Bradykinin-mediated relaxation of isolated maternal resistance arteries in normal pregnancy and preeclampsia

OBJECTIVE: The aim of the study was to investigate bradykinin-mediated vasodilator function in small arteries from normotensive pregnant and nonpregnant women and from women with preeclampsia. STUDY DESIGN: Small subcutaneous arteries (approximately 250 μm luminal diameter) were dissected from biopsy specimens obtained at cesarean section from 24 normotensive pregnant women and 6 women with preeclampsia and during abdominal surgery in 15 nonpregnant women. Vascular function was assessed after arteries were mounted on a small vessel myograph. RESULTS: Preconstricted arteries from normotensive pregnant women demonstrated enhanced relaxation to bradykinin compared with those from nonpregnant women (p < 0.05), whereas arteries from women with preeclampsia showed blunted responses compared with those from normotensive pregnant women (p < 0.01). Relaxation in all groups was attenuated in the presence of the nitric oxide synthase inhibitor N^ω-nitro-l-arginine so that it became similar in the three groups. Indomethacin had a small but significant inhibitory effect on bradykinin-induced relaxation, but this component of relaxation was no different among groups. Sensitivity of arteries to norepinephrine and sodium nitroprusside showed no significant differences in the three groups of women. CONCLUSION: This study provides evidence for an increase in bradykinin-mediated nitric oxide synthesis from the vascular endothelium of small arteries from the peripheral circulation of normotensive pregnant women and a relative reduction in women with preeclampsia. In turn, these changes may contribute to vasodilation in normal pregnancy and elevation of the blood pressure in preeclampsia. (Am J Obstet Gynecol 1996;175:1668-74.)     

Isolated microparticles,but not whole plasma,from women with preeclampsia impair endothelium-dependent relaxation in isolated myometrial arteries from healthy pregnant women

OBJECTIVE: This study was performed to establish whether microparticles from plasma of women with preeclampsia cause endothelial dysfunction, as described for isolated myometrial arteries in preeclampsia. STUDY DESIGN: Myometrial arteries were isolated from biopsy specimens obtained at cesarean delivery from healthy pregnant women (n = 22) and mounted in a wire myograph. Bradykinin concentration-response curves were obtained before and after 1-hour incubation or after overnight incubation with one of the following preparations of plasma from individual women with preeclampsia (n = 16): Whole plasma, microparticle-free plasma, isolated microparticles resuspended in physiologic saline solution or physiologic saline solution. Overnight incubation was also performed with microparticles isolated from healthy pregnant women (n = 6). One-hour incubation was performed with 2% or 10% solution and overnight incubation with 5% solution. RESULTS: No effect of preeclamptic plasma, with or without microparticles, on bradykinin-mediated relaxation was observed. Overnight, but not 1-hour, incubation with preeclamptic microparticles caused abolishment of bradykinin-mediated relaxation in contrast to healthy pregnant microparticles (P <.005). CONCLUSION: Preeclamptic microparticles, but not healthy pregnant microparticles cause endothelial dysfunction in isolated myometrial arteries from healthy pregnant women after overnight incubation, whereas other preeclamptic plasma constituents protect the endothelium from this effect.     

Comparison of cerebral blood flow velocity as measured in preeclamptic, healthy pregnant, and nonpregnant women by transcranial Doppler sonography.

