Nitric oxide and Ca2+-activated high-conductance K+ channels mediate nothofagin-induced endothelium-dependent vasodilation in the perfused rat kidney.

Nothofagin is a natural 3'-C-ß-D-glucoside of the polyphenol phloretin that is mainly found in Aspalathus linearis, Nothofagus fusca, and Leandra dasytricha. In recent years, nothofagin has been described as a potential therapeutic agent for renal disorders, but the mechanisms that are involved in its renoprotective effects remain unclear. In the present study, perfused rat kidneys were used to test the hypothesis that nothofagin causes the direct relaxation of renal arteries. The molecular mechanisms that underlie these vascular effects were also investigated. The left kidney from Wistar rats was coupled in a perfusion system and continuously perfused with physiological saline solution (PSS). Initially, preparations with and without the endothelium were contracted with phenylephrine and received injections of 1-300 nmol nothofagin. The preparations were then perfused with PSS that contained phenylephrine plus KCl, indomethacin, l-NAME, tetraethylammonium, glibenclamide, 4-aminopyridine, iberiotoxin, charybdotoxin, and apamin. After 15 min under perfusion, nothofagin was injected again. In preparations with an intact endothelium, nothofagin dose-dependently reduced perfusion pressure. Endothelium removal or the inhibition of nitric oxide synthase by l-NAME prevented the vasodilatory effect of nothofagin at all doses tested. Perfusion with PSS that contained KCl or tetraethylammonium chloride also abolished the vasodilatory effect of nothofagin. Treatment with glibenclamide, 4-aminopyridine, and apamin did not affect the vasodilatory effect of nothofagin. Iberiotoxin (selective Ca2+-activated high-conductance K+ channel [KCa1.1] blocker) and charybdotoxin (selective KCa1.1 and Ca2+-activated intermediate-conductance K+ channel [KCa3.1] blocker) application blocked the vasodilatory effect of nothofagin at all doses tested, pointing to a predominant role for KCa1.1 in the action of nothofagin. However, these data cannot exclude a potential contribution of endothelial KCa3.1 channel in the nothofagin-induced vasodilation. Overall, our findings indicate that nothofagin induces vasodilation in renal arteries, an effect that is mediated by Ca2+ -activated high-conductance K+ channels opening and endothelial nitric oxide production.

Hydroethanolic extract of Tropaeolum majus promotes anxiolytic effects on rats

Abstract Tropaeolum majus L., Tropaeolaceae, popularly known in Brazil as 'capuchinha' is widely used due its anti-inflammatory, antiseptic, anti-hypertensive and anti-depressive properties. However, scientific investigations about its effects on the central nervous system are still scarce. This study investigated the central pharmacological actions of the prolonged treatment with a hydroethanolic extract of T. majus in male Wistar rats in the elevated plus maze and hole-board behavioral models. For this, rats were daily treated with distillated water (negative control); diazepam (1 mg/kg) or hydroethanolic extract of T. majus (75, 150 and 300 mg/kg), for 29 days (by gavage) and were submitted to elevated plus maze and hole-board. Animals treated with all hydroethanolic extract of T. majus or diazepam doses increased the percentage of entries in open arms when compared to control group. However, only treatment with diazepam increased the length of time spent in the open arms of the elevated plus maze. No differences between all groups were observed regardless rearing, grooming, stretched-attend postures and defecation rates. In the HB test, in opposite to diazepam, treatment with hydroethanolic extract of T. majus did not interfere in the exploratory activity of rats. The hydroethanolic extract of T. majus promotes anxiolytic-like effects when orally administered in rats.

In utero and lactational exposure to fluoxetine in Wistar rats: pregnancy outcomes and sexual development.

This study evaluated the reproductive effects of fluoxetine exposure in utero and during lactation on pregnancy outcomes and the sexual development of offspring. Pregnant Wistar rats were treated daily with fluoxetine (0.4, 1.7 and 17 mg/kg/day) or distilled water by gavage from gestation day (GD) 7 to lactation day (LD) 21. A significant reduction in maternal body weight was observed during pregnancy and lactation in dams exposed to 17 mg/kg fluoxetine. Hormone analysis revealed an increase in progestagen and glucocorticoid metabolites on GD 15 and oestrogen and progestagen metabolites on LD 7 in dams treated with 17 mg/kg fluoxetine. Oestrogen metabolites also were increased on LD 7 in dams treated with 0.4 mg/kg fluoxetine. Besides that, an increase in the weight of the adrenal glands and a reduction in uterine weight in dams exposed to highest dose of fluoxetine were observed. Finally, pup birthweight and the viability and weaning indices also were reduced in animals exposed to 17 mg/kg fluoxetine. Overall, maternal hormonal changes were only observed at the highest dose tested, which also induced maternal and foetal toxicity. No significant changes were seen in dams or offspring exposed to therapeutic-like doses.

In vivo and in vitro estrogenic activity of the antidepressant fluoxetine.

Recent years have seen an increase in the use of antidepressant drugs, especially fluoxetine (FLX), in sensitive populations, such as pregnant and lactating women. Although some evidence suggests a possible endocrine action of FLX, no specific studies have been performed to investigate this hypothesis. In the present study, we investigated the possible (anti)androgenic and (anti)estrogenic actions of FLX using Hershberger, uterotrophic (0.4, 1.7, and 17mg/kg), and reporter gene (7.6-129µM) assays. In the Hershberger assay, no differences were observed in androgen-dependent organ weights. However, the uterotrophic and gene reporter assays indicated a possible estrogenic action of FLX. Uterine weight increased in the 1.7 and 17mg/kg/day groups in the 3-day uterotrophic assay in immature rats. Additionally, noncytotoxic concentrations of FLX induced estrogenic responses and increased the estrogenic response of estradiol in MCF-7 breast cancer cells transfected with luciferase.