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1.
Active transport of Cl accounts for 90% of the short-circuit current (s.c.c.) in the isolated frog cornea. 1·10−5 M furosemide produced a 50% reversible inhibition of this s.c.c. 1·10−4 M ethacrynic acid reduced the corneal s.c.c. to 32% of the control. In the isolated frog skin epithelium furosemide had no effect on the s.c. at a concentration of 1·10−4 M and a small stimulation at a concentration of 1·10−3 M. The furosemide inhibitory effects seems to be specific for Cl, as it also inhibits Cl transport in the ascending limb of the loop of Henle (Burg, M.B. (1972) Proc. 5th Int. Congr. Nephrol., p. 50, Abstr.).  相似文献   

2.
Explants of human non-pregnant cervix produce collagenolytic enxymes which degrade collagen over a 10 day period in culture. This is significantly enhanced by the presence of very low concentrations of arachidonic acid (10−16−10−11M). Prostaglandin E2, F and 6-keto-F were synthesised in declining amounts over the 10 day period and synthesis was not increased by adding arachidonic acid (10−11M). Meclofenamic acid (10−6M) and indomethacin (10−5M), but not tranylcypromine (10−5) suppressed prostaglandin synthesis yet all reduced collagen dissolution. Mepacrine (phospholipase A2 inhibitor) also suppressed collagen dissolution. Remodelling of the structure of the cervix matrix may, in part, depend upon arachidonic acid or one of its cyclo-oxygenase or lipoxygenase derived products.  相似文献   

3.
The “in vitro” effects of α-tocopherol, butylhydroxytoluene (BHT) and butylhydroxyanisole (BHA) were studied on aggregation of human platelets induced by collagen and arachidonic acid (AA), on the metabolic conversion of 14C AA through the cyclooxygenase and lipoxygenase pathways and on the formation of thromboxane B2 (TXB2) in washed platelets after stimulation with collagen.Vitamin E completely inhibited AA induced platelet aggregation only at high concentration (mM) and after 10 minutes of preincubation, with limited effects on AA metabolism in platelets and no effect on TXB2 formation from endogenous substrate. BHA completely inhibited platelet aggregation in the 10−6M range, gave 50% inhibition of AA metabolism in the 10−5M range and almost complete inhibition of thromboxane formation in the 10−4M range. BHT was about 100 times less active on platelet aggregation and AA metabolism. The lipoxygenase and cyclooxygenase pathways were differentially affected at low concentrations of BHA and only at concentrations greater than 5×10−5M were both pathways depressed.  相似文献   

4.
Somatostatin (10−9 M) significantly elevated the synthesis of thromboxane B2 in rat platelets. The transformation of arachidonic acid to active lipoxygenase metabolites was suppressed by somatostatin (10−9 and 10−8 M). The ratio of the lipoxygenase/cyclooxygenase products was significantly reduced by the polypeptide (10−9 and 10−8 M) in rat platelets. Higher concentrations (10−7, 10−6 and 10−5 M) of somatostatin did not modify the lipoxygenase pathway of the platelets. The synthesis of the vasoconstrictor — proaggregatory cyclooxygenase products was stimulated by the polypeptide (10−9 and 10−8 M), while the formation of vasodilatator - antiaggregatory cyclooxygenase metabolites was induced by higher concentrations of somatostatin (10−7 and 10−6 M). Somatostatin might act on the deacylation process of phospholipids, reducing the free arachidonic acid substrate level, resulting in a lower lipoxygenation rate in the platelets, which could be responsible for the increased formation of thromboxane. The contradictory results reported by others concerning the action of somatostatin on the platelet function might be explained by our results that the effect of somatostatin depends on the applied dose.  相似文献   

