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C A Hubel

Publications and source records attributed to C A Hubel.

At least 19 recordsLinked to original sources
PubMed2003

Binding of fatty acids facilitates oxidation of cysteine-34 and converts copper-albumin complexes from antioxidants to prooxidants.

As a transition metal capable of undergoing one-electron oxidation-reduction conversions, copper (Cu) is essential for life and fulfills important catalytic functions. Paradoxically, the same redox properties of copper can make it extremely dangerous because it can catalyze production of free radical intermediates from molecular oxygen. Factors involved in regulation of redox activity of albumin-bound copper have not been well characterized. In the present study, effects of modification of the albumin cysteine-34 (Cys-34) and binding of nonesterified fatty acids on the redox-cycling activity of the complex of copper with human serum albumin (Cu/HSA) were studied. Because ascorbate is the most abundant natural reductant/scavenger of free radicals in blood plasma, the electron paramagnetic resonance assay of ascorbate radical formation was used as a method to monitor Cu/HSA redox-cycling activity. At Cu/HSA ratios below 1:1, the bound Cu was virtually redox inactive, as long as Cys-34 was in reduced state (Cu/HSA-SH). Alkylation, nitrosylation, or oxidation of Cu/HSA resulted in the appearance of redox-cycling activity. Experiments with ultrafiltration of Cu/HSA alkylated with N-ethylmaleimide (Cu/HSA-NEM) showed that at Cu/HSA-NEM ratios below 1:1, the ascorbate radicals were produced by Cu tightly bound to HSA rather than by Cu released in solution. The rate of ascorbate radical production in HSA-NEM and S-nitrosylated HSA (HSA-NO) was, however, more than one order of magnitude lower than that in a solution containing equivalent concentration of free copper ions. While Cu/HSA-SH was redox inactive, binding of oleic or linoleic acids induced Cu-dependent redox-cycling with maximal activity reached at a fatty acid to protein molar ratio of 3:1 for oleic acid and 2:1 for linoleic acid. Binding of fatty acids caused profound conformational changes and facilitated oxidation of the Cys-34 SH-group at essentially the same ratios as those that caused redox-cycling activity of Cu/HSA. We conclude that fatty acids regulate anti-/prooxidant properties of Cu-albumin via controlling redox status of Cys-34.

Antioxidants↗
PubMed2001

Elevated levels of S-nitrosoalbumin in preeclampsia plasma.

The availability of nitric oxide (NO), which is required for the normal regulation of vascular tone, may be decreased in preeclampsia, thus contributing to the vascular pathogenesis of this pregnancy disorder. Because ascorbate is essential for the decomposition of S-nitrothiols and the release of NO, we speculated that the ascorbate deficiency typical of preeclampsia plasma might result in decreased rates of decomposition of S-nitrosothiols. We tested the hypothesis that total S-nitrosothiol and S-nitrosoalbumin concentrations are increased in preeclampsia plasma, reflecting a decreased release of NO from these major reservoirs of NO. Gestationally matched plasma samples were obtained (before labor or intravenous MgSO(4)) from 21 women with preeclampsia and 21 women with normal pregnancy, and plasma samples were also obtained from 12 nonpregnant women of similar age and body mass index during the follicular phase of the menstrual cycle. All were nonsmokers. The assay included ultraviolet-induced decomposition of S-nitrosothiols to liberate NO captured by a florigenic reagent, 4,5-diaminofluoresceine, to produce diaminofluoresceine-Triazole. Preeclampsia plasma contained significantly higher concentrations of total S-nitrosothiols (11.1+/-2.9 nmol/mL) than normal pregnancy samples (9.4+/-1.5 nmol/mL). Even greater differences were found between preeclampsia plasma and plasma samples from normal pregnancies and nonpregnant women (294+/-110, 186+/-25, and 151+/-25 pmol/mg protein, respectively) when S-nitrosothiol content was expressed per milligram protein. The albumin fraction contained 49.4% of total plasma S-nitrosothiols in the control samples and 53.7% and 56.8% of plasma S-nitrosothiols in normal pregnancy and preeclampsia, respectively. The level of S-nitrosoalbumin was significantly higher in preeclampsia than in normal pregnancy or nonpregnancy plasma (6.3+/-1.4, 5.1+/-0.7, and 4.2+/-1.0 nmol/mL, respectively). The increased concentration of S-nitrosoalbumin in preeclampsia almost completely accounted for the increased levels of S-nitrosothiols in total plasma. Due to combined increases in nitrosothiols and decreases in protein, the preeclampsia plasma concentration of S-nitrosoalbumin was greatly increased on a per milligram of protein basis (271% and 186% compared with normal nonpregnancy and normal pregnancy plasma, respectively). We conclude that S-nitrosoalbumin and total S-nitrosothiol concentrations are significantly increased in preeclampsia plasma and may reflect insufficient release of NO groups in this condition.

