto(s)
Anhidrasas Carbónicas , Diabetes Mellitus , Intolerancia a la Glucosa , Células Secretoras de Insulina , Islotes Pancreáticos , Ratones , Animales , Secreción de Insulina , Tiazidas/farmacología , Inhibidores de los Simportadores del Cloruro de Sodio/metabolismo , Inhibidores de los Simportadores del Cloruro de Sodio/farmacología , Cloruros/metabolismo , Glucosa/metabolismo , Anhidrasas Carbónicas/metabolismo , Sodio/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/metabolismoRESUMEN
The sodium-chloride cotransporter (NCC) is critical for kidney physiology1. The NCC has a major role in salt reabsorption in the distal convoluted tubule of the nephron2,3, and mutations in the NCC cause the salt-wasting disease Gitelman syndrome4. As a key player in salt handling, the NCC regulates blood pressure and is the target of thiazide diuretics, which have been widely prescribed as first-line medications to treat hypertension for more than 60 years5-7. Here we determined the structures of human NCC alone and in complex with a commonly used thiazide diuretic using cryo-electron microscopy. These structures, together with functional studies, reveal major conformational states of the NCC and an intriguing regulatory mechanism. They also illuminate how thiazide diuretics specifically interact with the NCC and inhibit its transport function. Our results provide critical insights for understanding the Na-Cl cotransport mechanism of the NCC, and they establish a framework for future drug design and for interpreting disease-related mutations.
Asunto(s)
Microscopía por Crioelectrón , Inhibidores de los Simportadores del Cloruro de Sodio , Tiazidas , Humanos , Diuréticos/química , Diuréticos/farmacología , Diseño de Fármacos , Síndrome de Gitelman/genética , Inhibidores de los Simportadores del Cloruro de Sodio/química , Inhibidores de los Simportadores del Cloruro de Sodio/farmacología , Tiazidas/química , Tiazidas/farmacologíaRESUMEN
Sex differences in renal function and blood pressure have been widely described across many species. Blood pressure dips during sleep and peaks in the early morning. Similarly, glomerular filtration rate, filtered electrolyte loads, urine volume, and urinary excretion all exhibit notable diurnal rhythms, which reflect, in part, the regulation of renal transporter proteins by circadian clock genes. That regulation is sexually dimorphic; as such, sex and time of day are not two independent regulators of kidney function and blood pressure. The objective of the present study was to assess the effect of sex and administration time on the natriuretic and diuretic effects of loop, thiazide, and K+-sparing diuretics, which are common treatments for hypertension. Loop diuretics inhibit Na+-K+-2Cl- cotransporters on the apical membrane of the thick ascending limb, thiazide diuretics inhibit Na+-Cl- cotransporters on the distal convoluted tubule, and K+-sparing diuretics inhibit epithelial Na+ channels on the connecting tubule and collecting duct. We simulated Na+ transporter inhibition using sex- and time-of-day-specific computational models of mouse kidney function. The simulation results highlighted significant sex and time-of-day differences in the drug response. Loop diuretics induced larger natriuretic and diuretic effects during the active phase. The natriuretic and diuretic effects of thiazide diuretics exhibited sex and time-of-day differences, whereas these effects of K+-sparing diuretics exhibited a significant time-of-day difference in females only. The kaliuretic effect depended on the type of diuretics and time of administration. The present computational models can be a useful tool in chronotherapy, to tailor drug administration time to match the body's diurnal rhythms to optimize the drug effect.NEW & NOTEWORTHY Sex influences cardiovascular disease, and the timing of onset of acute cardiovascular events exhibits circadian rhythms. Kidney function also exhibits sex differences and circadian rhythms. How do the natriuretic and diuretic effects of diuretics, a common treatment for hypertension that targets the kidneys, differ between the sexes? And how do these effects vary during the day? To answer these questions, we conducted computer simulations to assess the effects of loop, thiazide, and K+-sparing diuretics.
