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Negligible role of catecholaminergic receptors in the anteroventral third ventricular region in mediating vasopressin-releasing and cardiovascular actions of prostaglandin E2.

The aim of this study was to pursue the roles of the catecholamine receptors in the anteroventral third ventricular region (AV3V), a cerebral site engaged in various stress responses, in prostaglandin (PG) E2-evoked vasopressin (AVP) release and cardiovascular action. Experiments were conducted in conscious rats in which cerebral and vascular cannulae had been implanted chronically. Local infusion (0.5 microliter, 1 min) of dopamine (150 nmol), a D1-dopaminergic agonist SKF 38393 (17 nmol) and an alpha-adrenergic agonist phenylephrine (150 nmol), as well as PGE2 (7 nmol), into the AV3V enhanced plasma AVP 5 min later, without affecting plasma osmolality and electrolytes. In contrast to the increases in both arterial pressure and heart rate observed when PGE2 was applied, dopamine and SKF 38393 did not affect these variables, and phenylephrine elevated only arterial pressure. The AV3V infusion of a beta-agonist isoproterenol (100 nmol) did not change plasma AVP, although it decreased arterial pressure and increased heart rate. The increase in plasma AVP by dopamine was not blocked by the preinfusion of the D2-antagonist sulpiride (13 nmol) into the AV3V 10 min before, but was abolished by that of the D1-antagonist SCH-23390 (8 nmol). The effects of phenylephrine on both plasma AVP and the blood pressure were prevented by the preadministration of the alpha-antagonist phenoxybenzamine (13 nmol). However, the pretreatments with phenoxybenzamine, sulpiride or SCH 23390 did not inhibit the responses of AVP, arterial pressure and heart rate caused by PGE2. These antagonists were without significant effect on AVP and other variables when given alone. The infusion sites of PGE2 and the other drugs identified histologically included the AV3V structures such as the organum vasculosum laminae terminalis or its vicinity, median preoptic nucleus, medial preoptic nucleus and periventricular hypothalamic nucleus. Dopamine or phenylephrine administered into the cerebral ventricle at the same dose as used in the AV3V application did not exert a significant effect on plasma AVP, arterial pressure and heart rate. These results suggest that catecholamine receptors in the AV3V may not be involved in the AVP-secreting, tachycardiac and pressor responses evoked by topical action of PGE2 on this area, despite their ability to influence hormone release and cardiovascular function.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

Effects of phenol red on CFU-f differentiation and formation.

Osteoblastic induction is commonly studied using the colony-forming unit-fibroblastic (CFU-f) assay, in which bone marrow stromal cells (BMC) are grown in a tissue culture environment permissive for osteoblastic differentiation (DMEM containing dexamethasone, ascorbic acid and beta-glycerophosphate). These cells form colonies, which express alkaline phosphatase, and form a collagenous matrix that becomes calcified. However, these same cells originate in the bone marrow where under normal circumstances they do not proliferate or differentiate despite being subjected to many of the same growth factors and hormones present within the tissue culture environment. We show here that phenol red, present within tissue culture medium as a pH indicator, may itself be a factor that permits osteoblastic recruitment. BMC cultured in the presence of the bone anabolic agents PGE2, PGA2, or bFGF, but in the absence of phenol red, failed to respond to these agents in terms of total or osteoblastic colony number. This effect was dose dependent, with low (2.5 mg/l) and high (15-20 mg/l) doses of phenol red being nonpermissive for the stimulatory effects of PGE2 whereas doses of 5-10 mg/l were permissive. Furthermore, the effects observed in the absence of phenol red could not be abrogated by the addition of 17beta-estradiol indicating that these effects cannot be attributed to estrogenic impurities within the phenol red preparation. This indicates that phenol red itself can affect the differentiation of BMC by a mechanism not previously described.

Animals↗

Prostaglandin E2 (PGE2) autoamplifies its production through EP1 subtype of PGE receptor in mouse osteoblastic MC3T3-E1 cells.

