RESUMO
This study aimed to investigate the potential effect of in vivo administration of immunosuppressive agent FK-506 (tacrolimus) on the endothelial function of rat thoracic aortas with respect to nitric oxide (NO) synthesis. In vitro effect of the drug on NO synthesis in cultured rat coronary microvascular endothelial cells (CMEC) was also studied.In vivo administration of tacrolimus (1 mg/kg/d, intramuscular) to rats for 14 days resulted in decreased relaxant responses to the higher concentrations (1 to 30 muM) of acetylcholine in the aortas; however, responses to calcium ionophore A23187, sodium nitroprusside, L-arginine, and L-NAME did not change significantly. No changes were observed in phenylephrine-induced contractions in endothelium-denuded or -intact preparations. Administration of the vehicle for 14 days did not affect these parameters. In order to evaluate the in vitro effect of tacrolimus on NO release, CMEC isolated from rat hearts were incubated with either tacrolimus (0.01, 0.1 microM) or the vehicle. Basal, calcium ionophore-stimulated, or interleukin-1 beta-induced NO synthesis was determined by measuring total nitrite in the media. Neither tacrolimus nor the vehicle changed nitrite accumulation. It has been concluded that therapeutic concentrations of tacrolimus do not alter NO production in rat thoracic aorta or cultured CMEC; however, it impairs relaxant responses of rat aorta induced by higher concentrations of acetylcholine, possibly through changes in the downstream of receptor activation or through an imbalance between endothelium-dependent relaxant and contracting factors within the endothelium in favor of the contracting factor(s).
Assuntos
Aorta Torácica/efeitos dos fármacos , Vasos Coronários/efeitos dos fármacos , Óxido Nítrico/biossíntese , Tacrolimo/farmacologia , Acetilcolina/farmacologia , Animais , Aorta Torácica/metabolismo , Arginina/farmacologia , Calcimicina/farmacologia , Células Cultivadas , Vasos Coronários/citologia , Vasos Coronários/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Imunossupressores/farmacologia , Técnicas In Vitro , Interleucina-1beta/farmacologia , Masculino , Músculo Liso Vascular/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Nitritos/metabolismo , Nitroprussiato/farmacologia , Fenilefrina/farmacologia , Cloreto de Potássio/farmacologia , Ratos , Ratos Wistar , Tacrolimo/sangue , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacosRESUMO
Histopathological changes in the brains of embryos from female rats treated with nicotine during pregnancy and possible involvement of nitric oxide (NO) and catecholamines in the nicotine-induced abnormalities of developing brain were investigated. Sexually mature female Wistar rats were given 1, 2, and 3 mg/kg nicotine hydrogen tartrate (NHT) subcutaneously for 20 days after mating. Levels of cotinine, a nicotine metabolite, in the maternal plasma increased dose-dependently. Fetus and fetal brain weights were significantly lower in all nicotine-treated groups. Light microscopy of hippocampal CA1 area showed a decrease in the number of cells per unit area. Electron microscopy of the same region revealed a dose-dependent increase in intracytoplasmic edema, mitochondrial swelling, dilation of rough endoplasmic reticulum, nuclear configurative abnormalities, and condensation of the nuclear chromatin. Nitrate + nitrite levels in fetal brain homogenates were significantly lower in the groups treated with 2 and 3 mg/kg NHT. Norepinephrine and normetanephrine (NMN) levels were significantly higher in 2 and 3 mg/kg NHT groups, as well as dopamine, 3-methoxy-4-hydroxyphenylethyleneglycole (MHPG), and dihydroxyphenylacetic acid levels in the 3-mg/kg NHT group. In conclusion, maternal nicotine exposure may lead to structural abnormalities of the fetal brain tissue and may result in decreased levels of NO and increased levels of catecholamines and their metabolites.
Assuntos
Catecolaminas/fisiologia , Feto/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Nicotina/toxicidade , Óxido Nítrico/fisiologia , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/embriologia , Encéfalo/patologia , Cotinina/sangue , Relação Dose-Resposta a Droga , Embrião de Mamíferos , Feminino , Feto/patologia , Hipocampo/embriologia , Hipocampo/patologia , Hipocampo/ultraestrutura , Masculino , Microscopia Eletrônica/métodos , Agonistas Nicotínicos/toxicidade , Tamanho do Órgão/efeitos dos fármacos , Placenta/efeitos dos fármacos , Gravidez , Células Piramidais/efeitos dos fármacos , Células Piramidais/ultraestrutura , RatosRESUMO
We aimed to study the alterations in serum homocysteine levels and endothelium-dependent and -independent vascular relaxant responses in adjuvant-induced arthritis of the rat and to determine the effects of vitamin E administration on these changes. Arthritis was induced by a single intradermal injection of Freund's complete adjuvant into the paw. 26 days after the induction of arthritis, serum homocysteine levels and relaxant responses to acetylcholine and sodiumnitroprusside in thoracic aortas were evaluated. The relaxant responses to acetylcholine were decreased in aortas from arthritic rats, whereas the responses to sodiumnitroprusside were not significantly different when compared to the aortas from control rats. A significant increase was observed in serum homocysteine levels of the arthritic rats in comparison to those of controls. Vitamin E administration (100 mg/kg/day, i.m. for 26 days) to arthritic rats resulted in a significant increase in endothelium-dependent aortic responses to acetylcholine and a significant decrease in serum homocysteine levels with respect to the non-treated arthritic rats. However, in healthy rats, vitamin E treatment significantly decreased the acetylcholine-induced relaxant responses. We conclude that adjuvant-induced arthritis in the rat is associated with increased serum homocysteine levels and this is accompanied by a reduction in endothelium-dependent vascular responses in the thoracic aortas. Vitamin E treatment leads to normalization of the increased serum homocysteine levels and improves the endothelium-dependent relaxant responses in this experimental model.