Molecular mechanisms regulating the vascular prostacyclin pathways and their adaptation during pregnancy and in the newborn.

Prostacyclin (PGI(2)) is a member of the prostanoid group of eicosanoids that regulate homeostasis, hemostasis, smooth muscle function and inflammation. Prostanoids are derived from arachidonic acid by the sequential actions of phospholipase A(2), cyclooxygenase (COX), and specific prostaglandin (PG) synthases. There are two major COX enzymes, COX1 and COX2, that differ in structure, tissue distribution, subcellular localization, and function. COX1 is largely constitutively expressed, whereas COX2 is induced at sites of inflammation and vascular injury. PGI(2) is produced by endothelial cells and influences many cardiovascular processes. PGI(2) acts mainly on the prostacyclin (IP) receptor, but because of receptor homology, PGI(2) analogs such as iloprost may act on other prostanoid receptors with variable affinities. PGI(2)/IP interaction stimulates G protein-coupled increase in cAMP and protein kinase A, resulting in decreased [Ca(2+)](i), and could also cause inhibition of Rho kinase, leading to vascular smooth muscle relaxation. In addition, PGI(2) intracrine signaling may target nuclear peroxisome proliferator-activated receptors and regulate gene transcription. PGI(2) counteracts the vasoconstrictor and platelet aggregation effects of thromboxane A(2) (TXA(2)), and both prostanoids create an important balance in cardiovascular homeostasis. The PGI(2)/TXA(2) balance is particularly critical in the regulation of maternal and fetal vascular function during pregnancy and in the newborn. A decrease in PGI(2)/TXA(2) ratio in the maternal, fetal, and neonatal circulation may contribute to preeclampsia, intrauterine growth restriction, and persistent pulmonary hypertension of the newborn (PPHN), respectively. On the other hand, increased PGI(2) activity may contribute to patent ductus arteriosus (PDA) and intraventricular hemorrhage in premature newborns. These observations have raised interest in the use of COX inhibitors and PGI(2) analogs in the management of pregnancy-associated and neonatal vascular disorders. The use of aspirin to decrease TXA(2) synthesis has shown little benefit in preeclampsia, whereas indomethacin and ibuprofen are used effectively to close PDA in the premature newborn. PGI(2) analogs have been used effectively in primary pulmonary hypertension in adults and have shown promise in PPHN. Careful examination of PGI(2) metabolism and the complex interplay with other prostanoids will help design specific modulators of the PGI(2)-dependent pathways for the management of pregnancy-related and neonatal vascular disorders.

[Methyldopa-induced acute reactive hepatitis in pregnancy, drug-metabolizing capacity of the liver]. / Methyldopa által indukált akut reaktív hepatitis terhességben, a máj gyógyszer-metabolizáló képességének alakulása.

Alpha-methyldopa is a regularly used antihypertensive drug during pregnancy. Methyldopa, which decreases the sympathoadrenal system, is the first drug of choice since decades. The reactive hepatitis is not frequent, but known serious side effect of alpha-methyldopa. In non-pregnant women the estimated rate of manifest hepatotoxicity is 2.5-10%. In our case, gestation hypertension developed at the 21st gestation week of a 35 year-old pregnant woman. Oral methyldopa, a central alpha adrenergic blocker therapy was introduced. On the 23rd gestation week acute hepatitis developed. During differential diagnosis of hepatitis, the etiology of methyldopa was taken into account. Viral and autoimmune origin was rolled out. No fetal aberration was found during ultrasound examination. The function of drug metabolizing function from blood was measured by CYP phenotyping (CYP gene expression analysis). CYP3A4 enzyme plays a primary role in the metabolism of nifedipine. Antihypertensive therapy was changed from methyldopa to nifedipine. Nifedipine dosage was based on the value of CYP3A4 gene expression. With the reduced nifedipine therapy (30 mg daily), blood pressure was successfully under control. The diagnosis of alpha-methyldopa induced hepatitis was based on anamnesis, clinical picture and the results of chemical and radiological examination and confirmed by the level of drug-metabolizing capacity. The gestation hepatotoxicity of alpha-methyldopa was reported first in 1969 by Elkington Smith, who suggested the monitoring of serum aminotransferase during alpha-methyldopa therapy in pregnancy in their case report. Our case report confirms that monitoring of serum aminotransferase level is still valuable when treating a pregnant woman with alpha-methyldopa.