Adult↗
PubMed2001

Mishandling of copper by albumin: role in redox-cycling and oxidative stress in preeclampsia plasma.

OBJECTIVE: To test the hypothesis that enhanced oxidative stress during pregnancies complicated by preeclampsia is associated with improper copper (Cu) binding by plasma albumin, resulting in enhanced Cu redox-cycling activity and that altered Cu binding, in turn, is caused by interactions of excessive amounts of free fatty acids with albumin. STUDY DESIGN: We studied binding and redox-cycling activity of Cu in 17 normal pregnancy and 17 preeclampsia plasma samples. Binding of exogenous Cu in plasma samples was quantified indirectly using spectrophotometric measurements of its complex with a specific chelator of Cu(I), bathocuproine disulfonate. Redox-cycling activity of Cu in plasma samples was estimated by electron paramagnetic resonance (EPR) spectroscopy of ascorbate radicals formed during one-electron oxidation of ascorbate by redox-active catalytic Cu. Formation of Cu/albumin complexes in model systems in the presence and absence of fatty acids was studied using EPR spectroscopy of Cu(II)/albumin. RESULTS: We found that preeclampsia plasma (as compared to normal pregnancy plasma) (1) displays elevated endogenous ascorbate redox-cycling that is normalized by a Cu(II) chelator, cuprizone I, (2) has lowered capacity to bind and redox-regulate exogenously added Cu, and (3) responds to treatment with fatty-acid-free albumin by diminished ascorbate oxidizing activity. Conversely, addition of free fatty acid (oleic acid) to normal pregnancy plasma sample yields increased ascorbate redox-cycling activity. Our model experiments showed that Cu-dependent redox-cycling activity of purified human serum albumin is significantly increased by excess free fatty acids. CONCLUSION: Mishandling of Cu by albumin contributes to oxidative stress in preeclampsia. Cu chelators may represent promising mechanism-based antioxidants to attenuate oxidative stress in preeclampsia.

Adult↗
PubMed2001

Endothelial function and myogenic reactivity in small mesenteric arteries of hyperlipidemic pregnant rats.

Supraphysiological increases in serum triglycerides and cholesterol often occur during pregnancy, but their effects on vascular function are poorly understood. Intraperitoneal injection of the nontoxic surfactant poloxamer 407 (P-407) results in sustained elevation of triglycerides and cholesterol. We asked if P-407-induced hyperlipidemia during late pregnancy adversely affects mesenteric resistance artery vasodilator function. On days 13-15 of pregnancy, rats were given a single intraperitoneal injection of P-407, sterile water vehicle, or non-lipid-altering pluronic F-88 (P-88). Four days postinjection, serum triglycerides, cholesterol, free fatty acids, and the lipid peroxidation product malondialdehyde were significantly increased in P-407-treated rats. Mesenteric arteries from P-407-treated rats displayed significant increases in myogenic reactivity (constrictor responses to step increases in intraluminal pressure). The nitric oxide (NO) blocker N(alpha)-methyl-L-arginine increased the myogenic response in control but not in P-407 arteries, normalizing group differences. Endothelial removal increased myogenic reactivity beyond that of prior NO synthase inhibition in controls and potentiated myogenic reactivity in P-407 arteries such that responses again converged. Relaxation responses to the endothelium-dependent vasodilator methacholine did not differ. We conclude that that P-407-induced hyperlipidemia during pregnancy increases myogenic reactivity due to selective attenuation of an NO-mediated vasodilator component of the myogenic response.

