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1.
Active tension is produced by the lower esophageal sphincter (LES) of North American opossum in vitro by a myogenic mechanism. Strips of LES, but not those from the esophageal body, contracted to prostaglandin (PG)F2 alpha, stable expoxymethano derivatives of PGH2 and to thromboxane B2. Stable endoperoxides were more than 500 times more potent than PGF2 alpha. PGI2 and 6-keto PGF1 alpha were weak relaxants of LES strips. LES strips transformed arachidonic acid into contractile substances. This transformation was prevented by agents which interfere with PG synthesis by inhibiting cyclo-oxygenase [indomethacin (IDM), 5,8,11,14-eicosatetraynoic acid (ETA) or thromboxane synthetase [imidazole]. Tranylcypromine 500 microgram/ml also inhibited contractions to arachidonic acid. These agents also reduced muscle tone, so that endogenous PG formation may contribute to active tension in the LES. ETA and IDM increased tone before inhibiting it, and this effect was prevented by prior treatment with ETA or imidazole. There may also be an endogenous PG which inhibits LES tone. The possibility that this may be PGI2 is discussed.  相似文献   

2.
Bovine articular chondrocytes, cultured as cell suspensions and monolayers, produced prostaglandin (PG) E2 and PGI2 (assayed as 6 keto PGF1α), rather less PGF2α and irregular quantities of thromboxane (Tx) B2. Addition of foetal calf serum to the medium greatly stimulated PG production (a sixfold increase in PGE2 and a twofold increase in 6 keto PGF1α).Prostanoid production by cell suspension grown in serum-free medium generally plateaued after 24 hours. In the presence of 20% foetal calf serum, prostanoid production in long-term monolayer cultures increased during the first 6 days of culture. Levels of PGE2α levels remained high. Indomethacin (10-6M) inhibited chondrocyte PG production both in the presence and absence of added arachidonic acid (10-4M). Prostanoids produced by chondrocytes may play a role in the modulation of cartilage metabolism in vivo.  相似文献   

3.
The role of prostaglandins in maintenance of basal myogenic tone of the lower esophageal sphincter (LES) of opossum has been studied in vivo. Intra-arterial infusion of arachidonic acid decreased LES tone, and this was inhibited by intravenous indomethacin (IDM) or intra-arterial 5,8,11,14-eicosatetraynoic acid (ETA). Alone these drugs did not reduce LES tone except transiently. In addition they did not affect relaxation of the LES to distention of a balloon located proximal to it or inhibit the “off” contractions of esophageal body and LES pressure which followed balloon deflation. Spontaneous oscillations of LES pressure were increased with IDM. Thus prostaglandin synthesis plays no essential role in maintenance of resting LES tone or in functioning of non-adrenergic inhibitory nerves in the esophagus in vivo. Endogenous inhibitory prostaglandins might reduce LES tone if synthesized in increased amounts.  相似文献   

4.
The anti-inflammatory analgesic drugs, aspirin, indomethacin, phenylbutazone, mefenamic acid, ibuprofen and flurbiprofen are shown to inhibit in a dose-dependent manner the force of contraction of isolated human pregnant myometrial strips which have been stimulated to contract by adding prostaglandin (PG) F to the tissue bath. These drugs and also flufenamic acid and salicin show a similar antagonism of the action of PGF with isolated rabbit non-pregnant myometrium. The ratio of the inhibitory concentration in vitro to the maximum plasma level after a normal dose in vivo suggests that phenylbutazone and possibly ibuprofen may be capable of inhibiting human uterine contractions in vivo. Patients who were treated with aspirin during induction of abortion using PGF during the second trimester of pregnancy showed no significant change in the induction-abortion interval compared with patients not taking aspirin.  相似文献   

5.
In vitro prostaglandin biosynthesis by uteri of ovariectomized rats and guinea pigs treated or untreated with oestradiol 17 β, administered subsutaneously, was measured by R.I.A. of PGF and PGE2. Incubations with [1-14C] arachidonic acid were also performed and labelled metabolites were analyzed by TLC. The main metabolite in rats was 6 keto PGF and in decreasing order of magniture, PGF and PGE2. In guinea pig PGF2ga was the main product. Ovariectomy in rats completely changed the pattern of synthesized prostanoids: PGI2 production was doubled when compared to cycling rats and PGE2 increased 10 fold. PGF walues were similar to the mean value measured during the cycle. OE2 treatment almost completely inhibited PGI2 synthesis and reduced PGE2 by half. Total PG synthesis in OE2 treated animals was decreased by 5 fold when compared to spayed rats. Endogenous PGF synthesis was slightly stimulated. In the guinea pig OE2 treatment of ovariectomized animals increased the total synthesis from 50 per cent. PGF was always the main metabolite. In conclusion OE2 regulation of uterine PG synthesis is depending on the animal species and cannot be explained by a unique effect on the cyclooxyhenase, but rather by an interplay on the various enzymes of the arachidonic acid cascade.  相似文献   