[Development of oxidative stress in complicated pregnancy].

The changes in the blood activity of antioxidative defense system enzymes were evaluated in pregnant and non-pregnant women with arterial hypertension (AH). The directionality of revealed changes may be regarded ambiguously. Specifically, the detected dysregulation of first-line antioxidative defense enzymes leads to the accumulation of different forms of active oxygen metabolites that are involved in the development of the molecular basis of the pathogenesis of AH. However, activation of peroxidation processes not only ensures the molecular mechanism of cellular damage, but also aims at developing compensatory and adaptive reactions. The degree of these impairments is likely to be affected by the influence of oxidative stress starting from the cell to organism level--the formation of a metabolic compensation or decompensation phase in arterial hypertension.

GNB3 C825T Polymorphism and Myocardial Recovery in Peripartum Cardiomyopathy: Results of the Multicenter Investigations of Pregnancy-Associated Cardiomyopathy Study.

BACKGROUND: Black women are at greater risk for peripartum cardiomyopathy (PPCM). The guanine nucleotide-binding proteins ß-3 subunit (GNB3) has a polymorphism C825T. The GNB3 TT genotype more prevalent in blacks is associated with poorer outcomes. We evaluated GNB3 genotype and myocardial recovery in PPCM. METHODS AND RESULTS: A total of 97 women with PPCM were enrolled and genotyped for the GNB3 T/C polymorphism. Left ventricular ejection fraction (LVEF) was assessed by echocardiography at entry, 6 and 12 months postpartum. LVEF over time in subjects with the GNB3 TT genotype was compared with those with the C allele overall and in black and white subsets. The cohort was 30% black, age 30+6, LVEF 0.34+0.10 at entry 31+25 days postpartum. The % GNB3 genotype for TT/CT/CC=23/41/36 and differed markedly by race (blacks=52/38/10 versus whites=10/44/46, P<0.001). In subjects with the TT genotype, LVEF at entry was lower (TT=0.31+0.09; CT+CC=0.35+0.09, P=0.054) and this difference increased at 6 (TT=0.45+0.15; CT+CC=0.53+0.08, P=0.002) and 12 months (TT=0.45+0.15; CT+CC=0.56+0.07, P<0.001.). The difference in LVEF at 12 months by genotype was most pronounced in blacks (12 months LVEF for GNB3 TT=0.39+0.16; versus CT+CC=0.53+0.09, P=0.02) but evident in whites (TT=0.50++0.11; CT+CC=0.56+0.06, P=0.04). CONCLUSIONS: The GNB3 TT genotype was associated with lower LVEF at 6 and 12 months in women with PPCM, and this was particularly evident in blacks. Racial differences in the prevalence and impact of GNB3 TT may contribute to poorer outcomes in black women with PPCM.

11 beta-Hydroxysteroid dehydrogenase and its inhibitors in hypertensive pregnancy.

Preeclampsia is accompanied by amplification of the sodium retention that is a feature of normal pregnancy. Recent evidence suggests that mineralocorticoid receptor activation is increased in preeclampsia, but classic mineralocorticoids (aldosterone, 11-deoxycorticosterone) are not present in excess. Cortisol can act as a mineralocorticoid receptor agonist only when its renal inactivation to cortisone by 11 beta-hydroxy-steroid dehydrogenase is impaired, for example, in congenital enzyme deficiency and after administration of exogenous inhibitors (eg, licorice). Endogenous inhibitors of this enzyme have been detected in human urine and are increased in pregnancy. To establish whether cortisol causes mineralocorticoid excess in hypertensive pregnancy and whether endogenous inhibitors of 11 beta-hydroxysteroid dehydrogenase are responsible, we studied 25 hypertensive pregnant patients (13 with preeclampsia and 12 with gestational hypertension), 16 normotensive pregnant subjects, and 13 nonpregnant control subjects. Concentrations of plasma renin and aldosterone were increased in pregnancy, but less so in hypertensive pregnancy. Plasma potassium and urinary electrolytes were not different between the groups. Plasma cortisol was increased in pregnancy but not different in hypertensive pregnancy, and urinary cortisol, plasma and urinary cortisone, and urinary tetrahydrocortisol and tetrahydrocortisone were not different between the groups. Endogenous inhibitors of 11 beta-hydroxysteroid dehydrogenase were more active in urine from pregnant women but were not increased further in hypertensive pregnancy. There were no differences in these parameters between patients with preeclampsia and gestational hypertension. We conclude that deficient inactivation of cortisol to cortisone does not contribute to the sodium retention of normotensive or hypertensive pregnancy and that endogenous inhibitors of 11 beta-hydroxysteroid dehydrogenase have no evident pathophysiological significance in pregnancy.

