Administration Of PGE2 Research Articles

Cervical ripening and induction of labor by prostaglandin E2: a comparison between intracervical gel and vaginal pessary

Objective: To compare the effectiveness and safety of two formulations of prostaglandin (PG) E2 (gel and pessary) for induction of labor. Primary outcomes were cervical ripening, initiation/duration of labor, and type of delivery.Study design: A total of 115 women with singleton gestations were consecutively enrolled and assigned to receive intracervical PGE2 (dinoprostone0.5 mg) by gel (n = 66) or PGE2 (dinoprostone 10 mg) by intravaginal pessary (n = 49).Results: Independently from parity, the vaginal pessary induced successful cervicalripening with a slightly higher but not statistically significant occurrence of vaginal delivery with respect to gel induction. The mean time interval from induction to vaginal delivery did not differ betweengroups, despite being shorter for the pessary group in inducation-delivery intervals > 12 h. No significant differences were found between the groups with respect to patients who required a second courseof PGE2 (9% vs. 2%), as well as oxytocin (11% vs. 13%) induction. No significant difference was found in the incidence of uterine hyperstimulation and other adverse reactions in nulliparas, orin fetal and neonatal outcome.Conclusion: Independently from parity, both PGE2 administration routes appeared to be effective in achieving cervical ripening, initiation of labor andoptimal type of delivery, and showed the same incidence of side-effects.

Fetal exposure to nicotine does not alter the core temperature response of 7- to 8-week-old rats to intracerebroventricular administration of PGE 1

Prenatal exposure to nicotine attenuates stress-induced hyperthermia in adult male and female rats upon exposure to a novel environment. Given that prostaglandins play an important role in mediating stress-induced hyperthermia, our current experiments were carried out to determine if prenatal exposure to nicotine alters the thermogenic response of adult rats to an E-series prostaglandin. Forty-eight chronically instrumented adults rats (24 males and 24 females) received an intracerebroventricular injection of prostaglandin E 1 (PGE 1; 0.2 μg in 10 μl of artificial cerebrospinal fluid [aCSF]) or vehicle (10 μl aCSF) at 7–8 weeks of postnatal life (i.e. adulthood as defined by the ability to reproduce) following prenatal exposure to nicotine (6 mg of nicotine tartrate per kilogram of maternal body weight per day) or vehicle via a maternally implanted osmotic mini-pump from Day 6 or 7 of gestation to term. In female rats, intracerebroventricular injection of PGE 1 following prenatal exposure to vehicle produced a monophasic fever with a magnitude of ∼1.5 °C and a duration of ∼66 min. In male rats, however, intracerebroventricular injection of PGE 1 following prenatal exposure to vehicle produced a monophasic fever with a magnitude of only ∼0.9 °C and a duration of ∼42 min. Prenatal exposure to nicotine did not significantly alter the febrile responses of male or female rats to intracerebroventricular injection of PGE 1 as compared to that observed following prenatal exposure to vehicle. Thus, prenatal exposure to nicotine does not significantly alter the thermogenic response of adult rats to central administration of the pyrogen PGE 1. It is unlikely, therefore, that an altered thermoregulatory effector response to E-series prostaglandins is responsible for mediating the attenuated stress-induced hyperthermia in adult male and female rats upon exposure to a novel environment following prenatal exposure to nicotine.

Inhibition of cyclo-oxigenase-2 activity does not abolish the anabolic effect of prostaglandin E2 in vivo or in vitro.