Asunto(s)
Diuréticos , Hipertensión , Femenino , Masculino , Ratones , Animales , Diuréticos/farmacología , Inhibidores de los Simportadores del Cloruro de Sodio/farmacología , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico/farmacología , Hipertensión/metabolismo , Túbulos Renales Distales/metabolismo , Sodio/metabolismo , Tiazidas/metabolismo , Tiazidas/farmacología , Tiazidas/uso terapéuticoRESUMEN
The thiazide-sensitive Na+-Cl- cotransporter (NCC) is the major pathway for salt reabsorption in the mammalian distal convoluted tubule, and the inhibition of its function with thiazides is widely used for the treatment of arterial hypertension. In mammals and teleosts, NCC is present as one ortholog that is mainly expressed in the kidney. One exception, however, is the eel, which has two genes encoding NCC. The eNCCα is located in the kidney and eNCCß, which is present in the apical membrane of the rectum. Interestingly, the European eNCCß functions as a Na+-Cl- cotransporter that is nevertheless resistant to thiazides and is not activated by low-chloride hypotonic stress. However, in the Japanese eel rectal sac, a thiazide-sensitive NaCl transport mechanism has been described. The protein sequences between eNCCß and jNCCß are 98% identical. Here, by site-directed mutagenesis, we transformed eNCCß into jNCCß. Our data showed that jNCCß, similar to eNCCß, is resistant to thiazides. In addition, both NCCß proteins have high transport capacity with respect to their renal NCC orthologs and, in contrast to known NCCs, exhibit electrogenic properties that are reduced when residue I172 is substituted by A, G, or M. This is considered a key residue for the chloride ion-binding sites of NKCC and KCC. We conclude that NCCß proteins are not sensitive to thiazides and have electrogenic properties dependent on Cl-, and site I172 is important for the function of NCCß.
Asunto(s)
Cloruros , Inhibidores de los Simportadores del Cloruro de Sodio , Animales , Cloruros/metabolismo , Anguilas/metabolismo , Mamíferos/metabolismo , Cloruro de Sodio , Inhibidores de los Simportadores del Cloruro de Sodio/metabolismo , Inhibidores de los Simportadores del Cloruro de Sodio/farmacología , Simportadores del Cloruro de Sodio/genética , Simportadores del Cloruro de Sodio/metabolismo , Miembro 3 de la Familia de Transportadores de Soluto 12/genética , Tiazidas/farmacologíaRESUMEN
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.
Asunto(s)
Hipertensión , Inhibidores de los Simportadores del Cloruro de Sodio , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Presión Sanguínea , Diuréticos/uso terapéutico , Quimioterapia Combinada , Humanos , Hidroclorotiazida/uso terapéutico , Inhibidores de los Simportadores del Cloruro de Sodio/farmacología , Resultado del TratamientoRESUMEN
Two orthologues of the gene encoding the Na+-Cl- cotransporter (NCC), termed ncca and nccb, were found in the sea lamprey genome. No gene encoding the Na+-K+-2Cl- cotransporter 2 (nkcc2) was identified. In a phylogenetic comparison among other vertebrate NCC and NKCC sequences, the sea lamprey NCCs occupied basal positions within the NCC clades. In freshwater, ncca mRNA was found only in the gill and nccb only in the intestine, whereas both were found in the kidney. Intestinal nccb mRNA levels increased during late metamorphosis coincident with salinity tolerance. Acclimation to seawater increased nccb mRNA levels in the intestine and kidney. Electrophysiological analysis of intestinal tissue ex vivo showed this tissue was anion absorptive. After seawater acclimation, the proximal intestine became less anion absorptive, whereas the distal intestine remained unchanged. Luminal application of indapamide (an NCC inhibitor) resulted in 73% and 30% inhibition of short-circuit current (Isc) in the proximal and distal intestine, respectively. Luminal application of bumetanide (an NKCC inhibitor) did not affect intestinal Isc. Indapamide also inhibited intestinal water absorption. Our results indicate that NCCb is likely the key ion cotransport protein for ion uptake by the lamprey intestine that facilitates water absorption in seawater. As such, the preparatory increases in intestinal nccb mRNA levels during metamorphosis of sea lamprey are likely critical to development of whole animal salinity tolerance.