Tissue-type plasminogen activator after venous occlusion in pregnancy and puerperium.

Pregnancy is associated with depressed fibrinolysis as judged from the decreased fibrinolytic response to venous occlusion. In order to elucidate if this decreased response is due to an increase in plasminogen activator inhibitors 1 and 2 (PAI-1, PAI-2), and/or to decreased release of tissue-type plasminogen activator (t-PA) antigen during venous occlusion, 36 women (18 women with normal pregnancy and 18 with gestational hypertension without proteinuria) were followed during pregnancy and puerperium. In each women a 20 min venous occlusion was performed in the second and in the third trimester of pregnancy and 3 days after delivery. The increase in t-PA antigen after venous occlusion relative to basal value was in the second trimester of pregnancy on average 3.7 fold, in the third trimester 4.4 fold, and so not reduced compared to non-pregnant women (3.7 fold increase). After delivery the increase in t-PA antigen was significantly enhanced (8.5 fold, p < 0.005). The fibrinolytic response to venous occlusion measured by euglobulin and t-PA activity was significantly decreased in the third trimester compared to non-pregnant values (both p < 0.005) and returned to somewhat higher (euglobulin clot lysis) or significantly higher (t-PA activity, p < 0.01) values 3 days after delivery. Decreased euglobulin and t-PA activity after venous occlusion in the third trimester coincided with significant increases in basal PAI activity, PAI-1 antigen and PAI-2 antigen (2.9, 2.5 and > 30 fold increase relative to non-pregnant values, respectively, all p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Nitric oxide synthase activity in placentae from women with pre-eclampsia.

The syncytiotrophoblast (ST) cell layer of the human villous placenta expresses nitric oxide (NO) synthase. Because NO is a potent relaxant of vascular smooth muscle and inhibitor of platelet activity, we postulated that exaggerated intervillous aggregation of platelets and reduced fetoplacental blood flow in pre-eclampsia result from reduced expression of NO synthase (and production of NO) by the ST. Conversion of [3H]arginine to [3H]citrulline and Lineweaver-Burk transformation were used to derive the Vmax and K(M) of NO synthase. Contrary to our expectations, the Vmax was not significantly different between villous placenta obtained from nulliparous normal and pre-eclamptic women (n = 11 each). The Vmax and K(M) were 22.3 +/- 2.3 pmol/mg per min and 1.3 +/- 0.1 microns, and 22.0 +/- 2.7 pmol/mg per min and 1.4 +/- 0.1 microns, for villous placenta from the nulliparous normal and pre-eclamptic women, respectively. The Vmax and K(M) of placental NO synthase were also comparable among multiparous normal and pre-eclamptic women, as well as women with gestational hypertension. When compared with the enzyme activity of the villous, that of the basal plate was reduced by approximately one-half in all placentae. The calcium-independent activity was consistently 40-fold less than the calcium-dependent activity, and it was similar between villous and basal plate, and between placentae from normal and hypertensive women. We suggest that expression of NO synthase is not different in placentae obtained from normal and pre-eclamptic women.

No association of the Asp298 variant of the endothelial nitric oxide synthase gene with preeclampsia.

BACKGROUND: Preeclampsia, the most common serious complication of pregnancy, is characterized by vasoconstriction, dysfunction of the vascular endothelium, and hypertension. Unidentified genetic factors and impaired nitric oxide (NO)-mediated vasodilation are thought to contribute to the development of the syndrome. Polymorphisms of the endothelial nitric oxide synthase (eNOS) gene affect NO production and have been associated with hypertension and preeclampsia in a Japanese population. METHODS: We compared the frequency of the Glu298Asp eNOS polymorphism in 397 Hispanic and white normotensive pregnant control subjects with the gene frequencies in 64 women with preeclampsia (systolic blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg, on at least two occasions 6 hours apart, and proteinuria >0.3 g/L or a dipstick proteinuria reading of 2+). RESULTS: Preeclampsia was not associated with the presence of Asp at position 298 of eNOS. CONCLUSIONS: In contrast to the findings in Japanese women, preeclampsia was not associated with the Asp variant of eNOS in an American population.

