Evaluation of aerosols of prostaglandins E1 and E2 as bronchodilators

Summary Aerosols of prostaglandin E₁ (PGE₁) and E₂ (PGE₂) were evaluated as bronchodilators in 32 subjects (6 normals, 15 with bronchial asthma and 11 with chronic bronchitis). PGE₂ caused a significant decrease in pulmonary resistance (mean values 3.2 and 2.6 cm H₂O/l/sec before and after inhalation, respectively). There were no significant changes in pulmonary resistance after PGE₁. Bronchoconstriction occurred in some subjects whose pulmonary resistance had been within normal limits. Static pulmonary compliance did not show any definite change. The frequency dependence of dynamic compliance was measured in 19 subjects; in 3 the results suggested that bronchoconstriction after PGE₁ preferentially affected small airways; in 1 other subject bronchodilatation occurred exclusively in the small airways. Arterial Po₂ decreased in 4 out of 5 patients after inhalation of PGE₁. This was thought to be due to greater unevenness of the ventilation perfusion ratio, since the dynamic pulmonary compliance became more dependent on respiratory frequency even though pulmonary resistance improved in these subjects. The pulse rate did not change significantly, but mean blood pressure decreased in 8 out of 15 subjects. Cough and irrtation of the pharynx were noted in 42 and 62 per cent of subjects during and after the inhalation of PGE₁ and PGe₂, respectively. Five and 23 percent of the subjects complained of headache after inhaling PGE₁ and PGE₂. The results suggest that aerosols of PGE₂ have a bronchodilating action which could be of use in clinical practice, if untoward responses such as irritation of the pharynx, cough and headache could be avoided.Presented in part on April 13, 1972 at the National Meeting of the Japanese Society of Chest Diseases, Hiroshima, Japan.     

Neuronally mediated and direct effects of prostaglandins on ion transport in rat colon descendens

Summary Two preparations of rat colon descendens were used in order to localize the action sites of iloprost and prostaglandin E₂ (PGE₂). One preparation, the mucosa-submucosa preparation contained the submucosal and mucosal plexus whereas for the mucosa preparation in addition the submucosa with the submucosal plexus was removed. Iloprost (10^–6 mol · 1^–1) caused an increase in short-circuit current (Isc), potential difference (Pd) and tissue conductance (Gt) of the mucosa-submucosa preparation reflecting net Cl^– secretion as confirmed by unidirectional ion flux measurements. The Cl^– secretion was due to an increase in J _infsm ^supCl and a decrease in J _infms ^supCl . These effects were completely abolished by addition of 5 × 10^–5 mol · l^–1 atropine. Iloprost had only small and inconsistent effects in the mucosa preparation. In contrast PGE₂ (10^–6 mol · l^–1) increased Isc, Pd and Gt due to Cl^– secretion in both preparations. The Cl^– secretion was caused by an increase in J _infsm ^supCl and a decrease in J _infms ^Cl Only the PGE₂ effect in the mucosa-submucosa preparation but not in the mucosa preparation was inhibited by about 50% by atropine. The results suggest that the prostacyclin derivative iloprost induces a Cl^– secretion only by an activation of submucosal neurons whereas PGE₂ acts both on the epithelium and the submucosal plexus. The neuronal effects of prostaglandins appear to be, at least in part, mediated by muscarinic receptors. Send offprint requests to M. Diener     

Diphlorethohydroxycarmalol,Isolated from Ishige okamurae,Increases Prostaglandin E2 through the Expression of Cyclooxygenase-1 and -2 in HaCaT Human Keratinocytes