Animals↗
PubMed2000

Invasive cytotrophoblasts manifest evidence of oxidative stress in preeclampsia.

In preeclampsia, poor placental perfusion may result in maternal endothelial dysfunction, but the pathways involved are largely unknown. Candidate placental mediators include products of oxidative stress released into the maternal circulation. Xanthine oxidase has been implicated in postischemic-reperfusion injury via the generation of superoxide anion radicals (superoxide; O(2)(.-)) and hydrogen peroxide. We examined placentas and placental bed curettings and/or biopsies from preeclamptic control pregnant women to test the hypothesis that xanthine oxidase is a mediator of oxidative stress in placentas from women with preeclampsia. The expression of xanthine dehydrogenase/xanthine oxidase holoenzyme and the activity of xanthine oxidase, the isoform known to generate reactive oxygen species, were increased in a subpopulation of cytotrophoblasts of preeclamptic women. Additionally, the expression of superoxide dismutase, which would scavenge superoxide produced by xanthine oxidase, was reduced in the same cells. Furthermore, fluorescence immunostaining for nitrotyrosine, which was suggestive of superoxide-nitric oxide interactions to form peroxynitrite anion (ONOO(-)) in vivo, was increased in these cells and in villous vessels. Thus, our data indicate an increased capacity of placental cells to generate reactive oxygen species in preeclampsia.

Adult↗
PubMed2000

Dyslipoproteinaemia in postmenopausal women with a history of eclampsia.

OBJECTIVE: To test the hypothesis that postmenopausal women with a history of eclampsia manifest a more high risk lipid profile than postmenopausal women with a history of normal pregnancy. SETTING: The Department of Obstetrics and Gynaecology, National University Hospital, Reykjavik, Iceland, and the Magee-Womens Research Institute, Pittsburgh, Pennsylvania, USA. PARTICIPANTS: Thirty Icelandic women with a history of eclampsia, aged between 50 and 67 years at the time of re-examination (cases) were individually matched for current age, and for age and parity at index pregnancy, to 30 unrelated Icelandic women with a history of normal pregnancy (controls). METHODS: The participating women completed a health and family history questionnaire and underwent a physical examination. Fasting plasma low density lipoprotein diameter, serum lipids, insulin, and glucose were measured. RESULTS: Mean low density lipoprotein size was significantly smaller and apolipoprotein B concentration was higher in women with prior eclampsia. The percentage of cases receiving blood pressure medication (33%) was significantly greater than controls (6.7%). Thirteen cases had had hypertensive complications in at least one other pregnancy (recurrent subgroup); postmenopausally, these women displayed significantly increased diastolic blood pressures, smaller-sized low density lipoprotein, increased apolipoprotein B, decreased high density lipoprotein2 (HDL2) cholesterol, and increased total cholesterol: HDL cholesterol ratio compared with their controls. Fourteen cases were normotensive in all other pregnancies (nonrecurrent); these showed no differences from their controls. CONCLUSIONS: Dyslipoproteinaemia is more prevalent among postmenopausal women with prior eclampsia, especially with recurrent hypertension in pregnancy, than in postmenopausal women with prior normal pregnancies.

Aged↗
PubMed1999

Association of pre-eclampsia with common coding sequence variations in the lipoprotein lipase gene.

