Inhibited Prostaglandin Release Research Articles

Intracameral Use of Nepafenac: Safety and Efficacy Study

ABSTRACTPurpose: To test the intracameral safety of nepafenac and its efficacy in inhibiting prostaglandin synthesis during phacoemulsification surgery.Methods: The safety evaluation was conducted in normal eyes of rabbits, 0.1ml of 0.3% and 1% nepafenac was injected intracamerally. Extensive studies to detect adverse response ranged from a gross examination of eyes under slit lamp biomicroscope, fluorescein dye test, Schirmer tear test, test for corneal sensitivity, intraocular pressure measurement (IOP), specular microscopy, electroretinography(ERG), and histopathological examination of intraocular tissues. Efficacy of nepafenac was studied by intracameral injection of 0.1%, 0.3% nepafenac, nepafenac 0.3%+1% lignocaine, and 1% lignocaine alone, before phacoemulsification surgery and intraoperative mydriasis along with PGE2(ProstaglandinE2) secretion were recorded.Results: Single 0.1ml of 0.3% or 1% nepafenac did not significantly (p > 0.05) alter physiological parameters and histology of cornea, iris, and retina. Nepafenac 0.3% effectively inhibited PGE2 secretion. No significant (p > 0.05) prevention of miosis was recorded with 0.1% or 0.3% nepafenac. However, a combination of 0.3% nepafenac + 1% lignocaine and 1% lignocaine alone significantly (p < 0.05) arrested miosis during the intraoperative period.Conclusion: An intracameral concentration of up to 1% nepafenac does not adversely affect the rabbit eye. Nepafenac fails to prevent miosis but inhibits prostaglandin release during phacoemulsification surgery.

NSAID Pretreatment Inhibits Prostaglandin Release in Femtosecond Laser-Assisted Cataract Surgery.

To investigate whether short-term nonsteroidal anti-inflammatory drug (NSAID) pretreatment on the day of surgery inhibits prostaglandin release. Previous studies detected elevated prostaglandin levels after femtosecond laser treatment and identified them as a potential mediator for laser-induced miosis. Patients underwent either image-guided femtosecond laser cataract surgery or conventional cataract surgery (n = 75). Half of the eyes per group received topical NSAID treatment on the day of surgery. Aqueous humor was collected from all patients. ELISA measurements were performed to detect aqueous humor prostaglandin levels. Femtosecond laser cataract surgery led to higher prostaglandin levels than conventional cataract surgery (P = .007). In both groups, NSAID pretreatment led to reduced prostaglandin release. In the femtosecond laser group, patients pretreated with NSAIDs had significantly lower prostaglandin values (65.3 ± 13.2 pg/mL) than patients not pretreated with NSAIDs (294.4 ± 66.5 pg/mL) (P = .0009). The short-term NSAID treatment prevented prostaglandin release in patients treated with image-guided femtosecond laser. Therefore, it has potential to limit intraoperative laser-induced miosis.

Celecoxib inhibits ureteral contractility and prostanoid release

To evaluate the efficacy and potency of clinically available celecoxib for inhibition of ureteral contractility and prostanoid release. We have previously reported that the selective cyclooxygenase (COX)-2 inhibitor NS-398 inhibits ureteral contractility. We evaluated the release of prostaglandin (PG) E2, F2alpha, D2, thromboxane B2 (a thromboxane2 metabolite), and 6-keto-PGF1alpha (a prostacyclin metabolite) by gas chromatography-mass spectrometry from porcine ureters in the presence and absence of tumor necrosis factor-alpha (TNF-alpha), a putative cyclooxygenase (COX)-2 inducer. PGE2 and PGF2alpha were the prostanoids released in greatest quantity in response to TNF-alpha. We subsequently measured spontaneous contractility and prostanoid release in porcine ureters treated with 0.1, 1.0, or 10 microM concentrations of indomethacin (nonselective COX inhibitor), NS-398, celecoxib, or 0.1% dimethyl sulfoxide (vehicle) for 2 hours. Ureteral contractility and prostanoid release were measured every 15 minutes after the addition of the various compounds. We also treated ureters with 10 ng/mL TNF-alpha and all three COX inhibitors or dimethyl sulfoxide for 2 and 4 hours and measured the PGE2 and PGF2alpha release. Celecoxib, indomethacin, and NS-398 inhibited ureteral contractility and prostanoid release with similar efficacy and potency. All three compounds also reduced TNF-alpha-induced prostanoid release to control levels at concentrations as low as 0.1 microM. Our data have indicated that celecoxib and indomethacin inhibit PG release by the ureter to a similar degree, even in the presence of COX-2 induction. Animal experiments and clinical trials evaluating the safety and efficacy of celecoxib for the treatment of symptomatic ureteral obstruction are warranted.