Prostaglandin (PG) E₂, the most abundant prostaglandin in the human body, is synthesized from arachidonic acid via the actions of cyclooxygenase (COX) enzymes. PGE₂ exerts homeostatic, cytoprotective, inflammatory, and in some cases anti-inflammatory effects. Also, it has been reported that PGE₂ is involved in hair growth. Diphlorethohydroxycarmalol (DPHC) is a phlorotannin compound isolated from the brown algae Ishige okamurae, with various biological activities in vitro and in vivo. In this study, the biological effect and mechanism of action of DPHC on prostaglandin synthesis in HaCaT human keratinocytes was examined. The results showed that, in these cells, DPHC significantly and dose-dependently induced PGE₂ synthesis by increasing the protein and mRNA levels of COX-1 and COX-2. Interestingly, DPHC-induced COX-1 expression preceded that of COX-2. Also, while both rofecoxib and indomethacin inhibited PGE₂ production, the latter was seems to be the more potent. From above results, we can expect that DPHC has some beneficial effects via increasing of PGE₂ production.     

Prostanoid receptors of the EP3 subtype mediate the inhibitory effect of prostaglandin E2 on noradrenaline release in the mouse brain cortex

Mouse or rat brain cortex slices were preincubated with ³H-noradrenaline and superfused with physiological salt solution containing desipramine. We studied the effects of prostaglandin E₂ (PGE₂), prostaglandin D₂ (PGD₂) and related drugs on the electrically evoked (50 mA, 2 ms, 0.3 Hz) tritium overflow.PGE₂ inhibited the electrically evoked tritium overflow from mouse brain cortex slices; the maximum effect of PGE₂ (79010) was attenuated by the ₂-adrenoceptor agonist talipexole (to 52010) and enhanced by the ₂-adrenoceptor antagonist rauwolscine (to 92%). Rauwolscine was added to the superfusion medium in all subsequent experiments. The effect of PGE₂ was readily reversible upon withdrawal from the medium and remained constant upon prolonged exposure of the tissue to the prostanoid. Studies with EP receptor agonists, mimicking the inhibitory effect of PGE₂, showed the following potencies (pIC₅₀): sulprostone (8.22); misoprostol (8.00); PGE₂ (7.74); PGEZ (7.61); iloprost (5.86). The concentration-response curve of PGE₂ was marginally shifted to the right by the EP₁ receptor antagonist AH 6809 (6-isopropoxy-9-oxoxanthene-2-carboxylic acid; apparent pA₂ 3.97) and by the TP receptor antagonist vapiprost (4.50). AH 6809, by itself, did not affect the evoked overflow whereas vapiprost increased it. PGD2 inhibited the evoked overflow at high concentrations (pIC₅₀ 4.90); this effect was not altered by the DP receptor antagonist BW A868C (3-benzyl-5-(6-carboxyhexyl)-1-(2-cyclohexyl-2hydroxyethylamino)hydantoin), which, by itself, did not affect the evoked overflow. Indometacin slightly increased the evoked overflow and tended to increase the inhibitory effect of PGE₂. PGE₂ inhibited the electrically evoked tritium overflow also in rat brain cortex slices. The maximum effect (obtained in the presence of rauwolscine) was 61%; the pIC₃₀ value was 7.67.The present study suggests that PGE₂ inhibits noradrenaline release from mouse brain cortex via EP₃ receptors and that its maximum effect is more marked in the mouse than in the rat. The inhibitory effect of PGD₂ (in the mouse brain) does not involve DP receptors and may also be related to EP₃ receptors. The EP₃ receptors interact with a2-adrenoceptors and may be activated by endogenous prostanoids.     