Marked dyslipidemia may contribute to endothelial cell dysfunction in pre-eclampsia. Carriers of N291S or D9N missense mutations in the lipoprotein lipase (LPL) gene exhibit reductions in LPL activity and are predisposed to dyslipidemia and cardiovascular disease. In Caucasians, the D9N variant is in strong linkage disequilibrium with the - 93T --> G promoter variant. A fourth LPL variant, S447X, is often associated with a beneficial lipid profile. We asked if the N291S and the combination D9N/- 93T --> G variants are more prevalent, and if the S447X variant is less prevalent, in Caucasian women with pre-eclampsia as compared with normal pregnancies. DNA amplification was followed by an allele-specific oligonucleotide ligation assay. Allele frequencies were analyzed with a chi2 table and Yates' correction. The N291S variant was identified in 11.1% of pre-eclamptics as compared with 2.9% of pregnancy controls (p = 0.008). All carriers of D9N were also carriers of - 93T --> G. The D9N/ - 93T --> G combined variant was found in 7.1% of pre-eclamptics as compared with 1.4% of pregnancy controls (p = 0.02). No individuals were carriers of both N291S and D9N/ - 93T --> G. Thus, 18.2% of pre-eclamptics had either of these LPL mutations compared with 4.3% of pregnancy controls (and 4.4% of population controls). The frequency of the S447X variant did not differ among groups. We conclude that carriers of N291S or combined D9N/ - 93T --> G mutations in the LPL gene are at substantially increased risk of pre-eclampsia.

Adult↗
PubMed1999

Oxidative stress in the pathogenesis of preeclampsia.

The etiology and pathogenesis of the pregnancy syndrome preeclampsia remain poorly understood. There is substantial evidence to suggest that the diverse manifestations of preeclampsia, including altered vascular reactivity, vasospasm, and discrete pathology in many organ systems, are derived from pathologic changes within the maternal vascular endothelium. With the theme of endothelial cell dysfunction emphasized, this review focuses on the role of oxidative stress (an imbalance favoring oxidant over antioxidant forces) in the pathogenesis of preeclampsia. Data are summarized regarding 1) the role of the placenta in preeclampsia; 2) evidence and mechanisms of oxidative stress in the preeclampsia placenta; 3) markers of oxidative stress in the maternal circulation; and 4) the potential role of maternal dyslipidemia in generation of oxidative stress. A recurrent theme is that free radical reactions, promoted by "cross-talk" between the diseased placenta and maternal dyslipidemia, promote a vicious cycle of events that make cause and effect difficult to distinguish but likely contribute to the progression of preeclampsia.

Ascorbic Acid↗
PubMed1998

Small low-density lipoproteins and vascular cell adhesion molecule-1 are increased in association with hyperlipidemia in preeclampsia.

The pregnancy disorder preeclampsia is characterized by endothelial cell dysfunction that may be promoted by abnormal increases in circulating lipids, particularly triglycerides and free fatty acids. Serum triglyceride concentration is a major regulatory determinant of low-density lipoprotein (LDL) size and density distribution. Smaller, denser LDL particles have several intrinsic properties capable of inducing endothelial dysfunction. The present nested, case-control study of gestationally matched preeclamptic and normal pregnant women tested the hypothesis that hypertriglyceridemia in preeclampsia is accompanied by decreases in LDL peak particle diameter (predominant LDL size). Plasma LDL peak particle diameter was determined by nondenaturing 2% to 16% polyacrylamide gel electrophoresis. Correlations of LDL diameter with the concentration of serum triglycerides, free fatty acids, total cholesterol, LDL-cholesterol, and apolipoprotein B (apo B) were determined. In the same individuals, we measured serum concentrations of a marker of vascular dysfunction previously reported to be increased in preeclampsia, soluble vascular cell adhesion molecule-1 (VCAM-1), and examined the association of VCAM-1 with LDL diameter and serum lipids. LDL peak particle diameter was decreased in preeclampsia relative to normal pregnancy (P < .01). The LDL-cholesterol:apo B ratio, which frequently decreases with decreasing LDL diameter, was also decreased (P < .04). Triglyceride concentrations were increased in preeclampsia (P < .0002), and there was a significant inverse relationship between LDL peak particle diameter and triglycerides (r = -.55, P < .02). Serum soluble VCAM-1 concentrations were markedly increased in preeclampsia (P < .0003). Apo B (P < .004), free fatty acids (P < .01), total cholesterol (P < .01), and LDL-cholesterol (P < .02) were also increased. VCAM-1 correlated with apo B (r = .50, P < .03) and LDL-cholesterol (r = .50, P < .03), but showed no relationship with the LDL diameter, LDL-cholesterol:apo B ratio, or other lipids. We conclude that the predominance of smaller, denser LDL, a potential contributor to endothelial cell dysfunction, is a feature of preeclampsia. However, the serum VCAM-1 level, one indicator of endothelial involvement, may be influenced more by quantitative lipoprotein changes (serum apo B or LDL-cholesterol) than by LDL particle size.