Asunto(s)
Transporte Iónico/genética , Osmorregulación/genética , Petromyzon/genética , Tolerancia a la Sal/genética , Miembro 3 de la Familia de Transportadores de Soluto 12/genética , Secuencia de Aminoácidos , Animales , Bumetanida/farmacología , Agua Dulce/química , Branquias/metabolismo , Indapamida/farmacología , Intestinos/metabolismo , Transporte Iónico/efectos de los fármacos , Metamorfosis Biológica/efectos de los fármacos , Metamorfosis Biológica/genética , Petromyzon/metabolismo , Filogenia , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Salinidad , Tolerancia a la Sal/efectos de los fármacos , Agua de Mar/química , Inhibidores de los Simportadores del Cloruro de Sodio/farmacología , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico/farmacología , Simportadores de Cloruro de Sodio-Potasio/genética , Simportadores de Cloruro de Sodio-Potasio/metabolismo , Miembro 3 de la Familia de Transportadores de Soluto 12/metabolismo , Agua/metabolismoRESUMEN
BACKGROUND: In typical cases of Bartter syndrome (BS), assessing response to diuretics (furosemide and thiazide), hereinafter referred to as diuretic loading test, may be used to diagnose the type by detecting which part of the kidney tubule is not functioning correctly. However, the diuretic loading test may not always agree with the results of genetic analyses. CASE PRESENTATION: A 5-year-old boy was admitted due to lower extremity weakness and abnormal gait. He had a recurrent episode of muscle weakness and laboratory results showed severe hypokalemia. The direct genomic sequencing of the case revealed a new mutation in the SLC12A1 gene, which is associated with type I Bartter syndrome. Because there was the difference between the phenotype and genotype, we conducted a diuretic loading test to confirm the diagnosis. However, the results showed a clear increase in urine excretion of Na and Cl. These results were not consistent with typical type I BS, but consistent with the patient's phenotype. CONCLUSION: The diuretic loading test has limited utility for diagnosis especially in atypical cases. On the other hand, this test, which allows assessment of channel function, is useful for better understanding of the genotype-phenotype correlation.
Asunto(s)
Síndrome de Bartter/diagnóstico , Diuresis/efectos de los fármacos , Diuréticos/farmacología , Pruebas Genéticas , Síndrome de Bartter/complicaciones , Síndrome de Bartter/genética , Preescolar , Furosemida/farmacología , Genotipo , Humanos , Hipopotasemia/etiología , Masculino , Inhibidores de los Simportadores del Cloruro de Sodio/farmacologíaRESUMEN
OBJECTIVE: The pharmacological additional information for many medications includes warnings stating that the blood sugar control may be worsened by the intake of certain drugs. However a quantification of the effects is missing. This may result in confusion for patients as well as for their physicians. The aim of this study was to assess a potential association between medication (beta blockers, thiazides, levothyroxine) and HbA1c in people without diabetes. METHODS: In this cross-sectional study we analysed data from 2 921 people (7 699 visits) without diabetes (age 46.6 y; 69.1% women; BMI 27.6±6.4 kg/m²; HbA1c 5.2%) who had at least one HbA1c determination and a complete documentation of their drug intake. An oral glucose tolerance test was not performed. The participants were divided in 8 groups (no regular drug intake, levothyroxine alone, beta blockers alone, thiazides alone, combination 2 of 3, combination of all 3). Patients with known distorting influences of the HbA1c were excluded. RESULTS: People with no regular drug intake had an HbA1c of 5.4% [35.8 mmol/mol]. The HbA1c of the group that took all 3 drugs in combination was 5.6% [38.2 mmol/mol]. A multiple linear mixed model showed an increase in HbA1c for thiazides (ß=0.0558, p=0.025) and a decrease for combination of levothyroxine and thiazide (ß=-0.0765, p=0.010). CONCLUSION: Thiazides and the combination of levothyroxine and thiazides were associated with slight changes in HbA1c. In this study there was no association between the intake of beta blockers and HbA1c. At least for people without diabetes these effects seem to be of minor importance.