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L Myatt

Publications and source records attributed to L Myatt.

At least 55 records · Page 3Linked to original sources
PubMed1995

Interleukin-1 beta induces the synthesis and activity of cytosolic phospholipase A2 and the release of prostaglandin E2 in human amnion-derived WISH cells.

The objective of this study was to examine the expression and activity of cytosolic phospholipase A2 (cPLA2) in relation to prostaglandin E2 (PGE2) synthesis in human amnion-derived WISH cells in response to stimulation by interleukin-1 beta (IL-1 beta). cPLA2 activity was characterized by sensitivity to heat and acid treatment, stability to dithiothreitol, and inhibition by the specific inhibitor, arachidonyl trifluoromethyl ketone (AACOCF3). Treatment of WISH cells with IL-1 beta (0.01-1 ng/mL) for up to 24 h resulted in a significant increase in PGE2 release in a concentration- and time-dependent manner accompanied by increases both in total cellular cPLA2 activity and in cPLA2 protein levels detected by Western blot analysis. The parallel increase in total cellular cPLA2 activity and cPLA2 protein level indicates that IL-1 beta may induce the synthesis of cPLA2. Incubation of the cells with 10 microM AACOCF3 for 24 h significantly inhibited IL-1 beta-induced PGE2 production strongly suggesting that cPLA2 mediates IL-1 beta-induced PGE2 formation. In unstimulated cells, there is appreciable total cellular cPLA2 activity and protein, but these cells produce low amounts of PGE2 until stimulated by IL-1 beta, suggesting that cPLA2 translocation from cytosol to the membrane is necessary for its bioactivity. In contrast to IL-1 beta, treatment with phorbol ester (12-O-tetradecanoyl phorbol-13-acetate, TPA, 10(-10)-10(-6)M) for 24 h significantly inhibited total cellular cPLA2 activity in a concentration-dependent manner. The amount of total cellular cPLA2 protein seen on Western blot remained unchanged following TPA treatment. These data suggest that in WISH cells, IL-1 beta induces both translocation to the membrane and de novo synthesis of cPLA2 protein to sustain prostaglandin (PG) synthesis. In contrast, TPA may only cause cPLA2 translocation but no increase in cPLA2 protein synthesis, resulting in limited PG synthesis. Our results provide a mechanism for the effect of IL-1 beta on prostaglandin synthesis in human amnion cells and provide support for a role of cPLA2 in the mechanism initiating human parturition.

Amnion↗
PubMed1995

Immunohistochemical localization of endothelial nitric oxide synthase in human villous and extravillous trophoblast populations and expression during syncytiotrophoblast formation in vitro.

We have examined the distribution of the endothelial isoform of nitric oxide synthase (eNOS) in villous and extravillous trophoblast populations by immunohistochemistry and have further studied expression of eNOS during differentiation of cytotrophoblast into syncytiotrophoblast in culture. In first trimester villous tissue, NADPH diaphorase activity and eNOS immunostaining were present in syncytiotrophoblast but not the progenitor cytotrophoblast layer. Extravillous trophoblast in the basal plate of the placenta was identified by anticytokeratin immunostaining and displayed NADPH diaphorase activity, but not eNOS immunostaining. Both amnion epithelial cells and chorion cytotrophoblast had NADPH diaphorase activity but no eNOS immunostaining, whereas eNOS immunostaining was seen in the fibroblast layer of amnion. Purified villous cytotrophoblast cells from term placentae aggregated and fused to form a syncytium with increasing time in culture as assessed by antidesmosomal protein and antinuclear antibody immunostaining. Following 24 h in culture, the majority of cells were still mononucleate cytotrophoblast which did not display eNOS immunostaining, whereas a few syncytial aggregates had formed which were both eNOS positive and hPL positive. By 3 to 5 days in culture, the majority of cells were present as syncytiotrophoblast. However, eNOS and hPL immunostaining was more diffuse and not all syncytial aggregates were positive. Of the trophoblast populations, only syncytiotrophoblast appears to express eNOS. Differentiation of cytotrophoblast into syncytiotrophoblast is associated with eNOS expression.