It was previously reported that the expression of cyclo-oxigenase-2 (COX-2) is induced by prostaglandin E(2) (PGE(2)) in vitro in an osteogenic cell line and organ culture, suggesting an autoamplification mechanism. In this study, we first tested whether this phenomenon also occurs in bone tissue in vivo and found that a single anabolic dose of PGE(2) (5 mg/kg) induced (between 30 and 120 min) in rat tibiae, an increase in the mRNA level of COX-2 (2.5- to 9-fold) but not that of COX-1. Secondly, to test whether COX-2 activity in generating endogenous prostaglandins (PGs) is required for the in vivo anabolic properties of PGE(2), young male rats were injected daily with either vehicle (8% ethanol) or 5 mg/kg PGE(2) for 21 days. PGE(2)-injected rats received, 45 min prior to PGE(2), either dimethyl sulphoxide (as vehicle) or one of two doses of NS-398, a selective COX-2 inhibitor: a low dose (3 mg/kg) or a high dose (10 mg/kg). PGE(2) increased bone formation (measured as cancellous mineralizing surface, mineral apposition rate and bone formation rate) and bone mass (measured as cancellous bone area and surface and cortical width). None of these increases was suppressed by pre-administration of NS-398. In contrast, the high dose of NS-398 effectively suppressed an increase in rat hind-paw volume induced by a local carrageenan injection. Furthermore, since COX-2 inactivation may affect PG receptor expression, we found that pre-administration of NS-398 did not abolish the induction in EP(4) receptor mRNA levels, caused by PGE(2) in rat bone tissue. For in vitro testing, rat femoral bone marrow stromal cell cultures were initiated and were incubated in the absence or presence of PGE(2) at 100 nM (as an inducer) and with increasing concentrations of NS-398 (10(-8) M to 10(-5) M) for 21 days, after which time mineralized (Von-Kossa positive) nodules were counted. PGE(2) increased nodule formation as previously reported; however, NS-398 reduced nodule formation in both control and PGE(2)-treated cultures to the same extent. We conclude that while the level of COX-2 mRNA is increased in vivo by administration of PGE(2), inhibition of its activity (i.e. generation of endogenous PGs) does not abolish the anabolic effect of PGE(2).

Mechanisms of pain in arthritis.

Inflammation in the joint causes peripheral sensitization (increase of sensitivity of nociceptive primary afferent neurons) and central sensitization (hyperexcitability of nociceptive neurons in the central nervous system). The processes of sensitization are thought to be the basis of arthritic pain that appears as spontaneous pain (joints at rest) and hyperalgesia (augmented pain response on noxious stimulation and pain on normally nonpainful stimulation). Sensitization also facilitates efferent neuronal processes through which the nervous system influences the inflammatory process. Peripheral sensitization is produced by the action of inflammatory mediators such as bradykinin, prostaglandins, neuropeptides, and cytokines which activate corresponding receptors in proportions of nerve fibers. In addition, the expression of receptors, for example, bradykinin and neurokinin 1 receptors, is upregulated during inflammation. The development of hyperexcitability of spinal cord neurons is produced by various transmitter/receptor systems that constitute and modulate synaptic activation of the neurons. The key transmitter is glutamate that activates N-methyl-d-aspartate (NMDA) and non-NMDA receptors on spinal cord neurons. Blockade of these receptors prevents and reduces central sensitization. Excitatory neuropeptides (substance P and calcitonin gene-related peptide) further central sensitization. Central sensitization also is facilitated by mediators that have complex actions (e.g., prostaglandin E(2)). Spinal PGE(2) binds to receptors at presynaptic endings of primary afferent neurons (thus influencing synaptic release) and to receptors on postsynaptic spinal cord neurons. The administration of PGE(2) to the spinal cord surface produces changes of responsiveness of spinal neurons similar to peripheral inflammation, and spinal indomethacin to the spinal cord attenuates development of hyperexcitability significantly.

PGE(2) increases release of substance P from renal sensory nerves by activating the cAMP-PKA transduction cascade.