Tumor necrosis factor-alpha-induced hypertension in pregnant rats results in decreased renal neuronal nitric oxide synthase expression.

BACKGROUND: Preeclampsia is associated with increases in plasma levels of tumor necrosis factor-alpha (TNF-alpha), a cytokine known to contribute to endothelial dysfunction. We recently reported that a twofold elevation in plasma TNF-alpha produces significant reductions in renal function and hypertension in pregnant rats. The purpose of this study was to determine the role of the nitric oxide (NO) system in TNF-alpha-induced hypertension in pregnant rats. METHODS: Tumor necrosis factor-alpha (50 ng/day) was chronically infused starting at day 14 of gestation. Mean arterial pressure, 24-h urinary nitrite/nitrate excretion, and renal nitric oxide synthase (NOS) protein expression by Western blot analysis was measured at day 19 of gestation. RESULTS: A twofold increase in plasma TNF-alpha levels in pregnant rats resulted in a significant increase in arterial pressure (97 +/- 3.6 v 116 +/- 2.1 mm Hg, pregnant versus TNF-alpha pregnant, respectively, P < .05), but no significant change in urinary nitrite/nitrate excretion (22.0 +/- 1.9 v 20.8 +/- 2.5 micromol/24 h, pregnant versus TNF-alpha pregnant, respectively), a measure of whole body NO production. As abnormalities in renal production of NO would not be reflected in the measure of whole body NO production, changes in renal NOS protein levels were determined. The protein expression of both neuronal (nNOS) and inducible (iNOS) nitric oxide synthase were significantly decreased in the medulla of TNF-alpha pregnant rats (nNOS: 10.6 +/- 0.7 v 8.2 +/- 0.8 densitometric units, P < .05; and iNOS: 19.2 +/- 0.9 v 15.4 +/- 0.8 densitometric units, P < .05, pregnant versus TNF-alpha pregnant, respectively). CONCLUSION: The hypertension associated with a chronic twofold increase in TNF-alpha in pregnant rats is associated with significant decreases in renal nNOS and iNOS protein production.

Placental 11beta-hydroxysteroid dehydrogenase in Dahl and spontaneously hypertensive rats.

Studies in normotensive rats showed that excessive fetal exposure to maternal glucocorticoids retards growth and programs hypertension in later life. This excessive exposure is proposed to occur due to a reduction of the placental barrier to maternal glucocorticoids that is provided by 11beta-hydroxysteroid dehydrogenase (11betaHSD). To assess the possible alterations of glucocorticoid placental barrier in two genetic models of hypertension - spontaneously hypertensive (SHR) and Dahl salt-sensitive rats (DS) and their normotensive counterparts Wistar-Kyoto (WKY) and Dahl salt-resistant rats (DR)-we performed real-time reverse transcriptase-polymerase chain reaction analysis and bioactivity measurements of placental 11betaHSD in the last third of gestation. Whereas 11betaHSD2 mRNA expression was not different among the investigated strains, 11betaHSD1 mRNA abundance was 2.4 times higher in WKY than in SHR and 9.6 times higher in DS than in DR placentae. The 11betaHSD2 activity studies performed in placental homogenates revealed activity that did not differ among the strains. Concomitant with 11betaHSD1 mRNA expression 11-oxoreductase activity was clearly evident in all strains and was higher in WKY and DS rats than in SHR and DR, respectively. Nevertheless, the net 11betaHSD activity of tissue fragments (11beta-dehydrogenase minus 11-oxoreductase) was tended toward dehydrogenase action, ie, toward corticosterone inactivation and was significantly lower in DS than in DR rats. The 11beta-dehydrogenase/11-oxoreductase ratio was less than 2:1 in SHR and WKY rats, whereas this ratio was 9:1 in DR and 4.5:1 in DS rats. These data suggest that the placental glucocorticoid barrier is not decreased in SHR rats in comparison with normotensive WKY but is lower in DS than in DR counterparts. It cannot be excluded, therefore, that the placental glucocorticoid barrier in Dahl rats influences the pathways that might lead to the sensitivity of blood pressure to high salt intake in later life.