Amino Acid Oxidoreductases↗
PubMed1995

Steroid hormone regulation of rat myometrial gap junction formation: effects on cx43 levels and trafficking.

The formation of myometrial gap junctions coincides with onset of labor in many mammalian species, including humans. The assembly of gap junction protein into functional gap junction plaques is a final step in a cascade that begins with estrogen-dependent expression of the connexin43 (cx43) gene and continues with synthesis of cx43 in the rough endoplasmic reticulum (RER) and transport to the Golgi, followed by its trafficking to the plasma membrane and its assembly into functional gap junctions. Moreover, in several models of preterm labor in rats, precocious synthesis, trafficking, and assembly of cx43 follow an increase in the estrogen:progesterone ratio. The actions of these steroids on cx43 expression, gap junction formation, and labor led us to consider whether or not the cascade of cx43 expression and gap junction assembly typical of preterm and term labor would be disrupted by manipulations that inhibit labor through experimental reduction of the estrogen:progesterone ratio. Ovariectomized and non-ovariectomized pregnant rats were treated with minimal doses of progesterone or the anti-estrogenic compound ICI 182780 over a time course sufficient to inhibit labor. We found that cx43-positive gap junction formation was prevented in all animals treated with ICI 182780 or progesterone but that the mechanism by which this disruption occurred was different in anti-estrogen- and progesterone-treated animals. We found that ICI 182780 significantly inhibited the typical rise in myometrial cx43 concentrations normally observed just before labor. In contrast, it was surprising to find that significant cx43 was synthesized in myometrium of progesterone-treated intact and ovariectomized animals even though labor was inhibited. However, we found that the trafficking of myometrial cx43 from the Golgi and assembly into gap junctions at the plasma membrane were suppressed in these progesterone-treated animals, providing further support for the hypothesis that it is not synthesis of cx43 per se but trafficking of cx43 to the plasma membrane and its assembly into gap junctions that are required for effective synchronized myometrial contractions typical of labor.

Animals↗
PubMed1995

Ontogeny of the expression and regulation of interleukin-6 (IL-6) and IL-1 mRNAs by human trophoblast cells during differentiation in vitro.

During human placental differentiation, mononuclear cytotrophoblast cells fuse and differentiate into syncytiotrophoblast cells. Although syncytiotrophoblast cells have been shown to express interleukin-1 alpha (IL-1 alpha), IL-1 beta and IL-6, the pattern of expression of these cytokines during placental differentiation is unknown. We have examined the expression of IL-1 alpha, IL-1 beta and IL-6 mRNA during differentiation of cytotrophoblast cells in culture. IL-1 alpha, IL-1 beta and IL-6 mRNA levels were determined by semiquantitative reverse transcription-PCR analysis using glyceraldehyde phosphate dehydrogenase as an internal control. All three cytokine mRNA levels decreased markedly during trophoblast differentiation. After 6 days in culture, when almost all the cytotrophoblast cells had fused and differentiated into syncytiotrophoblast cells, the amounts of IL-1 alpha, IL-1 beta and IL-6 mRNA were decreased by 87.1, 72.1 and 60.9% respectively. Exogenous IL-6 had differential effects on cytokine mRNA expression. When added to placental cultures during the first 6 days of culture, IL-6 markedly inhibited IL-6, IL-1 alpha and IL-1 beta mRNA expression. However, when added to the cells during days 6-9 of culture, when most of the cells were syncytiotrophoblast cells, IL-6 stimulated IL-1 alpha and IL-1 beta mRNA expression. The results of these studies indicate that IL-1 alpha, IL-1 beta and IL-6 mRNA expression decreases markedly during cytotrophoblast differentiation in vitro and that the regulation of trophoblast cytokine mRNA levels changes during differentiation.

Base Sequence↗
PubMed1995

Urinary nitrite and nitrate concentrations in patients with idiopathic persistent pulmonary hypertension of the newborn and effect of extracorporeal membrane oxygenation.