Antiphospholipid antibodies inhibit prostaglandin release by decidual cells of early pregnancy: possible involvement of extracellular secretory phospholipase A 2

Objective: To investigate the effect of antiphospholipid antibodies on eicosanoid production by human decidual cells and the in vitro interaction between antiphospholipid antibodies and secretory phospholipase A 2. Design: Cultures of human decidual cells from early pregnancy. Setting: All decidual specimens were obtained from the Obstetrics and Gynecology Department of the Catholic University, Rome, Italy. Patient(s): Patients were undergoing operative laparoscopy for extrauterine pregnancy, with a period of amenorrhea ranging from 6 to 9 weeks. Intervention(s): Decidual samples were collected at laparoscopy by routine uterine curettage. Main Outcome Measure(s): Decidual cells were incubated with antiphospholipid antibodies, and eicosanoids (prostaglandin [PG] E 2, PGF 2α, and thromboxane B 2) were assayed by RIA after 24 hours of culture. In vitro interactions between antiphospholipid antibodies and secretory phospholipase A 2 were investigated with use of a modified ELISA for phospholipase A 2. Result(s): Antiphospholipid antibodies reduced eicosanoid release from decidual cells in a dose-dependent fashion. In vitro assays showed that antiphospholipid antibodies bound secretory phospholipase A 2 and that a competition occurred between antiphospholipid antibodies and secretory phospholipase A 2 for the common substrate cardiolipin. Conclusion(s): In light of the critical role played by eicosanoids in decidual function, we suggest that an interaction between antiphospholipid antibodies and secretory phospholipase A 2 occurring in vivo might impair important cellular communications at the decidual level in the antiphospholipid antibody syndrome.

Bradykinin-evoked sensitization of neuropeptide release from afferent neurons in the guinea-pig lung.

1. It has been shown that bradykinin (BK) causes sensitization of airway sensory neurons and an enhancement of the cough reflex in guinea-pigs. In the present study, the guinea-pig isolated perfused lung was used to investigate the possible enhancement by BK of histamine-evoked neuropeptide release from peripheral terminals of primary afferent neurons, and to determine the contribution of cyclooxygenase products of arachidonate metabolism to this effect. 2. The lung was perfused with oxygenated physiological salt solution containing peptidase inhibitors (thiorphan, bestatin and captopril, 1 microM each). BK and histamine were added to the perfusate for 10 and 5 min, respectively. 3. BK alone (0.1 microM) evoked the release of 10.35+/-2.4 fmol immunoreactive calcitonin gene-related peptide (CGRP), histamine alone (100 microM) evoked the release of 12.7+/-1.6 fmol CGRP. Stimulation with 100 microM histamine in the presence of 0.1 microM BK (added 5 min before histamine and present during histamine) evoked the release of 67.1+/-5.3 fmol CGRP. 4. Prostaglandin (PG) release was stimulated by BK (418+/-71 pmol 15-keto-13,14-dihydro-PGF2alpha and 345+/-59 pmol 6-keto-PGF1alpha), and, to a lesser extent, by histamine (36.1+/-7.4 pmol 15-keto-13,14-dihydro-PGF2alpha, and 24.6+/-3.9 pmol 6-keto-PGF1alpha). Prostaglandin release induced by histamine in the presence of BK was not significantly higher than with BK alone. 5. Indomethacin (5 microM) as well as the bradykinin B2 receptor antagonist HOE140 (icatibant, 1 microM) inhibited prostaglandin release following stimulation with histamine in combination with BK. CGRP release evoked by histamine in combination with BK was attenuated by indomethacin and HOE140 to 22.1+/-7.8 fmol and 16.4+/-3.8 fmol, respectively, significantly less than the value obtained in control experiments (67.1+/-5.3 fmol). 6. The results suggest that BK-induced stimulation of prostaglandin synthesis results in facilitation of histamine-evoked release of pro-inflammatory neuropeptides from afferent neurons, a mechanism that probably becomes relevant during inflammation, and that can be blocked by a bradykinin B2 receptor antagonist.