5.
Acetylcholine (ACh) induced dilation of precontracted strips of rabbit aorta by a mechanism dependent on an intact endothelium, probably by releasing an unknown endothelial relaxing factor (ERF). The relaxation was completely inhibited by the lipoxygenase inhibitor nor-dihydroguaiaretic acid (10−5 M) but not by the cyclo-oxygenase inhibitor indomethacin (10−5 M). The aortic strips were found to release small amounts of a material with a leukotriene-like activity. Its action on the guinea pig ileum was antagonized by FPL 55712 (10−6 M). However, FPL 55712 (10−6 - 10−4 M) did not alter the response of rabbit aortic strips to ACh. Also when decreasing intracellular concentrations of glutathion (GSH) by incubating the strips with diethylmaleat or 2-cyclohexen-1-one (both 10−3 M) the vasodilator response could still be elicited. Leukotriene (LT) C4 and LTD4 (10−9 - 10−10 M) were found to be ineffective on oartic strips under basal or induced tension. The same held true for LTE4 ( 10−9 - 10−7 M). At 10−6 M, however, LTE4 induced slight relaxations of the vascular tissues. For reasons discussed this is likely to be a pharmacological action independent of the effects of endogenous ERF (e.g. inhibition of the formation of the LTE4 precursor LTD4 by high extracellular GSH concentrations did not reverse the ACh-induced vasodilation). It is concluded from these data, that C-6-sulfidopeptide leukotrienes, although probably produced by vascular tissue, are unlikely to be involved in the ACh-induced relaxation of rabbit aorta.  相似文献   

6.
The effect of platelet activating factor (PAF), a potent lipid mediator of inflammation, was examined in the induction of airway hyperreactivity to known mediators of anaphylaxis. Concentration-dependent contractions of the isolated guinea-pig trachea to PAF (10−7 − 10−5M) were produced and an EC50 value was found to be 7.5 × 10−7M. Pretreatment for 30 min with a known PAF inhibitor, CV-3988 (10−5 or 10−4M), produced significant inhibition of PAF contractions; however, at 10−6M, CV-3988 had no effect. In the presence of meclofenamic acid (10−6M), the concentration-response curve to PAF was shifted significantly upward and to the left. This potentiation could be reversed by pretreating the tissues with the peptidoleukotriene antagonists, FPL 55712 or SK&F 102922 (10−5M). Pretreatment with PAF concentrations having essentially no intrinsic activity (10−8, 10−7) significantly enhanced the contraction of guinea-pig trachea to various concentrations of LTD4 and to certain concentrations of a thromboxane mimic (U-46619). Pretreatment with lyso-PAF failed to potentiate the LTD4 response, while pretreatment with CV-3988 reverse the potentiation by PAF of the lower concentrations of LTD4. However, PAF failed to enhance contractions (with or without the presence of meclofenamic acid) to acetylcholine, histamine, PGD2 or LTC4 (in the presence of serine borate). These results indicate a possible role for PAF as a mediator of airway hyperreactivity.  相似文献   

7.
We examined the effects of FMRFamide, serotonin, and acetylcholine on the isolated crop-gizzard of the earthworm, Lumbricus terrestris. FMRFamide caused a decrease in contraction amplitude with a threshold between 10−9 and 10−8 M and a biphasic change in contraction rate. The contraction rate increased with a threshold between 10−8 and 10−7 M and decreased with a threshold between 10−6 and 10−5 M. Serotonin decreased the contraction rate with a threshold between 10−8 and 10−7 M and the amplitude with a threshold between 10−8 and 10−7 M. Acetylcholine increased the contraction rate with a threshold between 10−8 and 10−7 M and caused a biphasic change in contraction amplitude. Amplitude rose with a threshold between 10−9 and 10−8 M and decreased with a threshold between 10−6 and 10−5 M. These results suggest that all three neurotransmitters may play a role in controlling the movement of the digestive tract in L. terrestris.  相似文献   