Persistent pulmonary hypertension of the newborn (PPHN) often requires extracorporeal membrane oxygenation (ECMO), during which time pulmonary vascular resistance gradually declines. Nitric oxide (NO) is a recently recognized pulmonary vasodilator, but its role in PPHN is unknown. We tested the hypothesis that the concentrations of the urinary metabolites of NO, i.e. nitrite and nitrate, are reduced in patients with PPHN and increase during ECMO as the PPHN resolves. Eight newborn infants with PPHN on ECMO were studied. Daily urinary concentrations of nitrite/nitrate were measured. We found that mean urinary concentrations of nitrite/nitrate were lower in patients with PPHN than in 47 controls without pulmonary disease (p < 0.005). Urinary nitrite/nitrate concentration showed an initial increase after initiation of ECMO. However, a decrease to concentrations still lower than controls occurred on the day before decannulation. We conclude that intrinsic NO production is significantly lower in patients with PPHN than in controls but increases with oxygenation. We speculate that decreased urinary NO metabolite concentrations imply a role for NO deficiency in the pathogenesis of PPHN.

Extracorporeal Membrane Oxygenation↗
PubMed1994

Nitric oxide metabolites and preterm pregnancy complications.

OBJECTIVE: Intraamniotic infection may play a significant role in preterm labor and premature rupture of membranes. Synthesis of nitric oxide and its metabolites nitrite and nitrate purportedly are increased in infection. This project was designed to evaluate whether plasma or urine nitrate concentrations are increased in patients with either preterm labor or premature rupture of membranes in comparison with pregnant controls. STUDY DESIGN: A total of 42 patients between 24 and 35 weeks' gestation (20 with preterm labor; 14 with premature rupture of membranes, and 8 with premature rupture of membranes and contractions) and 35 additional patients without preterm labor or premature rupture of membranes (controls) had blood and urine collected for nitrate determination. Nitrate was reduced to nitrite and quantitated with the Griess reagent. RESULTS: The urine nitrate concentrations were significantly higher only in the preterm labor group compared with the control group (1.23 +/- 0.22 vs 0.67 +/- 0.05 mumol/mg creatinine, p < 0.05). The plasma nitrate level, however, was significantly higher in both the preterm labor and the premature rupture of membranes groups compared with the control group (52.47 +/- 10.11 and 40.05 +/- 5.38 mumol/L vs 16.29 +/- 2.89 mumol/L, p < 0.05). However, the concentrations of nitrate in the urine or plasma did not correlate with time from admission to delivery (p > 0.2). Finally, the presence of positive cervical or urine cultures, a clinical examination consistent with chorioamnionitis, or a maternal temperature > 100.4 degrees F was not associated with higher levels of nitrates in this small series of patients. CONCLUSION: Patients with preterm labor or premature rupture of membranes do have increased nitrate concentrations; however, this increased concentration is not predictive of impending delivery but may indicate that a subclinical infectious process is occurring.

Analysis of Variance↗
PubMed1994

Identification and changes in concentrations of prostaglandin H synthase (PGHS) isoforms in rat myometrium at parturition.

The isoform(s) of prostaglandin H synthase (PGHS) present in pregnant rat myometrium have been identified and the ontogeny of their expression studied during late gestation and parturition. Concentrations of PGHS have been related to changes in concentration of nuclear and cytosolic estrogen (ER) and progesterone receptors (PR) occurring at this time. Nuclear PR concentrations were maximal on days 16-18 of pregnancy, decreased from days 18 to 22 (delivery) and fell 24 hours postpartum. Nuclear ER concentrations increased significantly from days 20 to 22 of pregnancy and fell postpartum. Whereas the ratio of nuclear ER/PR was firmly in favour of progesterone action on days 16-20 it increased on day 22 corresponding to increased estrogen action. Western immunoblotting with specific antibodies revealed a single 72 kDa PGHS-1 isoform in myometrium at each timepoint. There was no evidence for the inducible PGHS-2 isoform in myometrium. Densitometric analysis showed the concentration of PGHS-1 increased significantly from day 16 to a maximum at the time of delivery on day 22 and decreased immediately afterwards. Expression of the constitutive PGHS-1 isoform is associated with the changing ratio of nuclear ER/PR and may therefore be hormonally regulated.

Animals↗
PubMed1994

Modulation of phorbol ester-induced contraction by endogenously released cyclooxygenase products in rat aorta.