Prostaglandin E2 (PGE2) is known to autoamplify its production in the osteoblasts through the induction of prostaglandin G/H synthase-2 (PGHS-2), which is the inducible form of the rate-limiting enzyme in PG synthesis, PGHS. To elucidate the cellular mechanism mediating this process, we have employed the PGE2 analogs, which are specific agonists for four subtypes of PGE receptor, and studied the potency of these analogs to induce PGHS-2 mRNA in mouse osteoblastic MC3T3-E1 cells. The induction was mainly observed by 17-phenyl-omega-trinor PGE2 (EP1 agonist) and sulprostone (EP3/EP1 agonist), but not by butaprost (EP2 agonist) or 11-deoxy PGE1 (EP4/EP2 agonist). Since EP3 subtype was undetectable in MC3T3-E1 cells, these data indicate that PGHS-2 mRNA induction is mediated through EP1 subtype of PGE receptor in MC3T3-E1 cells. PGE2 production determined by radioimmunoassay was also increased by 17-phenyl-omega-trinor PGE2 and sulprostone. The autoamplification of PGE2 production is considered to be important in elongating the otherwise short-lived PGE2 action in certain physiological conditions such as mechanical stress and fracture healing, as well as the pathological inflammatory bone loss. The observations in the present study provide us with the better understanding of these processes.

3T3 Cells↗

Duplication of CYP2D6 predicts high clearance of desipramine but high clearance does not predict duplication of CYP2D6.

OBJECTIVE: Duplication of CYP2D6 causes very rapid metabolism of CYP2D6 substrates such as desipramine. However, we have previously shown that in the Danish population, only about 15% of very rapid metabolisers, defined as subjects with a metabolic ratio of sparteine of 0.15 or less, carried a duplicated allele. The question is whether gene duplication is a relatively rare cause (perhaps predictor) of very rapid metabolism or whether a low metabolic ratio is a poor predictor of this. METHODS: After measuring metabolic ratios anew, we selected six volunteers with duplication of CYP2D6 and metabolic ratios ranging from 0.07 to 0.17 and six volunteers without duplication with metabolic ratios ranging from 0.08 to 0.21. Each subject took 100 mg of desipramine. Blood and urine were collected for 48 h. RESULTS: The median total oral clearance of desipramine was 372 l/h and 196 l/h [median difference 108 l/h (95.9% c.i., -304-598 l/h)] and the median partial clearance of desipramine by 2-hydroxylation was 155 l/h and 87 l/h [median difference 47 l/h (95.9% c.i., -124-141 l/h)] for the group with duplication and the group without duplication, respectively. CONCLUSION: The predictive value of duplication of CYP2D6 is poor; there must be other causes (or predictors) of very rapid metabolism and with much higher frequency than duplication of CYP2D6.

Administration, Oral↗

Cl- channels in basolateral TAL membranes. XIX. Cytosolic Cl- regulates mmCIC-Ka and mcCIC-Ka channels.

We evaluated the effects of culturing mouse MTAL cells under conditions that suppressed steady-state cytosolic Cl- on chloride channels fused into bilayers from basolateral vesicles of cultured MTAL cells. We used two agents to suppress Cl- entry: 10(-6) M PGE2 and 10(-4) M bumetanide. Basolateral Cl- channels from control cultured MTAL cells exhibited the signature characteristics of mmCIC-Ka channels: increased open-time probability (Po) either by raising cytosolic-face [Cl-] or, at 2 mM cytosolic Cl-, by adding (ATP + PKA), and first-order conductance kinetics. Either 10(-6) M PGE2 or 10(-4) M bumetanide in culture media reduced steady-state MTAL cytosolic Cl-. Chloride channels from these cells exhibited characteristics unique to CTAL mcCIC-Ka channels, namely: no augmentation of Po either by raising cytosolic Cl- or with cytosolic (ATP + PKA), and multi-ion occupancy. Semi-quantitative RT-PCR and real-time quantitative PCR showed that culturing MTAL cells with 10(-6) M PGE2 or 10(-4) M bumetanide reduced mRNA levels encoding mmCIC-Ka but not mRNA levels encoding mcCIC-Ka. However, when MTAL cells were cultured under control conditions, and then pre-incubated for 60 minutes with 10(-4) M bumetanide, cytosolic Cl- fell acutely but Cl- channels exhibited characteristics of mmCIC-Ka channels. Thus PGE2 and bumetanide, both of which lower steady-state MTAL cytosolic Cl- concentrations, inhibit either the transcriptional and/or the translational processes for mmCIC-Ka synthesis.