Increasing renal pelvic pressure increases afferent renal nerve activity (ARNA) by a PGE(2)-mediated release of substance P (SP) from renal pelvic nerves. The role of cAMP activation in the PGE(2)-mediated release of SP was studied by examining the effects of the adenylyl cyclase (AC) activator forskolin and AC inhibitor dideoxyadenosine (DDA). Forskolin enhanced the bradykinin-mediated release of SP from an isolated rat renal pelvic wall preparation, from 7.3 +/- 1.3 to 15.6 +/- 3.0 pg/min. PGE(2) at a subthreshold concentration for SP release mimicked the effects of forskolin. The EP(2) receptor agonist butaprost, 15 microM, and PGE(2), 0.14 microM, produced similar increases in SP release, from 5.8 +/- 0.8 to 17.0 +/- 2.3 pg/min and from 8.0 +/- 1.3 to 21.6 +/- 2.7 pg/min. DDA blocked the SP release produced by butaprost and PGE(2). The PGE(2)-induced release of SP was also blocked by the PKA inhibitors PKI(14-22) and H-89. Studies in anesthetized rats showed that renal pelvic administration of butaprost, 10 microM, and PGE(2), 0.14 microM, resulted in similar ARNA responses, 1,520 +/- 390 and 1,170 +/- 270%. s (area under the curve of ARNA vs. time) that were blocked by DDA. Likewise, the ARNA response to increased renal pelvic pressure, 7,180 +/- 710%. s, was blocked by DDA. In conclusion, PGE(2) activates the cAMP-PKA pathway leading to a release of SP and activation of renal pelvic mechanosensory nerve fibers.

Roles of the central prostaglandin EP3 receptors in cardiovascular regulation in rats

In this study, we examined the effects of an intracerebroventricular (i.c.v.) administration of prostaglandin E 2 (PGE 2) and of selective agonists for PGE 2 receptor subtypes, EP1, EP2, EP3 and EP4, on central cardiovascular regulation and renal sympathetic nerve activity (RSNA) in urethane-anesthetized rats. The central administration of PGE 2 (0.01–1.0 nmol) resulted in increases in blood pressure, heart rate (HR) and RSNA in a dose-dependent manner. Cardiovascular responses to PGE 2 (0.5 nmol, i.c.v.) were attenuated by pretreatment with ganglionic and adrenoceptor blocking agents, but not with SC-19220 (20 nmol, i.c.v.), an EP1 receptor antagonist. An i.c.v. administration of the EP3 agonist ONO-AE-248 (50.0 nmol) resulted in an increase in RSNA with pressor and tachycardia responses, while administration of the EP2 agonist ONO-AE1-259 and the EP4 agonist ONO-AE1-329 caused transient hypotension and slight increases in HR and RSNA. The administration of the selective EP1 agonist ONO-DI-004 showed no effect. These results suggest that the central PGE 2-induced activation of the sympathetic nerve activity with hypertension and tachycardia may depend on stimulation of the EP3 receptors in the central nervous system.

Prostaglandin E 1 protects cultured spinal neurons against the effects of nitric oxide toxicity

The effects of prostaglandin (PG) E 1 on NO neurotoxicity were examined using rat cultured spinal neurons. Rat cultured spinal neurons exposed to the NO donor, 2,2’-(hydroxynitrosohydrazono) bis-ethanamine (NOC18), showed neurotoxic effects that were accompanied by apoptotic nuclear change, free radical generation, a reduction in glutathione, and mitochondrial dysfunction. PGE 1, at concentrations of 1–100 nM, protected cultured spinal neurons from NO toxicity by reversing the oxidative and pro-apoptotic properties elicited by NOC18 exposure. The administration of PGE 1 increased the intracellular cyclic AMP (cAMP) levels in cultured spinal neurons. In addition, reverse transcriptase–polymerase chain reaction (RT–PCR) analysis confirmed the existence of EP4, a cAMP-elevating PGE receptor, in cultured spinal neurons. The protective effects of PGE 1 against NO neurotoxicity was partially blocked by an inhibitor of MEK [the mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK) kinase], suggesting that the MAPK/ERK pathway may play a significant role in the activity of PGE 1. PGE 1 up-regulated the expression of the anti-apoptotic protein, Bcl-2, as determined by Western blot analysis. PGE 1 also induced the expression of thioredoxin in cultured spinal neurons. Our data indicate that PGE 1 exerts a protective action against NO neurotoxicity in cultured spinal neurons, and suggests a therapeutic potential of PGE 1 against spinal cord disease, such as amyotrophic lateral sclerosis.