This study tests the hypothesis that prostaglandins (PGs) released in response to phorbol esters act as modulators of the phorbol ester-induced smooth muscle contraction. The rate and magnitude of the phorbol 12-myristate 13-acetate (PMA)-induced contraction of deendothelialized rat aorta were decreased by the cyclooxygenase inhibitor, indomethacin. The thromboxane (Tx) A2/PGH2 receptor antagonist, SQ-29548, also inhibited PMA-induced contraction, and the magnitude of inhibition was greater than that due to indomethacin. PMA induced the release of PGI2, PGE2, PGF2 alpha, and arachidonic acid, but not TxA2. The amount of PGI2 released was greater than that of PGE2 and PGF2 alpha. Indomethacin blocked the PMA-induced release of PG, but not of arachidonic acid. In PMA-contracted tissues, PGF2 alpha, PGE2, and the stable PGI2 and PGH2 analogues, carbacyclin and U-46619, respectively, induced further contraction. Pretreatment of PMA-contracted tissues with SQ-29548 partially inhibited the PGF2 alpha- and PGE2-induced contractions, completely inhibited contraction to U-46619, and reversed the carbacyclin-induced contraction to relaxation. These results demonstrate that, in rat aorta, PMA induces the release of PGs that exert both contractile and relaxant effects but whose net effect is to accelerate and augment the contraction induced by PMA. The PG-induced increase in PMA contraction is mediated, in large part, through TxA2/PGH2 receptor activation. The ability of various PGs, including carbacyclin, to activate the TxA2/PGH2 receptor suggests that one or more of these PGs, in addition to, presumably, PGH2, may be responsible for the increase in PMA contraction. PGI2 is the only endogenously released PG that can account for the relaxant effect.

Analysis of Variance↗
PubMed1992

Changes in annexin (lipocortin) content in human amnion and chorion at parturition.

Arachidonic acid is mobilized from fetal membrane phospholipids at parturition leading to increased production of oxytocic prostaglandins which may initiate or maintain myometrial contractions. Phospholipid mobilization requires activation of phospholipase A2 or C, both of which require calcium for activity. The annexins (lipocortins) are a superfamily of proteins which bind to calcium and phospholipids and thereby may alter phospholipase activity through two mechanisms: modulation of intracellular free Ca2+ concentrations or regulation of the accessibility of phospholipids to hydrolyzing enzymes. Using Western immunoblotting with monospecific polyclonal antibodies, annexins I-VI were identified in human amnion and chorion/decidua at term in tissues obtained from patients in labor or not in labor. Each annexin was present in two distinct pools: a pool which only associated with the membrane in the presence of calcium (calcium-dependent pool) and a calcium-independent pool that remained membrane bound in the presence of calcium chelators. Annexin I was present as two species, resolving at 36 kDa and 68 kDa. The total concentration of annexin I in both amnion and chorion/decidua was significantly decreased with labor, while the total concentration of annexin V in chorion significantly increased with labor. The size of individual pools of annexins also changed with labor: the calcium-dependent pool of annexins I and II in both amnion and chorion significantly decreased; the calcium-dependent pool of annexin V increased in chorion; and calcium-independent pools of annexin I in amnion and annexins I, II, and V in chorion significantly decreased with labor. The decrease in total annexin I concentration with labor in amnion reflects a substantial decrease (80-90%) in the pool tightly bound to the membrane in a calcium-independent manner. This striking change distinguishes annexin I as a potential candidate inhibitor which is specifically downregulated at parturition, potentially leading to increased access of phospholipases to substrate phospholipids and increased prostaglandin production at labor.

Amnion↗
PubMed1992

The comparative effects of big endothelin-1, endothelin-1, and endothelin-3 in the human fetal-placental circulation.