Adenosine Triphosphate↗

Vascular endothelial growth factor inhibits maturation of dendritic cells induced by lipopolysaccharide, but not by proinflammatory cytokines.

PURPOSE: Dendritic cells (DCs) play an important role in the host's immunosurveillance against cancer. It has been shown that the function of DCs is impaired and their population decreased in a cancer-bearing host. In the present study, we investigated the mechanism of down-regulation of DCs in a cancer-bearing host. METHODS: We evaluated the relationship between DC infiltration and production of vascular endothelial growth factor (VEGF) in carcinoma tissue by immunohistochemistry. Furthermore, functional and phenotypical alterations of DCs were evaluated when monocyte-derived, mature DCs were treated with VEGF in vitro. Monocyte-derived DCs were generated in a culture of monocyte with interleukin 4 (IL-4) and granulocyte-macrophage colony-stimulating factor, and the maturation of DCs was induced by either lipopolysaccharide (LPS) or a proinflammatory cytokine cocktail: tumor-necrosis factor alpha, prostaglandin E2, IL-6, and IL-1beta. RESULTS: A significant inverse correlation was found between the density of DCs and the quantity of VEGF production in gastric carcinoma tissue (r=-0.39, p<0.05). In LPS-induced maturation, the ability of mature DCs to stimulate allogenic T cells and produce IL-12 (p70 heterodimer) was suppressed by the addition of VEGF in a dose-dependent manner. A lesser expression of costimulatory molecules (CD80 and CD86) was seen in DCs treated with exogenous VEGF than in DCs not treated with VEGF. The population of dead DCs (early and late apoptosis) treated with VEGF increased more than that without VEGF treatment, using the annexin V and propidium iodide evaluation in DCs matured by LPS. In contrast, in DCs matured by the proinflammatory cytokine cocktail, the down-regulation of costimulatory molecules and induction of DC apoptosis was not seen. CONCLUSIONS: These findings show that the inhibition of DC maturation by VEGF differs depending on the maturation status of the DCs.

Adenocarcinoma↗

Can magnetic resonance imaging predict the success of parturition in oxytocin-induced pregnant women?

The aim of this study was to assess whether magnetic resonance imaging could predict the outcome of attempted vaginal delivery in a group of pregnant women whose parturition had to be induced by oxytocin. The signal intensity and morphology alterations in the cervix of 21 full-term pregnant women were analyzed before the induction of parturition. T2-weighted gradient echo sequences were utilized and signal intensity in the cervix was measured from the anterior and posterior lips of the cervix. An index indicating the brightness range of the cervix was formulated to overcome the effects of the individual intensity changes. Imaging features including the signal intensity and the evidence of effacement were correlated with the actual type of delivery performed. Images were also assessed visually by two independent radiologists. Statistical analysis of brightness indexes that were considered to have a predictive value as an indicator for possible delivery was not significant. However, visually assessed signal intensity of the cervix correlated strongly with the type of delivery. Effacement itself was the most reliable parameter in predicting the progress of the delivery. In conclusion, MR imaging seems to be useful for predicting normal parturition in full-term pregnant women who need oxytocin induction. However, the presence of effacement seems to be a more reliable and practical parameter that will be preferred in that prediction.