AIM: To test the hypothesis that the middle cerebral artery blood flow velocity (MCAV) is altered in preeclamptic pregnant women as compared with healthy pregnant and nonpregnant women. METHODS: Preeclamptic (n = 21) and healthy pregnant (n = 17) as well as healthy nonpregnant (n = 29) women underwent transcranial Doppler MCAV measurements. The mean MCAV values were compared between the different groups. Anova combined with Bonferroni correction was used for statistical analysis. RESULTS: The MCAV was significantly higher in nonpregnant women (mean +/- SE 73.0 +/- 2.12 cm/s) as compared with healthy pregnant women (67.0 +/- 1.8 cm/s, p = 0.0356). Preeclamptic women showed significantly higher MCAV values (83.5 +/- 2.1 cm/s) as compared with nonpregnant females (73.0 +/- 2.12 cm/s, p = 0.0014). Similar to nonpregnant women, healthy pregnant women showed lower MCAV values (67.0 +/- 1.8 cm/s) as compared with preeclamptic women (83.5 +/- 2.1 cm/s, p = 0.001). After Bonferroni correction the MCAV values in patients suffering from preeclampsia were still statistically significantly higher as compared with the two other groups. CONCLUSIONS: We detected increased resting MCAV values in pregnant women with preeclampsia. In our opinion, this finding refers to arteriolar dilation of the resistance vessels of the brain. Further studies are needed to prove altered vasoreactivity responses of the brain resistance arterioles in preeclampsia.     

Pulse wave reflection in currently and previously preeclamptic women.

OBJECTIVE: Disturbed maternal endothelial function is believed to be central in the pathogenesis of preeclampsia and has been observed to persist for several years following the preeclamptic pregnancy. Endothelial dysfunction has been reported to cause increased pulse wave reflection, a measure of systemic arterial stiffness. This study tested the hypothesis that preeclampsia and a history of preeclampsia are associated with increased pulse wave reflection. DESIGN AND METHODS: We carried out a cross-sectional case-control study of 26 pregnant women with preeclampsia, 26 pregnant controls, 22 normotensive nonpregnant previously preeclamptic women, and 22 nonpregnant controls. Pulse wave reflection was assessed by applanation tonometry on the radial artery. RESULTS: Pregnant preeclamptic women had a significantly higher heart rate-adjusted augmentation index than did pregnant controls (23 +/- 1 vs. 8 +/- 1%, P < 0.001). The augmentation index of women with a history of preeclampsia was similar to that of the nonpregnant controls (9 +/- 2 vs. 9 +/- 2%, P = 0.78). In a multiple linear regression analysis (R2 = 0.76) the augmentation index of pregnant women was independently associated with a diagnosis of preeclampsia (P < 0.001) and heart rate (P < 0.001), but not with mean arterial blood pressure (P = 0.59). CONCLUSIONS: This study demonstrates that pulse wave reflection and, thus, systemic arterial stiffness are increased in pregnant women with preeclampsia, but not in normotensive nonpregnant women with a history of preeclampsia. The results support the concept of generalized vascular dysfunction in preeclampsia.     

Circadian rhythm of plasma atrial natriuretic peptide, aldosterone, and blood pressure during the third trimester in normal and preeclamptic pregnancies

The influence of pregnancy on circadian variations of plasma atrial natriuretic peptide and aldosterone was studied. In those women with normal pregnancies, the mean 24-hour values of atrial natriuretic peptide and aldosterone increased, compared with the levels in normal nonpregnant subjects. In cases of severe preeclampsia, levels of atrial natriuretic peptide were significantly higher than in the other subjects, but aldosterone levels decreased to nearly those seen in the nonpregnant subjects. Atrial natriuretic peptide did not establish a rhythm in normal nonpregnant and pregnant subjects, but in the studies of aldosterone levels, a clear circadian rhythm was evident. In severe cases of preeclampsia, atrial natriuretic peptide established a circadian rhythm similar to that of blood pressure, and the circadian rhythm of aldosterone disappeared. The main characteristic of the rhythm in atrial natriuretic peptide and blood pressure in women showing preeclamptic signs is that the acrophase occurred at midnight. This evidence suggests that in women with symptoms of preeclampsia the load to the atria increases at midnight.     