6.
Human cortical hydronephrotic microsomes converted [14C] arachidonic acid to [14C] thromboxane B2 as the major metabolic product. Using [14C] PGH2 as substrate, similar enzymatic conversions were noted with HHT>TXB26KPGF1αPGE2PGF2α as the major products. Inhibition of thromboxane synthetase with imidazole 5 mM reduced thromboxane B2 production by 60% and the major product then was 6 keto PGF. After addition of imidazole, the metabolic profile showed 6KPGF1αPGE2HHT>PGF2α. Control experiments were carried out using normal cortical tissue obtained from kidneys removed surgically for carcinoma of kidney and rejected for transplantation secondary to fracture as a consequence of blunt trauma. These control kidneys, while they demonstrated an ability to generate thromboxane B2in vitro, had much less activity than hydronephrotic kidneys and with PGH2 as substrate PGE2TxB2. In addition, inhibition with imidazole produced mainly PGE2. Thus, like the rabbit and rat, there is enhanced thromboxane and prostacyclin synthesis in human ureteral obstruction and are, therefore, potential vasoactive compounds which may in part be responsible for the hemodynamic alterations occurring in human obstructive uropathy.  相似文献   

7.
Effect of various prostaglandins on the release of arachidonic acid from [14C]arachidonic acid labeled fibroblasts was studied. Prostaglandin(PG) F was found to enhance the release of radioactive arachidonic acid from the cells. The stimulatory effect was dose dependent, and was greater than that of bradykinin. The active compounds can be ranked in potency for the release of arachidonic acid from the pre-labeled cells per cent of control: PGF(200.1%)>PGF (141.8%)>PGD2 (137.1%)>thromboxane B2 (113.7%)>PGE2 (109.4%). On the other hand, PGI2 showed a strong inhibitory effect on the arachidonic acid release from the pre-labeled cells (the value was only 69% of the control), while 6-ketoPGF, an end metabolite of PGI2, had no effect.  相似文献   

8.
Immunoglobulins raised against 5,6-dihydro PGI2 crossreact with PGI2. When infused in vivo into the rat, these immunoglobulins are capable of I) neutralising the vasodepressor effects (bolus or continuous infusion) of exogenous PGI2, 2) blocking the catabolism of exogenous 3H-PGI2 and prolonging its life-time in the circulation (t12 approx 60 min) while that of 3H-PGE2 is unaffected, 3) trapping an endogenously produced substance which after extraction from blood and dissociation from the ligand-antibody complex, is immunoreactive with 6-keto PGF-specific antiserum. Yet the anti-5,6-dihydro PGI2 immunoglobulins have no effect on resting arterial blood pressure both in the normotensive and spontaneously hypertensive rat. These experiments indicate that endogenously produced PGI2 does not play a significant systemic role in blood pressure control although in combination with other vasodilators it could still participate in the regulation of vascular tone at a local level.  相似文献   

9.
The effects of imidazole, 1-methyl-imidazole and benzimidazole on bone metabolism in vitro were investigated. The relative potencies of these compounds with respect to the inhibition of bone resorption was found to be comparable to their relative effectiveness as inhibitors of platelet microsome thromboxane synthetase activity. Since studies by others have shown that thromboxanes are produced by resorbing bone in vitro, these results suggest that the inhibition of bone resorption by imidazole is related to the inhibition of thromboxane A2 formation. This could imply that thromboxane A2 is an additional arachidonic acid oxidation product that is of importance in the regulation of bone metabolism.  相似文献   

10.
Platelets from vitamin E-deficient and vitamin E-supplemented rats generate the same amount fo thromboxane A2 (TxA2) when they are incubated with unesterified arachidonic acid. Platelets from vitamin E-deficient rats produce more TxA2 than platelets from vitamin E-supplemented rats when the platelets are challenged with collagen. Arterial tissue from vitamin E-deficient rats generates less prostacyclin (PGI2) than arterial tissue from vitamin E-supplemented rats. The vitamin E effect with arterial tissue is observed when the tissue is incubated with and without added unesterified arachidonic acid. These data show that arterial prostacyclin synthesis is diminished in vitamin E-deficient rats. Vitamin E, invivo, inhibits platelet aggregation both by lowering platelet TxA2 and by raising arterial PGI2.  相似文献   

