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Hypertensive disorders of pregnancy (HDP), comprising gestational hypertension (GH) and pre-eclampsia (PE), are leading causes of maternal and perinatal morbidity and mortality. Both GH and PE are characterized by new-onset hypertension, but PE additionally includes proteinuria and/or end-organ damage. Impaired nitric oxide (NO) bioavailability may lead to endothelial dysfunction in GH and PE, and the primary source of vascular NO is endothelial NO synthase (eNOS). However, no previous study has investigated plasma eNOS concentrations in patients with GH and PE. In this study, we compared plasma eNOS concentrations in healthy pregnancies and HDP in two independent cohorts. The primary study included 417 subjects, with 43 non-pregnant (NP) and 156 healthy pregnant (HP) women and 122 patients with GH and 96 with PE. The replication study included 85 pregnant women (41 healthy and 44 pre-eclamptic). Plasma concentrations of eNOS were measured using a commercial ELISA kit provided by R&D Systems, and plasma nitrite concentrations were assessed using two ozone-based chemiluminescence assays. Correlations between plasma eNOS concentrations and plasma nitrite concentrations, as well as clinical and biochemical parameters, were evaluated by either Spearman’s or Pearson’s tests. In the primary study, NP women and HDP had significantly lower plasma eNOS concentrations compared to HP; concentrations were even lower in PE compared to GH. Plasma eNOS concentrations were reduced but not significant in early-onset PE, PE with severe features, preterm birth, and intrauterine growth restriction. No correlation was observed between plasma eNOS and nitrite levels. In HDP, there was a significant positive correlation between levels of eNOS and hemoglobin (r = 0.1496, p = 0.0336) as well as newborn weight (r = 0.1487, p = 0.0316). Conversely, a negative correlation between eNOS levels and proteinuria was observed (r = −0.2167, p = 0.0179). The replication study confirmed significantly reduced plasma concentrations of eNOS in PE compared to HP. Our findings provide evidence of reduced plasma eNOS concentrations in HDP; they were particularly lower in PE compared to GH and HP in two independent studies.

Purpose The antihypertensive effects of angiotensin-converting enzyme inhibitors (ACEi) are explained, at least in part, by enhanced bradykinin-dependent nitric oxide (NO) formation and decreased angiotensin II-induced oxidative stress and vasoconstriction. We examined for the first time whether treatment with enalapril increases the plasma levels of markers of NO formation and decreases oxidative stress in mild to moderate hypertensive patients. Methods Eighteen untreated hypertensive patients were treated with enalapril 10 mg/day (n = 10) or 20 mg/day (n = 8) for 60 days. Eighteen normotensive healthy controls were followed for the same period. Venous blood samples were collected at baseline and after 30/60 days of treatment with enalapril. Plasma NOx (nitrites + nitrates) concentrations were determined by using the Griess reaction. Plasma nitrite and whole blood nitrite concentrations were determined by using an ozone-based chemiluminescence assay. Plasma thiobarbituric acid-reactive species (TBARS) and 8-isoprostane concentrations were determined by a fluorimetric method and by ELISA, respectively. Results Treatment with enalapril decreased blood pressure in hypertensive patients. However, we found no significant changes in plasma NOx, nitrite, whole blood nitrite, and in the levels of markers of oxidative stress in both normotensive controls and hypertensive patients treated with enalapril. Conclusions Our data show that enalapril 10-20 mg/day does not affect the concentrations of relevant markers of NO formation or markers of oxidative stress in mild to moderately hypertensive subjects, despite satisfactory blood pressure control. Our findings do not rule out the possibility that ACEi may produce such effects in more severely hypertensive patients treated with higher doses of ACEi.

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.

