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1.
External calcium dependence of the uterine contraction induced by prostaglandins E2 and F2 alpha and its antagonism with natural progestins. 总被引:1,自引:0,他引:1
Prostaglandins (PGs) E2 and F2 alpha are strong inducers of uterine contraction by promoting a Ca2+ increase into the cell through specific receptors coupled with the calcium channels. On the contrary, progesterone and 5 beta-reduced progestins promote smooth muscle relaxation by blocking the ion calcium influx. Thus, this study was designed to emphasize the importance of external calcium in the PGs-induced rat uterus contraction. Likewise, also studied was the antagonism and the interaction between PGs and progestins (progesterone and its 5 alpha and 5 beta-reduced derivatives) in the myometrium. Results showed that uterine contraction induced by PGs depends on external calcium, since verapamil or extracellular calcium depletion abolished the PGs effect. Regarding the PGs-progestins antagonism, it was observed that pregnanedione, pregnanolone and epipregnanolone were quite effective for counteracting of PGs-induced contraction. However, progesterone was effective in a middle range, whereas 5 alpha-reduced progestins (allopregnanedione and allopregnanolone) were almost ineffective. It has been concluded that the participation of PGs and progestins in the modulation of uterine contraction might be achieved through the control of calcium influx by opening (PGs) or blocking (progestins) receptor-operated calcium channels. 相似文献
2.
Non-genomic mechanism of action of delta-4 and 5-reduced androgens and progestins on the contractility of the isolated rat myometrium 总被引:1,自引:0,他引:1
Effective concentrations50 of androgens, i.e. testosterone, androsterone, androstanediol, 5 beta-dihydrotestosterone and progestins: progesterone, pregnanolone, pregnanedione, epipregnanolone, allopregnanolone and allopregnanedione were assayed on the tonic contractions of the isolated rat myometrium induced by calcium in high-potassium calcium-free depolarizant solutions. Steroids showed their relaxant effect by fadding the sustained contraction induced by calcium in a depolarized state. Also, the addition of the calcium ionophores A-23187 and X-537A reversed the steroid relaxant effect by increasing sharply the tonic contraction. The possibility of steroid-induced relaxation through release of noradrenaline or histamine was discarded by blocking their specific receptors. From the results it is concluded that delta-4 and 5-reduced androgens and progestins produce relaxation by a myogenic mechanism acting on the smooth muscle cell, most likely by directly blocking the calcium channels they causing modulation of: the contraction-relaxation cycle. 相似文献
3.
4.
Modulatory action of 5-reduced androgens and progestins on the excitability of CNS and smooth muscle
C Kubli-Garfias 《Journal of steroid biochemistry》1987,27(1-3):631-634
A hypothesis is proposed for the physiological role of the many 5 alpha and 5 beta-reduced metabolites of both testosterone and progesterone. The effects of 5-reduced steroids are observed mostly in excitable tissues. The outstanding effects are depression of neuronal activity, inhibition of neurotransmitters and smooth muscle relaxation. A clear chemical-structure-biological-activity relationship is observed. Thus, 5 beta-progestins are the most prominent, whereas 5 alpha-3-keto compounds are practically ineffective. An intermediate effect is observed with the delta 4 precursors and compounds with the configuration 3 alpha-hydroxy-5 alpha. Membranal stabilization and a Ca2+ antagonism are proposed as mechanisms of action. The main conclusion is that testosterone and progesterone are pre-hormones in the membranal effects of 5-reduced steroids. Likewise, these compounds participate in the cellular control of calcium influx, thereby modulating excitability in general. 相似文献
5.
Background
Thromboxane A2 (TxA2)-induced smooth muscle contraction has been implicated in cardiovascular, renal and respiratory diseases. This contraction can be partly attributed to TxA2-induced Ca2+ influx, which resulted in vascular contraction via Ca2+-calmodulin-MLCK pathway. This study aims to identify the channels that mediate TxA2-induced Ca2+ influx in vascular smooth muscle cells.Methodology/Principal Findings
Application of U-46619, a thromboxane A2 mimic, resulted in a constriction in endothelium-denuded small mesenteric artery segments. The constriction relies on the presence of extracellular Ca2+, because removal of extracellular Ca2+ abolished the constriction. This constriction was partially inhibited by an L-type Ca2+ channel inhibitor nifedipine (0.5–1 µM). The remaining component was inhibited by L-cis-diltiazem, a selective inhibitor for CNG channels, in a dose-dependent manner. Another CNG channel blocker LY83583 [6-(phenylamino)-5,8-quinolinedione] had similar effect. In the primary cultured smooth muscle cells derived from rat aorta, application of U46619 (100 nM) induced a rise in cytosolic Ca2+ ([Ca2+]i), which was inhibited by L-cis-diltiazem. Immunoblot experiments confirmed the presence of CNGA2 protein in vascular smooth muscle cells.Conclusions/Significance
These data suggest a functional role of CNG channels in U-46619-induced Ca2+ influx and contraction of smooth muscle cells. 相似文献6.