OBJECTIVE: This study compared the effects of big endothelin-1, endothelin-1, and endothelin-3 and whether endothelin-converting enzyme was present in the human fetal-placental circulation. STUDY DESIGN: Single cotyledons of term placentas were dually perfused in vitro, and increases in fetal-placental perfusion pressure to bolus injections of big endothelin-1, endothelin-1, and endothelin-3 (8 x 10(-10) to 1 x 10(-7) mol/L) were recorded. Responses to big endothelin-1 (10(-7) mol/L) were measured in the same placenta before and after perfusion of the fetal-placental circulation with the neutral metalloprotease inhibitor phosphoramidon (10(-5) mol/L), which acts as an endothelin-converting enzyme inhibitor. All experiments were performed in at least five separate placentas. RESULTS: Significant concentration-dependent increases in fetal-placental perfusion pressure were seen with endothelin-1 (p < 0.0005), endothelin-3 (p < 0.0256), and big endothelin-1 (p < 0.0034, analysis of variance). Big endothelin-1 always elicited transient vasodilatation before constriction. Phosphoramidon significantly inhibited the vasoconstrictor effect of big endothelin-1 (p < 0.039, paired t test). CONCLUSION: The three endothelins tested are vasoconstrictors, and endothelin-converting enzyme is present in the fetal-placental circulation.

Blood Circulation↗
PubMed1992

Decrease in annexin I messenger ribonucleic acid expression in human amnion with labor.

OBJECTIVE: Annexins are a superfamily of proteins that are thought to inhibit phospholipase A2 activity and hence inhibit prostaglandin production. The purpose of this study was to test the hypothesis that annexin I concentration in human amnion is reduced with labor and that this reduction is mediated by a decrease in annexin I messenger ribonucleic acid expression. STUDY DESIGN: Amnion and choriodecidua were collected from term singleton pregnancies, eight after spontaneous vaginal delivery and eight from elective cesarean section without labor. Annexin I protein was quantitated by Western blotting. Ribonucleic acid was isolated from amnion, and then annexin I messenger ribonucleic acid was identified by Northern hybridization and quantitated by slot blotting. RESULTS: Annexin I (35 kd) was identified in amnion tissue. The concentration in the group undergoing labor (320 +/- 45 integrated optical density units, mean +/- SE) was significantly reduced (p < 0.05) compared with that in the group not undergoing labor (635 +/- 65 units). The size of the annexin I messenger ribonucleic acid was approximately 1.8 kb. The mean integrated optical density for the labor group (840 +/- 139 units, mean +/- SE) was significantly reduced (p < 0.05) compared with that of the nonlabor group (1912 +/- 464 units). CONCLUSION: There is a significant decrease in annexin I messenger ribonucleic acid expression in human amnion with labor, corresponding to a significant decrease in annexin I protein concentration. This may contribute to the increased phospholipase A2 activity, arachidonic acid mobilization, and prostaglandin production at labor in humans.

Amnion↗
PubMed1992

Attenuation of the vasoconstrictor effects of thromboxane and endothelin by nitric oxide in the human fetal-placental circulation.

OBJECTIVE: We hypothesized that the endothelial-derived relaxing factor nitric oxide may contribute to low resting vascular tone and may attenuate vasoconstrictor action in the human fetal-placental circulation. STUDY DESIGN: Isolated human placental cotyledons were dually perfused in vitro, and the effects of N-monomethyl-L-arginine and N-nitro-L-arginine (3 x 10(-4) mol/L), which are nonmetabolizable analogs of L-arginine, the substrate for nitric oxide synthase, on resting perfusion pressure and on the fetal-placental circulation preconstricted with U46619 (10(-8) mol/L) or endothelin-1 (10(-8) mol/L) were established. Responses before and after inhibition were compared by paired t test. The effects of glyceryl trinitrate (10(-6) mol/L), acetylcholine (10(-4) mol/L), the calcium ionophore A23187 (10(-6) mol/L), and histamine (10(-8) to 10(-4) mol/L) were also determined in the preconstricted fetal-placental circulation. RESULTS: Both N-monomethyl-L-arginine and N-nitro-L-arginine (3 x 10(-4) mol/L) increased resting perfusion pressure (p less than 0.06), and N-nitro-L-arginine promptly and significantly increased perfusion pressure in the fetal-placental circulation preconstricted with U46619 (p less than 0.0004) or endothelin-1 (p less than 0.06). Nitric oxide generated by addition of glyceryl trinitrate (10(-6) mol/L) attenuated the vasoconstrictor effects of U46619 (p less than 0.026) or endothelin-1 (p less than 0.01). Neither acetylcholine nor the calcium ionophore A23187 had an effect on the fetal-placental circulation, whereas bradykinin further increased perfusion pressure. Histamine only relaxed the preconstricted preparations at concentrations (10(-6) to 10(-4) mol/L) above those shown to release nitric oxide in other systems. CONCLUSION: The stimulus to nitric oxide generation in the fetal-placental circulation may be hydrodynamic. Nitric oxide appears to contribute to maintenance of basal vascular tone and to attenuate the actions of vasoconstrictors in this circulation.