Erythrocyte insulin and insulin-like growth factor-I receptor tyrosine kinase activity in hypertension in pregnancy.

We have shown that preeclampsia is associated with insulin resistance. In the present study, we examined young normal, preeclamptic (PE), and gestational hypertensive (GH) nulliparous African-American women at term to investigate cellular determinants of this resistance and insulin and insulin-like growth factor-I (IGF-I) binding to partially purified erythrocyte receptors and receptor tyrosine kinase activity (TKA). Blood pressure was significantly elevated in PE and GH subjects as compared with controls. Insulin binding was similar in number and affinity in the three groups (femtomoles per microgram). IGF-I binding was increased in PE subjects as compared with either normals or GH subjects (0.2 +/- 0.02, 0.15 +/- 0.01, and 0.14 +/- 0.02 fmol/microgram protein). Insulin receptor TKA was increased in PE subjects as compared with normals when assessed either per microgram protein or per femtomole insulin binding (P < .01). In contrast, IGF-I-potentiated TKA was elevated in PE subjects only when assessed per microgram protein (P < .03). Thus, the increased number of IGF-I receptors in erythrocytes of PE subjects yields a net increase in receptor tyrosine kinase. Also, there is an augmentation of insulin receptor TKA in PE subjects. Together, these two alterations may be a compensatory mechanism for the insulin resistance associated with hypertensive diseases of pregnancy.

Platelet-activating factor-acetylhydrolase activity in maternal and umbilical venous plasma obtained from normotensive and hypertensive pregnancies.

OBJECTIVE: To elucidate whether plasma platelet-activating factor-acetylhydrolase activities in women with pregnancy-induced hypertension and in their fetuses are different from those in normotensive mothers and fetuses. METHODS: We measured platelet-activating factor-acetylhydrolase activity in the plasma of 11 normotensive nonpregnant women, 39 normotensive pregnant women, 30 pregnant women with pregnancy-induced hypertension, 31 fetuses delivered from normotensive pregnant women, and 12 fetuses delivered from women with pregnancy-induced hypertension. RESULTS: Plasma platelet-activating factor-acetylhydrolase activity in normotensive pregnant women at 28-31 weeks' gestation was significantly lower than that in normotensive nonpregnant women (P < .001). In contrast, in women with pregnancy-induced hypertension at 28-31 weeks' gestation, the activity of this enzyme was significantly higher than that in gestational age-matched, normotensive pregnant women (P < .01). Platelet-activating factor-acetylhydrolase activity in the umbilical venous plasma of fetuses delivered from women with pregnancy-induced hypertension at 37-40 weeks' gestation was significantly higher than that in the gestational age-matched term fetuses of normotensive mothers (P < .001). CONCLUSION: These findings indicate that the hydrolysis of platelet-activating factor is decreased during a normal pregnancy and that such modulation does not occur in pregnant women with pregnancy-induced hypertension or in their fetuses.

Platelet inhibitory activity in placentas from normal and abnormal pregnancies.

Retroplacental blood flow requires inhibition of coagulation in the absence of an endothelial lining. We confirmed that trophoblast releases an inhibitor of platelet aggregation which functions via degradation of adenosine diphosphate. This inhibitor appears to be deficient in some pregnancies with abruptio placentae and intrauterine growth retardation. Unimpeded retroplacental blood flow may depend upon the local inhibition of platelet aggregation. Placental tissue contains an inhibitor of platelet aggregation which appears to be an adenosine diphosphatase distinct from heat-stable alkaline phosphatase. Placental tissue from patients with abruptio placentae contains abnormally low amounts of this enzyme.

Maternal serum heat-stable alkaline phosphatase. In normal and high-risk pregnancies.

To evaluate its specificity as an indicator of placental function or fetal status, maternal serum heat-stable alkaline phosphatase (HSAP) was measured serially in 76 normal and 161 high-risk pregnancies (1272 determinations). The previously reported curvilinear HSAP rise starting at about 28 gestational weeks was noted. No relation was seen between HSAP levels and milk or moderate hypertension, gestational diabetes, nontoxemic placental insufficiency, or maternal blood group. HSAP levels were mostly above normal in proteinuric hypertension and were low normal in pregnant insulin-dependent diabetics. Two neonatal deaths were associated with normal HSAP levels. Of 4 intrauterine deaths, 1 was associated with high, 1 with low, and 2 with rising values in the normal range. Serial maternal HSAP values are apparently not a specific indicator of placental function or fetal status.