Adult↗

Timing of parturition in two species of viviparous lizard: influences of beta-adrenergic stimulation and temperature upon uterine responses to arginine vasotocin (AVT).

The southern snow skink Niveoscincus microlepidotus is a viviparous alpine lizard with biennial reproduction, in which embryos are fully developed before winter but parturition is delayed until spring. We aimed to determine whether, in this species, in vitro uterine preparations are responsive to arginine vasotocin (AVT) and prostaglandin (PGF(2alpha)) in autumn and spring, and whether pre-treatment with the beta-adrenergic agonist isoproterenol decreases the effectiveness of AVT in stimulating uterine contractions. Using the spotted snow skink (Niveoscincus ocellatus), an annually breeding species, we aimed to determine influences of temperature and the beta-adrenergic system upon the response to AVT in vivo. In both N. microlepidotus and N. ocellatus females are more responsive to AVT than to PGF(2alpha), and that the response to AVT is decreased, but not prevented, by beta-adrenergic stimulation. In N. microlepidotus, uteri are equally responsive in both seasons to the hormones administered. In N. ocellatus environmental conditions, specifically, temperature, modulate the response to AVT in vivo with the time to parturition increasing as temperature decreases. We conclude that in these viviparous squamates the endocrine cascade leading to parturition is modulated by the beta-adrenergic system, and that this may reflect the mechanism by which the timing of parturition is tied to suitable environmental conditions.

Adrenergic beta-Agonists↗

A comparison of induction with vaginal prostaglandin E2 versus spontaneous of labor in grand multiparous women.

OBJECTIVE: To compare the outcome of labor in grand multiparous women (para 6 or more) who had induction of labor with vaginal prostaglandin E2 with grand multiparous women in spontaneous labor. METHODS: A retrospective case-control study was performed, 202 grand multiparous women were induced labor with vaginal prostaglandin E2 and compared with outcomes with grand multiparous women who entered in spontaneous labor and delivered during the same study period and served as control group. RESULTS: There were no statistically significant differences in the duration of labor, fetal birth weight, use of oxytocin augmentation, and Apgar scores in the two groups. Fourteen women (6.9%) in the induction group delivered by cesarean section compared to six woman (3.0%) in the control group. This was a statistically significant difference (P = 0.01). In the induction group, the mean duration of the hospital stay was longer (P = 0.003) and there was one neonatal fetal death and one uterus rupture. CONCLUSION: Induction of labor with vaginal prostaglandin E2 in grand multiparous women is still relatively safe.

Administration, Intravaginal↗

Rupture of the pregnant uterus: a 9-year review.

OBJECTIVE: To investigate the frequency of ruptured uterus, possible etiologic factors and fetomaternal outcomes. STUDY DESIGN: A retrospective chart view of all patients with ruptured uterus over a 9-year period from 1995 to 2003 was carried out. Relevant data relating to the clinical features, characteristics of labour, operative procedures, and fetomaternal outcomes were assessed. RESULTS: During the study period there were 17 cases of ruptured uterus among a total of 117,095 deliveries, giving an incidence of 1 in 6,888 deliveries. Thirteen patients (76.5%) were multiparous and mean parity was 1.9. Uterine rupture occurred following vaginal delivery in ten patients. Caesarean delivery was performed in seven (41.2%) patients, of which five (29.4%) patients had a history of previous caesarean section. Abdominal hysterectomy was performed in 12 patients (70.6%), of which 9 (75.0%) were total and 3 (25.0%) were subtotal. The other five patients (29.4%) had suture repairs. In seven patients (41.2%), uterine rupture was associated with oxytocin use. There were one maternal and three perinatal (17.6%) deaths. CONCLUSION: Sudden fetal heart abnormalities in labouring patients should be taken as a potential sign of danger. Early diagnosis and immediate preoperative resuscitation are of great importance in cases of ruptured uterus. The fetomaternal outcomes can be improved with the experience and skill of the surgical team.

Adult↗

Maternal mean corpuscle volume and oxytocin augmentation during vaginal delivery.