Prostaglandin and tumor necrosis factor secretion by peritoneal macrophages isolated from normal and arthritic rats treated with liposomal methotrexate

The effect of a novel liposomal preparation containing a phospholipid conjugate of methotrexate (MTX-LIPO) upon macrophage mediator release was investigated in normal and arthritic rats ex vivo. Peritoneal macrophages isolated from MTX-LIPO-treated arthritic rats and stimulated with lipopolysaccharide produced significantly less tumor necrosis factor (TNF) and prostaglandin (PGE 2) than did macrophages isolated from saline-treated controls. In the same experimental system, free methotrexate only inhibited prostaglandin release, but it was more potent than MTX-LIPO in this respect. Additional studies are presently underway to investigate the effect of MTX-LIPO and MTX treatment upon the lipopolysaccharideinduced rise in plasma levels of various proinflammatory mediators in vivo. Haematopoietic toxicity was demonstrated in blood isolated from rats treated with free MTX, and this was as characterized by a significant reduction in reticulocyte count compared with MTX-LIPO and saline-treated rats.

Enhanced prostaglandin synthesis after ultraviolet injury is mediated by endogenous histamine stimulation. A mechanism for irradiation erythema.

Acute ultraviolet light B (UVB) injury is associated with dermal mast cell histamine release. The possibility that histamine-stimulated prostaglandin (PG) synthesis could be a mechanism for irradiation erythema was therefore examined using human skin explants. Explants responded to UV irradiation (120 mJ/cm2) with a fivefold increase in synthesis of prostaglandins E2, F2 alpha and 6-keto PGF1 alpha. Incubating explants with the H1 antihistamines brompheniramine (50 microM) or pyrilamine (30 microM) inhibited PG release from irradiated explants 63 +/- 4.9% (mean +/- SEM) 6 h after UV exposure. Antihistamines did not affect PG synthesis in control explants. Irradiation increased the histamine concentration in explant conditioned medium only 50% over basal values, suggesting that irradiation enhanced histamine responsiveness. Explants were therefore incubated with exogenous histamine. In irradiated explants, PG synthesis was stimulated threefold by 3 microM histamine. Unirradiated explants' PG synthesis was unaffected by histamine. Enhanced histamine sensitivity was also examined in epidermal cell cultures. In irradiated cultures, histamine sensitivity was again markedly potentiated: as little as 1 microM histamine stimulated significant PGE2 release and the response to 10-30 microM histamine was increased six to eight times compared with that of unirradiated cultures. These studies demonstrate that endogenous histamine stimulates PG synthesis in human skin after UV injury by potentiation of histamine-induced prostaglandin release. Potentiated agonist responses induced by UV exposure may contribute to the effects of UVB irradiation injury and in particular to irradiation erythema.

