Gender differences of sodium metabolism and hyponatremia as an adverse drug effect.
Gender-related differences in sodium (Na+) metabolism, Na+ transport through cell membrane, intracellular Na+ concentration, and Na+ urinary excretion review is presented in the article. Literature data on gender-related differences in the occurrence of hyponatremia and related neurology are overviewed. Some of the drugs used in neurology (carbamazepine, oxcarbazepine, thiazides, antidepressants) are pointed out as eventual sources of hyponatremia. This disorder shows a clear-cut preference of the feminine gender. The authors present literature data on gender-related differences in the mechanisms of Na+ transport (Na+/H+ exchange, Na+/K+/2Cl- cotransport, Na+, K+-ATPase). The reasons for such differences are not yet known. Investigative tests with animals of both genders, cellular studies and clinical investigations with human males and females could help to answer question why females are more prone to hyponatremia, to select more efficient measures for prevention of hyponatremia and to differentiate specific peculiarities of treatment for patients of either sex. (+info)
Gitelman syndrome: genetic and expression analysis of the thiazide-sensitive sodium-chloride transporter in blood cells.
Gitelman syndrome is caused by mutations of the SLC12A3 gene, which encodes the thiazide-sensitive NaCl transporter NCCT. Although several mutations causing Gitelman syndrome have been described, their molecular consequences have been rarely studied. We report a patient with Gitelman syndrome due to a mutation in the GT donor splicing site of intron 9. The analysis of RNA from peripheral blood cells showed a complete deletion of exon 9. This case report confirms the feasibility of using readily accessible blood cells to study the expression of the SLC12A3 gene, a procedure that may facilitate further studies of the functional genomics of Gitelman syndrome. (+info)
Sexual dysfunction in female hypertensives.
PURPOSE: Hypertension and its treatment are known to produce sexual dysfunction in males. In our culture, women are not free to discuss issues of sexuality with their doctors. Hence, this phenomenon has not been explored in them. Notwithstanding this, cases occur in practice where noncompliance with dire consequences result from sexual dysfunction. This study was done to determine if any dysfunction existed among women as is commonly reported in males. METHODOLOGY: As part of a larger study on serum uric acid and lipid profile of adult Nigerian hypertensives, we sought information on sexual function in females. One group was newly diagnosed and treatment naive, while the other was made up of known hypertensives on thiazides. The third group consisted of normotensive age-matched controls. FINDINGS: Six out of 44 (13.6%) in the first group, five out of 29 (17.2%) in the second group and two out of 43 (4.7%) in the control group reported sexual dysfunction. The commonest aspect encountered was reduced desire for intercourse. CONCLUSION: There was a tendency for hypertensive women to have more sexual dysfunction even before treatment than did controls. Larger studies should be undertaken and clinicians should probe this subject if poor compliance is suspected. (+info)
Affinity-defining domains in the Na-Cl cotransporter: a different location for Cl- and thiazide binding.
The thiazide-sensitive Na+-Cl- cotransporter (NCC) is the major pathway for salt reabsorption in the distal convoluted tubule, serves as a receptor for thiazide-type diuretics, and is involved in inherited diseases associated with abnormal blood pressure. Little is known regarding the structure-function relationship in this cotransporter. Previous studies from our group reveal that mammalian NCC exhibits higher affinity for ions and thiazides than teleost NCC and suggest a role for glycosylation upon thiazide affinity. Here we have constructed a series of chimeric and mutant cDNAs between rat and flounder NCC to define the role of glycosylation status, the amino-terminal domain, the carboxyl-terminal domain, the extracellular glycosylated loop, and the transmembrane segments upon affinity for Na+, Cl-, and metolazone. Xenopus laevis oocytes were used as the heterologous expression system. We observed that elimination of glycosylation sites in flounder NCC did not affect the affinity of the cotransporter for metolazone. Also, swapping the amino-terminal domain, the carboxyl-terminal domain, the glycosylation sites, or the entire extracellular glycosylation loop between rat and flounder NCC had no effect upon ions or metolazone affinity. In contrast, interchanging transmembrane regions between rat and flounder NCC revealed that affinity-modifying residues for chloride are located within the transmembrane 1-7 region and for thiazides are located within the transmembrane 8-12 region, whereas both segments seem to be implicated in defining sodium affinity. These observations strongly suggest that binding sites for chloride and thiazide in NCC are different. (+info)
Antihypertensive treatment with beta-blockers and the spectrum of glycaemic control.
Hypertension and type 2 diabetes mellitus (DM) are major cardiovascular risk factors, and often cluster in the same individual in the context of the metabolic syndrome. Management of hypertension in the diabetic patient is extremely important, and agents from all major antihypertensive classes are effective towards this goal. Conventional beta-blockers are associated with detrimental effects on insulin sensitivity, glycaemic control, and the incidence of type 2 DM and thus are less often used in hypertensive patients with DM. In contrast, the newer vasodilating beta-blockers appear to be free of adverse effects on the above metabolic parameters, and could be a valuable tool for hypertension treatment in patients with DM or the metabolic syndrome. This review summarizes the evidence on the effects of antihypertensive treatment with both traditional and vasodilating beta-blockers on parameters related to carbohydrate metabolism, and discuss the pathophysiological mechanisms that may be responsible. (+info)
The effects of mandatory prescribing of thiazides for newly treated, uncomplicated hypertension: interrupted time-series analysis.