Contribution of endogenous endothelin-1 to basal vascular tone during normal pregnancy and preeclampsia

OBJECTIVE: The aim of this study was to determine the physiologic role for endogenous endothelin in the regulation of vascular tone during normal pregnancy and preeclampsia. The vascular sensitivity to endothelin-1 during pregnancy was studied also. STUDY DESIGN: Forearm blood flow was measured by venous occlusion plethysmography during intra-arterial infusion of phosphoramidon, an endothelin-converting enzyme inhibitor, for 60 minutes, which was followed by co-infusion with endothelin-1 for 30 minutes. Three groups were studied: healthy nonpregnant women, normal pregnant women, and women with preeclampsia. RESULTS: There was a significant increase in forearm blood flow in the nonpregnant group after phosphoramidon infusion alone (73%+/-37%; P<.05). Phosphoramidon did not change forearm blood flow in pregnant subjects. Co-infusion with endothelin-1 significantly decreased forearm blood flow in both the nonpregnant and normal pregnant women (53%+/-7% and 40%+/-11%, respectively; P<.01). No response to endothelin-1 was found among women with preeclampsia. CONCLUSION: The vascular sensitivity to endothelin-1 is not altered during normal pregnancy in contrast to preeclamptic pregnancy, where no effect of endothelin-1 was seen. Reduced endothelin dependence during pregnancy might be one mechanism behind the fall in peripheral vascular resistance.     

Endothelial dysfunction in uterine circulation in preeclampsia: can estrogens improve it?

OBJECTIVE: The purpose of this study was to evaluate whether a 3-hour incubation with 17beta-estradiol will enhance blood flow- and bradykinin-mediated dilatation and alter pressure-induced basal tone in myometrial resistance arteries from women with preeclampsia and to evaluate the role of nitric oxide in the responses that were observed. STUDY DESIGN: Blood flow- and bradykinin-mediated dilatation and responses to intraluminal pressure of 60 and 80 mm Hg were compared before and after 3 hours of incubation with 17beta-estradiol (10(-8) mol/L) in isolated myometrial arteries with the pressure myography technique. In separate experiments, the role of nitric oxide on 17beta-estradiol-induced responses was evaluated in the presence of the nitric oxide synthase inhibitor (10(-4) mol/L). Endothelial morphologic condition was evaluated by scanning electron microscopy. RESULTS: Incubation with 17beta-estradiol significantly improved blood flow-mediated dilatation compared with initial blood flow-mediated response in arteries from women with preeclampsia. This effect was nitric oxide mediated, because the nitric oxide synthase inhibitor abolished the response. Arteries from women with preeclampsia demonstrated impaired bradykinin-mediated dilatation compared with that obtained in arteries from normal pregnant women. The 17beta-estradiol had no effect on bradykinin-mediated dilatation in arteries from women with preeclampsia. The enhanced pressure-induced tone at 80 mm Hg compared with the tone that developed at 60 mm Hg in arteries from women with preeclampsia was reduced after incubation with 17beta-estradiol. This reduction was also nitric oxide mediated. Morphologic signs of endothelial dysfunction were evident in arteries from women with preeclampsia. CONCLUSION: The 17beta-estradiol improved impaired blood flow-mediated dilatation and reduced basal tone through a nitric oxide-mediated pathway in isolated myometrial arteries from women with preeclampsia.     

Resistance artery smooth muscle function in pregnancy and preeclampsia.

OBJECTIVE: The purpose of this study was to investigate whether the altered vascular resistance in pregnancy and preeclampsia results from alterations in intrinsic vascular smooth muscle properties or from external influences on vascular smooth muscle function. STUDY DESIGN: We studied subcutaneous resistance arteries from women with preeclampsia, from normal pregnant women, and from nonpregnant women, that were obtained during cesarean delivery or gynecologic surgical procedures, in a pressure myograph. Arteries were denervated, and smooth muscle cells were loaded with calcium indicator fura-2. Contractile properties were tested in physiologic saline solution and during potassium- and norepinephrine-induced constriction at various pressures. In addition, endothelial function was assessed. Intracellular calcium and tone were measured continuously. RESULTS: No significant differences in basal tone, constrictor, and myogenic responses were found between groups. Contractile element calcium sensitivity was significantly increased in women with preeclampsia. Norepinephrine caused an increase in calcium sensitivity in all groups. CONCLUSION: Vascular smooth muscle calcium sensitivity is increased in preeclampsia.     

