Abstract
Upregulation of inducible nitric oxide synthase (iNOS) has been reported in both experimental and clinical hypertension. However, although pro-inflammatory cytokines that up-regulate iNOS contribute to pre-eclampsia, no previous study has tested the hypothesis that a selective iNOS inhibitor (1400 W) could exert antihypertensive effects associated with decreased iNOS expression and nitrosative stress in pre-eclampsia. This study examined the effects of 1400 W in the reduced uteroplacental perfusion pressure (RUPP) placental ischaemia animal model and in normal pregnant rats. Sham-operated and RUPP rats were treated with daily vehicle or 1 mg/kg/day N-[3-(Aminomethyl) benzyl] acetamidine (1400 W) subcutaneously for 5 days. Plasma 8-isoprostane levels, aortic reactive oxygen species (ROS) levels and nicotinamide adenine dinucleotide phosphate (NADPH)-dependent ROS production were evaluated by ELISA, dihydroethidium fluorescence microscopy and lucigenin chemiluminescence respectively. Inducible nitric oxide synthase expression was assessed by western blotting analysis and aortic nitrotyrosine was evaluated by immunohistochemistry. Mean arterial blood pressure increased by ∼30 mmHg in RUPP rats, and 1400 W attenuated this increase by ∼50% (P < 0.05). While RUPP increased plasma 8-isoprostane levels, aortic ROS levels, and NADPH-dependent ROS production (P < 0.05), treatment with 1400 W blunted these alterations (P < 0.05). Moreover, while RUPP increased iNOS expression and aortic nitrotyrosine levels (P < 0.05), treatment with 1400 W blunted these alterations (P < 0.05). These results clearly implicate iNOS in the hypertension associated with RUPP. Our findings may suggest that iNOS inhibitors could be clinically useful in the therapy of pre-eclampsia, especially in particular groups of patients genetically more prone to express higher levels of iNOS. This issue deserves further confirmation.
Highlights
Pre-eclampsia is an important complication of pregnancy and multiple hypotheses have been proposed to elucidate its pathogenesis, including inadequate placentation that activates complex mechanisms leading to systemic maternal vascular dysfunction [1,2,3,4,5]
Treatment with 1400 W attenuated this alteration, as revealed by lower aortic nitrotyrosine levels in the reduced uteroplacental perfusion pressure (RUPP) 1400 W group (106 Æ 3 A.U.) compared with the RUPP Saline group (Fig. 6; P = 0.012). This is the first study to show that treatment with inducible nitric oxide synthase (iNOS) inhibitor 1400 W exerts antihypertensive effects in the RUPP model of preeclampsia
The most important findings of this study were as follows: (i ) vascular iNOS expression is up-regulated in the RUPP model of pre-eclampsia; (ii ) the iNOS inhibitor 1400 W blunted the increases in iNOS expression as well as the oxidative and nitrosative stress associated with RUPP; (iii ) the iNOS inhibitor 1400 W
Summary
Pre-eclampsia is an important complication of pregnancy and multiple hypotheses have been proposed to elucidate its pathogenesis, including inadequate placentation that activates complex mechanisms leading to systemic maternal vascular dysfunction [1,2,3,4,5]. Nitric oxide plays an important role in cardiovascular homoeostasis, and it is formed from L-arginine by a family of nitric oxide synthases, including inducible nitric oxide synthase (iNOS). Increased oxidative stress has been reported in pre-eclampsia, and this alteration contributes to the pathogenesis of this critical condition [8]. Elevated levels of circulating proinflammatory cytokines that up-regulate iNOS have been shown in pre-eclampsia [9,10,11], no previous study has examined whether up-regulated iNOS expression contributes to the vascular alterations found in this condition.
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