Effect of angiotensin-converting enzyme gene polymorphism on pregnancy outcome, enzyme activity, and zinc concentration.

OBJECTIVE: To evaluate the effect of angiotensin-converting enzyme (ACE) genotypes on pregnancy outcome, the incidence of pregnancy-induced hypertension, and changes in blood pressure (BP) during pregnancy; and the relationship between plasma ACE activities and plasma and erythrocyte zinc concentrations in each genotype. METHODS: The subjects (n = 191) were selected from 580 indigent African-American pregnant women who enrolled toward the end of a trial to evaluate the effect of zinc supplementation on pregnancy outcome. This selection resulted in 93 subjects who received zinc and 98 who received placebo. Sample size was calculated with a 0.50 correlation coefficient between plasma ACE activities and zinc levels and a power of 80%. This calculation indicated that the sample size in each ACE genotype should be more than 28. Angiotensin-converting enzyme genotypes were identified using polymerase chain reaction. Blood pressure, plasma ACE activities, and plasma and erythrocyte zinc concentrations were measured at each prenatal clinical visit. RESULTS: Pregnancy outcome, the incidence of pregnancy-induced hypertension, and BP were not different among the three ACE genotypes. There was no significant correlation between plasma ACE activities and zinc concentrations. Zinc supplementation did not have a significant effect on either plasma ACE activities or zinc concentrations, probably because of the small sample size in our study. CONCLUSION: There was no effect of ACE gene polymorphism on pregnancy outcome, the incidence of pregnancy-induced hypertension, or changes in BP during pregnancy. Among each ACE genotype, plasma ACE activities did not correlate significantly with plasma zinc concentrations.

Sequence analysis of the coding region of human methionine synthase: relevance to hyperhomocysteinaemia in neural-tube defects and vascular disease.

Elevated homocysteine (Hcy) levels are observed in two apparently unrelated diseases: neural-tube defects (NTD) and premature vascular disease. Defective human methionine synthase (MS) could result in elevated Hcy levels. We sequenced the coding region of MS in 8 hyperhomocysteinaemic patients (4 NTD patients and 4 patients with pregnancies complicated by spiral arterial disease, SAD). We identified only one mutation resulting in an amino acid substitution: an A-->G transition at bp 2756, converting an aspartic acid (D919) into a glycine (G). We screened genomic DNA for the presence of this mutation in 56 NTD patients, 69 mothers of children with NTD, 108 SAD patients and 364 controls. There was no increased prevalence of the GG and AG genotypes in NTD patients, their mothers or SAD patients. The D919G mutation does not seem to be a risk factor for NTD or vascular disease. We then examined the mean Hcy levels for each MS genotype. There was no correlation between GG- or AG-genotype and Hcy levels. The D919G mutation is thus a fairly prevalent, and probably benign polymorphism. This study, though limited, provides no evidence for a major involvement of MS in the aetiology of homocysteine-related diseases such as NTD or vascular disease.

Normal superoxide dismutase (SOD) gene in pregnancy-induced hypertension: is the decreased SOD activity a secondary phenomenon?

Reactive oxygen species (ROS) have been implicated in the pathogenesis of pregnancy-induced hypertension (PIH). A genetic factor is also thought to be associated with the disease. The aim of the present study was to investigate whether decreased superoxide dismutase (SOD) activity in PIH resulted from gene abnormalities. Fourteen patients with PIH were enrolled in the study. Normal pregnant women and normal nonpregnant women served as controls. Genomic DNA and mRNA were isolated from white cells and subjected to Southern and Northern blot analysis with a 600 bp CuZn-SOD probe. SOD activity was also determined in the white blood cells and red blood cells. The results showed that SOD activity was significantly reduced in patients with PIH compared to both control groups. There were no significant differences in the size of the CuZn-SOD gene and its expression between the patients with PIH and the controls. This study confirmed that there was a decreased SOD activity in PIH but revealed neither major structural changes in the genomic DNA nor mRNA size of CuZn-SOD. Our results suggest that the decreased SOD levels in PIH are not due to abnormalities in the CuZn-SOD gene and are an acquired phenomenon which occurs during the development of the disease.