Decreased levels of polyunsaturated fatty acids in preeclampsia

Plasma levels of polyunsaturated fatty acids in the n-3 and n-6 classes, which include linoleic, linolenic, arachidonic, eicosapentaenoic, and docosahexaenoic acids, were quantified with high-performance liquid chromatography in nonpregnant volunteers and in patients with normal pregnancies or preeclampsia at term. The total polyunsaturated fatty acid levels were not significantly different between nonpregnant and normal pregnant patients but was significantly lower in the preeclamptic patients compared with normal pregnant patients. This decreased level could represent altered fatty acid metabolism or altered storage and mobilization from lipid pools. Compared with nonpregnant patients, normal pregnant patients had significantly higher levels of eicosapentaenoic and docosahexaenoic acid. This may reflect normal physiologic changes in pregnancy, and the decreased level of eicosapentaenoic acid seen in preeclamptic patients may play a significant role in the pathophysiology of preeclampsia.     

Effects of the thromboxane-receptor antagonists AH 23848 and BM 13.177 on human uteroplacental arteries.

OBJECTIVE: We studied the effects of the thromboxane (Tx)A2-receptor antagonists AH 23848 and BM 13.177 in small isolated human uteroplacental arteries. METHODS: Fetal stem villous arteries and maternal intramyometrial arteries were dissected from placental specimens and from myometrial biopsies obtained at cesarean or from nonpregnant women after hysterectomy. Vascular ring preparations were prepared and mounted in organ baths, and isometric tension was recorded. RESULTS: AH 23848 produced competitive, concentration-dependent inhibition of responses to the TxA2-mimic U46619 in all vessel types tested. Mean (+/- standard error of the mean) pA2 values (the negative logarithm of the concentration of antagonist needed to double the half maximum response [EC50] value for U46619) were 8.69 +/- 0.16 in the stem villous arteries, 9.58 +/- 0.33 in intramyometrial arteries from term pregnant women, and 9.25 +/- 0.47 in intramyometrial arteries from nonpregnant women. In stem villous arteries, the pA2 value for BM 13.177 was 6.15 +/- 0.13, whereas these values in intramyometrial arteries could not be assessed. However, the concentrations needed to produce inhibition of U46619-induced contractions were considerably higher for BM 13.177 than for AH 23848. Both drugs inhibited responses to prostaglandin (PG)F2 alpha and PGE2 in stem villous arteries, while leaving responses to vasopressin in intramyometrial arteries unaffected. No differences in the effects of the two antagonists were found between intramyometrial arteries from nonpregnant and term pregnant women. CONCLUSIONS: Our results suggest that TxA2-receptor antagonists effectively inhibit responses to TxA2 in human uteroplacental arteries, and such drugs may represent an interesting therapeutic approach in preeclampsia.     

Plasma concentration of atrial natriuretic peptide in normal pregnant women and in pregnant women with preeclampsia.

Plasma concentration of atrial natriuretic peptide (ANP) was determined in pregnant women with preeclampsia, in normal pregnant and in nonpregnant women by a specific radioimmunoassay. Results did not show important differences between nonpregnant controls and normal pregnant women, but a significant rise was seen in women with preeclampsia compared to nonpregnant controls. Marked interindividual variation was found in all three groups. The mechanism of ANP release may differ between those women with normal pregnancy and those with preeclampsia. It is unclear whether the increased level of ANP in preeclampsia is an effect or a cause of the disease.     

