Methylmercury stimulates the exhalation of volatile selenium and potentiates the toxicity of selenite

The aim of the present experiments was to investigate whether a single dose of 24 mumol/kg methylmercuric chloride (MeHgCl) in rats can influence the effect of an equimolar dose of sodium selenite (Na2SeO3) on body weight or the exhalation of dimethylselenide, a volatile metabolic product of selenium. Due to the difference in their single-dose toxicities, only selenite depressed body weight gain, when given alone. The experiments indicated that methylmercury, irrespective of whether it was given 1-2 h before, or at the same time as sodium selenite, potentiated the effect of the latter on body weight. Methylmercury also increased the exhalation of volatile selenium, but this effect decreased when the administration of selenite was delayed.     

Carbon tetrachloride metabolism in vivo and exhalation of volatile alkanes: dependence upon oxygen partial pressure

Metabolism of carbon tetrachloride in rats at atmospheric and reduced oxygen pressure has been determined indirectly by its disappearance from the inhaled air; it is inversely related to oxygen concentration and increases with decreasing partial pressure, as expected for reductive dehalogenation; oxygen partial pressure has been reduced to about a third of normobaric conditions. Concurrently exhalation of ethane and pentane as indication of lipid peroxidation has been monitored, showing a drastic increase when the oxygen partial pressure is reduced in the presence of carbon tetrachloride. Time course and duration of these processes indicate that the total metabolism of carbon tetrachloride is limited by the concomitant destruction of cytochrome P-450; also, oxidative destruction of polyunsaturated fatty acids apparently does not proceed beyond the end of metabolic activation of carbon tetrachloride. The molar ratios of the amount of metabolized carbon tetrachloride to the amounts of exhaled hydrocarbons lead to the same conclusion, namely that "lipid peroxidation" in this case does not proceed as an autocatalytic, self-propagating chain reaction.     

Effects of ligands on gold inhibition of selenium glutathione peroxidase

Gold inhibits selenium-dependent glutathione peroxidase (GSH Px) in vitro. Chrysotherapy has been used for over five decades without complete understanding of its pharmacodynamics. This study shows that gold is potentially an inhibitor of GSH Px in vivo. Reported are conditions for assay of GSH-Px activity showing that the inhibition by gold species can be reversed. The study demonstrates the high affinity of gold for the selenohydryl-active site of GSH Px relative to the affinities of other physiological ligands; GSH Px was inhibited to a greater extent by a small molecular-weight fraction isolated from kidneys of gold-treated rats than by the fraction isolated from kidneys of rats not treated with gold. The data provide a new perspective on the action of gold-containing drugs in vivo.     

The protection of selenium on cadmium-induced inhibition of spermatogenesis via activating testosterone synthesis in mice

Selenium (Se) is an essential trance element in testis. However, the potential protective effects of Se against cadmium (Cd)-induced reproductive toxicity remained to be elucidated. Male ICR mice were orally administered by gavage with Na₂SeO₃ (0.1, 0.2, 0.4 mg/kg BW) for 1 h prior to CdCl₂ (5 mg/kg BW) alone or in combination for 15, 25 or 35 days. Cd exposure caused a significant decrease in body weight, sperm concentration and motility as well as plasma testosterone level which was accompanied by decreased antioxidant enzymatic activity of SOD and GSH-Px and by increased lipid peroxidation (as malondialdehyde, MDA). Se pretreatment compensated deficits in the sperm parameters (concentration, motility and morphology) induced by Cd. Se (0.4 mg/kg BW) treatment significantly increased serum testosterone level that was reduced by Cd (on 15th, 25th and 35th day) (P < 0.01). Se treatment ameliorated Cd-induced reduction in testicular steroidogenic acute regulatory (StAR) and 17β-hydroxysteroid dehydrogenase (17β-HSD) activities. The present study suggest that the protective potential of Se against Cd-induced reprotoxicity might be due to up-regulation StAR and testosterone synthetic enzyme activity, which could be useful for increasing testosterone synthesis for achieving optimum protection in sperm quality and spermatogenesis.     