Relationship between prostaglandin E2 and vascular endothelial growth factor (VEGF) in angiogenesis in human vascular endothelial cells

To address the role of prostaglandin E2 (PGE2) in tube formation of endothelial cells and the relationships between the action of PGE2 and vascular endothelial growth factor (VEGF), cultured human umbilical vein endothelial cells (HUVECs) were used to evaluate tube formation on Matrigel and the expression of angiogenesis-related genes. PGE2 treatment stimulated the tube-like formation of HUVECs. Whereas VEGF-induced tube formation was significantly suppressed by ETYA, an inhibitor of arachidonic acid metabolism, or SU5614, an inhibitor of VEGF-receptor tyrosine kinase, the stimulatory effect of PGE2 was observed in the presence of ETYA or SU5614. Thus, PGE2 counteracted both ETYA- and SU5614-induced blockage of angiogenesis in the presence of VEGF. VEGF induced cyclooxygenase (COX) -2 mRNA expression in HUVECs and increased the PGE2 concentration in the medium. PGE2 treatment enhanced the expression of VEGF mRNA. These findings suggest that PGE2 directly stimulates angiogenesis, apart from VEGF signaling, and further induces VEGF expression in HUVECs. In addition, the effect of VEGF on angiogenesis may be mediated, in part, by PGE2 secretion.     

Neuropharmacological and behavioral evaluation of prostaglandin E2 and 11-thiol-11-desoxy prostaglandin E2 in the mouse and rat

Prostaglandin E₂ (PGE₂) and 11-thiol-11-desoxy Prostaglandin E₂ (SHPGE₂) were evaluated in a variety of behavioral and neuropharmacological procedures that are sensitive to neuroleptics. Clozapine (C), thioridazine (T), haloperidol (H), and fluphenazine (F) were also tested for comparison. All agents except T suppressed avoidance responses in trained rats at one or more doses without concurrently disrupting escape behavior. T, H, and F dose-responsively antagonized lesioned rat rotational behavior at nontoxic doses. T, H, and F induced catalepsy at doses considerably higher than those effective on rotational behavior. SHPGE₂, PGE₂, and C did not cause catalepsy and did not show statistically significant dose-responsive antagonism of rotational behavior at less than toxic doses. All agents tested blocked d-amphetamine-induced lethality and caused motor incoordination doseresponsively. SHPGE₂, PGE₂, C, and T caused statistically significant blockade of physostigmine-induced lethality. H and F were ineffective against physostigmine lethality. It was concluded that SHPGE₂ and PGE₂ demonstrated, qualitatively, a spectrum of neurolepticlike properties remarkably similar to C.     

Formation of 8-isoprostaglandin F2alpha and prostaglandin E2 in carrageenan-induced air pouch model in rats

To investigate a possible role of 8-isoprostaglandin F2alpha in inflammation, 8-isoprostaglandin F2alpha and prostaglandin E2 levels were determined by enzyme immunoassay (EIA) in carrageenan-induced air pouch model in rats. In this model, 8-isoprostaglandin F2alpha and prostaglandin E2 levels were found to be increased significantly. To evaluate whether this increase was due to the development of inflammation or solely to cyclooxygenase-2 induction, a lipopolysaccharide-induced air pouch model, in which only cyclooxygenase-2 induction occurs without inflammation, was used. In this model, 8-isoprostaglandin F2alpha was also found to be increased parallel to the increase in prostaglandin E2 level. Cyclooxygenase-dependent formation of 8-isoprostaglandin F2alpha was investigated in carrageenan-induced air pouch model by administrating nonselective cyclooxygenase inhibitor indomethacin, selective cyclooxygenase-1 inhibitor valeryl salicylate or selective cyclooxygenase-2 inhibitor SC-582368 (4-(5-(4-chlorophenyl)-3-3-trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonanmide) 1 h before carrageenan injection. All these inhibitors significantly inhibited the production of 8-isoprostaglandin F2alpha and prostaglandin E2. These findings show that 8-isoprostaglandin F2alpha can be formed in carrageenan-induced air pouch model in rats. The formation of 8-isoprostaglandin F2alpha in lipopolysaccharide-induced air pouch model and the inhibition of its production by various cyclooxygenase inhibitors provide evidence for cyclooxygenase-dependent formation of isoprostanes in this model.     

