Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia.

Thiazide diuretics enhance renal Na+ excretion by blocking the Na+-Cl- cotransporter (NCC), and mutations in NCC result in Gitelman syndrome. The mechanisms underlying the accompanying hypocalciuria and hypomagnesemia remain debated. Here, we show that enhanced passive Ca2+ transport in the proximal tubule rather than active Ca2+ transport in distal convolution explains thiazide-induced hypocalciuria. First, micropuncture experiments in mice demonstrated increased reabsorption of Na+ and Ca2+ in the proximal tubule during chronic hydrochlorothiazide (HCTZ) treatment, whereas Ca2+ reabsorption in distal convolution appeared unaffected. Second, HCTZ administration still induced hypocalciuria in transient receptor potential channel subfamily V, member 5-knockout (Trpv5-knockout) mice, in which active distal Ca2+ reabsorption is abolished due to inactivation of the epithelial Ca2+ channel Trpv5. Third, HCTZ upregulated the Na+/H+ exchanger, responsible for the majority of Na+ and, consequently, Ca2+ reabsorption in the proximal tubule, while the expression of proteins involved in active Ca2+ transport was unaltered. Fourth, experiments addressing the time-dependent effect of a single dose of HCTZ showed that the development of hypocalciuria parallels a compensatory increase in Na+ reabsorption secondary to an initial natriuresis. Hypomagnesemia developed during chronic HCTZ administration and in NCC-knockout mice, an animal model of Gitelman syndrome, accompanied by downregulation of the epithelial Mg2+ channel transient receptor potential channel subfamily M, member 6 (Trpm6). Thus, Trpm6 downregulation may represent a general mechanism involved in the pathogenesis of hypomagnesemia accompanying NCC inhibition or inactivation.

On the hypocalciuric action of chlorothiazide.

Clearance experiments were performed in female mongrel dogs, either intact or thyro-parathy-roidectomized (T-PTX), under pentobarbital anesthesia, to examine the unusual hypocalciuric property of thiazide diuretics. The relationship between calcium clearance (C(Ca)) and sodium clearance (C(Na)) was determined in normal dogs, C(Ca) = 0.79 C(Na); constant infusion of chlorothiazide (CTZ) to provide drug concentrations in plasma of approximately 40 mug/ml modified this relationship; C(Ca) = 0.30 C(Na) (P < 0.001). The magnitude of the dissociating effect of CTZ on the urinary Ca/Na relationship was found to be most highly correlated with urinary drug concentration. Infusion of CTZ (1 mg/min) into one renal artery caused a unilateral decrease (25%) in C(Ca)/GFR while producing a unilateral increase (80%) in C(Na)/GFR. The same dose of CTZ in T-PTX dogs produced an increase in C(Na)/GFR without causing a change in C(Ca)/GFR. The defective response in T-PTX dogs could be ascribed to poor tubular secretion of the drug; when urinary drug concentrations were elevated in T-PTX dogs to the levels found in intact dogs (by infusing more drug), C(Ca)/GFR fell to an equivalent extent. T-PTX dogs showed substantially lower renal extraction of CTZ (42%) than intact dogs (57%); PTH administration to T-PTX dogs increased extraction toward normal (49%). The defective secretion of CTZ could not be attributed to either a decreased tubular maximum or a decreased renal blood flow.

Drug-induced endocrine and metabolic disorders.