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacología , Hemoglobina Glucada/efectos de los fármacos , Control Glucémico , Inhibidores de los Simportadores del Cloruro de Sodio/farmacología , Tiroxina/farmacología , Antagonistas Adrenérgicos beta/efectos adversos , Adulto , Estudios Transversales , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de los Simportadores del Cloruro de Sodio/efectos adversos , Tiroxina/efectos adversosRESUMEN
Pulse pressure naturally increases over time as individuals' age due to arteriosclerosis and diffuse vascular stiffening. However, the differential for widened pulse pressure is broad and includes causes of hyperdynamic circulation and high-output heart failure, such as aortic regurgitation and hyperthyroidism. In the absence of an underlying cause, wide pulse pressure is a sign of deteriorating cardiovascular health and carries increased risk for mortality, disease progression, and adverse clinical outcomes in chronic diseases including cardiovascular disease and chronic kidney disease. Current emphasis of antihypertensive treatment on systolic and diastolic blood pressure does not always address pulse pressure, thus subjecting many patients to an independent risk factor for poor outcomes. Pulse pressure control is more successfully achieved with thiazide diuretics and long-acting nitrates when compared to other antihypertensive agents, but further research is needed to quantify the additional benefits of pulse pressure control over conventional blood pressure therapy. This case review provides an overview of the pathogenesis, pathologic causes, and treatment of widened pulse pressure and evaluates current evidence for pulse pressure as a predictor of clinical outcomes.
Asunto(s)
Enfermedades Cardiovasculares , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Enfermedades Cardiovasculares/tratamiento farmacológico , Humanos , Inhibidores de los Simportadores del Cloruro de Sodio/farmacologíaRESUMEN
Zn2+ deficiency (ZnD) is a common comorbidity of many chronic diseases. In these settings, ZnD exacerbates hypertension. Whether ZnD alone is sufficient to alter blood pressure (BP) is unknown. To explore the role of Zn2+ in BP regulation, adult mice were fed a Zn2+-adequate (ZnA) or a Zn2+-deficient (ZnD) diet. A subset of ZnD mice were either returned to the ZnA diet or treated with hydrochlorothiazide (HCTZ), a Na+-Cl- cotransporter (NCC) inhibitor. To reduce intracellular Zn2+ in vitro, mouse distal convoluted tubule cells were cultured in N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN, a Zn2+ chelator)- or vehicle (DMSO)-containing medium. To replete intracellular Zn2+, TPEN-exposed cells were then cultured in Zn2+-supplemented medium. ZnD promoted a biphasic BP response, characterized by episodes of high BP. BP increases were accompanied by reduced renal Na+ excretion and NCC upregulation. These effects were reversed in Zn2+-replete mice. Likewise, HCTZ stimulated natriuresis and reversed BP increases. In vitro, Zn2+ depletion increased NCC expression. Furthermore, TPEN promoted NCC surface localization and Na+ uptake activity. Zn2+ repletion reversed TPEN effects on NCC. These data indicate that 1) Zn2+ contributes to BP regulation via modulation of renal Na+ transport, 2) renal NCC mediates ZnD-induced hypertension, and 3) NCC is a Zn2+-regulated transporter that is upregulated with ZnD. This study links dysregulated renal Na+ handling to ZnD-induced hypertension. Furthermore, NCC is identified as a novel mechanism by which Zn2+ regulates BP. Understanding the mechanisms of ZnD-induced BP dysregulation may have an important therapeutic impact on hypertension.
