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Naunyn Schmiedebergs Arch Pharmacol ; 394(11): 2273-2287, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34468816


Morbidity and mortality risks are enhanced in preeclamptic (PE) mothers and their offspring. Here, we asked if sexual dimorphism exists in (i) cardiovascular and renal damage evolved in offspring of PE mothers, and (ii) offspring responsiveness to antenatal therapies. PE was induced by administering NG-nitro-L-arginine methyl ester (L-NAME, 50 mg/kg/day, oral gavage) to pregnant rats for 7 days starting from gestational day 14. Three therapies were co-administered orally with L-NAME, atrasentan (endothelin ETA receptor antagonist), terutroban (thromboxane A2 receptor antagonist, TXA2), or α-methyldopa (α-MD, central sympatholytic drug). Cardiovascular and renal profiles were assessed in 3-month-old offspring. Compared with offspring of non-PE rats, PE offspring exhibited elevated systolic blood pressure and proteinuria and reduced heart rate and creatinine clearance (CrCl). Apart from a greater bradycardia in male offspring, similar PE effects were noted in male and female offspring. While terutroban, atrasentan, or α-MD partially and similarly blunted the PE-evoked changes in CrCl and proteinuria, terutroban was the only drug that virtually abolished PE hypertension. Rises in cardiorenal inflammatory (tumor necrosis factor alpha, TNFα) and oxidative (isoprostane) markers were mostly and equally eliminated by all therapies in the two sexes, except for a greater dampening action of atrasentan, compared with α-MD, on tissue TNFα in female offspring only. Histopathologically, antenatal terutroban or atrasentan was more effective than α-MD in rectifying cardiac structural damage, myofiber separation, and cytoplasmic alterations, in PE offspring. The repair by antenatal terutroban or atrasentan of cardiovascular and renal anomalies in PE offspring is mostly sex-independent and surpasses the protection offered by α-MD, the conventional PE therapy.

Toxicol Appl Pharmacol ; 426: 115615, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34102242


Current therapies for preeclampsia (PE) and its complications are limited and defective. Considering the importance of endothelin (ET) and thromboxane A2 (TXA2) signaling in PE pathophysiology, we tested the hypothesis that prenatal blockade of endothelin ETA or thromboxane TXA2 receptors favorably reprograms preeclamptic cardiovascular and renal insults. PE was induced by daily oral administration of L-NAME (50 mg/kg) to pregnant rats for 7 consecutive days starting from gestational day 14. The effects of co-exposure to atrasentan (ETA receptor blocker, 10 mg/kg/day) or terutroban (TXA2 receptor blocker, 10 mg/kg/day) on cardiovascular and renal anomalies induced by PE were assessed on gestational day 20 (GD20) and at weaning time and compared with those evoked by the sympatholytic drug α-methyldopa (α-MD, 100 mg/kg/day), a prototypic therapy for PE management. Among all drugs, terutroban was basically the most potent in ameliorating PE-evoked increments in blood pressure and decrements in creatinine clearance. Cardiorenal tissues of PE rats exhibited significant increases in ETA and TXA2 receptor expressions and these effects disappeared after treatment with atrasentan and to a lesser extent by terutroban or α-MD. Atrasentan was also the most effective in reversing the reduced ETB receptor expression in renal tissues of PE rats. Signs of histopathological damage in cardiac and renal tissues of PE rats were mostly improved by all therapies. Together, pharmacologic elimination of ETA or TXA2 receptors offers a relatively better prospect than α-MD in controlling perinatal cardiorenal irregularities sparked by PE.

Atrasentana/uso terapêutico , Antagonistas do Receptor de Endotelina A/uso terapêutico , Cardiopatias/prevenção & controle , Nefropatias/prevenção & controle , Naftalenos/uso terapêutico , Pré-Eclâmpsia/tratamento farmacológico , Propionatos/uso terapêutico , Receptores de Tromboxano A2 e Prostaglandina H2/antagonistas & inibidores , Animais , Atrasentana/farmacologia , Antagonistas do Receptor de Endotelina A/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Cardiopatias/genética , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Nefropatias/genética , Nefropatias/patologia , Nefropatias/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Naftalenos/farmacologia , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/patologia , Pré-Eclâmpsia/fisiopatologia , Gravidez , Propionatos/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina A/genética , Receptores de Tromboxano A2 e Prostaglandina H2/genética
Artigo em Inglês | MEDLINE | ID: mdl-23750311


Venlafaxine is an antidepressant of choice, whose effectiveness could be modified by a commonly used medicinal plant and nutrient. The current study had evaluated the barley extract (1 g/kg) when compared to or combined to venlafaxine (32 mg/kg) in a rat stress model. The present study was conducted on 40 male Wister albino rats; divided to five groups. Four groups were subjected to social chronic mild stress. Drugs or saline were orally daily administered one week before stress induction and extended up to ten weeks. Behavioral, brain biochemical tests and serum magnesium were assessed at the end. The study revealed significant change in the combined group on behavioral tests; forced swim test, elevated plus maze and saccharin preference test when compared to barley extract group. Furthermore, there was significant reduction in brain malondialdehyde level, no significant change in brain nitric oxide level, while significant increase in serum magnesium level was noticed. Whereas, the barley extract group recorded a lowest significant improvement in behavioral, brain and serum biochemical tests. It could be concluded that barley and venlafaxine together had muffled the oxidant stress and increased brain serotonin, serum magnesium level that might had a crucial role in experimental induced chronic mild stress in rats.