Case-Control Studies↗
PubMed1998

Dyslipidemia, iron, and oxidative stress in preeclampsia: assessment of maternal and feto-placental interactions.

The etiology and pathogenesis of the pregnancy syndrome preeclampsia remain poorly understood. There is evidence that oxidative stress (am imbalance between oxidant and antioxidant forces in favor of oxidants) occurs in preeclampsia, and it has been hypothesized that reactive oxygen species or their metabolites ultimately comprise the "defensive" vasodilatory, antiaggregatory, and barrier functioning of the vascular endothelium. Oxidative stress may be point at which feto-placental and maternal factors converge, resulting in the protean manifestations of preeclampsia. This review highlights the evidence for maternal dyslipidemia and altered iron kinetics in preeclampsia and gives a critical assessment of their potential impact on disease progression. The theme is developed that interaction of maternal components, particularly neutrophils and oxidation-susceptible lipids, with placental cells and placental-derived factors engenders feed-forward cycles of oxidative stress that ultimately cause widespread endothelial cell dysfunction and its clinical manifestations.

Endothelium, Vascular↗
PubMed1997

Increased ascorbate radical formation and ascorbate depletion in plasma from women with preeclampsia: implications for oxidative stress.

There is evidence that oxidative stress accompanies preeclampsia and plasma ascorbate concentrations are reported to be decreased in the disorder. We tested the hypothesis that an ascorbate-oxidizing activity is increased in plasma from women with preeclampsia relative to normal pregnancy. Electron paramagnetic resonance (EPR) spectroscopy was used to determine (1) plasma functional reserves of ascorbate and total thiols, (2) temporal changes in ascorbate and thiol concentrations during incubation of whole blood in vitro, and (3) ascorbate radical signal kinetics in plasma after equalization of ascorbate concentrations. High-pressure liquid chromatography (HPLC) was used to measure plasma alpha-tocopherol. Ascorbate concentrations were 50% lower in preeclampsia relative to normal pregnancy plasma but thiols and alpha-tocopherol did not differ. The elapsed time prior to half-consumption of plasma ascorbate was decreased approximately three-fold during incubation of whole blood from preeclamptics. No concomitant decrease in thiols was evident. The initial ascorbate radical signal amplitude was greater in preeclampsia plasma and then, in contrast to normal pregnancy plasma, decreased progressively. The iron chelator, deferoxamine had no effect on plasma ascorbate radical formation. We conclude that an ascorbate-oxidizing activity is increased in preeclampsia plasma which might contribute to vascular dysfunction in the disorder.

Adult↗
PubMed1996

Fasting serum triglycerides, free fatty acids, and malondialdehyde are increased in preeclampsia, are positively correlated, and decrease within 48 hours post partum.