OBJECTIVE: The aim of this study was to assess whether low maternal MCV values are associated with adverse course of vaginal delivery. STUDY DESIGN: A retrospective analysis of 92 consecutive vertex singleton vaginal deliveries in nulliparous women in a university tertiary health care facility. MCV was considered as major outcome variable. RESULTS: 54.1% of Parturients with higher MCV needed oxytocin augmentation during labor as compared to 79.5% of parturients with lower MCV (P<0.05). The need for oxytocin for augmentation of labor was decreased with larger MCV (OR 0.90 per fL, 95% CI 0.82-0.98, P<0.05). No correlation was found between MCV and other parameters of labor course. CONCLUSION: Low maternal MCV values were associated with increased use of oxytocin augmentation during vaginal delivery.

Adult↗

A randomized comparison between intravaginal misoprostol and prostaglandin E2 for labor induction.

OBJECTIVE: The aim of this randomized study was to compare the effectiveness, safety, and side effects of 6 h vaginal misoprostol versus vaginal prostaglandin E(2) (PGE(2)) for labor induction. STUDY DESIGN: Fifty microgram of misoprostol was given intravaginally in the misoprostol group (204 women), and 3 mg PGE(2) was given intravaginally in the PGE(2) group (211 women). In both groups, the dose was repeated every 6 h for a maximum of three doses, until active labor was achieved. Artificial rupture of membranes and oxytocin infusion was used during labor in both groups where it was indicated. RESULTS: The mean interval from the institution of labor induction to delivery was 11.3 +/- 8.6 h for the misoprostol group, and 15.7 +/- 9.3 h for PGE(2 )group (P < 0.05). In the misoprostol group, oxytocin was used less frequently, but there was a higher prevalence of tachysystole. No statistically significant differences were observed between the two groups as regard abnormal patterns of fetal heart rate, the mode of delivery, and the need for neonatal intervention. CONCLUSION: In conclusion, the intravaginal administration of 50 mug misoprostol at 6 h interval (maximum three doses) is comparable in safety, but more effective for induction of labor than 3 mg intravaginal PGE(2).

Administration, Intravaginal↗

Efficacy and safety of six hourly vaginal misoprostol versus intracervical dinoprostone: a randomized controlled trial.

OBJECTIVE: To compare the efficacy and safety of intravaginal misoprostol versus dinoprostone cervical gel for cervical ripening and labour induction. METHODS: We carried out an experimental clinical trial in which we enrolled 130 cervical consecutive patients with cervical ripening, randomly assigned to one of the following two treatment groups: (1) intravaginal misoprostol and (2) intracervical dinoprostone gel. A total of 50 microm of misoprostol was placed in the posterior vaginal fornix every 6 h for a maximum period of 24 h and 0.5 mg of dinoprostone was administrated in the uterine cervix every 6 h, for a maximum period of 24 h. The primary outcome measure was the number (rate) of women who went to vaginally deliver within 24 h of the protocol initiation. RESULTS: Among 130 patients evaluated, 65 were allocated to the misoprostol group and 65 to the dinoprostone group. The proportion of vaginal delivery within 24 h was significantly higher in the misoprostol group (75%) than in the dinoprostone group (53.8%) (RR = 1.40, 95% CI [1.07-1.45], P = 0.02). There was no significant difference between the mean time interval of delivery in the misoprostol group and the dinoprostone group (14.9 vs.15.8 h) (P = 0.51). The Bishop score was significantly higher in the misoprostol group, 6 h after the onset of the study (1.38; relative risk, 95% CI [1.02-1.85], P = 0.03). The Caesarean delivery rate for fetal distress was higher in the dinoprostone group (21 vs. 10.8%, P = 0.15). The tachysystole (Misoprostol 6.1% vs. dinoprostone 4.6%, relative risk 1.15, 95% CI [0.6-2.24]) and hyperstimulation syndrome rates (Misoprostol 7.6% vs. dinoprostone 4.6%, relative risk 1.26, 95% CI [0.72-2.24]) were slightly increased in the misoprostol group than in the dinoprostone group without reaching the level of statistical signification. CONCLUSION: Misoprostol as used in this protocol is more effective than cervical dinoprostone gel application in the cervical ripening and labour induction. There is a tendency for an increase in the rate of tachysystole and hyperstimulation syndrome.

