Efeitos do nitrito de sódio e sua associação ao sildenafil na hipertensão gestacional experimental em ratas
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Data
2018-02-26
Autores
Rizzi, Victor Hugo Gonçalves
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Universidade Estadual Paulista (Unesp)
Resumo
As desordens hipertensivas gestacionais são complicações que acometem em torno de 5-10% das gestações. Essas desordens são as maiores causas de morbidade e mortalidade tanto materna quanto fetal. Estudos demonstram redução da biodisponibilidade do óxido nítrico (NO) em doenças hipertensivas gestacionais, tornando uma das condições responsáveis por agravar a disfunção endotelial durante o curso desta doença. Neste sentido, trabalhos demonstram que a administração oral de nitrito de sódio (NaNO2) e a administração de citrato de sildenafil podem reverter a redução da biodisponibilidade de NO e potencializar a via de sinalização NO-GMPc respectivamente. Para realização dos trabalhos foram utilizadas ratas Wistar, no qual, após confirmação da prenhez receberam L-NAME i.p para indução da hipertensão e tratamentos com nitrito de sódio e/ou citrato de sildenafil via oral entre os dias 14-21 de prenhez. A pressão arterial sistólica foi aferida pelo método de pletismografia de cauda. Parâmetros materno-fetais como: peso fetal e placentário, número de fetos viáveis e reabsorvidos foram realizados após a morte das ratas no 21º dia gestacional. O plasma das ratas foram armazenados para dosagens dos níveis plasmáticos de nitrito+nitrato, guanosina monofosfato cíclico (GMPc), mieloperoxidase (MPO), peroxidação lipídica (TBARS), TEAC, MTT sFlt-1 e VEGF. Além disso o plasma das ratas foram incubadas com células endoteliais de cordão umbilical humano (HUVECS) para avaliar a produção de NO endotelial. Em ambos os trabalhos, nós encontramos redução da pressão arterial sistólica com nitrito e sildenafil, tanto isolado quanto em associação. Somente o sildenafil foi capaz de aumentar o peso fetal, enquanto o peso placentário foi melhorado por ambas as drogas. Tanto nitrito quanto sildenafil foram capaz de reduzir a reabsorção, possivelmente por aumentar a viabilidade fetal. Foi encontrado aumento de NO plasmático em todos os grupo que receberam nitrito, enquanto curiosamente a síntese de NO em HUVECS incubadas com plasma das ratas foi aumentada em ambas as drogas. Ainda em relação a cultura celular, nós encontramos aumento da viabilidade celular em ratas hipertensas tratadas com sildenafil. A concentração plasmática de GMPc estava aumentada em ratas normotensos que receberam sildenafil. Ambas as drogas apresentam efeito antioxidante, mas somente o sildenafil foi capaz de reduzir a atividade plasmática da MPO. Fatores angiogênicos (VEGF) e anti-angiogênicos (sFlt-1) presentes em doenças hipertensivas gestacionais estavam aumentados em ratas que receberam L-NAME, porém o nitrito de sódio foi capaz de reduzir esses fatores. Nosso dados sugerem que o nitrito e o sildenafil, tanto isolado 2 quanto em associação apresentam efeitos anti-hipertensivos e antioxidantes. Portanto, nossos resultados sugerem que a ativação da via NO-GMPc aumentou o fluxo sanguíneo na interface materno-fetal e protegeu contra a hipertensão e a restrição do crescimento fetal induzidas pelo L-NAME.