8.
The antagonistic effect of calcium (Ca2+), zinc (Zn2+) and selenium (Se4+) at different concentrations (10−2–10−6 M) against cadmium (Cd2+) induced genotoxic effects in root cells of Hordeum vulgare were studied. The results showed that 10−3–10−5 M could induce chromosomal aberrations and micronuclei formation. But in the treatment with 10−2–10−6 M of Ca2+, Zn2+ and Se4+ together with Cd2+ (10−3–10−5 M), respectively, the frequencies of chromosomal aberrations and micronuclei effectively decreased after 48 h of treatment. The treatment with 10−4–10−6 M of Ca2+ together with 10−4–10−5 M Cd2+, 10−6 M of Zn2+ together with 10−5 M Cd2+ and 10−6 M of Se4+ together with 10−5 M Cd2+ suggested rather obvious antagonistic effects. The order of the antagonisms of Ca2+, Se4+ and Zn2+ against Cd2+ toxicity was Ca2+>Se4+>Zn2+. The degree of antagonisms of Ca2+, Se4+ and Zn2+ against Cd2+ related to their concentration ratio.  相似文献   

9.
Continuously superfused rat anterior pituitary cells were used to study the effects of exogenous prostaglandins (PGs) and thromboxanes (TXz) on the secretion of prolactin (PRL). No change in hormone release was observed upon superfusion with TXB2 (10−5M) or the TX synthesis inhibitor, imidazole (1.5 mM). PGs A2, B2, d2, e1, e2, f1α, F2α, and endoperoxide analogs, U-44069 and U-46619, also had no effect on PRL secretion (all at 10−5M), In contrast 10−5M PGI2 was repeteadly found to stimulate PRL release to a level at least 125% above control, while producing no apparent change in the amount of hormone secreted in response to TRH. Somatostatin (SRIF), at a dose of 10M, maximally inhibited TRH-induces PRL output, but failed to alter the PRL response to PGI2. These studies indicate that PGI2 may have a direct effect on the anterior pituitary to modify PRL secretion.  相似文献   

10.
The role of arachidonic acid metabolites in norepinephrine (NE)-induced N-acetyltransferase (NAT) activity and melatonin release was examined from 6 h-incubations of rat pineal glands. A cyclooxygenase inhibitor, indomethacin (5×10−8 − 5×10−6 M) was ineffective on melatonin release, in the presence of absence of NE (5×10−6 M) while a lipoxygenase inhibitor, nordihydroguaiaretic acid (5×10−7 −5×10−5 M) had an inhibitory effect. Among the lipoxygenase metabolites, 12-hydroperoxyeicosatetraenoic acid (12-HPETE) and 15-HPETE stimulated both NAT activity and melatonin release in a dose-dependent manner, with a maximal effect occuring at 10−6 M, while 5-HPETE or hydroxy derivatives of these compounds (12-HETE, 15-HETE and 5-HETE) were ineffective. These results indicate that 12-HPETE and 15-HPETE can be involved in NE-induced melatonin release.  相似文献   

11.
The role of prostaglandins (PGs) in the mechanism of action of acetylcholine (ACh) on frog adrenocortical cells has been examined. Administration of a single dose of ACh (5 × 10−5 M) to perifused frog interrenal fragments, for 20 min, stimulated the production of corticosterone, aldosterone, PGE2 and 6-keto-PGF. In contrast ACh did not significantly alter TXB2 production. The effect of ACh could be mimicked by muscarine (10−5 M). Conversely, nicotine (10−6 to 10−4 M) was totally inactive. The increase in PG biosynthesis preceded the peak of corticosteroid release. Repeated 20-min pulses of ACh (5 × 10−5 M) or muscarine (10−5 M) given at 130-min intervales induced a desensitization phenomenon. In presence of indomethacin (5 × 10−6 M), the effect of ACh on PG and steroid secretion was totally abolished. In calcium-free medium, the effect of ACh on PG and corticosteroid production was completely blocked. These results indicated that, in the frog, ACh stimulates corticosteroid secretion through a PG-dependent mechanism.  相似文献   