Methysergide and spinal inhibition from electrical stimulation in the periaqueductal grey

In barbiturate anaesthetized cats, electrical stimulation in the periaqueductal grey (PAG) selectively inhibited the excitation of multireceptive dorsal horn neurons by noxious heating of the skin or by electrical stimulation of unmyelinated primary afferents. Intravenous methysergide (0.2-1.0 mg/kg) had opposing effects on uninhibited responses, increasing excitation by noxious heat but reducing responses to C fibre stimulation. Evidence was obtained that the increases to noxious heat resulted from increased firing of peripheral nociceptors secondary to decreased cutaneous blood flow. Intravenous methysergide reduced inhibition from PAG stimulation. When administered electrophoretically from micropipettes however, methysergide did not reduce such inhibition. The mechanism whereby systemic methysergide reduces PAG spinal inhibition is unknown and cannot necessarily be related to a blockade of spinally released 5-hydroxytryptamine.     

The biochemistry of selenium and the glutathione system

In the context of defense against pro-oxidants, selenium and the glutathione (GSH) system play key functions. Major roles of GSH include direct interception of pro-oxidants, as well as a reduction of other antioxidants from their oxidized forms. Furthermore, GSH has ancillary functions, such as metabolism, cell signaling, and protein interactions, that can also mediate defense against oxidants. Protection by selenium in the mammalian cell is mediated by selenol-aminoacids, either as selenocysteine or selenomethionine. The active site of the potent glutathione peroxidases (GPx) contains selenocysteine residues. Furthermore, other selenoproteins (e.g. selenoprotein P and thioredoxin reductase) also have been shown to possess antioxidant properties. Synthetic organoselenium compounds (e.g. ebselen) have also shown promise as pharmacologic antioxidants in in vivo models of tissue damage due to oxidative stress. The specific function of selenoproteins and organoselenium compounds in defense against peroxynitrite, by reduction of this potent oxidizing and nitrating species to nitrite, is also discussed.     

Dopa-induced locomotor stimulation after inhibition of extracerebral decarboxylase

In rats, a combination of small doses of the dopa decarboxylase inhibitor Ro 4–4602 [N-(DL-seryl)-N'-(2,3,4-trihydroxybenzyl)hydrazine] with dopa causes a marked enhancement of the spontaneous locomotor activity which is not seen with dopa alone. If high instead of low doses of Ro 4–4602 are used, locomotor stimulation does not occur. Low doses of Ro 4–4602, owing to selective inhibition of extracerebral decarboxylase, enhance the dopa-induced rise of dopa and catecholamines in the brain, whereas high doses of Ro 4–4602, which also inhibit the cerebral dopa decarboxylase, increase only the level of dopa but not that of the catecholamines. It is concluded that the locomotor activation after small doses of Ro 4–4602 in combination with dopa is due to cerebral accumulation of catecholamines which consist mainly of dopamine.     

The effects of sympathetic nerve stimulation and guanethidine on parasympathetic neuroeffector transmission; the inhibition of acetylcholine release

The effect of noradrenaline released either by sympathetic nerve stimulation or guanethidine added to the organ bath has been studied on acetylcholine release from parasympathetic nerve terminals and compared with the effect of exogenous noradrenaline. Sympathetic nerve stimulation, guanethidine and noradrenaline reduced the release of acetylcholine from resting rabbit intestine by up to 70%. Sympathetic stimulation and guanethidine failed to reduce acetylcholine release in preparations previously depleted of noradrenaline. Noradrenaline added to the bath still remained effective. The fact that noradrenaline released is capable of inhibiting acetylcholine release supports the concept that noradrenaline physiologically controls the release of acetylcholine.     

Protective effect of selenium on the inhibition of erythrocyte 5-aminolevulinate dehydratase activity by tin

The protective effect of selenium (Se) on the inhibition of erythrocyte 5-aminolevulinate dehydratase (ALAD) activity by tin (Sn) was examined in mice. When mice were intraperitoneally (i.p.) administered 10 mumol/kg of stannous chloride, the activity of erythrocyte ALAD decreased to 35% of control. When more than an equimolar dose of sodium selenite was injected i.p. simultaneously with Sn, the ALAD activity was completely protected. Mortalities and weight gains of mice treated with Se were also reduced when Sn was administered simultaneously.     