11.
We have compared the production of prostaglandins in fibroblast-like cells and endothelial cells in culture. Of the fibroblasts studied 10T12, SHE, BP6T and KD produce significant amounts of PGI2, PGE2 and PGF2F2 under optimal culture conditions, but only 3T3 and BHK produce TxA2 in addition to PGI2. The adult bovine aortic endothelial cells (ABAE) and fetal bovine heart endothelium (FBHE) synthesise PGI2 but not TxA2, either from endogenous or exogenous substrates. Both cultured endothelial cells and fibroblasts apparently lack 15-hydroxyprostaglandin dehydrogenase pathway and the ability to convert 6-Keto PGF into 6-Keto PGE1. PGI2 production by ABAE was 3–5 times that of FBHE, about twice that of SHE cells and 6–8 times that of 10T12 or BP6T cells. Supernatants or media obtained from these cells inhibited aggregation of human platelet-rich plasma, a known biological effect of PGI2. This effect was abolished when cell monolayers were preincubated with indomethacin or tranylcypromine. RIA and chromatographic data of 6-Keto PGF from these experiments confirmed that the inhibition of platelet aggregation was due to the formation of PGI2. The production of all prostanoids by endothelial cells or fibroflasts was significantly higher during the exponential phase of growth as compared to confluent monolayers. We propose that fibroblasts 10T12 or SHE can serve as useful experimental models for the study of metabolism and transport of PGI2 and/or TxA2 in cells of nonendothelial nature.  相似文献   

12.
Bovine coronary arterial strips (BCA) exhibiting spontaneous tone, relax in response to a decrease in the PO2 of the batching medium. Experiments were performed to determine if prostaglandins (PGs) mediate the oxygen-induced changes in tension. BCA were equilibrated in Krebs-bicarbonate solution at 37 °C gassed with 95% O2, 5% CO2 and tension was measured isometrically. When the PO2 of the bathing medium was decreased, BCA exhibited reversible reductions in tension. Switching from 95% O2, 5% CO2 to 95% N2, 5% CO2 (anoxia) elicited an initial relaxation followed by a contraction. In contrast, a change to 5% O2, 5% CO2, 90% N2 (hypoxia) was followed by a sustained relaxation. Re-introduction of O2 to anoxic strips produced a biphasic response: relaxation followed by contraction. Indomethacin or eicosatetraynoic acid (EYA) increased tone and inhibited the relaxation produced by anoxia or hypoxia. Indomethacin or EYA did not inhibit the relaxation of anoxic strips during re-introduction of O2, but did inhibit the contraction partially. Relaxation of arterial strips to arachidonic acid (AA) was similar to relaxation to prostacyclin (PGI2). Anoxia limited the relaxation to AA but not to PGI2. We conclude that PG synthesis contributes to the basal tone and the hypoxia-induced relaxation of CBA. In addition, hypoxia, unless severe, does not prevent the conversion of AA to PGI1.  相似文献   

13.
Isolated rat aortae were incubated at 22°C in tris-buffered saline (pH 7.4). The incubation medium was changed every 10 min, and the amounts of prostacyclin (PGI2) in the medium were immediately bioassayed as an inhibitory activity against rabbit platelet aggregation induced by ADP. The addition of arachidonic acid to the medium increased the generation of PGI2 but this was followed by a gradual decrease even in the presence of the same amount of arachidonic acid. The decrease of PGI2 generation from exogenous arachidonic acid was prevented by tryptophan, which is required by PG hydroperoxidase with heme compound as cofactors. MK-447 and its analogues, which are phenolic compounds and exerted tryptophan-like action on the PG endoproxide biosynthesis by bovine seminal vesicle microsomes, also prevented the decrease of PGI2 generation in isolated rat aortae. The phenolic compounds enhanced PGI2 generation from endogenous arachidonic acid. These results indicate that theh phenolic compounds enhanced PGI2 generation in vascular tissue, acting as a tryptophan-like cofactor of PG hydroperoxidase.  相似文献   

14.
The ability of aortae from young and mature swine to produce prostacyclin (PGI2) has been determined. PGI2 was measured as its hydration product, 6-keto-PGF and assayed by stable isotope dilution GC-MS. There was no significant difference in 6-keto-PGF production between intimal strips from young and mature aortae in the basal state. In the presence of saturating concentrations of arachidonic acid, however, intimal strips from young aortae synthesized twice as much 6-keto-PGF as did older tissues. Fatty acid compositions of young and mature aortae were virtually identical, making dietary differences an unlikely explanation for the age-related decrease in PGI2 synthesis. Both young and mature vascular tissues produced essentially only PGI2; insignificant amounts of PGE2 and PGF were found.  相似文献   