It is very well known that progesterone induces uterine relaxation on myometrium contractile activity. However, little attention has been paid to the effect induced by its metabolites on human uterine contractility. Therefore, we set out to analyze the potential relaxing effect of some 5alpha- and 5beta-reduced progesterone derivatives on the spontaneous contractility of myometrium from pregnant women. Samples were obtained by caesarian section at 38-40 weeks of pregnancy. Spontaneous uterine contractions were recorded in vitro in the presence of progesterone, or progestins independently, at different non-cumulative microM concentrations. The progestins elicited an immediate relaxing effect that was concentration-dependent. With the exception of two 5alpha-reduced progestins (5alpha and 3beta,5alpha), the remaining progestins used in the present study were more potent than progesterone. The potency order with respect to their IC50 values was: 3alpha,5alpha (35 microM) > 5beta (81 microM) > 3beta,5beta (156 microM) > 3alpha,5beta (205 microM) > P4 (225 microM) > 5alpha (19 mM) > 3beta,5alpha (28 mM). When tissues were washed, the contractile activity was recovered. This rapid and reversible relaxing effect was not blocking by antiprogestin RU 486, suggesting that is not through receptor-mediated genomic action. The metabolites from progesterone may also determine the pattern of motility, ensuring the necessary quiescent environment to prevent abortion during gestation. 相似文献
7.
M.F. Gimeno A.M. Franchi E.T. Gonzlez A.L. Gimeno 《Prostaglandins & other lipid mediators》1987,33(1)
The accumulation and output of 3H -prostaglandins (PGs), E2 and F2α, into and from uterine strips isolated from ovariectomized rats, either in presence or in absence of exogenous progesterone, were explored. Tissue-to-medium ratio of 3H - counts (T/M-ratio), was determined. The same was done in solutions containing 14C-sucrose. During a 60 min incubation period in a solution containing 3H -PGF2α, a net accumulation of radioactivity was evident in control (no progesterone) uterine slices. The T/M-ratio for 3H-PGF2α, increased with time, reaching maximal values at 45 min. Progesterone (100 ug.ml−1) attenuated the uptake process, as evidenced by stable values of T/M-ratio, as time progressed. On the other hand, control T/M-ratio for fluenced by the presence of exogenous progesterone. Regarding labelled PG release from the tissue, it was observed that, during an experimental period of 60 min, most tritium from control slices was released within the first 30 min after incubation with 3H -PGF2α, whereas, following the presence and subsequent removal of exogenous progesterone, the bulk of 3H -released took place at 6–70 min. On the other hand, the release of 3H after an incubation with 3H -PGE2, was also maximal as that for 3H -PGF2, α within the first 30 min and resulted not altered after a period of exposure and removal of progesterone. The foregoing results suggest an specific pharmacological effect of progesterone, attenuating the uptake and retarding the outflow of PGF2α, but not that of PGE2, into and from uterine slices of ovariectomized rats. Findings reported herein are discussed in terms of progesterone priming and withdrawal, in relation to PGF2α fluxes in the rat uterus during the sex cycle, as well as in relation to PG binding to tissue receptors. 相似文献
8.
17ß-estradiol and progesterone were administered to post-menopausal women to determine their effects
on the capacity of human endometrium to synthesize prostaglandins (PGs) F2α and E. Basal amounts of PGF2α and PGE synthesized by endometrium exposed to 17ß-estradiol and progesterone were significantly higher than the levels produced by endometrium exposed to 17ß-estradiol alone (p < 0.02 for both PGs). Levels found in the former endometrium were broadly comparable to levels in secretory endometrium and in the latter to amounts found in proliferative endometrium of spontaneous, ovulatory cycles. 相似文献
9.
The mechanism of stimulatory and inhibitory action of PGF2α on ovarian steroidogenesis both under
and
conditions has been studied in the pseudo-pregnant rabbits. Short term incubation of the ovaries with PGF2α (2.82 × 10−5M) resulted in an increased synthesis of progesterone and 20α-OH P. The addition of PGF2α in the medium and further incubation of the ovaries obtained from rabbits that had been constantly infused with PGF2α (0.5 μg/min.) for two hours resulted in increased synthesis of these progestins. The ratio of progesterone to 20α -OH P was also enhanced under these conditions and thus supported the luteotropic action of small doses of PGF2α under short term incubations. However, as the amount of PGF2α infused was increased to 5 μg/min., the addition of PGF2α under
conditions strikingly decreased the production of these progestins. The ratio of progesterone to 20α -OH P was also decreased and thus was indicative of luteolytic action of higher doses of PGF2α. High doses of PGF2α (5.64 × 10−4M) failed to I cause any significant change in the progestin synthesis under short term incubation. These results thus suggest that the luteotropic and luteolytic action of PGF2α in the luteinized rabbit ovary is dose and time dependent. 相似文献
10.