The role of spinal neurokinin-1 and glutamate receptors in hyperalgesia and allodynia induced by prostaglandin E 2 or zymosan in the rat

Recent research has focused on prostaglandins in the central nervous system and their contribution to hyperalgesia and allodynia. This study sought to establish whether neurokinin-1 (NK-1) receptors and glutamate receptors are involved in the hyperalgesic and allodynic effects of spinally administered prostaglandin E 2 (PGE 2) in rats, and also to determine if the same receptors are involved the hyperalgesia induced by intraplantar administration of zymosan, an inflammatory agent which is known to evoke spinal PGE 2 release. Spinal application of antagonists of the NK-1 receptor, the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate glutamate or metabotropic glutamate receptor significantly attenuated the decrease in mechanical paw withdrawal response thresholds produced by either spinal administration of PGE 2 or intraplantar administration of zymosan. The decrease in thermal paw withdrawal response latencies induced by PGE 2, but not by zymosan, was significantly attenuated by spinal administration of an N-methyl- d-aspartate (NMDA) receptor antagonist, an AMPA/kainate receptor antagonist, or a metabotropic glutamate receptor antagonist. Allodynia induced by PGE 2 was significantly alleviated by antagonists of NMDA or AMPA/kainate receptors. These results suggest that both PGE 2-induced and zymosan-induced mechanical hyperalgesia are mediated in part through activation of NK-1, AMPA/kainate and metabotropic glutamate receptors. PGE 2-induced, but not zymosan-induced, thermal hyperalgesia is mediated in part by activation of NMDA, AMPA/kainate and metabotropic glutamate receptors. Activation of both NMDA and AMPA/kainate receptors contribute to PGE 2-induced allodynia.

Spinal administration of prostaglandin E 2 or prostaglandin F 2α primarily produces mechanical hyperalgesia that is mediated by nociceptive specific spinal dorsal horn neurons

The effects of intrathecal (i.t.) administration of prostaglandin E 2 (PGE 2) and prostaglandin F 2α (PGF 2α) on behavioral and spinal neuronal responses to mechanical and thermal stimuli were examined in rats. i.t. Administration of either PGE 2 (1–100 nmol) or PGF 2α (1–100 nmol) produced a robust, dose-dependent mechanical hyperalgesia, but only a weak thermal hyperalgesia and touch-evoked allodynia. Spinal administration of either PGE 2 (100 pmol–100 nmol) or PGF 2α (1–100 nmol) produced dose-dependent increases in responses of nociceptive specific (NS) neurons to mechanical stimuli, but only modest increases in wide dynamic range (WDR) neurons to mechanical stimuli. Spinal administration of PGE 2 produced a bi-directional, dose–response effect on thermally-evoked responses of both WDR and NS neurons when prostaglandin-induced changes in background discharges were controlled for. Thermally evoked responses of WDR and NS neurons were decreased at lesser doses of PGE 2, but this trend reversed with greater doses, such that responses of WDR neurons were significantly increased at the greatest dose tested at some test temperatures. PGF 2α generally produced non-significant increases in thermally evoked neuronal responses, and this trend occurred primarily in WDR neurons. Both PGE 2 and PGF 2α produced increases in background discharges of WDR and NS neurons, although this effect was most consistently observed with WDR neurons and PGE 2. These behavioral and electrophysiological data suggest that mechanical hyperalgesia induced by spinal administration of PGE 2 and PGF 2α is mediated mainly by changes in NS neurons. The weak thermal hyperalgesia may reflect changes in WDR neurons.

Inhibition of prostaglandin G/H synthase unveils a potent effect of platelet activating factor on the permeability of bovine aortic endothelial cells to albumin.

