ABSTRACT
Preeclampsia is manifested as maternal hypertension and fetal growth restriction. Matrix metalloproteinases (MMPs) are involved in hypertension and doxycycline reduces blood pressure by inhibition of MMPs. Moreover, excessive levels of MMPs and reduced nitric oxide (NO) bioavailability have been related to preeclampsia. We investigated the involvement of MMPs in hypertension in pregnancy induced by Nω-Nitro-L-arginine methyl ester (L-NAME) in rats. To this end, zimography was performed to evaluate the activity of MMPs -2 and -9 in placenta, uterus and thoracic aorta, and systolic blood pressure, feto-placental development and metabolites of NO were evaluated. Also, plasma antioxidant capacity, plasma levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PLGF) were examined. Doxycycline prevented hypertensive pregnancy and significant reductions in number of pups induced by L-NAME. Low NO bioavailability was found in hypertensive pregnant rats treated (or not) with doxycycline. Increased activity of placental MMP-2 and MMP-9 and uterine MMP-2 were attenuated by doxycycline. MMP-2 activity of thoracic aorta showed no change after hypertension. Increases in PLGF with concomitant decreases in sFlt-1 levels were found with doxycycline treatment. Also, plasma antioxidant capacity was improved with doxycycline. Also, elevations of plasma antioxidant capacity were observed in hypertensive rats treated with doxycycline. Therefore, we suggest that L-NAME reduced NO and this triggered the increases in MMP-2 and -9 activities during hypertensive pregnancy. Importantly, increases in MMPs activation and angiogenic imbalance were attenuated by doxycycline and these effects were associated with decreases in systolic blood pressure.
Subject(s)
Doxycycline/pharmacology , Hypertension, Pregnancy-Induced/drug therapy , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Neovascularization, Physiologic/drug effects , Animals , Antioxidants/metabolism , Doxycycline/therapeutic use , Female , Hypertension, Pregnancy-Induced/enzymology , Hypertension, Pregnancy-Induced/physiopathology , Litter Size/drug effects , Nitric Oxide/biosynthesis , Organ Size/drug effects , Placenta/drug effects , Placenta/pathology , Pregnancy , Rats , Rats, Wistar , Uterus/drug effects , Uterus/metabolismABSTRACT
Myeloperoxidase (MPO) is released from activated neutrophils. The inflammation in preeclampsia was found to be associated with endothelial dysfunction. We hypothesized that cardiac and circulating MPO levels are elevated in hypertensive pregnancy. Systolic and diastolic blood pressure and heart rate were measured on pregnancy days 14, 16, 18 and 20 in normal pregnant and hypertensive pregnant rats. Left and right ventricle weights, the number of viable fetuses, litter size, fetal and placenta weights were recorded on gestational day 21. Circulating and cardiac MPO activities, soluble fms-like tyrosine kinase-1 (sFlt-1) and vascular endothelial growth factor (VEGF) and nitric oxide (NO) were detected. The results showed increases in cardiac (left, but not right ventricle) and circulating MPO activities, and concomitantly lower number of viable fetuses, litter size, and fetal and placenta weights, and decreases in NO in hypertensive pregnant rats. Also, the increases in circulating sFlt-1 and VEGF were found in hypertensive pregnant group. In conclusion, maternal and fetal detrimental changes along with increases in circulating sFlt-1 and VEGF in hypertensive pregnancy may be associated with increases in cardiac and circulating MPO activities, confirming the causative role of inflammatory response in preeclampsia.
Subject(s)
Heart Ventricles/metabolism , Peroxidase/genetics , Pre-Eclampsia/genetics , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor Receptor-1/genetics , Animals , Disease Models, Animal , Female , Fetus , Gene Expression Regulation , Gestational Age , Heart Ventricles/pathology , Humans , Litter Size , Nitric Oxide/metabolism , Peroxidase/metabolism , Placenta/metabolism , Placenta/pathology , Pre-Eclampsia/metabolism , Pre-Eclampsia/pathology , Pregnancy , Rats , Rats, Inbred SHR , Rats, Wistar , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor Receptor-1/metabolismABSTRACT
Taking into account that there are controversial antioxidative effects of inhalational anesthetics isoflurane and sevoflurane and absence of comparison of genotoxicity of both anesthetics in animal model, the aim of this study was to compare DNA damage and antioxidant status in Wistar rats exposed to a single time to isoflurane or sevoflurane. The alkaline single-cell gel electrophoresis assay (comet assay) was performed in order to evaluate DNA damage in whole blood cells of control animals (unexposed; n = 6) and those exposed to 2% isoflurane (n = 6) or 4% sevoflurane (n = 6) for 120 min. Plasma antioxidant status was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. There was no statistically significant difference between isoflurane and sevoflurane groups regarding hemodynamic and temperature variables (P > 0.05). Sevoflurane significantly increased DNA damage compared to unexposed animals (P = 0.02). In addition, Wistar rats anesthetized with isoflurane showed higher antioxidative status (MTT) than control group (P = 0.019). There were no significant differences in DNA damage or antioxidant status between isoflurane and sevoflurane groups (P > 0.05). In conclusion, our findings suggest that, in contrast to sevoflurane exposure, isoflurane increases systemic antioxidative status, protecting cells from DNA damage in rats.