Administration, Intravaginal↗

Induction of labor with intravaginal misoprostol versus intracervical dinoprostone.

Sixty five pregnant women who had the indication for labor induction were randomized in a clinical trial to receive 100 micrograms intravaginal misoprostol or intracervical gel of 0.5 mg dinoprostone. The mean time from induction to delivery for the misoprostol group was 7.6 +/- 1.9 versus 8.2 +/- 5.9 (hours +/- SD) for the dinoprostone group. There were no significant differences between groups in gestational age, induced labor rates, type of delivery, fetal outcome and maternal complications. We found that intravaginal misoprostol tablet is as effective as intracervical dinoprostone for inducing second and third trimester labor.

Administration, Intravaginal↗

Randomized controlled trial of 50 and 100 mcg of misoprostol for induction of labor at term.

To compare the safety and efficacy of two different regimens of misoprostol for labor induction at term, we conducted a randomized controlled trial on women presenting for induction of labor at > or =37 weeks' gestation. Eligible women were randomized to receive intravaginal misoprostol 50 microg every 4 h or 100 microg every 6 h until any of the following: 1) adequate contraction pattern (3 contractions/10 min); 2) dilatation >3 cm; 3) artificial rupture of membranes; or 4) signs of uterine hyperstimulation. Use of oxytocin during labor was at the discretion of the managing clinician. The main outcome variable considered for analysis was cesarean section rate. Secondary outcome measures were induction to delivery interval and neonatal outcome (Apgar scores, meconium staining, and umbilical artery pH). A total of 58 women were randomized to receive either misoprostol 100 microg (n=26) or 50 microg (n=32). The 100 and 50 microg groups had similar mean Bishop's scores at induction (4.0+/-2.3 vs 4.1+/-2.2, p=0.87), rates of nulliparity, use of epidural anesthesia, and oxytocin augmentation. The number of doses of misoprostol used was similar in the two groups (1.4+/-0.6 vs 1.8+/-1.2). The mean+/-standard deviation time to delivery (hours) (11.9+/-7.3 vs 14.3+/-9.6 h, p=0.30) and cesarean section rate (35% vs 19%, p=0.30, relative risk: 1.8, 95% confidence interval 0.7-5.4) were not different in the 100 vs 50 microg group. Power analysis demonstrated that 132 women would be required in each group to achieve statistical significance in the primary outcome measure (alpha=0.05, beta=0.80). Similarly, rates of 5-minute Apgar scores <7 (4% vs 3%, p=1.0), and of meconium passage (17% vs 25%, p=0.73) were not significantly different between the two groups.

Administration, Intravaginal↗

Cytoplasmic Ca2+ at low submicromolar concentration stimulates mitochondrial metabolism in rat luteal cells.