Acetylcholine↗
PubMed1992

Endothelin transfer and endothelin effects on water transfer in human fetal membranes.

Although endothelin-1 is synthesized by human amnion, its physiologic role and its ability to be transferred to myometrium for oxytocic action remain unclear. We investigated the transfer of endothelin-1 itself and the effects of endothelin-1 on the transfer of tritiated water across human amnion or amnion/chorion/decidua in vitro with an Ussing chamber technique. Permeability coefficients (mean +/- standard error) for 3H2O across amnion/chorion/decidua in the fetal to maternal direction were 1.26 +/- 0.21 and 1.25 +/- 0.10 x 10(-4) cm/second (N = 6) and in the maternal to fetal direction 0.90 +/- 0.07 and 0.98 +/- 0.15 x 10(-4) cm/second (N = 5) in the absence or presence, respectively, of 10(-9) mol/L endothelin-1 in the fetal reservoir. Comparable values were found in either direction with 10(-9) mol/L endothelin-1 in the maternal reservoir. Apparent permeability coefficients for 125I endothelin-1 in the fetal to maternal direction were 3.34 +/- 0.79 and 2.43 +/- 0.68 x 10(-5) cm/second (N = 5) for amnion or amnion/chorion/decidua. However, appreciable trapping of 125I endothelin-1 by the fetal membranes was apparent. Endothelin-1 does not appear to affect water movement across the human fetal membranes, and only a small proportion of endothelin-1 itself is transferred across the membranes.

Biological Transport↗
PubMed1992

Human retinal vascular cells differ from umbilical cells in synthetic functions and their response to glucose.

Cell culture systems have commonly been used to study mechanisms implicated in the pathogenesis of diabetic retinopathy, but the great majority of cell preparations used have been either of nonhuman retinal origin or nonretinal human origin. Because of questions of species and organ specificity in the function of cells of vascular origin, in this study, cultured microvascular endothelial cells (HREC), pericytes (HRPC), and pigment epithelial cells from the postmortem human retina, and endothelial cells from human umbilical vein (HUVEC) were evaluated with respect to cell proliferation, and secretory products potentially important in diabetic retinopathy, i.e., prostaglandins (PG) and plasminogen activators (PA), normalized to DNA content/well, under both basal (5 mM) and high (25 mM) glucose conditions. Glucose (25 mM) reduced DNA content similarly in both types of endothelial cells, had a lesser effect on HRPC, and did not significantly alter the proliferation of pigment epithelial cells. Basal secretion of PGI2 (measured as 6-keto-PGF1 alpha) was in the order HRPC much greater than HREC greater than HUVEC, whereas PGE2 secretion was in the order HREC much greater than HRPC greater than HUVEC. Glucose (25 mM) stimulated PGI2 secretion by HRPC, but not by either type of endothelial cell, and enhanced PGE2 secretion by HREC, but not by HUVEC or HRPC. Release of plasminogen activator activity differed between HUVEC and HREC under basal conditions and addition of 25 mM glucose stimulated release only from HREC. Glucose (25 mM) stimulated PA secretion by HREC, but not by HUVEC. These findings provide evidence that human retinal pericytes are an important source of prostacyclin, and that there are differences between HREC and HUVEC with respect to secretory functions and their modulation by glucose, indicating regional specificity of these functions. Extrapolation to human retinal vascular cells from experiments using cells from heterologous vascular beds to draw inferences about the pathophysiology of diabetic retinopathy are not valid for these cellular functions.

Adult↗
PubMed1991

Endothelin-1-induced vasoconstriction is not mediated by thromboxane release and action in the human fetal-placental circulation.