Effect of strontium chloride on bone resorption induced by prostaglandin E2 in cultured bone

We examined whether the bone resorption induced by PGE₂ was inhibited by SrCl₂ using⁴⁵Ca-labelled calvaria of CD-strain mice in tissue culture. It was found that Sr salts inhibited physiological bone resorption in a dose-dependent manner (0.1–5.0 mM) and did not act via PGE₂. Accordingly, it was suggested that Sr salts did not inhibit bone resorption induced by exogenous PGE₂.Abbreviations PGE₂ Prostaglandin E₂ - PTH Parathyroid hormone - CT Calcitonin - Vit. D₃ Vitamin D₃ - HSDM₁ Harvard School of Dental Medicine 1     

The cyclooxygenase-2/prostaglandin E2 pathway is involved in the somatostatin-induced decrease of epileptiform bursting in the mouse hippocampus

The neuromodulatory peptide somatostatin-14 (SRIF) plays an important inhibitory role in epilepsy, but little is known on the signalling mechanisms coupled to this effect of SRIF. We have previously demonstrated that SRIF induces reduction of epileptiform bursting in a model of interictal-like activity in mouse hippocampal slices. In this same model, we investigated whether the cyclooxygenase 2 (COX-2)/prostaglandin E(2) (PGE(2)) pathway is part of those signalling mechanisms mediating SRIF anti-epileptic actions. Both the expression of COX-2 (mRNA and protein) and the endogenous release of PGE(2) increased in concomitance with epileptiform bursting. In particular, COX-2 protein increased in CA1/CA3 pyramidal layer and in the granular layer of the dentate gyrus. In addition, the selective inhibition of COX-2 by NS-398 markedly decreased endogenous PGE(2) release induced by epileptiform bursting and the epileptiform bursting itself. Similar effects on epileptiform bursting were obtained with another COX-2 inhibitor, i.e., meloxicam. SRIF application counteracted the increase of both COX-2 expression and PGE(2) release which occurred in concomitance with epileptiform bursting. Interestingly, SRIF and NS-398 comparably reduced epileptiform bursting in a non-additive manner and PGE(2) abolished the inhibitory effect of SRIF on epileptiform bursting. These results demonstrate that: i) the COX-2/PGE(2) pathway facilitates epileptiform bursting; and ii) SRIF exerts an anti-epileptic role by coupling to the COX-2/PGE(2) pathway. In conclusion, we have identified a key set of signalling events that underlie anti-convulsant effects of SRIF in a mouse model of hippocampal bursting, thus providing useful data not only to identify alternative intervention points for the modulation of SRIF function, but also to exploit new chemical space for drug-like molecules.     

Suppressive effects of antimycotics on tumor necrosis factor-alpha-induced CCL27, CCL2, and CCL5 production in human keratinocytes

Antimycotic agents are reported to improve cutaneous symptoms of atopic dermatitis or psoriasis vulgaris. Keratinocytes in these lesions excessively produce chemokines, CCL27, CCL2, or CCL5 which trigger inflammatory infiltrates. Tumor necrosis factor-alpha (TNF-alpha) induces production of these chemokines via activating nuclear factor-kappaB (NF-kappaB). We examined in vitro effects of antimycotics on TNF-alpha-induced CCL27, CCL2, and CCL5 production in human keratinocytes. Antimycotics ketoconazole and terbinafine hydrochloride suppressed TNF-alpha-induced CCL27, CCL2, and CCL5 secretion and mRNA expression in keratinocytes in parallel to the inhibition of NF-kappaB activity while fluconazole was ineffective. Anti-prostaglandin E2 (PGE2) antiserum or antisense oligonucleotides against PGE2 receptor EP2 or EP3 abrogated inhibitory effects of ketoconazole and terbinafine hydrochloride on TNF-alpha-induced NF-kappaB activity and CCL27, CCL2, and CCL5 production, indicating the involvement of endogenous PGE2 in the inhibitory effects. Prostaglandin H2, a precursor of PGE2 can be converted to thromboxane A2. Ketoconazole, terbinafine hydrochloride and thromboxane A2 synthase (EC 5.3.99.5) inhibitor, carboxyheptyl imidazole increased PGE2 release from keratinocytes and reduced that of thromboxane B2, a stable metabolite of thromboxane A2. Carboxyheptyl imidazole also suppressed TNF-alpha-induced NF-kappaB activity and CCL27, CCL2, and CCL5 production. These results suggest that ketoconazole and terbinafine hydrochloride may suppress TNF-alpha-induced NF-kappaB activity and CCL27, CCL2, and CCL5 production by increasing PGE2 release from keratinocytes. These antimycotics may suppress thromboxane A2 synthesis and redirect the conversion of PGH2 toward PGE2. These antimycotics may alleviate inflammatory infiltration in atopic dermatitis or psoriasis vulgaris by suppressing chemokine production.     