15.
At low concentrations (i.e., 10?12–10?9 mol/l), PGF and PGF very intensely stimulated both the DNA-synthetic and mitotic activities of hepatocytes in 4-day-old primary cultures of neonatral rat liver. DNA replication was more intensely enhanced by PGF than by PGF, whereas mitotic activity was nearly equally affected by the two prostaglandins. On the whole, the growth-promoting activity of PGF used by itself or in equimolar mixtures with other prostaglandins (e. g., A1, E1, etc.) mimicked that of arachidonic acid we previously reported (1). On a molar basis, PGF by itself stimulated hepatocytes′ DNA synthesis is more powerfully than arachidonate did, and when used in equimolar mixtures with other prostaglandins was at least as potent as arachidonic acid. These observations establish prostaglandins of the F series as quite powerful commitment factors and, though by a lesser degree, also intracycle regulators for neonatal rat hepatocytes in primary culture. However, the understanding of the role(s) of prostaglandins of F and other series in the physiological control of hepatocytes′ proliferative activation must wait the clarification of their interaction(s) with other arachidonate derivative(s) and polypeptide growth factor(s) which also may be involved in the process.  相似文献   

16.
The activity of prostaglandins (PG) in producing vascular permeability was quantitated by dye extraction method in skin of anaesthetized rabbits. PGE1 and PGE2 (0.01–10 μg) produced increase in vascular permeability. Activity was approximately equal to that of histamine (Hist) and 120 of that of bradykinin (BK) on a weight basis. The activity of PGF and PGF was only 120 of that of PGE1 or PGE2.In spite of the relatively low potency of PGE1 and PGE2 in the rabbit, near threshold doses (0.1 or 1 μg) of PGE2 could potentiate permeability responses to bradykinin (0.1 μg) by 10 or 100-fold, respectively. Equivalent doses (0.1 or 1 μg) of histamine could not potentiate the bradykinin responses. Arachidonic acid (AA) at 1 μg, produced a 10-fold potentiation in the permeability response to bradykinin (0.1 μg). Pretreatment of the rabbits with indomethacin (20 mg/kg, i.p.) reduced the responses of BK (0.1 μg) + AA (1 μg) down to a similar magnitude of those seen with bradykinin alone. However, indomethacin did not block responses to either, BK alone, BK + PGE2, or BK + Hist. Various doses (1, 10, 100 and 300 μg) of arachidonic acid alone also produced increase in cutaneous vascular permeability, although its potency was only 1318 of that of PGE2. This activity of arachidonic acid was attributed in part to its bioconversion to PGE2, since its activity was significantly reduced by the prostaglandin antagonist, diphloretin phosphate (DPP) (60 mg/kg, i.v.) and by indomethacin (20 mg/kg, i.p.), which blocks conversion of arachidonic acid to prostaglandins. Arachidonic acid may owe some of its permeability increaseing effects to histamine release, since its effects were also reduced by the antihistamine, pyrilamine (2.5 mg/kg, i.v.).  相似文献   

17.
Both intact cortical tissue and isolated cortical cells from the adrenal gland of the rat were analyzed for 6-keto-PGF, the hydrolysis metabolite of PGI2, using high-performance liquid chromatography and gas chromatography-mass spectrometry. 6-Keto-PGF was present in both incubations of intact tissue and isolated cells of the adrenal cortex, at higher concentrations than either PGF or PGE2. Thus, the cortex does not depend upon vascular components for the synthesis of the PGI2 metabolite. Studies in vitro, using isolated cortical cells exposed to 6-keto-PGF (10?6-10?4M), show that this PG does not alter cAMP levels or steroidogenesis. Cells exposed to PGI2 (10?6-10?4M), however, show a concentration-dependent increase of up to 4-fold in the levels of cAMP without altering corticosterone production. ACTH (5–200 μU/ml) increased cAMP levels up to 14-fold, and corticosterone levels up to 6-fold, in isolated cells. ACTH plus PGI2 produced an additive increase in levels of cAMP, however, the steroidogenic response was equal to that elicited by ACTH alone. Adrenal glands of the rat perfused in situ with PGI2 showed a small decrease in corticosterone production, whereas ACTH greatly stimulated steroid release. Thus, while 6-keto-PGF is present in the rat adrenal cortex, its precursor, PGI2, is not a steroidogenic agent in this tissue although it does stimulate the accumulation of cAMP.  相似文献   