Platelet Activating Factor (PAF) is a very potent stimulant of various cell functions but little is known about the mechanisms responsible for its marked effect on endothelial permeability. An in vitro assay system was used to assess the direct effect of PAF on the permeability of a bovine aortic endothelial cell (BAEC) monolayer to albumin. PAF produced a small but not significant increase of the permeability of BAEC monolayer to albumin. However, pre-treatment of the monolayer with indomethacin (10 microM) resulted in a significant increase of BAEC permeability following PAF administration. This increase was concentration-dependent up to a maximal effect of 105% above basal value (for 0.1 microM PAF). Addition of the PAF antagonist SRI 63 441ZI (5 microM) abolished this effect. Exogenous administration of PGE2 (10(-7) M) inhibited the effect of PAF on the BAEC permeability suggesting that prostaglandins synthesized by the endothelium behave as a negative autoregulatory factor. Compound SRI 63 441ZI also partially inhibited bradykinin-induced permeability to albumin but did not significantly modify the activity of thrombin. These findings show that PAF can increase endothelial permeability to albumin when the synthesis of prostaglandins is inhibited. Our results also show that PAF might have an autocrine activity by mediating part of BK-induced permeability.

Bone biomechanical properties in prostaglandin EP 1 and EP 2 knockout mice

Prostaglandins play an important role in regulating the bone adaptation response to mechanical stimuli. Prostaglandin E2 (PGE 2) is an effective modulator of bone metabolism. Administration of PGE 2 to rodents results in increased cancellous and cortical bone mass translating into enhanced mechanical strength. The PGE 2 influence on bone is mediated through four well-characterized receptors (EP 1, EP 2, EP 3, and EP 4). Although the PGE 2 pathways and mechanisms of action on cells involved in bone adaptation are still under investigation, it is now known that each receptor plays a unique role in regulating PGE 2-related bone cell function. The EP 1 subtype is coupled with Ca 2+ mobilization. The EP 2 subtype stimulates cyclic adenosine monophosphate (cAMP) formation. cAMP in turn is responsible for the early cellular signal that stimulates bone formation. This study compared physical and biomechanical properties of bone in EP 1 and EP 2 knockout mice to their corresponding wild-type controls. Ash weight was measured in the ulnae, and femurs and vertebral bodies were tested in three-point bending and compression, respectively. The results suggest: (a) EP 1 receptors have a minimal influence on skeletal strength or size in mice; and (b) EP 2 receptors have a major influence on the biomechanical properties of bone in mice. The absence of EP 2 receptors resulted in weak bone biomechanical strength properties in the EP 2 knockout model as compared with the corresponding wild-type control mice.

Objective Penile Vascular Response to Intraurethral Prostaglandin E2 (Dinoprostone)

Purpose: Intraurethral prostaglandin E₂ (PGE₂) administration is a noninvasive treatment modality for erectile dysfunction. The purpose of this study was to evaluate the objective effects of this agent by measuring peak systolic velocities of cavernosal arteries after intraurethral PGE₂ administration and comparing with the results obtained with an intraurethral placebo gel and intracavernous papaverine injection. Materials and Methods: The study group consisted of 22 consecutive impotent volunteers with a mean age of 46 years who had normal penile arterial responses as determined by penile arterial responses on papaverine-stimulated penile duplex ultrasonography. The peak systolic velocity in cavernosal arteries was recorded after intracavernous injection of 60 mg of papaverine. All patients received 1 mg of intraurethral PGE₂ gel and placebo at 15-day intervals. The peak systolic velocities were recorded after each treatment. Results: Mean peak systolic velocity achieved by intraurethral administration of PGE₂ gel (25 ± 8 cm/s) was less than that achieved by intracavernous papaverine (40 ± 6 cm/s) but higher than that obtained by placebo (15 ± 4 cm/s). Twelve patients had erections, while 9 had partial and 1 had no erection with intraurethral PGE₂. Placebo did not cause any erections. No serious side effects were observed. Conclusion: Intraurethral administration of PGE₂ appears to be an effective and simple method for increasing penile arterial flow and can be used during penile Doppler ultrasonography to stimulate the penile arterial system.