Prostaglandin E2 differentiates between two forms of glucose transport inhibition by lipolytic agents

Summary The inhibition of insulin-stimulated glucose transport by lipolytic agents was studied in isolated rat adipose cells. Two different mechanisms for the inhibition of glucose transport by lipolytic hormones and agents were distinguished by use of the antilipolytic agent prostaglandin E₂ (PGE₂). The inhibition of glucose transport induced by lipolytic hormones such as glucagon, catecholamines or ACTH in the presence of adenosine deaminase was antagonized by PGE₂. In contrast, inhibition of hexose transport by alkylxanthines was only partially (20–30%) attenuated by PGE₂, although the eicosanoid had antagonized cyclic AMP accumulation and stimulation of lipolysis in response to all tested lipolytic agents. The inhibition of glucose transport by IBMX was immediate, whereas the lipolytic hormones (isoprenaline and ACTH) exhibited a latency of 2–3 min. In addition, the inhibition induced by the lypolytic hormones disappeared after cooling of the cells to 22°C, at which temperature IBMX was still inhibitory. Thus, the PGE₂-sensitive component of the effect of lipolytic agents on glucose transport appears to be mediated by adenylate cyclase or its subunits N _s/N _i. The PGE₂-insensitive effect of alkylxanthines probably reflects a direct interaction of the agents with a regulatory site at the transporter or a related protein. Send offprint requests to H. J. Steinfelder at the above address     

Effect of a synthetic prostaglandin E2 analogue,RS-86505-007, on plasma lipids and lipoproteins in patients with moderate hypercholesterolaemia: efficacy and tolerance of treatment and response in different apolipoprotein polymorphism groups

A double-blind, placebo-controlled ascending dose trial was carried out to evaluate the hypocholesterolaemic efficacy and tolerance of RS-86505-007, a prostaglandin E₂ analogue, in moderately hypercholesterolaemic patients. Twenty-four patients received an oral dose of RS-86505-007 3 g t.i.d. and a separate group of 26 patients 6 g t.i.d. for 6 weeks. Plasma total and low-density lipoprotein (LDL) cholesterol concentrations decreased after 2 weeks of treatment, and the reductions were dose dependent. After 6 weeks of treatment (6 g t.i.d.), the reductions from baseline in total and LDL cholesterol concentration were 14.6% and 18.5%, respectively. No changes in the plasma concentration of triglycerides or high-density lipoprotein (HDL) cholesterol were observed. RS-86505-007 tended to reduce total and LDL cholesterol concentrations less in patients with the 4 allele of the apolipoprotein E than in those with 3 allele. In contrast, the XbaI or EcoRI polymorphisms of the apolipoprotein B gene seemed to have no effect on the hypocholesterolaemic efficacy of the drug. The drug had no effect on the lipoprotein (a) concentration. Sixty-three per cent of patients receiving 3 g t.i.d. and 81% receiving 6 g t.i.d. had adverse events, two-thirds of which related to the gastrointestinal tract. One patient in the 3-g group and three patients in the 6-g group terminated the study prematurely due to adverse effects. In conclusion, a prostaglandin E₂ analogue, RS-86505-007, has a potent cholesterol-lowering effect, but its grastrointestinal adverse effects are marked. RS-86505-007 could, however, be used as a tool in mechanistic studies of cholesterol metabolism.     