Calcium and sodium transport in gestational hypertension.

The enzymatic activities of Na+/K+ ATPase and Ca2+ ATPase were determined on erythrocyte membranes from 9 normotensive and 9 gestational hypertensive pregnant women near term. A reduction in the activity of the Na+/K+ ATPase and a relative increase in the activity of the Ca2+ ATPase were found in the hypertensive patients, possibly due to a conformational alteration of erythrocyte membranes. This observation supports the possible role of the transmembrane cation transport in the pathogenesis of gestational hypertension.

Activity of platelet-activating-factor-acetylhydrolase and the nitric oxide metabolite level in the plasma of pregnant women who develop transient hypertension during later pregnancy.

It is reported that plasma platelet-activating-factor-acetylhydrolase (PAF-AH) is elevated in patients with essential hypertension. In this study, plasma PAF-AH activity was measured during pregnancy and after delivery to examine the relationship between plasma PAF-AH activity and the development of transient hypertension (TH) during pregnancy. Moreover, in order to examine the involvement of endothelial injury in TH, the plasma level of nitric oxide metabolite (NOx; NO2+NO3) was measured. The plasma PAF-AH activity in 51 pregnant women was consecutively measured in the 1st, 2nd and 3rd trimesters of gestation, and after delivery. Forty-one cases were normal pregnancies and 10 cases were complicated by TH later during pregnancy. The PAF-AH activity in the normal pregnancy group decreased in the 2nd trimester of gestation compared with the 1st trimester, but was elevated in the TH group. The incidence of elevation of PAF-AH in the TH group was significantly (7/10; 70.0%; P<0.01, Chi-squared test) higher than in the normal pregnancy group (9/41; 22.0%). The plasma NOx levels in the 2nd trimester were higher than those in the 1st trimester in both the normotensive and TH group (P<0.05 for both comparisons). The 51 patients were classified into two groups according to the change in the PAF-AH in the 2nd trimester: group A consisted of 35 patients whose PAF-AH activity did not increase, and group B consisted of 16 patients whose PAF-AH activity increased. The incidence of development of TH during later pregnancy in group B was significantly (7/16; 43.8%; P<0.01, Chi-squared test) higher than in group A (3/35; 8.6%). Hypertension developed after 36 weeks' gestation in all patients in the TH group. The results of the present study suggest that changes in PAF metabolism may relate to regulation of blood pressure in pregnant women whose pregnancy is complicated with TH, whereas NO metabolism does not differ between women with TH and those having a normal pregnancy.

Xanthine oxidase activation in mild gestational hypertension.

OBJECTIVE: We hypothesized that activation of the xanthine oxidase (XO) enzyme system is a potential source of free radicals in pregnancy-induced hypertension (PIH). METHODS: A prospective observational study was carried out on 16 pregnant women who met the criteria of gestational hypertension [rise in blood pressure (BP) of 30 mm Hg systolic or 15 mm Hg diastolic after 20 weeks gestation or BP>140/90 mm Hg if earlier pressure is unknown] without proteinuria or any signs of renal impairment. Fourteen women with a clinically normal pregnancy matched for maternal age, parity, and gestational age acted as pregnant controls. Nonpregnant control women were members of the laboratory staff ( n=15). MAIN OUTCOME MEASURES: Concentrations of free sulfhydryl (SH) groups, purine catabolites, lipid peroxidation products in plasma, and blood carboxyhemoglobin levels were used to follow oxidative stress and potential hemolysis. A noninvasive measurement of functional XO activity was carried out (i.e., the urinary ratio of the two metabolites of caffeine was estimated). RESULTS: A pronounced oxidative stress was demonstrated in plasma samples of patients with hypertension by the elevated concentrations of uric acid and lipid peroxidation products. A reduced level of free sulfhydryl groups and an increased concentration of hypoxanthine (HX) were shown in normotensive pregnant individuals. The XO activity index was substantially higher in overweight pregnant subjects with mild hypertension [0.849+/-0.096 ( p<0.01)] than in normotensive pregnant women or in age-matched nonpregnant subjects [0.596+/-0.105, 0.542+/-0.049 (means+/-SD), respectively]. CONCLUSIONS: Our study of mildly hypertensive pregnant subjects provides additional evidence of the putative role of XO activation as a source of free radicals in the early stage of endothelial dysfunction.