Calcium, parathyroid hormone and calcitonin in normal pregnancy and preeclampsia

Calcium, parathyroid hormone (PTH) and calcitonin (CT) in serum, and the fractional renal excretion of calcium (FECa) were determined in (1) normal pregnant women, (2) patients with preeclampsia, and (3) normal nonpregnant control subjects. Serum calcium, corrected for individual variation in serum protein, was reduced and FECa increased in the normal pregnant group when compared to the nonpregnant control group. In preeclampsia serum calcium did not differ significantly from the normal pregnant group, but FECa was considerably lower and also reduced below the level in the nonpregnant control group. PTH was slightly lower during normal pregnancy than after delivery, but did not deviate significantly from the nonpregnant control group; in preeclampsia PTH did not deviate significantly from the levels in normal pregnancy. CT was the same in the third trimester of pregnancy in both groups. Changes in serum calcium and FECa were not correlated to PTH or CT. It is concluded that both normal pregnancy and preeclampsia are accompanied by considerable alterations in calcium metabolism, that PTH and CT in both groups are mainly unchanged and at nonpregnant level, and that the increase and decrease in renal calcium excretion in normal pregnancy and preeclampsia, respectively, may be attributed to changes in kidney function.     

Cytokine Production by Monocytes,NK Cells,and Lymphocytes Is Different in Preeclamptic Patients as Compared with Normal Pregnant Women

Objective. To measure cytokine production in ex vivo stimulated leukocyte populations of women with normal pregnancy and those with preeclampsia. Methods. Whole blood from preeclamptic and normal pregnant women was stimulated with LPS or PMA/Ca-ionophore. The percentages of IFNγ and IL-2, 4, and 10 producing lymphocytes and NK cells and the percentages of TNFα, IL-1β, and IL-12 producing monocytes were measured by flowcytometry. Results. In women with preeclampsia, there was a significantly increased percentage IL-4 producing cytotoxic T cells. Also, a significant decreased percentage IL-2 producing T helper cells and IL-12 producing monocytes was seen as compared with normal pregnancy. Conclusion. Th1 cytokine production of lymphocytes and monocytes appears to be decreased in our group of preeclamptic patients compared with normal pregnant women.     

Comparison of vagal baroreflex function in nonpregnant women and in women with normal pregnancy, preeclampsia, or gestational hypertension

OBJECTIVE: Our aim was to compare baroreflex function among nonpregnant women and among women with normal pregnancy, preeclampsia, or gestational hypertension. STUDY DESIGN: Baroreflex function was tested in 20 women with preeclampsia, in 20 age- and gestational age-matched normotensive gravid women, in 20 age-matched nonpregnant women, and in 20 nonmatched women with gestational hypertension. The baroreflex was measured by several modalities. RESULTS: Vagal baroreflex gain measured by cross-spectral analysis of parallel spontaneous heart rate and blood pressure changes is significantly decreased in normal pregnancy (15.8 +/- 7.2 vs 10.8 +/- 4.1 ms/mm Hg; P = 0.001), in comparison with vagal baroreflex gain in nonpregnant women. Baroreflex gain is further reduced in preeclamptic pregnancy (10.8 +/- 4.1 vs 7.2 +/- 2.6 ms/mm Hg; P = 0.003) and in gestational hypertension (10.8 +/- 4.1 vs 6.5 +/- 2.7 ms/mm Hg; P = 0.001), compared with that in normal pregnancy. Similar differences were seen with other baroreflex testing modalities. CONCLUSIONS: The normal reduction of baroreflex gain in pregnancy is further depressed in subjects with hypertensive disorders of pregnancy.     

Plasma IL-4, IL-8, IL-12, interferon-γ and CRP levels in pregnant women with preeclampsia,and their relation with severity of disease and fetal birth weight