Gestational hypertensive disorders are complications that affect around 5-10% of pregnancies. These disorders are the major causes of both maternal and fetal morbidity and mortality. Studies have demonstrated a reduction in the bioavailability of nitric oxide (NO) in gestational hypertensive diseases, making it one of the conditions responsible for aggravate the endothelial dysfunction during the course of this disease. In this sense, studies demonstrate that oral administration of sodium nitrite (NaNO2) and administration of sildenafil citrate may reverse the reduction of NO bioavailability and potentiate the NO-cGMP signaling pathway, respectively. Wistar rats were used to perform the study, in which, after confirmation of pregnancy, they received L-NAME i.p for induction of hypertension and treatments with sodium nitrite and/or sildenafil citrate orally between days 14-21 of pregnancy. Systolic blood pressure was measured by the tail plethysmography method. Maternal-fetal parameters such as: fetal and placental weight, number of viable and reabsorbed fetuses were performed after the death of the rats on the 21st gestational day. Plasma of the rats were stored for plasma levels of nitrite + nitrate, cGMP, myeloperoxidase (MPO), lipid peroxidation (TBARS), TEAC, MTT sFlt-1 and VEGF. In addition the plasma of the rats were incubated with human umbilical vein endothelial cells (HUVECS) to evaluate endothelial NO production. In both studies, we found reduction of systolic blood pressure with nitrite and sildenafil, both alone and in combination. Both nitrite and sildenafil were able to reduce reabsorption, possibly by increasing fetal viability. No increase in plasma NO was found in all groups receiving nitrite, while curiously NO synthesis in HUVECS incubated with plasma from rats was increased in both drugs. Still in relation to cell culture, we found increased cell viability in hypertensive rats treated with sildenafil. Plasma cGMP concentration was increased in normotensive rats receiving sildenafil. Both drugs have an antioxidant effect, but only sildenafil was able to reduce plasma myeloperoxidase activity (MPO). Angiogenic (VEGF) and anti-angiogenic (sFlt-1) factors present in gestational hypertensive diseases were increased in rats receiving L-NAME, but sodium nitrite was able to reduce these factors. Our data suggest that both nitrite and sildenafil, both alone and in combination, have antihypertensive and antioxidant effects. Therefore, our results suggest that activation of the NO-cGMP pathway increased blood flow at the maternal-fetal interface and protected against hypertension and fetal growth restriction induced by L-NAME.
Gestational hypertensive disorders are complications that affect around 5-10% of pregnancies. These disorders are the major causes of both maternal and fetal morbidity and mortality. Studies have demonstrated a reduction in the bioavailability of nitric oxide (NO) in gestational hypertensive diseases, making it one of the conditions responsible for aggravate the endothelial dysfunction during the course of this disease. In this sense, studies demonstrate that oral administration of sodium nitrite (NaNO2) and administration of sildenafil citrate may reverse the reduction of NO bioavailability and potentiate the NO-cGMP signaling pathway, respectively. Wistar rats were used to perform the study, in which, after confirmation of pregnancy, they received L-NAME i.p for induction of hypertension and treatments with sodium nitrite and/or sildenafil citrate orally between days 14-21 of pregnancy. Systolic blood pressure was measured by the tail plethysmography method. Maternal-fetal parameters such as: fetal and placental weight, number of viable and reabsorbed fetuses were performed after the death of the rats on the 21st gestational day. Plasma of the rats were stored for plasma levels of nitrite + nitrate, cGMP, myeloperoxidase (MPO), lipid peroxidation (TBARS), TEAC, MTT sFlt-1 and VEGF. In addition the plasma of the rats were incubated with human umbilical vein endothelial cells (HUVECS) to evaluate endothelial NO production. In both studies, we found reduction of systolic blood pressure with nitrite and sildenafil, both alone and in combination. Both nitrite and sildenafil were able to reduce reabsorption, possibly by increasing fetal viability. No increase in plasma NO was found in all groups receiving nitrite, while curiously NO synthesis in HUVECS incubated with plasma from rats was increased in both drugs. Still in relation to cell culture, we found increased cell viability in hypertensive rats treated with sildenafil. Plasma cGMP concentration was increased in normotensive rats receiving sildenafil. Both drugs have an antioxidant effect, but only sildenafil was able to reduce plasma myeloperoxidase activity (MPO). Angiogenic (VEGF) and anti-angiogenic (sFlt-1) factors present in gestational hypertensive diseases were increased in rats receiving L-NAME, but sodium nitrite was able to reduce these factors. Our data suggest that both nitrite and sildenafil, both alone and in combination, have antihypertensive and antioxidant effects. Therefore, our results suggest that activation of the NO-cGMP pathway increased blood flow at the maternal-fetal interface and protected against hypertension and fetal growth restriction induced by L-NAME.
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Palavras-chave
Hipertensão gestacional, citrato de sildenafil, nitrito de sódio, L-NAME, ratas, Gestational hypertension, sildenafil citrate, sodium nitrite, rats