12.
Amylase secretion and changes in the levels of cyclic AMP and GMP were studied in rabbit parotid gland slices incubated in vitro with a variety of neurohumoral transmitters, their analogs and inhibitors. Cyclic GMP levels increased 8-fold 5 min after exposure to carbachol (10−4 M), without a change in cyclic AMP levels; amylase output also rose. These effects were completely inhibited by muscarinic blockade with atropine, but were unaffected by α-adrenergic blockade with phenoxybenzamine. Epinephrine (4 · 10−5 M) produced a rapid increase in the levels of both cyclic nucleotides and in amylase release. The increase in cyclic GMP level was inhibited by previous exposure of the slices to phenoxybenzamine, while the cyclic AMP rise was prevented by the β-blocking agent, propranolol. Pure α-adrenergic stimulation with methoxamine (4 · 10−4 M) produced modest elevations in cyclic GMP content and amylase output, effects blocked by pre-treatment of slices with either atropine or phenoxybenzamine. At a concentration of 4 · 10−6 M, isoproterenol (a β-agonist) failed to affect cyclic GMP levels, but promptly stimulated increases in cyclic AMP levels, and after a short lag, amylase secretion. At a higher dose (4 · 10−5 M) isoproterenol produced elevations in the levels of both nucleotides. The carbachol-induced effects on cylcic GMP content and amylase release were greatly potentiated by the addition of isoproterenol (4 · 10−6 M).These data strongly suggest that cholinergic muscarinic agonists and α-adrenergic agonist stimulate amylase output in rabbit parotid gland by mechanisms involving cyclic GMP. The atropine-sensitive intracellular events effected by α-stimulation may be dependent upon endogenous generation of acetylcholine. Both cyclic nucleotides seem to be required for the early rapid secretion of amylase. The unique responses achieved by the combination of carbachol and isoproterenol suggest that isoproterenol may increase the sensitivity of this issue to the effects of cholinergic stimuli.  相似文献   

13.
Single-cell and DNA fiber autoradiography, cytophotometry and velocity sedimentation in alkaline sucrose gradients were used to analyse DNA replication and nascent replicon maturation in 5-fluorodeoxyuridine (FUdR)-synchronized cells of Pisum sativum. The replicon size was not significantly changed by the protracted FUdR treatment. When the synchronized cells were released from the inhibitor, labeled with [3H]TdR for 30 min, and chased in medium containing 1 × 10−6 M or lower concentrations of cold thymidine, DNA replication stopped after approx. 25% of the genome had replicated, and the nascent strands failed to grow above 9–12 × 106 D single-stranded (ss) DNA. When the cells were chased in medium with 1 × 10−5 M cold thymidine, the DNA content of the labeled cells steadily increased with time and the size of the nascent molecules grew continuously until replicon size was achieved; then they were accumulated at replicon size until the cells arrived in late S or G2. When the FUdR-synchronized cells were chased in medium containing 1 × 10−4 M cold thymidine, the size of the nascent strands increased continuously with time, indicating that some neighbouring nascent replicons were joined as soon as they completed their replication. These observations led us to postulate that in FUdR-synchronized cells the rates of chain elongation, cell progression through the S phase and nascent replicon maturation are controlled by thymidine availability.  相似文献   

14.
The effects of prostaglandin E2 (PGE2) and indomethacin on excitatory neuro-effector transmission in the human bronchus were investigated by tension recording and microelectrode methods. PGE2 (10−10–10−9M) suppressed the amplitude of twitch contractions and excitatory junction potentials (e.j.ps) evoked by field stimulation at a steady level of basal tension obtained by the combined application of indomethacin (10−5M) and FPL55712 (10−6M). In doses over 10−8M, PGE2 reduced the muscle tone and dose-dependently suppressed the amplitude of twitch contractions. Indomethacin (10−5 or 5 × 10−5M) reduced the muscle tone and enhanced the amplitude of twitch contractions and e.j.ps evoked by field stimulation in the presence of FPL55712. PGE2 (10−9M) had no effect on the post-junctional response of smooth muscle cells to exogenously applied acetylcholine (ACh) (4 × 10−7M). However, indomethacin (10−5M) significantly enhanced the ACh-induced contraction of the human bronchus. These results indicate that PGE2 in low concentrations has a pre-junctional action to inhibit excitatory neuro-effector transmission in addition to a post-junctional action, presumably by suppressing transmitter release from the vagus nerve terminals in the human bronchial tissues.  相似文献   