Asunto(s)
Hipertensión/metabolismo , Riñón/metabolismo , Sodio/metabolismo , Zinc/deficiencia , Animales , Presión Sanguínea/efectos de los fármacos , Células Cultivadas , Quelantes/farmacología , Dieta , Etilenodiaminas/farmacología , Hidroclorotiazida/farmacología , Hipertensión/etiología , Túbulos Renales Distales/efectos de los fármacos , Túbulos Renales Distales/metabolismo , Ratones , Ratones Endogámicos C57BL , Natriuresis/efectos de los fármacos , Inhibidores de los Simportadores del Cloruro de Sodio/farmacologíaAsunto(s)
Hidroclorotiazida/uso terapéutico , Hipertensión/tratamiento farmacológico , Tiazidas/uso terapéutico , Monitoreo Ambulatorio de la Presión Arterial/métodos , Anhidrasas Carbónicas/efectos de los fármacos , Clortalidona/farmacocinética , Clortalidona/uso terapéutico , Diuréticos/uso terapéutico , Endotelio/efectos de los fármacos , Endotelio/metabolismo , Endotelio/fisiología , Guías como Asunto , Humanos , Hipertensión/fisiopatología , Agregación Plaquetaria/efectos de los fármacos , Estudios Retrospectivos , Inhibidores de los Simportadores del Cloruro de Sodio/farmacología , Inhibidores de los Simportadores del Cloruro de Sodio/uso terapéuticoAsunto(s)
Hipertensión , Osteoporosis/complicaciones , Fracturas Osteoporóticas/prevención & control , Inhibidores de los Simportadores del Cloruro de Sodio/farmacología , Antihipertensivos/farmacología , Humanos , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Inhibidores de los Simportadores del Cloruro de Sodio/uso terapéutico , Resultado del TratamientoRESUMEN
Left ventricular hypertrophy develops in 36%-41% of hypertensive patients and independently predicts cardiovascular events and total mortality. Moreover, drug-induced reduction in left ventricular mass (LVM) correlates with improved prognosis. The optimal thiazide-type diuretic for reducing LVM is unknown. Evidence regarding potency, cardiovascular events, sodium, and potassium suggested the hypothesis that "CHIP" diuretics (CHlorthalidone, Indapamide, and Potassium-sparing diuretic/hydrochlorothiazide [PSD/HCTZ]) would reduce LVM more than HCTZ. Systematic searches of five databases were conducted. Among the 38 randomized trials, a 1% reduction in systolic blood pressure (SBP) predicted a 1% reduction in LVM, P = 0.00001. CHIP-HCTZ differences in reducing LVM differed across trials (ie, heterogeneity), making interpretation uncertain. However, among the 28 double-blind trials, heterogeneity was undetectable, and HCTZ reduced LVM (percent reduction [95% CI]) by -7.3 (-10.4, -4.2), P < 0.0001. CHIP diuretics surpassed HCTZ in reducing LVM: chlorthalidone -8.2 (-14.7, -1.6), P = 0.015; indapamide -7.5 (-12.7, -2.3), P = 0.005; and all CHIP diuretics combined -7.7 (-12.2, -3.1), P < 0.001. The comparison of PSD/HCTZ with HCTZ had low statistical power but favored PSD/HCTZ: -6.0 (-14.1, +2.1), P = 0.149. Thus, compared to HCTZ, CHIP diuretics had twice the effect on LVM. CHIP diuretics did not surpass HCTZ in reducing systolic or diastolic blood pressure: -0.3 (-5.0, +4.3) and -1.6 (-5.6, +2.4), respectively. The strength of evidence that CHIP diuretics surpass HCTZ for reducing LVM was high (GRADE criteria). In conclusion, these novel results have demonstrated that CHIP diuretics reduce LVM 2-fold more than HCTZ among hypertensive patients. Although generally related to LVM, blood pressure fails to explain the superiority of CHIP diuretics for reducing LVM.
