Hydrochlorothiazide and high-fat diets reduce plasma magnesium levels and increase hepatic oxidative stress in rats.

This study was designed to develop a rodent model of hydrochlorothiazide (HCTZ) toxicity by associating its intake with a high-fat (HF) diet. Rats were fed for 16 weeks with a control diet or with an HF diet supplemented or not with different doses of HCTZ. HCTZ, in a similar way to the HF diet, caused a significant increase in fructosamine levels. HCTZ and HF diet intake caused a significant reduction in magnesium and potassium levels, as well as an increase in lipid peroxidation and vitamin C in liver. Importantly, negative correlations were found between magnesium and glucose levels as well as between magnesium and fructosamine levels. The association between HCTZ and the HF diet caused additional worsening of biochemical parameters related to glucose homeostasis, and further increased hepatic oxidative stress. Our results suggest that chronic intake of HCTZ or an HF diet causes metabolic changes that are consistent with the development of insulin resistance. In addition, the association of an HF diet and HCTZ treatment can exacerbate some of these biochemical alterations, suggesting that this model might be useful for studying HCTZ metabolic toxicity.

Diphenyl diselenide supplementation reduces biochemical alterations associated with oxidative stress in rats fed with fructose and hydrochlorothiazide.

The study evaluated whether a diet containing diphenyl diselenide (PhSe)2, a synthetic antioxidant, could reduce the biochemical alterations induced by chronic consumption of highly enriched fructose diet and/or hydrochlorothiazide (HCTZ). Rats were fed a control diet (CT) or a high fructose diet (HFD), supplemented with or not HCTZ (4.0g/kg) and/or (PhSe)2 (3ppm) for 18weeks. HFD intake increased significantly plasma glucose, fructosamine, triglycerides and cholesterol levels. (PhSe)2 supplementation significantly reduced triglycerides and cholesterol but could not restore them to control levels. The combination of HFD and HCTZ significantly altered plasma glucose, fructosamine, triglycerides and cholesterol levels which were not restore by (PhSe)2 supplementation. Lipid peroxidation, protein carbonyl formation, vitamin C level and catalase activity decreased after HFD, HCTZ or HFD plus HCTZ ingestion. Remarkably (PhSe)2 supplementation restored the oxidative stress parameters. HCTZ decreased renal superoxide dismutase (SOD) activity, which was restored to control levels by (PhSe)2. Furthermore, the association of HFD and HCTZ decreased plasma potassium levels and aggravated HCTZ-induced hypomagnesemia and hypertriglyceridemia. Here we provided evidence of the involvement of oxidative stress and metabolic disorders in a rat model of HFD associated or not with HTCZ. (PhSe)2 supplementation reduced the oxidative stress and this compound should be considered for the treatment of biochemical disturbances and oxidative stress in other animal models of metabolic disorders.

High-fat diet and hydrochlorothiazide increase oxidative stress in brain of rats.

This study evaluated the effect of possible synergic interaction between high fat diet (HF) and hydrochlorothiazide (HCTZ) on biochemical parameters of oxidative stress in brain. Rats were fed for 16 weeks with a control diet or with an HF, both supplemented with different doses of HCTZ (0.4, 1.0, and 4.0 g kg(-1) of diet). HF associated with HCTZ caused a significant increase in lipid peroxidation and blood glucose levels. In addition, HF ingestion was associated with an increase in cerebral lipid peroxidation, vitamin C and non-protein thiol groups (NPSH) levels. There was an increase in vitamin C as well as NPSH levels in HCTZ (1.0 and 4.0 g kg(-1) of diet) and HF plus HCTZ groups. Na(+)-K(+)-ATPase activity of HCTZ (4.0 g kg(-1) of diet) and HCTZ plus HF-fed animals was significantly inhibited. Our data indicate that chronic intake of a high dose of HCTZ (4 g kg(-1) of diet) or HF change biochemical indexes of oxidative stress in rat brain. Furthermore, high-fat diets consumption and HCTZ treatment have interactive effects on brain, showing that a long-term intake of high-fat diets can aggravate the toxicity of HCTZ.

alpha-Tocopherol protects against pentylenetetrazol- and methylmalonate-induced convulsions.

Increased excitatory amino acid transmission and decreased GABAergic inhibitory responses seem to be important mechanisms in the genesis of convulsions, where reactive oxygen species (ROS) have recently been suggested to play a critical role. Therefore, administration of antioxidants may be potentially beneficial for the treatment of convulsive states. In the current study we investigated the effect of the systemic Vitamin E administration, an antioxidant, on the convulsions and oxidative damage induced by two convulsant agents with different mechanisms of action: methylmalonic acid (MMA), which induces convulsions through energy depletion and secondary activation of glutamatergic mechanisms and ROS production and pentylenetetrazol (PTZ), which is a chemical convulsant that causes convulsions by blocking the GABAA receptor-coupled chloride ionophore. Adult male Wistar rats (270-300 g) were injected with vehicle (5% Tween 80 in 0.9% NaCl; 1 ml/kg, i.p.) or alpha-tocopherol (25, 75 or 225 mg/kg, i.p.), once a day for 7 days. On the seventh day of antioxidant treatment, the animals were injected with the antioxidant (or vehicle) and, 30 min later, they were intrastriatally injected with NaCl (9 micromol/2 microl) or with MMA (6 micromol/2 microl) or PTZ (3.26 mmicromol/2 microl). The animals were observed for the appearance of convulsive behavior and the striatal content of thiobarbituric acid-reactive substances (TBARS) and total protein carbonylation were determined. Intrastriatal injection of increasing amounts of PTZ and of MMA caused the appearance of convulsive behavior. PTZ- and MMA-induced convulsions, TBARS production and total protein carbonylation were attenuated by alpha-tocopherol in a dose-dependent manner.

Ammonia potentiates methylmalonic acid-induced convulsions and TBARS production.

Hyperammonemia is a common finding in children with methylmalonic acidemia, an inherited metabolic disease characterized by mental retardation, convulsions, and accumulation of methylmalonic acid (MMA). Although it has been suggested that MMA induces convulsions through succinate dehydrogenase (SDH) inhibition, very little is known about the contribution of hyperammonemia to the development of convulsions in these patients. In the present study we investigated the effects of ammonium ions on the convulsant action of MMA, MMA-induced inhibition of striatal succinate dehydrogenase, and the striatal content of thiobarbituric acid-reactive substances (TBARS). Adult rats were injected with ammonium acetate (1.5 mmol/kg, sc) or sodium acetate (1.5 mmol/kg, sc), followed 5 min later by buffered MMA (3 micromol/microl) or NaCl (4.5 micromol/microl) injected into the striatum. The animals were observed in an open field for the appearance of convulsive episodes. After 30 min of behavioral evaluation, the animals were sacrificed and had their striatal TBARS content measured. Ammonium acetate pretreatment caused no behavioral effects per se, but potentiated MMA-induced convulsions and increased basal TBARS content and MMA-induced TBARS production in the striatum. Ammonium chloride had no effect on basal succinate dehydrogenase activity and did not alter MMA-induced inhibition of SDH in vitro. These results suggest that ammonia potentiates MMA-induced behavioral effects through a mechanism that does not involve further succinate dehydrogenase inhibition, but may involve facilitation of MMA-induced oxidative damage and provide evidence that ammonia and MMA may have mutually additive toxicity.