The effect of acteoside on histamine release and arachidonic acid release in RBL-2H3 mast cells

The effect of acteoside, a phenylpropanoid glycoside isolated from Clerodendron trichotomum Thunberg, on histamine and arachidonic acid release was investigated in RBL 2H3 cells. Histamine was dose-dependently released from RBL 2H3 cells by melittin, arachidonic acid and thapsigargin. In extracellular Ca2+-free solution, basal secretion of histamine increased by two fold. The response of histamine release to melittin and thapsigargin in Ca2+-free solution was significantly decreased, whereas the response to arachidonic acid was significantly increased as compared with those in normal solution. Acteoside inhibited histamine release induced by melittin, arachidonic acid and thapsigargin in a dose-dependent manner in the presence or absence of extracellular Ca2+. However, the inhibitory activity of acteoside was more potent in normal solution than that in Ca2+-free solution. These data suggest that inhibitory mechanism of acteoside on histamine release may be related to extracellular Ca2+. On the other hand, acteoside significantly inhibited arachidonic acid release and prostaglandin E2 production induced by 0.5 microM melittin. It is possible that acteoside may be developed as an anti-inflammatory agent.     

Decreased antinociceptive effect of morphine in rats treated intraventricularly with prostaglandin E1

The administration of prostaglandin E₁ intracerebrally through a cannula implanted in a lateral ventricle, antagonizes morphine analgesia in rats.An electrical stimulation technique was adopted on the rat's tail to measure the antinociceptive activity of morphine. Some hypotheses are advanced in order to explain the sensitizing activity of prostaglandin E₁.     

Inhibitory effects of azelastine on substance P-induced itch-associated response in mice

The anti-pruritic mechanisms of azelastine were studied in mice. Scratching induced by intradermal histamine was inhibited by azelastine (30 mg/kg) and chlorpheniramine (30 mg/kg). Substance P-induced scratching was dose dependently suppressed by azelastine (3-30 mg/kg), but not by chlorpheniramine (10 and 30 mg/kg). Azelastine (30 mg/kg) inhibited the substance P-induced production of leukotriene B4, but not prostaglandin E2, in the skin. Azelastine (3-30 mg/kg) suppressed scratching induced by intradermal injection of leukotriene B4. The results suggest that inhibition of the production and action of leukotriene B4, as well as an anti-histamine action, is involved in the anti-pruritic action of azelastine.     

Roles of cyclooxygenase-2 and prostaglandin E receptors in gastric mucosal defense in <Emphasis Type="Italic">Helicobacter pylori</Emphasis>-infected mice

Background/Aim: Helicobacter pylori (H. pylori) induces cyclooxygenase-2 (COX-2) expression. The aim of this study was to assess the roles of COX-2 and PGE₂ receptors (EPs) in gastric defense in H. pylori-infected mice. Methods: Gastric lesions were induced by oral administration of 0.15 N HCl in 60 % ethanol (HCl/EtOH) to mice infected with H. pylori, and macroscopically evaluated 30 min later. Mice were administered NS-398 (COX-2 selective inhibitor) concomitantly with selective EP agonists 4 hours before HCl/EtOH challenge. Results: H. pylori infection prevented the gastric damage induced by HCl/EtOH, and this protective effect was abolished by NS-398. Selective agonists of EP1, EP2, and EP4, but not the EP3 agonist, reversed the inhibitory effect of NS-398 on prevention of damage by H. pylori infection. The EP4 agonist and EP2/EP4 agonists inhibited the increase in TNF-α mRNA expression and neutrophilic infiltration caused by NS-398, respectively. Conclusion: COX-2-derived PGE₂ may play an important role in resistance to HCl/EtOH damage in H. pylori-infected mice by activating EP1, EP2, and EP4. Received 1 August 2006; accepted 21 August 2006     