The Effect of Toxoplasma gondii Infection in Flunixin Meglumine Treated Pregnant Ewes as Monitored by Plasma Levels of 15‐Ketodihydroprostaglandin F2α, Progesterone, Oestrone Sulphate and Ultrasound Scanning

The aim of this study was to examine the endocrinological response (15-ketodihydro-PGF2 alpha, progesterone and oestrone sulphate) of pregnant ewes which were constantly treated with flunixin meglumine (FM) after infection with Toxoplasma gondii. Seven Swedish Peltsheep ewes were dosed orally with 2,000 T. gondii oocysts at 90.5 (82-94) days of pregnancy. The ewes were treated with FM, 1 mg/kg, intramuscularly twice a day, starting one day before infection until the end of the gestation period. Further three ewes were treated with FM alone during the corresponding time of pregnancy. Another four ewes were used as uninfected and untreated controls. All infected ewes developed antibodies to T. gondii and aborted, but the FM treated control group and the non-treated control group, which remained seronegative, delivered the lambs in the normal gestation range. No early abortions (less than 10 days after infection) were seen in the infected group. The endocrinological changes reflected the pathological changes in the uterus and foetuses. FM could neither completely inhibit prostaglandin release during abortion nor the physiological change of the hormone before parturition even though it depressed prostaglandin release before abortion or parturition and eliminated fever. The infectious process caused by the organism was probably not affected. FM treatment alone had no observed negative effects on pregnant ewes and their foetuses.

PGE 2 and PGF 2α in the nasal lavage fluid from healthy subjects: Methodological aspects

Prostaglandins E 2 and F 2α were estimated in nasal secretions from ten healthy volunteers by high performance liquid chromatography and radioimmunological assay. Prostaglandin concentrations determined in five consecutive nasal washes with saline at room temperature showed that the nasal mucosa was stimulated after instillation. A substantial increase of basal levels was associated with the second nasal lavage. In all volunteers aspirin treatment inhibited prostaglandin release.

Reduction in coronary vasodilator reserve following coronary occlusion and reperfusion in anesthetized dog: Role of endothelium-derived relaxing factor, myocardial neutrophil infiltration and prostaglandins

To examine the effects of acute myocardial ischemia and reperfusion on regional coronary vasodilator (or flow) reserve, peak reactive hyperemic blood flow following a 10 s occlusion was obtained in dogs subjected to circumflex (Cx) coronary artery occlusion for 1 h followed by reperfusion for 1 h. Acute myocardial ischemia resulting from Cx artery occlusion-reperfusion caused an attenuation in peak reactive hyperemic Cx flow (mean +/- S.E., from 215 +/- 29% to 87 +/- 17%, P less than or equal to 0.001). Acetylcholine-induced increase in Cx flow was also significantly (P less than or equal to 0.01) attenuated following Cx occlusion-reperfusion. These alterations were not observed in the left anterior descending (LAD) coronary artery, which was not subjected to occlusion. Pre-treatment of four dogs with indomethacin inhibited prostaglandin release (P less than or equal to 0.01), but did not affect peak reactive hyperemic coronary flow or acetylcholine-induced increase in coronary flow before or after occlusion-reperfusion. Histopathology revealed extensive myocardial neutrophil infiltration in the Cx-supplied region compared to the LAD-supplied region. Myocardial myeloperoxidase activity, an index of neutrophil infiltration, was also increased in the Cx compared to the LAD region (P less than or equal to 0.02). Myocardial neutrophil accumulation and myeloperoxidase activity were similar in the control and indomethacin-treated animals. These observations suggest that acute myocardial ischemia resulting from coronary artery occlusion-reperfusion impairs coronary vasodilator reserve in anesthetized dogs. This impairment, which was not modified by prostaglandin inhibition, may be related to the loss of endothelium-derived relaxing factor and/or decreased microvascular cross-sectional area resulting from capillary plugging by neutrophils.