BACKGROUND: The purpose of our study was to evaluate the effects of a new reimbursement rule for antihypertensive medication that made thiazides mandatory first-line drugs for newly treated, uncomplicated hypertension. The objective of the new regulation was to reduce drug expenditures. METHODS AND FINDINGS: We conducted an interrupted time-series analysis on prescribing data before and after the new reimbursement rule for antihypertensive medication was put into effect. All patients started on antihypertensive medication in 61 general practices in Norway were included in the analysis. The new rule was put forward by the Ministry of Health and was approved by parliament. Adherence to the rule was monitored only minimally, and there were no penalties for non-adherence. Our primary outcome was the proportion of thiazide prescriptions among all prescriptions made for persons started on antihypertensive medication. Secondary outcomes included the proportion of patients who, within 4 mo, reached recommended blood-pressure goals and the proportion of patients who, within 4 mo, were not started on a second antihypertensive drug. We also compared drug costs before and after the intervention. During the baseline period, 10% of patients started on antihypertensive medication were given a thiazide prescription. This proportion rose steadily during the transition period, after which it remained stable at 25%. For other outcomes, no statistically significant differences were demonstrated. Achievement of treatment goals was slightly higher (56.6% versus 58.4%) after the new rule was introduced, and the prescribing of a second drug was slightly lower (24.0% versus 21.8%). Drug costs were reduced by an estimated Norwegian kroner 4.8 million (0.58 million Euros, US$0.72 million) in the first year, which is equivalent to Norwegian kroner 1.06 per inhabitant (0.13 Euros, US$0.16). CONCLUSIONS: Prescribing of thiazides in Norway for uncomplicated hypertension more than doubled after a reimbursement rule requiring the use of thiazides as the first-choice therapy was put into effect. However, the resulting savings on drug expenditures were modest. There were no significant changes in the achievement of treatment goals or in the prescribing of a second antihypertensive drug. (+info)
Effects of furosemide on renal calcium handling.
Furosemide is a loop diuretic agent that has been used to treat hypercalcemia because it increases renal calcium excretion. The effect of furosemide on calcium transport molecules in distal tubules has yet to be investigated. We conducted studies to examine the effects of furosemide on renal calcium excretion and expression of calcium transport molecules in mice. Mice were administered with a single dose of furosemide (15 mg/kg) and examined 4 h later or were given twice-daily furosemide injections for 3 days. To evaluate the effects of volume depletion, drinking water was supplemented with salt. Our results showed that, in acute experiments, furosemide enhanced urinary calcium excretion, which was associated with a significant increase in mRNA levels of TRPV5, TRPV6, and calbindin-D28k but not calbindin-D9k as measured by real-time PCR (TRPV5 and TRPV6 are transient receptor potential vanilloid 5 and 6). Chronic furosemide administration induced three- to fourfold increases in urinary calcium excretion and elevated mRNA levels of TRPV5, TRPV6, calbindin-D28k, and calbindin-D9k without or with salt supplement. Similar upregulation of calcium transport molecules was observed in mice with gentamicin-induced hypercalciuria. Coadministration of chlorothiazide decreased furosemide-induced calciuria, either acutely or chronically, although still accompanied by upregulation of these transport molecules. Immunofluorescent staining studies revealed comparably increased protein abundance in TRPV5 and calbindin-D28k. We conclude that furosemide treatment enhances urinary calcium excretion. Increased abundance of calcium transport molecules in the distal convoluted tubule represents a solute load-dependent effect in response to increased calcium delivery and serves as a compensatory adaptation in the downstream segment. (+info)
Renal expression of parvalbumin is critical for NaCl handling and response to diuretics.
The distal convoluted tubule (DCT) plays an essential role in the reabsorption of NaCl by the kidney, a process that can be inhibited by thiazide diuretics. Parvalbumin (PV), a Ca(2+)-binding protein that plays a role in muscle fibers and neurons, is selectively expressed in the DCT, where its role remains unknown. We therefore investigated the renal phenotype of PV knockout mice (Pvalb(-/-)) vs. wild-type (Pvalb(+/+)) littermates. PV colocalized with the thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC) in the early DCT. The Pvalb(-/-) mice showed increased diuresis and kaliuresis at baseline with higher aldosterone levels and lower lithium clearance. Acute furosemide administration increased diuresis and natriuresis/kaliuresis, but, surprisingly, did not increase calciuria in Pvalb(-/-) mice. NaCl supplementation of Pvalb(-/-) mice increased calciuria at baseline and after furosemide. The Pvalb(-/-) mice showed no significant diuretic response to hydrochlorothiazide, but an accentuated hypocalciuria. A decreased expression of NCC was detected in the early DCT of Pvalb(-/-) kidneys in the absence of ultrastructural and apoptotic changes. The PV-deficient mice had a positive Ca(2+) balance and increased bone mineral density. Studies in mouse DCT cells showed that endogenous NCC expression is Ca(2+)-dependent and can be modulated by the levels of PV expression. These results suggest that PV regulates the expression of NCC by modulating intracellular Ca(2+) signaling in response to ATP in DCT cells. They also provide insights into the Ca(2+)-sparing action of thiazides and the pathophysiology of distal tubulopathies. (+info)