OBJECTIVE: We tested the hypothesis that serum free (nonesterified) fatty acid and triglyceride concentrations are increased in nulliparous women with preeclampsia relative to women with uncomplicated pregnancies and that these lipids decrease post partum, consistent with the known resolution of clinical symptoms. The relationships between serum concentrations of these lipids and the lipid peroxidation metabolite malondialdehyde were also examined. STUDY DESIGN: Predelivery and 24 to 48 hour postpartum venous blood samples were collected from eight women with preeclampsia and nine women with uncomplicated pregnancies after an 8- to 10-hour fast. Sera were analyzed for concentrations of triglycerides, free fatty acids, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and malondialdehyde. RESULTS: Antepartum serum triglyceride and free fatty acid concentrations were increased approximately twofold in women with preeclampsia relative to uncomplicated pregnancies (p <0.02 and 0.004, respectively). Total, high-density lipoprotein, and low-density lipoprotein cholesterol concentrations did not differ between groups. Concentrations of all lipids decreased significantly in both groups within 48 hours post partum. However, triglyceride and free fatty acid concentrations remained higher in women with preeclampsia (p<0.006, both variables). Triglyceride and free fatty acid concentrations correlated positively, both ante partum (R2 0.42, p<0.01) and post partum (R2 0.39, p<0.02). Antepartum concentrations of malondialdehyde were 50% higher in women with preeclampsia (p<0.01) and decreased post partum (p <0.02) but did not decrease in controls (p = 0.07). Antepartum serum triglycerides and free fatty acids correlated positively with malondialdehyde concentrations (R2 0.38, p <0.02, both cases). CONCLUSION: Triglycerides and free fatty acids, but not cholesterol, are increased in preeclampsia and correlate with the lipid peroxidation metabolite malondialdehyde. We speculate that these interactions may contribute to endothelial cell dysfunction in preeclampsia.

Adult↗
PubMed1996

Hyperuricemia and xanthine oxidase in preeclampsia, revisited.

Hyperuricemia is associated with the severity of preeclampsia and with fetal outcome. Traditionally the high uric acid concentration in preeclampsia has been attributed soley to renal dysfunction. Preeclampsia is also characterized by increased free radical formation and elevated oxidative stress. Xanthine dehydrogenase/oxidase produces uric acid. Xanthine dehydrogenase/oxidase is present as two isoforms in vivo. Uric acid production is coupled with formation of reactive oxygen species when the enzyme is in the oxidase form. Several factors can increase the holoenzyme activity and the conversion of xanthine dehydrogenase/oxidase to its oxidase form. These factors include hypoxia-reperfusion, cytokines, and increased substrate availability (xanthine and hypoxanthine). Preeclampsia is characterized by hyperuricemia and signs of increased formation of reactive oxygen species and decreased levels of antioxidants. Preeclampsia is also characterized by shallow implantation, producing a relatively hypoxic maternal-fetal interface, and increased turnover of trophoblast tissue, which can result in higher xanthine and hypoxanthine concentrations and higher levels of circulating cytokines. These mechanisms can lead to increased production of uric acid and free radicals and contribute to the hyperuricemia and increased oxidative stress present in preeclampsia.

Female↗
PubMed1996

Decreased transferrin and increased transferrin saturation in sera of women with preeclampsia: implications for oxidative stress.

OBJECTIVE: The concerted iron-binding antioxidant activity of transferrin and ceruloplasmin decreases with increasing transferrin saturation by iron. We examined interactions between serum iron and iron-binding capacity and concentrations of the lipid peroxidation metabolite malondialdehyde in normal and preeclamptic pregnancies. We also asked if the release of iron from free hemoglobin by lipid hydroperoxides is a potential mechanism to increase transferrin saturation in preeclampsia. STUDY DESIGN: Predelivery and 24 to 48 hour postpartum venous blood was collected from 19 women with uncomplicated pregnancies and 17 with preeclampsia. Serum iron, iron binding capacity, and malondialdehyde were measured. In a subset of predelivery samples electron paramagnetic resonance spectroscopy was used to determine diferric transferrin, total transferrin, and ceruloplasmin concentrations and to examine interactions of an organic hydroperoxide with hemoglobin and transferrin. RESULTS: Antepartum serum iron concentrations were 46% greater, percent saturation of iron binding capacity was 98% greater, and malondialdehyde 50% greater, whereas total iron-binding capacity was 14% lower, in women with preeclampsia. By 48 hours post partum group differences between these variables other than total iron-binding capacity were not observed. Electron paramagnetic resonance spectroscopy confirmed antepartum differences and that total iron-binding capacity and percent saturation were equivalent to total transferrin and the ratio diferric transferrin/total transferrin, respectively. Antepartum concentrations of ceruloplasmin were not different. Antepartum malondialdehyde concentrations correlated positively with percent transferrin saturation and negatively with unsaturated iron-binding capacity (apotransferrin). Electron paramagnetic resonance spectroscopy demonstrated that the release of iron from free hemoglobin by lipid hydroperoxides in serum is a potential mechanism to increase transferrin saturation. CONCLUSION: Increased transferrin saturation and decreased unsaturated iron-binding capacity in preeclampsia may occur consequent to oxidative stress and then further promote oxidative stress by decreasing serum antioxidant buffering against redox-active iron.