18.
This report outlines the activity of a new thromboxane synthase inhibitor sodium, 5-(3-pyridinymethyl)-2-benzofurancarboxylate, (U-63557A). U-63557A is a potent inhibitor of the thromboxane synthase in human platelets invitro, as well as in rhesus monkey platelets ex vivo. A single oral dose of 3.0 mg/kg U-63557A inhibits the platelet thromboxane synthase in rhesus monkeys approximately 80% for at least 12 hrs. U-63557A has been administered to monkeys twice a day, (10 mg/kg) for 14 days, without evidence of drug tachyphylaxis or rebound. U-63557A does not inhibit thrombin-stimulated PGI2 biosynthesis in human endothelial cells, the 5-lipoxygenase in human neutrophils, or the cyclo-oxygenase in a variety of test systems. In anesthetized dogs, U-63557A injected i.v. at 0.1 at 5 mg/kg prevented the blockage of stenosed coronary arteries caused platelet aggregation,. Similar effects were obtained by oral administration of 1–5 mg/kg. The thromboxane synthase inhibitor was more efficacious than cyclooxgenase inhibitors and equal to PGI2 in efficacy. Under appropriate conditions the protective effects of U-63557A could be reversed by i.v. cylooxygenase inhibitors suggesting that its efficacy dependened in part of endogenous PGI2 formation. Due to its specificity, oral activity, and extended duration of action, U-63557A is a promising compound for the evaluation of the role of thromboxane synthase in a variety of patho[hysiological states.  相似文献   

19.
The biosynthesis of PGE2 and PGF was measured in intact peritoneal exudate preparations obtained fom C. parvum-treated and control C3H mice. Although both the control and stimulated preparations biosynthesized PGF and PGE2 from [1–14C] arachidonic acid, the stimulated preparations generated more of both prostaglandins than did nonstimulated preparations, probably as a result of increased synthesis within macrophages. Increased transformation of PGE2 into PGF 9-ketoreductase was noted in stimulated preparations when compared to that in control cells. The data suggest that stimulated macrophages are capable of generating increased quantities of PGF and therefore might function as one source of this substance in resolving inflammatory reactions.  相似文献   

20.
Renal tubular epithelial cells isolated from dog and pig kidney (MDCK and LLC-PK1, respectively) transport water and electrolytes in culture. MDCK cells resemble collecting tubule cells by additional, but not all, morphologic and biochemical criteria. It has previously been reported that PGE2 appears to regulate transport activity by MDCK cells as well as their proliferation. We investigated prostaglandin biosynthesis by MDCK and LLC-PK1 cells and assessed the effects of peptide hormones, bradykinin and vasopressin, on the cells' prostaglandin biosynthesis. Thin-layer chromatography of radioactive products released by MDCK cells labelled with octatritiated of [14C] arachidonic acid indicated the presence of materials comigrating with PGE2, PGI2 (detected as 60oxo0PGF1α) and PGF2α, in decreasing order of abundance. Maclofenamate inhibited the biosynthesis of all radioactive peaks comigrating with PGs, thus confirming their identities as product of fatty acid cyclo-oxygenase activity. The chemical identities of [3H] PGE2 and [3H] 6-oxo-PGF1α made by the cells were further confirmed by treatment with KOH. Radioimmunoassay of culture fluids incubated with MDCK cells verified that PGE2 was the most abundant prostaglandin. Tranylcypromine, thought to be a specific inhibitor of prostacyclic synthetase, inhibited PGE2 as well as PGI2 biosynthesis indicating a lack of specificity of the inhibitor. The observation of PGE2 and PGF2α as respectively the most and least abundant prostaglandinds made by MDCK was in disagreement with results from another laboratory in which the reverse order of abundance was found. This suggests the presence of more than one cell line identified as MDCK but having different biochemical properties.Bradykinin stimulated acylhydrolase activity as well as PGE2 and PGI2 biosynthesis in MDCK cells while vasopressin had little or no effect. These results support the hypothesis that bradykinin's natriuretic effects may be mediated by prostaglandinds and that vasopressin is unlikely to acutely stimulate prostaglandin biosynthesis in collecting tubule cells invivo. Endogenous PGE2 may also regulate the proliferation of MDCK cells in culture.In contrast to MDCK cells, LLC-PK1 cells lacked significant prostaglandin biosynthetic capability as documented by radiometric thin-layer chromatography and radioimmunoassay. This suggests that prostaglandins may have a modulatory rather than an obligatory role in regulating transport activity by tubular epithelial cells.  相似文献   

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