Asunto(s)
Clortalidona/farmacología , Diuréticos Conservadores de Potasio/farmacología , Hidroclorotiazida/farmacología , Hipertensión/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Indapamida/farmacología , Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Clortalidona/administración & dosificación , Clortalidona/uso terapéutico , Diuréticos Conservadores de Potasio/administración & dosificación , Diuréticos Conservadores de Potasio/uso terapéutico , Quimioterapia Combinada/métodos , Femenino , Humanos , Hidroclorotiazida/administración & dosificación , Hidroclorotiazida/uso terapéutico , Hipertensión/complicaciones , Hipertensión/fisiopatología , Hipertrofia Ventricular Izquierda/epidemiología , Hipertrofia Ventricular Izquierda/fisiopatología , Hipertrofia Ventricular Izquierda/prevención & control , Indapamida/administración & dosificación , Indapamida/uso terapéutico , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Inhibidores de los Simportadores del Cloruro de Sodio/farmacología , Tiazidas/farmacología , Tiazidas/uso terapéuticoRESUMEN
Active reabsorption of magnesium (Mg2+ ) in the distal convoluted tubule (DCT) of the kidney is crucial for maintaining Mg2+ homeostasis. Impaired activity of the Na+ -Cl- -cotransporter (NCC) has been associated with hypermagnesiuria and hypomagnesemia, while increased activity of NCC, as observed in patients with Gordon syndrome, is not associated with alterations in Mg2+ balance. To further elucidate the possible interrelationship between NCC activity and renal Mg2+ handling, plasma Mg2+ levels and urinary excretion of sodium (Na+ ) and Mg2+ were measured in a mouse model of Gordon syndrome. In this model, DCT1-specific expression of a constitutively active mutant form of the NCC-phosphorylating kinase, SPAK (CA-SPAK), increases NCC activity and hydrochlorothiazide (HCTZ)-sensitive Na+ reabsorption. These mice were normomagnesemic and HCTZ administration comparably reduced plasma Mg2+ levels in CA-SPAK mice and control littermates. As inferred by the initial response to HCTZ, CA-SPAK mice exhibited greater NCC-dependent Na+ reabsorption together with decreased Mg2+ reabsorption, compared to controls. Following prolonged HCTZ administration (4 days), CA-SPAK mice exhibited higher urinary Mg2+ excretion, while urinary Na+ excretion decreased to levels observed in control animals. Surprisingly, CA-SPAK mice had unaltered renal expression of Trpm6, encoding the Mg2+ -permeable channel TRPM6, or other magnesiotropic genes. In conclusion, CA-SPAK mice exhibit normomagnesemia, despite increased NCC activity and Na+ reabsorption. Thus, Mg2+ reabsorption is not coupled to increased thiazide-sensitive Na+ reabsorption, suggesting a similar process explains normomagnesemia in Gordon syndrome. Further research is required to unravel the molecular underpinnings of this phenomenon and the more pronounced Mg2+ excretion after prolonged HCTZ administration.
Asunto(s)
Artrogriposis/metabolismo , Fisura del Paladar/metabolismo , Pie Equinovaro/metabolismo , Deformidades Congénitas de la Mano/metabolismo , Magnesio/metabolismo , Reabsorción Renal , Sodio/metabolismo , Animales , Proteínas de Transporte de Catión/genética , Proteínas de Transporte de Catión/metabolismo , Femenino , Hidroclorotiazida/farmacología , Riñón/efectos de los fármacos , Riñón/metabolismo , Masculino , Ratones , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Inhibidores de los Simportadores del Cloruro de Sodio/farmacología , Miembro 3 de la Familia de Transportadores de Soluto 12/genética , Miembro 3 de la Familia de Transportadores de Soluto 12/metabolismo , Canales Catiónicos TRPM/genética , Canales Catiónicos TRPM/metabolismoRESUMEN
BACKGROUND: Currently, the vasopressin V2 receptor antagonist tolvaptan is the only available treatment for autosomal dominant polycystic kidney disease (ADPKD), but there are tolerability issues due to aquaretic side-effects such as polyuria. A possible strategy to ameliorate these side-effects may be addition of a thiazide diuretic, this is an established treatment in nephrogenic diabetes insipidus, a condition where vasopressin V2 receptor function is absent. CASE PRESENTATION: We describe a 46-year-old male ADPKD-patient, who was prescribed tolvaptan, which caused polyuria of around 5 l per day. Hydrochlorothiazide was added to treat hypertension, which resulted in a marked decrease in urine production. While using tolvaptan, rate of eGFR decline was - 1.35 mL/min/1.73m2 per year, whereas after hydrochlorothiazide was initiated this was - 3.97 mL/minute/1.73m2 per year. CONCLUSIONS: This case report indicates that while addition of hydrochlorothiazide may improve tolerability of vasopressin V2 receptor antagonists, co-prescription should only be used with great scrutiny as it may decrease tolvaptan effect on rate of ADPKD disease progression.