Effects of prostaglandin E(1) on the efficacy of xenogeneic extracorporeal pig liver perfusion in a canine model of acute liver failure.

Xenogeneic extracorporeal liver perfusion (ECLP) has the potential to become an important tool in the management of patients with severe liver failure. We previously showed that xenogeneic pig liver perfusion may be prolonged for up to 9 hours by the administration of prostaglandin E(1) (PGE(1)). In this study, we used a canine model of acute liver failure to evaluate the effects of PGE(1) on the efficacy of ECLP as a liver-assist device. Liver failure was surgically induced in 12 beagle dogs, with a control group (group 1, n = 4) not connected to the ECLP circuit. Direct cross-circulation between the dogs and the ECLP circuit using a pig liver was performed without (group 2, n = 4) or with (group 3, n = 4) continuous administration of PGE(1) through the portal vein of the pig liver. The duration of cross-circulation in group 3 (9.4 +/- 1.2 hours) was significantly longer than in group 2 (4.3 +/- 1.0 hours). In addition, elevation of blood ammonia, total bile acid, and hyaluronic acid levels was less marked in group 3 compared with the other 2 groups. The ratio of branched-chain amino acids to aromatic amino acids was also improved in group 3. The mean survival time in group 3 (26.6 +/- 0.4 hours) was significantly longer than in group 1 (15.5 +/- 1.3 hours) or group 2 (17.1 +/- 2.9 hours). Continuous administration of PGE(1) to xenogeneic ECLP resulted in a significant improvement in both liver function and survival time of dogs with surgically induced liver failure.

Effects of Tetramethylpyrazine on Prostaglandin E 2- and Prostaglandin E 2 Receptor Agonist-induced Disruption of Blood-Aqueous Barrier in Pigmented Rabbits

Purpose: To evaluate the effect of tetramethylpyrazine on the elevation of aqueous flare and intraocular pressure (IOP) induced by prostaglandin (PG) E 2 and PGE 2 receptor (EP) agonists. Methods: PGE 2 or EP agonists (11-deoxy PGE 1, EP 2 agonist; 17-phenyl trinor PGE 2, EP 1 and EP 3 agonist; or sulprostone, EP 1 and EP 3 agonist), 25 μg/mL, were transcorneally administered to pigmented rabbits. Animals were pretreated with tetramethylpyrazine intravenously (10 or 30 mg/kg) or topically (0.1% solution). Aqueous flare was measured using a laser flare-cell meter, and the intensity was expressed as the area under the curve (AUC). Intraocular pressure was measured using a noncontact tonometer. Results: After administration of PGE 2, aqueous flare and IOP increased and then gradually decreased. The AUC of eyes pretreated with tetramethylpyrazine, 10 or 30 mg/kg, intravenously, or topical 0.1% solution, was significantly smaller than that of the controls. The mean Δ IOP of eyes pretreated with tetramethylpyrazine, 30 mg/kg intravenously, was significantly lower than that of the controls. After administration of 11-deoxy PGE 1, aqueous flare increased and then gradually decreased. 17-phenyl trinor PGE 2 and sulprostone did not disrupt the blood-aqueous barrier. The AUC of eyes pretreated with tetramethylpyrazine, 10 or 30 mg/kg, intravenously, before 11-deoxy PGE 1 application was significantly smaller than that of the controls. Conclusion: The results indicated that tetramethylpyrazine inhibited PGE 2- or 11-deoxy PGE 1-induced elevation of aqueous flare and IOP.