The mathematical analysis of breath alcohol profiles generated during breath exhalation

The mathematical analysis of time domain data provides a useful tool for evaluating biological and instrumental systems. Breath alcohol profile measurements generated during exhalation constitute biological signals that can be subjected to a variety of mathematical treatments. The present paper discusses the application of a variety of mathematical procedures to breath alcohol profiles. These mathematical procedures include model approximation, data smoothing, integration, differentiation, and fourier transformation. The different mathematical procedures provide insight into the physiology of breath alcohol measurement and suggest forensic as well as instrumental applications.     

The effect of number of stimuli and rate of stimulation on the inhibition by PGE1 of adrenergic transmission

An inverse correlation was found between the number of pulses and sympathetic blockade by PGE₁ (10^?8g/ml) in guinea-pig isolated field stimulated atria and vas deferens. The higher the number of pulses applied at a given frequency the smaller was the inhibition by PGE₁ of neuroeffector transmission. At 100 shocks using 10 Hz stimulation, PGE₁ no longer decreased the height of twitches of the guinea-pig vas deferens, however, the velocity of contractions was decreased. Sympathetic transmission in the rabbit jejunum was blocked by a somewhat higher dose of PGE₁ (3 × 10^?8g/ml). In this organ an increase in pulse number produced no detectable change in PGE₁-induced blockad. At a temperature of 37°C the vas deferens of the guinea-pig was highly sensitive to PGE₁, whereas that of the rat was virtually insensitive. On cooling the guinea-pig vas deferens to a temperature of 20°C the sensitivity to PGE₁ decreased and the shape of the shock number-effect curve became similar to that observed in that rat vas deferens. It is suggested, that the different shape of the curve may be caused by reduced release and/or effect of an inhibitory substance, probably prostaglandin. The biological responsesobtained with racemic PGE₁ were qualitatively identical with those elicited by natural PGE₁ the latter being about twice as potent.     

The reversal by metoclopramide of apomorphine-induced inhibition of responses to stimulation of the cardioaccelerator nerves in the cat

The effect of metoclopramide on presynaptic dopamine receptors was investigated in the cat cardioaccelerator nerve preparation. Metoclopramide, a substituted benzamide derivative, antagonized inhibitory action of apomorphine on positive chronotropic responses induced by sympathetic nerve stimulation in cat hearts, in vivo. Neither phentolamine, an alpha-adrenergic blocking agent, nor indomethacin a prostaglandin synthesis inhibitor, antagonized the effect of apomorphine. Apomorphine did not alter the positive chronotropic effects of intravenously administered noradrenaline. Metoclopramide potentiated stimulation-induced positive chronotropic responses. These results suggest that metoclopramide blocks the presynaptic dopamine receptors at the cat heart.     

The facts and controversies about selenium

Selenium is a trace element, essential in small amounts, but it can be toxic in larger amounts. Levels in the body are mainly dependent on the amount of selenium in the diet, which is a function of the selenium content of the soil. Humans and animals require selenium for normal functioning of more than about 30 known selenoproteins, of which approximately 15 have been purified to allow characterisation of their biological functions. Selenoproteins are comprised of four glutathione peroxidases, three iodothyronine deiodinases, three thioredoxin reductases, selenoprotein P, selenoprotein W and selenophosphate synthetase. Selenium is essential for normal functioning of the immune system and thyroid gland, making selenium an essential element for normal development, growth, metabolism, and defense of the body. Supportive function of selenium in health and disease (male infertility, viral infections, including HIV, cancer, cardiovascular and autoimmune diseases) is documented in great number of clinical examinations. A great number of studies confirm that selenium supplementation plays a preventive and therapeutical role in different diseases. Definitive evidence regarding the preventive and therapeutical role of selenium as well as the exact mechanism of its action should be investigated in further studies. Investigations in Croatia indicate a possibility of inadequate selenium status of people in the area.     