Dysregulation of adipocytokines may be associated with endothelial dysfunction in women with preeclampsia (PE), who are at increased risk of future cardiovascular disease. Visfatin, an adipocytokine with a potential cardiovascular role, is also known as nicotinamide phosphorybosil transferase (NAMPT). NAMPT gene polymorphisms affect circulating visfatin/NAMPT levels in obesity. Most findings provide evidence for increased visfatin/NAMPT circulating levels in PE. However, no previous study has tested the hypothesis that NAMPT polymorphisms affect visfatin/NAMPT levels in hypertensive disorders of pregnancy. We studied the effects of the NAMPT polymorphisms T>C (rs1319501) and A>G (rs3801266), and the haplotypes formed by them on visfatin/NAMPT levels and whether these genetic markers are associated with gestational hypertension (GH) and PE. We studied 212 healthy pregnant (HP), 181 patients with GH and 208 with PE. Genotypes were determined by Taqman allele discrimination assays. Plasma visfatin/NAMPT levels were measured by ELISA. No significant differences in visfatin/NAMPT levels were found among the groups. However, higher visfatin/NAMPT levels (P<0.05) were found in GH patients carrying the AG or the GG genotypes for the rs3801266 polymorphism or the 'T, G' haplotype. The TC and CC genotypes and the C allele for the rs1319501 polymorphism were more frequent in the HP than in the PE group (P<0.05). Moreover, the 'C, A' haplotype was also more frequent in the HP than in the PE group (P<0.01). Our findings suggest that although the rs3801266 polymorphism and the 'T, G' haplotype affect visfatin/NAMPT levels in GH, the rs1319501 polymorphism and the 'C, A' haplotype affect the susceptibility to PE.

Pre-eclampsia (PE) is defined as pregnancy-induced hypertension and proteinuria, and is a major cause of maternal and perinatal morbidity and mortality. A large subgroup of pregnant women with PE is nonresponsive to antihypertensive drugs, including methyldopa, nifedipine and hydralazine. Pharmacogenomics may help to guide the individualized therapy for this nonresponsive subgroup. However, just a few pharmacogenetic studies examined the effects of genetic polymorphisms on response to antihypertensive drugs in PE, and the criteria of responsiveness used to define responsive or nonresponsive subgroups to antihypertensive therapy should be replicated by others. We review these gene-drugs interactions, novel approaches to pharmacogenomics research and potential novel drugs for PE therapy. Finally, we discuss the challenges and perspectives of pharmacogenetics in the treatment of PE.

Dietary nitrite and nitrate have been reported as alternative sources of nitric oxide (NO). In this regard, we reported previously that sodium nitrite added to drinking water was able to exert antihypertensive effects in an experimental model of hypertension in a dose-dependent manner. Taking into consideration that nitrite is continuously converted to nitrate in the bloodstream, here we expanded our previous report and evaluate whether a single daily dose of sodium nitrite could exert antihypertensive effects in 2 kidney-1 clip (2K1C) hypertensive rats. Sham-operated and 2K1C rats were treated with vehicle or sodium nitrite (15 mg/kg/day) for 4 weeks. We evaluated the effects induced by sodium nitrite treatment on systolic blood pressure (SBP) and NO markers such as plasma nitrite, nitrite + nitrate (NOx), cGMP, and blood levels of nitrosyl-hemoglobin. In addition, we also evaluated effects of nitrite on oxidative stress and antioxidant enzymes. Dihydroethidium (DHE) was used to evaluate aortic reactive oxygen species (ROS) production by fluorescence microscopy, and plasma levels of thiobarbituric acid-reactive species (TBARS) were measured in plasma samples from all experimental groups. Red blood cell superoxide dismutase (SOD) and catalase activity were evaluated with commercial kits. Sodium nitrite treatment reduced SBP in 2K1C rats ( P  < 0.05). We found lower plasma nitrite and NOx levels in 2K1C rats compared with normotensive controls (both P  < 0.05). Nitrite treatment restored the lower levels of nitrite and NOx. While no change was found in the blood levels of nitrosyl-hemoglobin ( P  > 0.05), nitrite treatment increased the plasma levels of cGMP in 2K1C rats ( P  < 0.05). Higher plasma TBARS levels and aortic ROS levels were found in hypertensive rats compared with controls ( P  < 0.05), and nitrite blunted these alterations. Lower SOD and catalase activities were found in 2K1C hypertensive rats compared with controls (both P  < 0.05). Nitrite treatment restored SOD activity ( P  < 0.05), whereas catalase was not affected. These data suggest that even a single daily oral dose of sodium nitrite is able to lower SBP and exert antioxidant effects in renovascular hypertension.