Antipyretic analgesics inhibit prostaglandin release from astrocytes and macrophages similarly

The effect of acid and non-acid antipyretic analgesics on prostaglandin (PG) release from cultured mouse astrocytes and peritoneal macrophages was investigated in order to test the hypothesis that the non-acid compounds are more potent inhibitors of PG formation in brain than in peripheral tissues. Stimulation of the cells by the divalent cation ionophore A 23187 (10 −6 mol/1) induced PG release from astrocytes and macrophages (mainly PGD 2 and PGE 2, respectively). This PG release was inhibited by acetylsalicylic acid (10 −5 – 10 −6 mol/1) and indomethacin (10 −6 – 10 −9 mol/1) but also by high concentrations (10 −3 – 10 −5 mol/1) of the non-acid compounds 4-methyl-aminophenazone, the main active metabolite of dipyrone (metamizol), and acetaminophen (paracetamol). No difference was found in the inhibitory potency of the drugs in astrocytes and macrophages, suggesting that a specific sensitivity of brain cells toward non-acid antipyretic analgesics does not contribute to their analgesic effect.

Dexamethasone inhibits prostaglandin release from rabbit coronary microvessel endothelium

The effects of dexamethasone on prostaglandin secretion by cultivated rabbit coronary microvascular endothelial (RCME) cells were investigated. Incubation of RCME cells with dexamethasone resulted in a time- and concentration-dependent decrease in prostaglandin accumulation in the culture media and reduced basal and A23187-stimulated prostaglandin (PG) E2 and 6-keto-PGF1 alpha release. The maximal effects of dexamethasone (50-80% inhibition) were achieved after 16-18 h of incubation with the steroid at a final concentration of 10(-7) M. The effects of dexamethasone treatment were partially reversed 24 h after removal of the steroid from the culture media. Dexamethasone treatment did not reduce arachidonic acid-stimulated prostaglandin synthesis, indicating that the level of inhibition was proximal to that of cyclooxygenase. The inhibitory effects of dexamethasone could be prevented by pretreatment of the RCME cells with actinomycin D or cycloheximide, suggesting a requirement for protein synthesis in the inhibitory action of dexamethasone. Conditioned media from dexamethasone-treated cells contained a factor that inhibited porcine pancreatic phospholipase A2 (PLA2) in vitro. Transfer of conditioned media from dexamethasone-treated cells to untreated cells did not reduce basal or stimulated prostaglandin release; in contrast, a stimulatory action was consistently observed. Adherence of rabbit peripheral polymorphonuclear leukocytes (PMN) to RCME cells was reduced when the leukocytes were pretreated with 10(-7) M dexamethasone (4 h). However, dexamethasone pretreatment of the RCME cells did not significantly effect granulocyte adhesion. Thus coronary microvascular endothelial cell prostaglandin production is regulated by glucocorticoids, and glucocorticoid-pretreated microvascular endothelial cell release an inhibitor of PLA2 activity into the culture media.(ABSTRACT TRUNCATED AT 250 WORDS)

Failure of anti-inflammatory steroids to inhibit prostaglandin release from the hydronephrotic rabbit kidney.

The release of prostaglandins E2, F2 alpha, I2 and thromboxane A2 from isolated perfused normal and hydronephrotic rabbit kidneys was investigated by extraction and radioimmunoassay. In both types of kidneys, basal PG efflux increased with time and was not altered by co-perfusion with dexamethasone or hydrocortisone. Several vasoactive substances at 1 to 4 micrograms (e.g., bradykinin, angiotensin II, substance P, noradrenaline and vasopressin) caused release of additional amounts of prostaglandins. PGE2 and 6-keto PGF1 alpha were the major prostanoids detected, but substantial amounts of PGF2 alpha were also found. Thromboxane A2 was not released from normal kidneys. In hydronephrotic kidneys there was greatly augmented release of prostaglandins E2 and I2, some increases in PGF2 alpha, and the appearance of substantial amounts of thromboxane A2 (measured as immunoreactive TXB2) when the kidneys were challenged with angiotensin, bradykinin and vasopressin, and smaller augmentation of the response to noradrenaline and substance P. There was no evidence that these evoked increases in renal PG output could be inhibited by dexamethasone or hydrocortisone. Some explanations for the failure of steroids to alter prostanoid metabolism from arachidonate in rabbit kidney are discussed, and it is proposed that there are clear exceptions to the concept that steroids inhibit prostaglandin generation in intact tissues.