The cytoplasmic Ca2+ signal is transferred to the mitochondrial matrix and activates mitochondrial dehydrogenases. The requirement for supramicromolar cytoplasmic [Ca2+] ([Ca2+]i) in perimitochondrial microdomains in this response has been suggested. We studied the correlation between [Ca2+]i, mitochondrial [Ca2+] ([Ca2+]m) and mitochondrial formation of reduced nicotinamide adenine dinucleotide (phosphate) [NAD(P)H] in the presence of submicromolar [Ca2+]i in cultured rat "large" luteal cells. [Ca2+]i was monitored fluorimetrically with fura-PE3, [Ca2+]m with rhod-2 and NAD(P)H with autofluorescence. In intact cells, prostaglandin F2alpha, which induces both intracellular Ca2+ release and Ca2+ entry, stimulated mitochondrial NAD(P)H formation. Thapsigargin-induced Ca2+ release and subsequent capacitative Ca2+ entry, both resulting in Ca2+ responses not exceeding 150-200 nM, also enhanced the reduction of pyridine nucleotides. As shown in inhibitor studies, the increased steady-state NAD(P)H level was due to activation of Ca2+-dependent dehydrogenases. [Ca2+]m, measured in permeabilized cells, increased moderately, but significantly, following elevation of [Ca2+]i from 50 to 180 nM, showed a further gradual increase at higher submicromolar [Ca2+]i values and rose steeply at supramicromolar [Ca2+]i. In summary, our results demonstrate that, in a steroid-producing cell type, net mitochondrial Ca2+ uptake and mitochondrial dehydrogenation can be activated even by low submicromolar increases of [Ca2+]i.

Animals↗

EP3 receptors inhibit antidiuretic-hormone-dependent sodium transport across frog skin epithelium.

We examined the effect of prostaglandin E2 (PGE2) on antidiuretic hormone (ADH)-dependent Na+ transport and cAMP production in isolated frog skin epithelium. ADH caused an increase in transepithelial Na+ transport and a decrease in cellular potential, indicating an increase in apical Na+ permeability. Subsequent addition of PGE2 decreased Na+ transport and repolarised the cells. The PGE2 receptor EP1/3-selective analogue sulprostone and the PGE2 receptor EP2/3-selective analogue misoprostol were able to mimic the effect of PGE2. ADH increased cellular cAMP levels, whereas PGE2, sulprostone and misoprostol were able to reduce the ADH-dependent cAMP production. Measurements of intracellular Ca2+ concentration ([Ca2+]i) revealed that it was unaffected by both PGE2 and sulprostone. The inhibitory effect of PGE2 on ADH-dependent Na+ transport was also observed in Ca2+-depleted epithelia. We conclude that ADH stimulates transepithelial Na+ transport by increasing cellular cAMP levels, whereas PGE2 inhibits ADH-dependent Na+ transport by activating EP3-type receptors, which decrease cellular cAMP levels. We have found no evidence that [Ca2+]i is involved in the regulation of ADH-dependent Na+ transport by PGE2.

Algorithms↗

Platelet activating factor increases ciliary activity in the hamster oviduct through epithelial production of prostaglandin E2.

We investigated the signal transduction mechanisms associated with an increase in ciliary beat frequency (CBF) produced by platelet activating factor (PAF) in oviductal ciliated cell cultures. In the range of concentrations similar to that produced by preimplantation embryos, PAF increased the CBF in a dose-dependent manner. The addition of PAF and prostaglandin E2 (PGE2) to the cultures produced a synergic increase of ciliary beating, suggesting that PAF and PGE2 signal transduction pathways may be associated. To demonstrate this hypothesis, cyclooxygenase-2 (COX-2) was selectively blocked by a specific inhibitor, NS-398, and the PAF-induced CBF increase was abolished. Moreover, a phospholipase A2 (PLA2) inhibitor, AACOCF3, blocks the PAF-induced CBF increase. PGE2 production by oviductal epithelial cells is stimulated by PAF, and WEB-2086, a PAF-receptor blocker, specifically blocks the PAF-induced PGE2 production. Using the fluorescent indicator fura-2, we measured the effect of PAF on intracellular Ca2+ concentration ([Ca2+]i) in individual ciliated cells. PAF induced a transient increase of [Ca2+]i that was blocked by WEB-2086 or by removal of extracellular Ca2+. We propose a mechanism for PAF-mediated signal transduction in the ciliated cells of the oviductal epithelium. Minimal doses of PAF trigger Ca2+ mobilization in tandem with increased PLA2 activity and a COX-2-mediated increase in PGE2. Local PGE2 production by the oviductal mucosa suggests the presence of an autocrine loop controlling ciliary activity.

Animals↗