Adult↗
PubMed1996

Impairment of vascular function is associated with an age-related increase of lipid peroxidation in rats.

We tested the hypothesis that an increase in endogenous lipid peroxidation over time is associated with an impairment of endothelium-dependent vascular function in resistance-sized mesenteric arteries that is due in part to alterations of arachidonate metabolism. Susceptibility to red blood cell hemolysis and sera levels of malondialdehyde were increased (P < 0.05) from 20 wk (n = 12) to 40 wk (n = 12) in female Sprague-Dawley rats. Arteries were studied in a myograph by examining the endothelial modification of phenylephrine vasoconstriction and the relaxation responses of the mesenteric arteries to methacholine. We observed the following. 1) An increase in sensitivity to alpha 1-adrenergic stimulation occurred between 20 and 40 wk of age. Cyclooxygenase inhibition decreased the sensitivity to phenylephrine only in the arteries from the 40-wk-old rats, indicating that a cyclooxygenase-dependent vasoconstrictor was modifying the phenylephrine response. 2) Nitric oxide synthase inhibition caused a greater increase in phenylephrine sensitivity in the arteries from the 20-wk-old rats than those from the 40-wk-old rats, indicating that nitric oxide modification of phenylephrine sensitivity decreased with age. 3) Endothelium-independent relaxations were not affected between 20 and 40 wk of age. 4) At 40 wk, the sensitivity to the methacholine-mediated relaxation response decreased without impairing the maximal relaxation response. This reduced sensitivity was removed with cyclooxygenase inhibition or thromboxane A2/prostaglandin H2 (PGH2) receptor blockade. 5) Aortas from the 40-wk-old rats had an increased expression of PGH synthase. Collectively, these observations indicate that, in the female rat, an increase in lipid peroxidation over time is associated with changes in endothelium-dependent vascular function that were due in part to a cyclooxygenase-dependent vasoconstrictor.

Aging↗
PubMed1996

Distinct factors in plasma of preeclamptic women increase endothelial nitric oxide or prostacyclin.

The pathogenesis of preeclampsia is proposed to be due to uncharacterized circulating factors that activate endothelial cells. Support for this hypothesis is provided by in vitro activation of endothelial cells by plasma from preeclamptic women, eg, increased nitric oxide and prostacyclin generation. We performed molecular sizing, lipid extraction, and lipoprotein fractionation of plasma from normal pregnant and preeclamptic women and determined the ability of these plasma fractions to increase nitric oxide or prostacyclin generation by endothelial cells. Fractions from plasma of preeclamptic women were consistently more active than fractions from normal pregnant women, although characterization was qualitatively similar. The factors stimulating nitric oxide and prostacyclin were different. The factor (or factors) stimulating nitric oxide generation was extractable by charcoal and present in lipid extracts and lipoprotein isolates with a molecular weight greater that 1.5 million daltons, which is characteristic of a lipoprotein or lipoprotein aggregate. By contrast, activity to stimulate prostacyclin persisted after charcoal stripping or lipoprotein removal, partitioned to the aqueous fraction, and had a molecular weight of approximately 50,000 D. Two distinct factors in the blood of preeclamptic women alter endothelial function in vitro. This information should guide the search for circulating factors contributing to the pathophysiology of preeclampsia.

6-Ketoprostaglandin F1 alpha↗