15.
The effect of various anti-inflammatory drugs on the production of prostaglandins E2 and F2α, 6 keto PGF1α and thromboxane B2 by bovine articular chondrocytes was measured by radioimmunoassay. While indomethacin and meclofenamic acid caused a dose-dependent inhibition of all prostanoids measured, the effects of hydrocortisone and colchicine varied with respect to different prostanoids. Hydrocortisone (10−7M – 10−3M) both in the presence and absence of added arachidonic acid, resulted in an inhibition of prostaglandins E2 and F2, and to a lesser extent, 6 keto PGF1α, but T×B2 production was only slightly inhibited by the drug in the absenced of arachidonic acid and markedly increased in its presence. Colchicine (10−7M – 10−3M) had the opposite effect, causing an inhibition of T×B2 and stimulating PGE2 and 6 keto PGF1α production. These findings suggest that certain anti-inflammatory drugs may, in addition to their action on phospholipase A2 and cyclo-oxygenase, exert potent effects at the level of the different synthetases. In order to see whether these alterations in relative prostanoid levels affected proteoglycan metabolism, the effect of anti-inflammatory drugs on proteoglycan synthesis by cultured chondrocytes was tested using 35SO4 labeling methodology. The results showed that the concentrations tested (10−5M to 10−7M), indomethacin, dexamethasone, hydrocortisone and colchicine inhibited 35SO4 incorporation into newly synthesized proteoglycan molecules both in the presence (10−6M) and absence of exogenous arachidonic acid. In the same concentration range choroquine had no effect.These results do not support the hypothesis of direct prostanoid involvement in the modulation of proteoglycan synthesis in articular cartilage.  相似文献   

16.
The metabolism of linoleic acid by washed human platelets was investigated. 1.14C linoleic acid was converted to 1.14C hydroxy octadecadienoic acids (HODES) at about the same rate with which 1.14C 12-HETE was produced from 1.14C arachidonic acid. The total radioactivity in HODEs was distributed among two isomers: 13-HODE (85%) and 9-HODE (15%) as defined by GC-MS. The production of HODES by intact washed platelets was inhibited by indomethacin (IC50:5×10−7M) which suggest that hydroxy fatty acids were produced by PGH-synthase. By contrast, the production of HODEs by platelet cytosolic fractions was not modified under indomethacin treatment but completely abolished by NDGA (10−3M) and inhibited by the platelet lipoxygenase inhibitors 15-HETE (2.10−5M) and baicalein (10−5M). Platelets thus contain two different active systems which may convert linoleic acid to hydroxy fatty acids. Since these compounds remained essentially associated with the platelets, their presence may significantly participate in the mechanisms of platelet activation.  相似文献   

17.
Noradrenalin (8 · 10−6 M) and adrenalin (6 · 10−6 and 6 · 10−7 M) were found to cause marked stimulation of short-circuit current (S.C.C.) in isolated toad bladder, but isoprenalin (8 · 10−7 M) was found to be without effect. The percentage rise in S.C.C. due to noradrenalin was found to be inversely proportional to the initial S.C.C. or total conductance of the bladder. Again in the case of noradrenalin the rise in S.C.C. was almost completely abolished by α-adrenergic blockade but not by β-blockade. This rise in S.C.C. was found not to be significantly different from the rise in net Na+ flux. Bidirectional Cl fluxes were estimated using 82Br as a companion radionuclide to 36Cl. No significant net Cl flux was apparent, either before or after addition of any of the three catecholamines tested. However, in some cases the unidirectional Cl fluxes rose markedly following addition of noradrenalin or of adrenalin and this change was not reflected in a change in total conductance. This anomaly was noted to occur in bladders whose initial conductance was of the order of 0.5 kΩ−1 · cm−2 or greater. The evidence presented suggests that two actions of catecholamines on ion transport in toad bladder are (a) to increase Na+ transport via stimulation of α-adrenergic sites and (b) at the concentrations tested to cause an increase in passive Cl permeability in bladders whose initial conductance is high.  相似文献   