Permissive role of neutrophils in pathogenesis of indomethacin-induced gastric lesions in rats

We examined the possible role of neutrophils in the pathogenesis of indomethacin-induced gastric lesions, in comparison with prostaglandin (PG) deficiency.Rats were given indomethacin (35 mg/kg, s.c.) and killed 4 hr later. Gastric motility, mucosal PGE2 levels, and myeloperoxidase (MPO) activity were measured following indomethacin. Atropine was given s.c. 30 min before administration of indomethacin, while 16, 16-dimethyl PGE2 (dmPGE2) or anti-rat neutrophil antiserum (ANS) was given i.v. 10 min or 1 hr, respectively, before indomethacin treatment.Indomethacin reduced PGE2 contents in the stomach and produced hemorrhagic lesions in the stomach, with an increase of gastric motility and MPO activity. Indomethacin-induced gastric lesions were significantly prevented by dmPGE2 as well as atropine, at any time points during a 4 hr-test period. By contrast, the pretreatment of ANS did not prevent the development of gastric lesions when examined at either 1, 2 or 3 hr following indomethacin, but significantly reduced the severity of these lesions at 4 hr after indomethacin treatment. Both dmPGE2 and atropine inhibited the increase of gastric motility and MPO activity in response to indomethacin, whereas ANS prevented the increase of MPO activity, without any effect on the gastric hypermotility.These results confirmed that indomethacin-induced gastric lesions occurred in association with gastric hypermotility, in both atropine and PG-sensitive manners, and further suggest that the neutrophil activation/migration is not sufficient by itself to induce damage in the stomach and may be implicated in the process of later extension of damage.

Endocrine-regulated and protein kinase C-dependent generation of superoxide by rat preovulatory follicles.

The ovulatory LH surge results in follicular inflammation with an increase in cytokines and PGs. Reactive oxygen species (ROS) are also produced during inflammatory processes. To study ROS generation during the ovulatory cascade, preovulatory follicles were dissected from immature female rats primed with PMSG. Follicles were isolated, and ROS generation was assessed by luminol-amplified chemiluminescence. Immature rat granulosa cells were also subjected to luminometry after isolation from immature rats treated with diethylstilbestrol. Phorbol ester-stimulated ROS generation by follicular cells was completely suppressed by superoxide dismutase and the NADPH/NADH oxidase inhibitor diphenylene iodonium bisulfate, whereas catalase was without effect. Fractionation of granulosa cells with an antibody against leukocyte common antigen-1 showed that leukocyte-enriched cells produced more than 95% of the superoxide measured. In vivo treatment with LH produced a 5-fold increase in phorbol-stimulated superoxide production by isolated follicles. This response was maximal within 4 h and was blocked by indomethacin. In vivo administration of PGE(2) and PGF(2alpha) did not reverse the blockade by indomethacin; however, isolated follicles incubated with PGE(2) produced a time-dependent increase in phorbol-stimulated superoxide generation. Thus, a superoxide generator is present in the preovulatory follicle that is leukocytic in origin, hormone regulated, and activated by a protein kinase C-dependent pathway. The regulated generation of superoxide by preovulatory follicles may indicate a role for ROS in the periovulatory period.

Regulation of leptin release and lipolysis by PGE 2 in rat adipose tissue

The role of eicosanoids formed by adipose tissue from rats was examined in the presence of the specific cyclooxygenase-2 inhibitor NS-398. This agent totally blocked the release of prostaglandin E 2 (PGE 2) by rat adipose tissue over a 24-h incubation in primary culture. The final concentration of PGE 2 after 24 h was 12 nM, and half-maximal inhibition of PGE 2 formation required 35 nM NS-398. While inhibition of PGE 2 formation by NS-398 had no effect on basal leptin release or lipolysis, it enhanced the lipolytic action of 10 nM isoproterenol by 36%. The in vivo administration of PGE 2 doubled serum leptin. PGE 2 also directly stimulated leptin release by rat adipose tissue incubated in the presence of 25 nM dexamethasone, which inhibited endogenous PGE 2 formation by 94%. The inhibition of lipolysis as well as the stimulation of leptin release by PGE 2 were mimicked by N 6-cyclopentyladenosine (CPA). These data indicate that exogenous PGE 2 can stimulate leptin release by adipose tissue when the basal formation of PGE 2 is blocked by dexamethasone. However, while the endogenous formation of PGE 2 does not appear to regulate basal lipolysis or leptin release, it may play a role in the activation of lipolysis by catecholamines.