The mechanisms of enhancement and inhibition of field stimulation responses of guinea-pig vas deferens by prostacyclin analogues

1. In the guinea-pig isolated vas deferens preparation bathed in Tyrode''s solution, the prostacyclin analogues, cicaprost, TEI-9063, iloprost, taprostene and benzodioxane-prostacyclin, enhanced twitch responses to submaximal electrical field stimulation (20%-EFS). The high potency of cicaprost (EC₁₅₀=1.3 nM) and the relative potencies of the analogues (equi-effective molar ratios=1.0, 0.85, 1.6, 17 and 82, respectively) suggest the involvement of a prostacyclin (IP-) receptor.
2. Maximum enhancement induced by cicaprost in 2.5 mM K⁺ Krebs-Henseleit solution was similar to that in Tyrode solution (2.7 mM K⁺), but was progressively reduced as the K⁺ concentration was increased to 3.9, 5.9 and 11.9 mM. There was also a greater tendency for the other prostacyclin analogues to inhibit EFS responses in 5.9 mM standard K⁺ Krebs-Henseleit solution; this may be attributed to their agonist actions on presynaptic EP₃-receptors resulting in inhibition of transmitter release.
3. The EFS enhancing action of cicaprost was not affected by the α₁-adrenoceptor antagonist prazosin (100 and 1000 nM). Cicaprost (20 and 200 nM) did not affect contractile responses of the vas deferens to either ATP (5 μM) or α,β-methylene ATP (1 μM) in the presence of tetrodotoxin (TTX, 100 nM). In addition, enhancement by cicaprost of responses to higher concentrations of ATP (30 and 300 μM) in the absence of TTX, as shown previously by others, was not seen. Prostaglandin E₂ (PGE₂, 10 nM) and another prostacyclin analogue TEI-3356 (20 nM) enhanced purinoceptor agonist responses. Unexpectedly, TTX (0.1 and 1 μM) partially inhibited contractions elicited by 10–1000 μM ATP; contractions elicited by 1–3 μM ATP were unaffected. Further studies are required to establish whether a pre- or post-synaptic mechanism is involved.
4. In a separate series of experiments, cicaprost (5–250 nM), TEI-9063 (3–300 nM), 4-aminopyridine (10–100 μM) and tetraethylammonium (100–1000 μM) enhanced both 20%-EFS responses and the accompanying overflow of noradrenaline to a similar extent. In further experiments with the EP₁-receptor antagonist AH 6809, TEI-3356 (1.0–100 nM) and the EP₃-receptor agonist, sulprostone (0.1–1.0 nM) inhibited both maximal EFS responses and noradrenaline overflow, thus confirming previous reports of the high activity of TEI-3356 at the EP₃-receptor. Cicaprost had no significant effect on noradrenaline overflow at 10 and 100 nM, but produced a modest inhibition at 640 nM.
5. In conclusion, our studies show that prostacyclin analogues (particularly TEI-3356) can inhibit EFS responses of the guinea-pig vas deferens by acting as agonists at presynaptic EP₃-receptors. Prostacyclin analogues (particularly cicaprost and TEI-9063) can also enhance EFS responses through activation of IP-receptors. The mechanism of the enhancement has not been rigorously established but from our results we favour a presynaptic action to increase transmitter release.

     

Behavioral effects of GABA(A) receptor stimulation and GABA-transporter inhibition

The present analysis addressed behavioral changes after treatment with 4.5 mg/kg or 18.5 mg/kg of the GABA-uptake inhibitor tiagabine combined with either the benzodiazepine diazepam (1.5 mg/kg) or the imidazopyridine zolpidem (0.05 mg/kg), the latter two acting differentially on GABA(A) receptor subtypes. The study included 97 male PVG/OIaHsd rats. A standard open field, an enriched open field, and an elevated plus-maze was used to study rat behavior. Treatment with the low dose of tiagabine alone induced no specific behavioral effects, whereas the high dose had an anxiolytic-like potential. Furthermore, diazepam but not zolpidem displayed anxiolytic-like effects. Combination of each benzodiazepine receptor agonist with tiagabine at the low dose decreased explorative activity. Diazepam plus the high dose of tiagabine increased the activity in the open-field test. Zolpidem together with 18.5 mg/kg tiagabine had an angiogenic-like effect compared to pure tiagabine treatment. These results provide evidence for a pharmacodynamic interaction between the GABA-uptake inhibitor tiagabine and diazepam or zolpidem. The interaction might be relevant in the clinic when combining the anticonvulsant tiagabine and a benzodiazepine receptor agonist.