The immunosuppressive effects of nicotine during human mixed lymphocyte reaction

Cell-to-cell interaction through binding intercellular adhesion molecule (ICAM)-1, B7.1, B7.2 and CD40 on monocytes and their ligands on T-cells plays roles in cytokine production and T-cell proliferation. Interleukin (IL)-18, which is elevated in the plasma during acute rejection after organ transplantation, induces the expression of ICAM-1, B7.1, B7.2 and CD40, production of interferon (IFN)-γ and IL-12 and proliferation of lymphocytes during human mixed lymphocyte reaction. Nicotine is known to inhibit the production of pro-inflammatory cytokines from macrophages through the stimulation of nicotinic acetylcholine receptor α7 subunit. In the present study, we examined the effect of increasing concentrations ranging from 0.1 to 100 μM of nicotine on the expression of ICAM-1, B7.1, B7.2 and CD40, production of IFN-γ and IL-12 and proliferation of lymphocytes during mixed lymphocyte reaction treated with IL-18 at 100 ng/ml for 48 h. Nicotine inhibited the expression of adhesion molecules, cytokine production and lymphocyte proliferation. The IC50 values of nicotine for inhibition of the IL-18-enhanced ICAM-1 expression, IFN-γ production and proliferation were 1, 1 and 2 μM, respectively. A non-selective and a selective antagonist for nicotinic acetylcholine receptor α7 subunit, mecamylamine and α-bungarotoxin abolished the effects of nicotine. The actions of nicotine might depend on stimulation of nicotinic acetylcholine receptor α7 subunit. Nicotine induced prostaglandin E₂ production during mixed lymphocyte reaction. The inhibitors of cyclooxygenase (COX)-2 and protein kinase A (PKA) at 100 μM inhibited the actions of nicotine, suggesting that the endogenous prostaglandin E₂ might be, at least, partially involved the actions of nicotine.     

A phospholipase A2 from Bothrops asper snake venom activates neutrophils in culture: Expression of cyclooxygenase-2 and PGE2 biosynthesis

In this study, the production of prostaglandin E₂ (PGE₂) and up-regulation in cyclooxygenase (COX) pathway induced by a phospholipase A₂ (PLA₂), myotoxin-III (MT-III), purified from Bothrops asper snake venom, in isolated neutrophils were investigated. The arachidonic acid (AA) production and the participation of intracellular PLA₂s (cytosolic PLA₂ and Ca²⁺-independent PLA₂) in these events were also evaluated. MT-III induced COX-2, but not COX-1 gene and protein expression in neutrophils and increased PGE₂ levels. Pretreatment of neutrophils with COX-2 and COX-1 inhibitors reduced PGE₂ production induced by MT-III. Arachidonyl trifluoromethyl ketone (AACOCF₃), an intracellular PLA₂ inhibitor, but not bromoenol lactone (BEL), an iPLA₂ inhibitor, suppressed the MT-III-induced AA and PGE₂ release. In conclusion, MT-III directly stimulates neutrophils inducing COX-2 mRNA and protein expression followed by production of PGE₂. COX-2 isoform is preeminent over COX-1 for production of PGE₂ stimulated by MT-III. PGE₂ and AA release by MT-III probably is related to cPLA₂ activation.     

Sensitization of the smooth muscle by prostaglandin E1 contributes to reversal of drug-induced inhibition of the guinea-pig ileum

Summary Prostaglandin (PG)E₁ reverses drug-induced inhibition of the electrically stimulated guineapig ileum. The effect of PGE₁ is in part related to a sensitizing action on the smooth muscle and in part to an increased acetylcholine release from the myenteric plexus.