Thiamine deficiency leads to reduced nitric oxide production and vascular dysfunction in rats.

BACKGROUND AND AIMS: Thiamine deficiency is a condition that is known to cause damage to the nervous and cardiovascular systems because it interferes with cellular metabolism. It is well known that the control of vascular function is highly dependent on the production of nitric oxide (NO) by NO synthases. Studies exploring the physiological relevance of NO signaling under conditions of thiamine deficiency are scarce. The present study sought to investigate whether chronic metabolic changes would cause alterations in vascular responsiveness. METHODS AND RESULTS: By removing thiamine from the diet, we observed a reduced acetylcholine-mediated relaxation and an increased phenylephrine-mediated vasoconstriction in the aortas containing functional endothelium. Removal of the endothelium or the pre-treatment of vessels with l-NAME restored the contractile responses to the level of controls. Conversely, indomethacin did not modify phenylephrine-mediated contractions. We also used carbon microsensors to continually measure NO production in situ while simultaneously measuring the vascular tone. The results revealed a significant decrease in NO production. Western blot analysis showed a decreased expression of the total eNOS in the thiamine-deficient aorta compared to the control. Concentration-response curves for phenylephrine indicated no difference between the control and deficient groups in the presence and absence of SOD or Tyron. The NO donor DEA-NONOate produced a concentration-dependent relaxation response in the endothelium-denuded vessels that did not differ between the control and thiamine-deficient rats. CONCLUSION: Thiamine deficiency modulates eNOS-dependent NO production, leading to a decreased vasorelaxation and an increased contractile response in the rat aorta.

Cardiac structural changes and electrical remodeling in a thiamine-deficiency model in rats.

AIMS: Thiamine is an important cofactor present in many biochemical reactions, and its deprivation can lead to heart dysfunction. Little is known about the influence of thiamine deprivation on the electrophysiological behavior of the isolated heart cells and information about thiamine deficiency in heart morphology is controversial. Thus, we decided to investigate the major repolarizing conductances and their influence in the action potential (AP) waveform as well as the changes in the heart structure in a set of thiamine deficiency in rats. MAIN METHODS: Using the patch-clamp technique, we investigated inward (I(K1)) and outward K(+) currents (I(to)), T-type and L-type Ca(2+) currents and APs. To evaluate heart morphology we used hematoxylin and eosin in transversal heart sections. KEY FINDINGS: Thiamine deficiency caused a marked decrease in left ventricle thickness, cardiomyocyte number, cell length and width, and membrane capacitance. When evaluating I(to) we did not find difference in current amplitude; however an acceleration of I(to) inactivation was observed. I(K1) showed a reduction in the amplitude and slope conductance, which implicated a less negative resting membrane potential in cardiac myocytes isolated from thiamine-deficient rats. We did not find any difference in L-type Ca(2+) current density. T-type Ca(2+) current was not observed. In addition, we did not observe significant changes in AP repolarization. SIGNIFICANCE: Based on our study we can conclude that thiamine deficiency causes heart hypotrophy and not heart hypertrophy. Moreover, we provided evidence that there is no major electrical remodeling during thiamine deficiency, a feature of heart failure models.

Exposure to sublethal concentrations of Zn(II) and Cu(II) changes biochemical parameters in Leporinus obtusidens.

The aim of the present study was to assess the effect of the exposure of Leporinus obtusidens (Piava) to zinc and copper on catalase activity in the liver, delta-aminolevulinate dehidratase (delta-ALA-D) activity in liver, muscle, brain and kidney, and thiobarbituric reactive species (TBARS) in brain, muscle and liver. In addition, hematological parameters were measured in blood. The fish were exposed to 10% and 20% of the derived LC(50) values, 2.3 and 4.6 mg Zn l(-1) and 0.02 and 0.04 mg Cu l(-1), and sampled on days 30 and 45. Exposure to Zn(II) and Cu(II) decreased hematological parameters and also delta-ALA-D activity mainly in liver and kidney at all concentrations tested. Liver catalase activity increased after zinc or copper exposure at all concentrations and exposure times tested. Thiobarbituric reactive substances (TBARS) increased in the brain and liver of the fish exposed to zinc(II) for 45 days at both metal concentrations. In muscle, zinc(II) increased TBARS production at both exposure times and concentrations tested. Copper(II) exposure reduced the TBARS levels in liver at both concentrations and times tested. In brain, there was a decrease in TBARS levels only after 45 days of exposure. In muscle, this decrease was observed after 30 days of exposure at both concentrations. Although zinc and copper are required as microelements in the cells, our results showed that the sublethal concentrations of these metals can change biochemical parameters which may alter normal cellular function. These results pointed out the differential sensitivity of fish tissues to essential, but also toxic and environmentally relevant metals. The alterations of distinct biochemical parameters in fish tissues certainly contribute to the toxicity of Zn and Cu, and are of importance for an area that has been growing and has still been poorly explored in the literature.

Chelating effect of novel pyrimidines in a model of aluminum intoxication.

Long time ago aluminum (Al) was considered as a non-toxic element and its use had no restrictions. However, over the last two decades, scientific publications have indicated that Al is a toxic element. In line with this, aluminum accumulation in the organism is associated with a variety of human pathologies. Efficient therapeutics approach to treat Al intoxication are still not available, but there is a consensus that chelation therapy is the procedure to be used. However, the development of new chelating agents are highly desirable to improve the efficacy of the treatment of Al intoxication. The present study evaluates the chelating effect of two novel pyrimidines: 4-tricloromethyl-1-H-pyrimidin-2-one (THP) and (4-methyl-6-trifluoromethyl-6-pyrimidin-2-il)-hydrazine (MTPH) in a mice model of aluminum intoxication and compares their efficacy with those of desferrioxamine (DFO), a classical agent used for treat Al accumulation. The animals were exposed to aluminum by gavage (0.1 mmol aluminum/kg/day) 5 days/week for 4 weeks. At the end of this period, DFO was injected i.p. and the novel pyrimidines were given by gavage at 0.2 mmol/kg/day for five consecutive days. Aluminum concentration in tissues (brain, liver, kidney and blood) was determined by graphite furnace atomic absorption spectroscopy (GFAAS). The results showed that when administered by gavage, aluminum accumulated in the brain, kidney and liver of mice. MTPH was able to decrease aluminum levels in aluminum plus citrate animal groups, whereas THP was inefficient for this purpose. However, the novel pyrimidines used in this study were unable to surpass the aluminum chelating property of DFO. Thus, new studies must be performed utilizing other chelating agents which can decrease aluminum toxicity.