Objective: The aim of the present study was to evaluate the hypothesis that preeclampsia is associated with increased systemic inflammatory responses of Th1-type as well as decreased Th2-type responses compared with normal pregnancy. We also sought to determine whether there was a correlation between these markers with severity of preeclampsia and fetal birth weight. Methods: The study population consisted of maternal age, gestational age, and body mass index matched 138 pregnant women; 56 normotensive healthy pregnant women (group 1), 42 women with mild preeclampsia (group 2), 40 women with severe preeclampsia (group 3). Results: Plasma interleukin (IL)-8 and C-reactive protein (CRP) levels were significantly higher in group 3 than group 1 (p?<?0.05). Plasma IL-4, IL-12, and interferon (IFN)-γ levels were similar in all groups. Although plasma IL-8 and CRP levels of mild preeclamptic group were higher than control group and lower than severe preeclamptic group, the differences were not statistically significant. There was a positive correlation between IL-12 and fetal birth weight in severe preeclamptic group (p?<?0.05). Conclusions: Elevated maternal serum pro-inflammatory cytokine IL-8 and CRP in severe preeclamptic women compared with normal pregnant women supports the hypothesis that preeclampsia is associated with increased inflammatory responses.     

The responses of isolated uterine arteries from pregnant sows to vasoconstrictive agents

Isometric contractions of isolated uterine arteries, mesenteric arteries and the thoracic aortae of nonpregnant and pregnant sows were measured in a modified Krebs-Henseleit solution in order to investigate the characteristics of the uterine artery responsiveness to vasopressor substances during pregnancy. Contractile response (delta T) of the uterine artery from pregnant sow to angiotensin II(A II) was significantly smaller than that from nonpregnant animal. On the other hand, delta T of uterine artery from pregnant sow to norepinephrine (NE) was greater than that from nonpregnant animal. NE-induced delta T of preparations from both pregnant and nonpregnant sow were suppressed nearly to the same level following the treatment of phentolamine, or verapamil in the incubation medium of 2.5mM Ca2+. In the Ca2+-free (EDTA 1mM) incubation medium, the responses decreased to the minimum degree. These results imply that conspicuous refractoriness of the uterine artery to A II during pregnancy is due to the changes in the characteristics of the uterine vascular wall, and the enhanced responsiveness to NE of the uterine artery may be due to the increased sensitivity in alpha-adrenergic receptor on the vasculature with the increase in Ca ion influx.     

Serum prolactin and thyroid stimulating hormone levels following thyreotropin releasing hormone stimulation in preeclamptic patients.

Serum prolactin and thyroid stimulating hormone (TSH) levels were measured following administration of thyreotropin releasing hormone (THR) in 17 preeclamptic patients and 18 normal pregnant controls. From the 31st to the 35th pregnancy week the preeclamptic patients showed increased basal serum prolactin and TSH levels compared to controls, but later in pregnancy the differences disappeared. Following TRH stimulation, the serum prolactin and TSH responses were similar in women with and without preeclampsia. A possible role of prolactin in the development of preeclampsia is discussed.     

The role of endothelium in normal pregnancy and pregnancy complicated by preeclampsia]

Endothelial cell dysfunction is thought to play a role in preeclampsia and the reduced production by vascular endothelial cells of the antiaggregatory and vasodilatory factors is well documented. The present study was designed to evaluate endothelial cells function in preeclamptic and healthy pregnant subjects. The nitric oxide plasma concentration in women with preeclampsia was significantly lower as compared with normotensive pregnant women. A significant increase in ET concentration was found in preeclamptic women as compared with normal pregnant patients and normal non-pregnant. The plasma concentrations of von Willebrand factor were significantly increased in healthy pregnancy as compared with preeclamptic patients. The results of our study demonstrate a significant endothelial cells damage in preeclamptic patients. Whether these observations contribute to the vascular pathophysiologic features of preeclampsia remains to be proved.     

Altered thiol status in preeclampsia

Thirty preeclamptic, 30 normotensive pregnant and 25 healthy nonpregnant women were analyzed with regard to the antioxidant system (thiols and superoxide dismutase, SOD). In preeclampsia both plasma and lysate thiol levels were significantly lower compared to controls (p < 0.001). SOD levels were higher in normotensive pregnant women, but were lower in preeclamptic compared to nonpregnant women. This finding of antioxidant changes in the red blood cell suggests that red cell dysfunction is fundamental in the development of preeclampsia, and similar alterations in the balance of the thiol could be present across the endothelial cell membrane.