The vasoconstrictor peptide endothelin-1 (8 x 10(-10) to 1 x 10(-8) mol/L) significantly increased fetal-placental perfusion pressure in vitro in a cumulative manner from 30 +/- 2 to 123 +/- 25 mm Hg (mean +/- SEM, n = 5, p less than 0.0005, analysis of variance). Accompanying this vasoconstriction was a corresponding reduction in fetal-placental perfusate flow rate. Measurement of thromboxane B2 and 6-keto-prostaglandin F1 alpha in the fetal-placental perfusate revealed a significant reduction in their release (p less than 0.0096 and p less than 0.0004, analysis of variance, respectively) when corrected for flow rate. Neither the thromboxane synthesis inhibitor dazoxiben (10(-6) mol/L) nor the thromboxane receptor antagonist SQ29548 (10(-6) mol/L) was able to block the vasoconstrictor actions of endothelin-1. Therefore endothelin-1-induced vasoconstriction in the human fetal-placental circulation does not appear to be mediated by thromboxane release or action. The stimulus to eicosanoid release in the fetal-placental circulation may be hydrodynamic, i.e., flow or shear stress.

6-Ketoprostaglandin F1 alpha↗
PubMed1991

Transfer of aspirin across the perfused human placental cotyledon.

Pregnancy-induced hypertension is associated with a reduction in prostacyclin synthesis that is relative to normotensive pregnancy, whereas thromboxane A2 synthesis is unchanged or increased. The net effect is a decreased prostacyclin/thromboxane ratio that may result in the reduced fetal-placental blood flow seen in pregnancy-induced hypertension because thromboxane is known to constrict this circulation. Low-dose aspirin (acetylsalicylic acid), which is used to treat pregnancy-induced hypertension, selectively inhibits thromboxane synthesis and therefore may alter fetal-placental blood flow. We have investigated the transfer of acetylsalicylic acid in the perfused human placental cotyledon and its effects on fetal-placental perfusion pressure. Human placental cotyledons were perfused with tissue culture medium 199 plus 5% polyvinylpyrrolidone that was gassed with 95% oxygen/5% carbon dioxide at flow rates of 10 ml/min (maternal) and 4 ml/min (fetal). Acetylsalicylic acid (10(-5) mol/L) was added to the maternal circuit, and cotyledons were perfused for 1 hour with aliquots taken from a closed fetal circuit every 5 minutes. Acetylsalicylic acid was assayed by spectrofluorometry at 306/412 nm. Our data indicate an initial rapid transfer of acetylsalicylic acid during the first 5 minutes into the fetal-placental circulation, the concentration then decreased to a steady state at 0.4 x 10(-5) mol/L. Resting perfusion pressure of both maternal and fetal circulation did not change after the addition of acetylsalicylic acid to maternal perfusate and transfer to the fetal circulation.

Aspirin↗
PubMed1991

The action of nitric oxide in the perfused human fetal-placental circulation.

Nitric oxide is thought to be the endogenous endothelium-derived relaxing factor. We investigated the effects of compounds that either generate nitric oxide intracellularly or inhibit its action on the vasculature of the human placental villus. Addition to perfusion medium of methylene blue (10(5) mol/L), which is an inhibitor of activation of guanylate cyclase by nitric oxide, significantly increased perfusion pressure of the fetal-placental circulation over a range of flow rates (1 to 10 ml/min) compared with the perfusion pressures seen in the absence of methylene blue. This suggests basal release of nitric oxide may contribute to maintenance of resting vascular tone. Both glyceryl trinitrate (10(-9) to 5 x 10(6) mol/L) and S-nitroso-N-acetylpenicillamine (10(-8) to 10(-4) mol/L), which generate nitric oxide intracellularly, were able to significantly vasodilate the fetal-placental circulation preconstricted with the thromboxane mimetic U46619 (1 to 5 x 10(-8) mol/L) in a concentration-dependent manner. These compounds had no effect in the absence of the vasoconstrictor. Thus it appears that the placental villus tree has the ability to both generate and respond to nitric oxide.

Blood Flow Velocity↗