18.
Both gonadotropins and prostaglandins stimulate the ornithine decarboxylase (ODC) activity of porcine granulosa cells (1,2). To investigate a possible intermediary role of prostaglandins in this gonadotropin action, the effects of indomethacin on gonadotropin-induced ODC activity were studied. Indomethacin had no effect at concentrations lower than 10−5 M; at higher concentrations indomethacin exerted a dose-dependent suppression of LH-stimulated ODC activity which was essentially complete at 5 × 10−4 M. The effects of PGE2 and 8-Bromo-cAMP, potent stimulators of ODC, were also blocked by indomethacin (5 × 10−4 M). This effect did not represent direct inhibition of enzyme activity, but appeared to be due to inhibition of protein synthesis by the drug. Thus, incorporation of 14C-leucine into proteins by these cells was blocked by indomethacin with a dose-response curve similar to that for ODC suppression. This distal effect of indomethacin may complicate the interpretation of some experiments if the inhibitor is assumed to act only at the prostaglandin synthetase step.  相似文献   

19.
7α-Hydroxydehydroepiandrosterone (7α-OHDHA) is a major metabolite of dehydroepiandrosterone (DHA) using adipose stromal cells. To gain a better understanding of the factors regulating DHA metabolism, we examined the effect of dexamethasone and cytochrome P 450 inhibitors on the formation of 7α-OHDHA. Dexamethasone (10−9 to 10−7 M) stimulated 7α-OHDHA formation in a dose-dependent manner with a 2- to 5-fold stimulation at 10−7 M. The dexamethasone stimulated 7α-OHDHA formation was inhibited by RU486 in a dose-dependent manner with suppression to basal levels at 10−6 M. Progesterone (10−7 M) had no effect on 7α-OHDHA formation suggesting that the dexamethasone stimulation was acting through the glucocorticoid receptor. Conversion of DHA to 7α-OHDHA was inhibited by ketoconazole and metyrapone. An inhibition of 70–80% was obtained with ketoconazole and 25–60% with metyrapone at concentrations of 10−5 M. Aminoglutethimide phosphate was less effective than either ketoconazole or metyrapone in inhibiting 7α-OHDHA formation with <30% inhibition at 10−5 M. These studies indicate that 7-hydroxylation provides an alternative pathway for the metabolism of DHA in peripheral tissues. This pathway, which is regulated by glucocorticoids, may influence the amount of DHA available for conversion to androstenedione and its subsequent aromatization to estrone. The biological role of the 7-oxygenated metabolites and their effects on other steroidogenic pathways have not been established.  相似文献   

20.
The binding and inhibitory properties of 11 benzimidazoles for bovine brain tubulin were investigated. The effects of the benzimidazoles on the initial rates of microtubule polymerization were determined by a turbidimetric assay. The median inhibitory concentrations (I50) for nocodazole, oxibendazole, parbendazole, mebendazole and fenbendazole ranged from 1.97 · 10−6 to 6.32 · 10−6 M. Benomyl, cambendazole and carbendazim had I50 values from 5.83 · 10−5 to 9.01 · 10−5 M. Thiabendazole had an I50 value of 5.49 · 10−4 M. Inhibitor constants (Ki) were determined by the colchicine binding assay. Oxibendazole, fenbendazole, and cambendazole had Ki values of 3.20 · 10−5, 1.73 · 10−5 and 1.10 · 10−4 M, respectively. Oxibendazole and fenbendazole were competitive inhibitors of colchicine. In contrast, cambendazole was a noncompetitive inhibitor of colchicine. The ability of these benzimidazoles to inhibit microtubule polymerization and the mode of action for the anthelmintic benzimidazoles is discussed.  相似文献   

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