Prostaglandin E(2) enhances chemical and mechanical sensitivities of pulmonary C fibers in the rat.

It has been recently reported that pulmonary reflex responses to injection or inhalation challenge of capsaicin are enhanced by exogenous Prostaglandin E(2) (PGE(2)). The present study was carried out to determine whether PGE(2) enhances the stimulatory effects of chemical stimulants and lung inflation on vagal pulmonary C fibers, and if so, whether the excitabilities of other types of lung afferents are also augmented by PGE(2). In anesthetized, open-chest rats, administration of PGE(2) (1.5 microgram/kg/min for 2 min) did not significantly change the baseline activity of vagal pulmonary C fibers, but it markedly enhanced the stimulatory effects of both low (0.25 microgram/kg) and high doses (0.5 microgram/kg) of capsaicin on these fibers. Similarly, potentiating effects of PGE(2) were found on the pulmonary C-fiber responses to injections of lactic acid and adenosine, although considerable variability existed in the degrees of potentiation between the different stimulants. Furthermore, PGE(2) infusion also significantly enhanced the C-fiber response to constant-pressure lung inflation (tracheal pressure [Pt] = 30 cm H(2)O). In contrast, PGE(2) did not alter the responses of either slowly adapting pulmonary receptors or rapidly adapting pulmonary receptors to lung inflation. In summary, these results show that the sensitivity of pulmonary C-fiber afferents to both mechanical and chemical stimuli is enhanced by PGE(2), suggesting that endogenous release of this autocoid may play a part in the airway irritation and dyspneic sensation associated with airway inflammation.

Amniotic Fluid Index and Labor Length of Pregnancies Induced Beyond 41 Weeks of Gestation with Unfavorable Cervix

We evaluated if the response to prostaglandin E₂ (PGE₂) induction, in pregnancies completing 41 gestational weeks, is correlated to amniotic fluid index (AFI) values. A follow-up was performed from the time of the induction to the time of delivery of 63 pregnancies resulting in a spontaneous delivery showing unfavorable cervical examination at 41 weeks of gestation. This was induced by means of intracervical administration of PGE₂ gel (Dinoprostone 0.5 mg). If the cervix was still unfavorable after 12 h, another gel administration followed. The number of PGE₂ administration and AFI were both used as variables to correlate the time remaining before the delivery and the probability of delivery (Kaplan-Meier and Cox algorithms). Gestational age, parity, neonatal weight, and APGAR 5′ were used as covariates. A cut-off of AFI >6 better discriminates two groups regarding the probability of delivery at paired hours from the beginning of the induction. A statistically significant difference was demonstrated in only those patients which did not deliver within 12 h (44 cases). Multivariate analysis (Cox regression) yielded an adjusted odds ratio associated to the probability of delivery of 0.47 (0.23–0.95, 95% CI, p value = 0.0354) for AFI≤6 vs. AFI >6.

Comparison of oral and intracavernosal vasoactive agents in penile erection

This discussion summarizes the potential differences in physiologically and pharmacologically induced erections and highlights the possible differences in the pathways facilitated by oral versus intracavernosal agents in penile erection. Oral agents act in conjunction with sexual stimulation either increasing corporal smooth muscle relaxation or attenuating smooth muscle contraction. However, their efficacy is dependent on sexual stimulation. Intracavernosal administration of phosphodiesterase type 5 inhibitor (sildenafil) or short-acting alpha adrenergic receptor antagonist (phentolamine), in the absence of sexual stimulation, does not initiate penile erection. In contrast, intracavernosal administration of PGE1 or papaverine induces erection independent of sexual stimulation. Thus, oral agents are not direct mediators of smooth muscle relaxation and act to facilitate relaxation in response to sexual stimulation, while intracavernosal agents directly mediate smooth muscle relaxation, independent of sexual stimulation. Although, considerable advances have been made in elucidating the physiology and pharmacology of erectile function, details of the signal transduction pathways affected by these agents in the penile corpus cavernosum are yet to be fully investigated.