Complex interactions exist amongst the various components of the neuroendocrine system in order to maintain homeostasis, energy balance and reproductive function. These components include the hypothalamus-pituitary- adrenal and -gonadal axes, the renin-angiotensin-aldosterone system, the sympathetic nervous system and the pancreatic islets. These hormones, peptides and neurotransmitters act in concert to regulate the functions of many organs, notably the liver, muscles, kidneys, thyroid, bone, adrenal glands, adipocytes, vasculature, intestinal tract and gonads, through many intermediary pathways. Endocrine and metabolic disorders can arise from imbalance amongst numerous hormonal factors. These disturbances may be due to endogenous processes, such as increased secretion of hormones from a tumour, as well as exogenous drug administration. Drugs can cause endocrine abnormalities via different mechanisms, including direct alteration of hormone production, changes in the regulation of the hormonal axis, effects on hormonal transport, binding, and signalling, as well as similar changes to counter-regulatory hormone systems. Furthermore, drugs can affect the evaluation of endocrine parameters by causing interference with diagnostic tests. Common drug-induced endocrine and metabolic disorders include disorders of carbohydrate metabolism, electrolyte and calcium abnormalities, as well as drug-induced thyroid and gonadal disorders. An understanding of the proposed mechanisms of these drug effects and their evaluation and differential diagnosis may allow for more critical interpretation of the clinical observations associated with such disorders, better prediction of drug-induced adverse effects and better choices of and rationales for treatment.

Vitamin D receptor modulators for inflammation and cancer.

1alpha, 25-Dihydroxyvitamin D3 [1,25-(OH)2D3], the biologically active form of vitamin D, is an important hormone that is critically required for the maintenance of mineral homeostasis and structural integrity of bones. 1,25-(OH)2D3 accomplishes this by facilitating calcium absorption from the gut and by a direct action on osteoblasts, the bone forming cells. Apart form its classical actions on the gut and bone, 1,25-(OH)2D3 and its synthetic analogs also possess potent anti-proliferative, differentiative and immunomodulatory activities. 1,25-(OH)2D3 exerts these effects through vitamin D receptor (VDR), a ligand-dependent transcription factor that belongs to the superfamily of steroid/thyroid hormone/retinoid nuclear receptors. The presence of VDR in various tissues other than gut and bone, along with their ability to exert differentiation, growth inhibitory and anti-inflammatory action, has set the stage for therapeutic exploitation of VDR ligands for the treatment of various inflammatory indications and cancer. However, the use of VDR ligands in clinic is limited by their major dose-related side effect, namely hypercalcemia/hypercalciuria. Efforts are being undertaken to develop vitamin D receptor modulators (VDRMs) that are tissue-selective and/or gene-selective in their action and these ligands may exhibit increased therapeutic indices. This review explores the recent advances in VDR biology, non-secosteroidal VDR ligands and the current and potential clinical applications of VDR ligands in inflammation and cancer.

Enamel demineralization by snack foods.

The amount of enamel destroyed by salivary fermentation of snack foods and confections was not dependent on their sugar content; starch, flavoring agents, and other components also played a part. Most enamel destruction was produced by fruit-flavored candies in which the inherent acid or high sugar concentration or both inhibited bacterial fermentation.

Solanum malacoxylon: a toxic plant which affects animal calcium metabolism.

The "enteque seco" is a disease of calcinosis, i.e., pathological deposition of calcium phosphate in soft tissues, which occurs in grazing cattle in Argentina and is of considerable economic importance. The ingestion of leaves of Solanum malacoxylon has been identified as the cause of the disease. Hypercalcemia and/or hyperphosphatemia and mineralization of the cardiovascular and pulmonary systems are usually seen in bovines or experimental animals exposed to this plant. The symptoms of the disease resemble those of vitamin D intoxication. In agreement with these observations, a glycoside derivative of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the hormonally active form of vitamin D in animals, has been identified as the toxic principle of S. malacoxylon. Glycoside conjugates of its precursors, 25-hydroxyvitamin D3 and vitamin D3, may also be present. Recent studies indicate that the plant factor is modified in the rumen of bovines through cleavage of the glycosidic linkage and further conversion of the released 1,25(OH)2D3 to a more polar metabolite, possibly 1,24,25-trihydroxyvitamin D3. Excess free 1,25(OH)2D3 may alter extracellular and intracellular Ca homeostasis in intoxicated animals through a receptor-mediated mechanism and activation of membrane Ca channels. In addition, 1,24,25(OH)3D3 may potentiate the effects of 1,25(OH)2D3 on intestinal Ca transport.