Prostaglandins and Estradiol-induced Attenuation of Hypoxic Pulmonary Vasoconstriction

Pretreatment with estradiol (20 mg IM) attenuated vasoreactivity to decreases in inspired PIO2, lowered baseline resistance measured under conditions of maximal vasodilation (PIO2 = 0 mm Hg), and appeared to increase prostaglandin release in isolated, blood-perfused lungs of juvenile female sheep. Indomethacin (40 micrograms/ml) inhibited prostaglandin release and restored hypoxic vasoreactivity in estrogen-treated lungs, but did not alter the estrogen-induced decrease in baseline resistance. These results suggest that estradiol enhanced the production of prostaglandins which secondarily attenuated hypoxic vasoreactivity. The estradiol-induced decrease in baseline resistance, however, must have been mediated by some other mechanism.

Pharmacological control of leukotriene and prostaglandin production from mouse peritoneal macrophages.

Leukotriene and prostaglandin production by mouse peritoneal macrophages was investigated. It could be shown that the tumour promoter 12-O-tetradecanoylphorbol-13-acetate initiated the release of prostaglandin E2 but had little effect on the release of leukotriene C4-like immunoreactivity. The divalent cation ionophore A 23187 at concentrations between 10(-6) and 10(-8) mol/l initiated prostaglandin as well as leukotriene release. This prostaglandin and leukotriene release could be modulated by drugs. Non-steroidal anti-inflammatory drugs including benoxaprofen inhibited prostaglandin release but simultaneously enhanced leukotriene production. The analgesics paracetamol and 4-methylaminoantipyrine had similar effects at high concentrations. The experimental compound BW 755 c inhibited prostaglandin and leukotriene production while the antithrombotic compound nafazatrom inhibited the production of leukotriene C4-like immunoreactivity but enhanced prostaglandin E2 production. Nordihydroguaiaretic acid inhibited prostaglandin and leukotriene production. The results show that the metabolism of arachidonic acid in macrophages via the cyclooxygenase or the lipoxygenase pathway is dependent on the stimulus applied. Both pathways can be inhibited conjointly or selectively by drugs. Our results do not provide evidence that differences in anti-inflammatory activity claimed for some of the drugs tested can be explained by differential inhibition of either pathway. The experimental system described may be used for assessing the potency of drugs to inhibit the lipoxygenase and the cyclooxygenase pathway of arachidonic acid metabolism.

Prostaglandin biosynthesis does not participate in isoproterenol-induced renin release

Rat renal slices were incubated in two different media. One was a normal K. physiological saline solution and the other a high K medium. Renin release was measured every 15 min in the presence and absence of 10 −6M isoproterenol and also in the presence and absence of aspirin, 0.8 or 1.6 ×10 −5M. In all experiments renin release was linear during the 75 min of incubation. Isoproterenol increased renin release by approximately 100%. This was the case even in the presence of aspirin which significantly inhibited prostaglandin release (PGE 2, PGF 2 α and 6-keto-PGF 1 α). Nor was there any reduction in the basal secretory rate by aspirin alone. These data are taken to indicate that aspirin in pharmacological doses does not interfere with either in vitro basal release rates of renin, nor the response to B agonists. It is also suggested that B agonists do not exert their effect by stimulating prostaglandin secretion.