Introduction Vascular endothelial growth factor (VEGF) is relevant for healthy pregnancy, and abnormalities in VEGF functions have been associated with hypertensive disorders of pregnancy. Our group recently demonstrated that VEGF genetic polymorphisms affect the susceptibility to preeclampsia (PE). Objective Therefore, in this study our aim is to examine whether VEGF polymorphisms affect the antihypertensive responses in women with PE. Methods We studied 113 white PE women who were stratified according to blood pressure levels after antihypertensive treatment (46 responsive, R group and 67 non-responsive, NR group). We then compared the frequencies of two VEGF genetic polymorphisms (C-2578A and G-634C) between R and NR groups. Results We found no significant differences in genotype or allele distributions between R and NR groups ( P  > 0.05). In addition, no difference was observed in overall distribution of haplotypes ( P  > 0.05). Conclusion Our data suggest that VEGF polymorphisms do not affect responsiveness to the antihypertensive therapy in PE.

Polymorphisms in the endothelial nitric oxide synthase (eNOS) gene have been inconsistently associated with preeclampsia. We compared genotype and haplotype frequencies of three eNOS gene polymorphisms in normotensive and hypertensive pregnancies. Genotypes and haplotypes for eNOS polymorphisms (T-786C, Glu298Asp and intron 4 b/a) were determined in 326 pregnant women (110 healthy pregnancies, 103 gestational hypertensives and 113 preeclamptic). No differences were observed in the frequencies of genotypes and alleles of the three polymorphisms among the groups (all p > 0.05). However, the haplotype 'T Glu a' was more common in healthy pregnancies than in gestational hypertensives or preeclamptic (20 vs 6 and 6%, respectively; p < 0.0032). Conversely, the haplotype 'C Glu a' was more common in gestational hypertensives and preeclamptic than in healthy pregnancies (17 vs 17 and 5%; p = 0.0061). These findings suggest a contribution of eNOS haplotypes to the development of hypertensive disorders of pregnancy that is obscured when specific eNOS genotypes alone are considered.

Preeclampsia (PE) is characterized by hypertension occurring after the twentieth week of pregnancy. It is a significant contributor to maternal and perinatal morbidity and mortality in developing countries and its pervasiveness is increasing within developed countries including the USA. However, the mechanisms mediating the pathogenesis of this maternal disorder and its rising prevalence are far from clear. A major theory with strong experimental evidence is that placental ischemia, resulting from inappropriate remodeling and widening of the maternal spiral arteries, stimulates the release of soluble factors from the ischemic placenta causing maternal endothelial dysfunction and hypertension. Aberrant maternal immune responses and inflammation have been implicated in each of these stages in the cascade leading to PE. Regarding the increased prevalence of this disease, it is becoming increasingly evident from epidemiological data that obesity, which is a state of chronic inflammation in itself, increases the risk for PE. Although the specific mechanisms whereby obesity increases the rate of PE are unclear, there are strong candidates including activated macrophages and natural killer cells within the uterus and placenta and activation in the periphery of T helper cells producing cytokines including TNF-α, IL-6 and IL-17 and the anti-angiogenic factor sFlt-1 and B cells producing the agonistic autoantibodies to the angiotensin type 1 receptor (AT1-aa). This review will focus on the immune mechanisms that have been implicated in the pathogenesis of hypertension in PE with an emphasis on the potential importance of inflammatory factors in the increased risk of developing PE in obese pregnancies.

In this review, we first provide a brief overview of the nitric oxide synthase (NOS) isoforms and biochemistry. This is followed by describing what is known about NOS-mediated blood pressure control during normal pregnancy. Circulating nitric oxide (NO) bioavailability has been assessed by measuring its metabolites, nitrite (NO2) and/or nitrate (NO3), and shown to rise throughout normal pregnancy in humans and rats and decline postpartum. In contrast, placental malperfusion/ischemia leads to systemic reductions in NO bioavailability leading to maternal endothelial and vascular dysfunction with subsequent development of hypertension in PE. We end this article by describing emergent risk factors for placental malperfusion and ischemic disease and discussing strategies to target the NOS system therapeutically to increase NO bioavailability in preeclamptic patients. Throughout this discussion, we highlight the critical importance that experimental animal studies have played in our current understanding of NOS biology in normal pregnancy and their use in finding novel ways to preserve this signaling pathway to prevent the development, treat symptoms, or reduce the severity of PE.