Postanesthetic myonecrosis in horses.

Two horses died of massive myonecrosis following surgery. The hematological, biochemical and pathological changes are described and compared with those previously reported in the literature.

The mechanism of hypocalciuria with NaCl cotransporter inhibition.

Thiazide diuretics are used to prevent the recurrence of calcium-containing kidney stones. The ability of these drugs to reduce urinary calcium excretion has a key role in this process. Although studies have shown a reduction in the recurrence rate of calcium-containing stones in patients treated with thiazides, whether hypocalciuria results from increased calcium reabsorption in the proximal or distal nephron is still unclear. When extracellular fluid volume is considerably reduced, the proximal tubule is likely to have a major role in thiazide-induced hypocalciuria. This process frequently occurs when high doses of thiazides and sodium restriction are prescribed for the treatment of kidney stone disease. The distal tubule is predominantly involved in NaCl cotransporter inhibition-induced hypocalciuria when the extracellular fluid volume is not reduced, a clinical scenario observed in patients with Gitelman syndrome. In this Perspectives article, we discuss the evidence supporting the hypocalciuric effects of NaCl cotransporter inhibition in the proximal and distal nephron.

Proton pump inhibitors, osteoporosis, and osteoporosis-related fractures.

Proton pump inhibitors (PPIs) are among the most commonly prescribed medications today with an excellent short-term safety profile. Recently, a number of studies from a variety of data sources have reported an association between PPI use and hip fractures. However, there is not yet any direct evidence of a causal link between PPI use and the development of hip fracture. In the following paper, we will review the recent studies which have described this association between PPI use and hip fracture, and discuss the evidence supporting the likelihood of this association being causal, using data from previous work on the effects of surgical and pharmacological inhibition of gastric acid secretion on calcium absorption and bone mineral density. We will conclude by summarizing the current state of evidence on the relationship between gastric acid inhibition and the risk of fracture, and suggest management strategies for patients who require the long-term use of gastric acid inhibiting medications who also may be at risk for metabolic bone disease and fracture.

Recent advances in renal tubular calcium reabsorption.

PURPOSE OF REVIEW: Knowledge of renal Ca2+ reabsorption has evolved greatly in recent years. This review focuses on two recent discoveries concerning passive and active Ca2+ reabsorption. RECENT FINDINGS: The thiazide diuretics are known for their hypocalciuric effect. Recently, it has been demonstrated that TRPV5-knockout mice, in which active Ca2+ reabsorption in the distal convoluted tubule is completely abolished, show the same sensitivity towards thiazides as wild-type mice. This indicates that thiazide affects Ca2+ reabsorption indirectly via contraction of the extracellular volume, independent of active Ca2+ reabsorption in the distal convoluted tubule, thereby increasing passive paracellular Ca2+ transport in the proximal tubule. Moreover, the antiaging hormone Klotho regulates Ca2+ reabsorption in the distal convoluted tubule via a novel molecular mechanism. Klotho stabilizes the TRPV5 Ca2+ channel in the plasma membrane by deglycosylation of the protein. SUMMARY: By showing that thiazide-induced hypercalciuria is due to increased passive Ca2+ reabsorption in the proximal tubule, a long-standing issue has been solved, underlining the importance of proximal paracellular Ca2+ reabsorption. Moreover, the molecular mechanism by which the antiaging hormone Klotho regulates TRPV5 activity may prove to be generally applicable in Klotho-mediated prevention of aging.

Barbiturates and serum calcium in the elderly.

In a retrospective study, based on a biochemical survey of people aged 65 and over in a general practice, subjects taking a barbiturate preparation for indications other than epilepsy had a significantly lower serum calcium concentration than did those taking nitrazepam or diazepam. Ordinary doses of barbiturate may adversely affect vitamin D metabolism in the elderly.