Sterols, fatty acids and free amino acids from two Helvella species

Sterols, fatty acids and free amino acids of Helvella crispa and H. monachella were investigated. They contained traces of ergosterol and a high amount of ergosta 5.22-dien-3β-ol. Linoleic acid and l-Dopa are the most abundant fatty acid and free amino acid, respectively. The aqueous extract of H. monachella inhibits prostaglandin release by rat peritoneal leucocyres in vitro.

The release of prostaglandin E2 from the skin of the plaice, Pleuronectes platessa L.

1 A fungal extract which produces a cutaneous hypersensitivity reaction in the plaice, Pleuronectes platessa L., was incubated in vitro with the skin of this teleost fish. Samples of incubation media were assayed for smooth muscle stimulating activity. 2 Prostaglandin E2 was identified by bioassay, thin-layer chromatography, ultraviolet absorption spectroscopy and gas chromatography--mass spectrometry. Release from challenged skin was maximum after 60 min incubation. 3 Analysis of the fatty acid composition of plaice skin showed that although arachidonic acid was present (3% of total fatty acids), the precursor of prostaglandin E3, eicosapentaenoic acid contributed 9% of total. 4 Indomethacin (50 mg/kg i.p) did not inhibit the erythema induced by the fungal extract, whilst a dose of 1 mg/kg maximally inhibited prostaglandin release from skin on incubation in vitro. 5 It is concluded that prostaglandins do not have an exclusive role in the mediation of the hypersensitivity reaction.

Ditazole and platelets. II. Effect of ditazole on in vivo platelet aggregation and bleeding time in rats.

Ditazole (4,5-diphenyl-2-bis-(2-hydroxyethyl)-aminoxazol) is a new drug shown to inhibit prostaglandin release from rat platelets. The present study indicates that ditazole, at doses similar to those inhibiting prostaglandin formation in rat, inhibits in vivo collagen--but not ADP-induced rat platelet aggregation. In addition, ditazole does not prolong the bleeding time in rats, but even tends to shorten it. This effect could be due to the inhibition of prostaglandin formation at the side of the vascular injury produced to induce bleeding.

Angiotensin II-induced contractions of rabbit splenic capsular strips and release of prostaglandins. Use of radioimmunoassays for prostaglandins E1 and E2.

Rabbit splenic capsular strips contract in response to angiotensin II and simultaneously release prostaglandins E and F into the bath fluid. Contractions, though not sustained, and prostaglandin release are dependent on the concentrations of angiotensin II. Addition of indometacin to the bath fluid inhibits prostaglandin release and potentiates the angiotensin II-induced contractions. Similarly, 5,8,11,14-eicosatetraynoic acid, another blocker of prostaglandin synthesis, potentiates contractions elicited by angiotensin II. Exogenous prostaglandin E1 (300 ng/ml) tends to decrease angiotensin II-induced contractions, while prostaglandin E2 (300 ng/ml) as well as prostaglandin F2alpha (300 ng/ml) significantly increase the contractions produced by angiotensin II. The prostaglandin endoperoxide analogues (15S)-hydroxy-9alpha,11alpha-(epoxymethano)prosta-5Z,13 E-dienoic acid and (15S)-hydroxy-11alpha,9alpha-(epoxymethano)-prosta-5Z,13 E-dienoic acid in concentrations of 300 ng/ml are either without effect or weak smooth muscle stimulants of their own, but do not influence the effect of angiotensin II. By the simultaneous use of sensitive and specific radioimmunoassays for prostaglandins E1 and E2 the prostaglandin E-like substance released by the rabbit splenic capsular strips was found to resemble serologically much more the dienoic prostaglandin E2 than prostaglandin E1. The potentation of the effect of angiotensin II by indometacin and 5,8,11,14-eicosatetraynoic acid might be caused by inhibition of synthesis of prostaglandins or related compounds in the splenic tissue. However, an undefined sensitizing effect of indometacin and 5,8,11,14-eicosatetraynoic acid, not related to their effect on prostaglandin synthetase, on the smooth muscle preparation cannot be excluded.