M. Viggiano A.M. Franchi A. Faletti M.A.F. Gimeno A.L. Gimeno 《Prostaglandins & other lipid mediators》1988,36(3)
The effects of exogenous histamine (H) on prostaglandin (PG) generation and release in uteri isolated from diestrous rats and the influences of H2-receptors blockers (cimetidine and mitiamide) on the output of uterine PGs, were explored. Moreover, the action of H on the uterine 9-keto-reductase, was also studied. Histamine (10−4M) failed to alter the basal output of PGE1 but reduced significantly the generation and release of PGE2 and augmented the output of PGF2α. On the other hand, cimetidine (10−5M) enhanced the basal release of PGE2 but had no action on the outputs of PGs E1 or F2α. The enhancing effect of H on the production and release of PGF2α was abolished in the presence of cimetidine. Also, the antagonist reversed the influence of H on the output of PGE2. Metiamide, another H2-receptor antagonist, did not alter the basal control generation and release of uterine PGs, but antagonized the augmenting influence of H on PGF2α uterine output, as much as cimetidine did, and prevented the depressive action of H on the release of PGE2 from uteri. Histamine (10−4M) significantly stimulated uterine formation of cyclic-adenosine monophosphate, an action which was antagonized by the presence of cimetidine (10−5M), a blocker of H2 receptors. Also, histamine (10−5M) and dibutyril-cyclic-adenosine monophosphate (DB-cAMP) at 10−3M, enhanced significantly the formation 3H-PGF2α from 3H-PGE2. Results presented herein demonstrate that H is able to diminish the generation of PGE2 in uteri from rats at diestrus augmenting the synthesis of PGF2α, apparently via the activation of H2-receptors, enhancing adenylate-cyclase. These effects appear to increase uterine 9-keto-reductase activity which transforms PGE2 into PGF2α. Relationships between the foregoing results and those evoked by estradiol, are also discussed. 相似文献
11.
Prostaglandins (PGs) F2α and D2 are bronchoconstrictor agents which are released under allergic conditions such as asthma. The efficacy and potency of PGF2α and PGD2 differ in some tissues. We compared the effects of these two PGs in sensitized human parenchymal strips. In six experiments, PGF2α 0.1 and 0.3 μM produced greater contractions than PGD2 at the same concentrations. There were no significant differences between the contractions from the two PGs at concentrations of 0.01, 0.03, 1.0–10 μM and the two PGs appeared to be equipotent.We studied the effects of the anti-asthmatic drug theophylline, and its analogue enprofylline, on the contraction caused by these PGs. Theophylline 100 μM caused no change to the cumulative concentration response curves. However, enprofylline 100 μM reduced the PGF2α-induced contractions. 相似文献
12.
Ovulation (active expulsion of oocyte from the mature follicle) of trout follicles matured
can be induced
by adding PGF2α at doses of 1 and 5 μg/ml. PGE2 is ineffective.The
induction of ovulation by PGF2α is inhibited in a calcium free medium or by inhibitors of calcium influx, particularly by Mn++ and La+++, suggesting that ovulation process implies active contraction of the smooth muscle cells of the theca.A significant but partial inhibition is also observed with cytochalasin B (1 and 5 μg/ml) demonstrating that contraction of other cell types than muscle, containing actin-like filaments, may also participate in the process. 相似文献
13.
Priya Putta Andrew H. Smith Pinaki Chaudhuri Rocio Guardia-Wolff Michael A. Rosenbaum Linda M. Graham 《The Journal of biological chemistry》2021,297(4)
During vascular interventions, oxidized low-density lipoprotein and lysophosphatidylcholine (lysoPC) accumulate at the site of arterial injury, inhibiting endothelial cell (EC) migration and arterial healing. LysoPC activates canonical transient receptor potential 6 (TRPC6) channels, leading to a prolonged increase in intracellular calcium ion concentration that inhibits EC migration. However, an initial increase in intracellular calcium ion concentration is required to activate TRPC6, and this mechanism remains elusive. We hypothesized that lysoPC activates the lipid-cleaving enzyme phospholipase A2 (PLA2), which releases arachidonic acid (AA) from the cellular membrane to open arachidonate-regulated calcium channels, allowing calcium influx that promotes externalization and activation of TRPC6 channels. The focus of this study was to identify the roles of calcium-dependent and/or calcium-independent PLA2 in lysoPC-induced TRPC6 externalization. We show that lysoPC induced PLA2 enzymatic activity and caused AA release in bovine aortic ECs. To identify the specific subgroup and the isoform(s) of PLA2 involved in lysoPC-induced TRPC6 activation, transient knockdown studies were performed in the human endothelial cell line EA.hy926 using siRNA to inhibit the expression of genes encoding cPLA2α, cPLA2γ, iPLA2β, or iPLA2γ. Downregulation of the β isoform of iPLA2 blocked lysoPC-induced release of AA from EC membranes and TRPC6 externalization, as well as preserved EC migration in the presence of lysoPC. We propose that blocking TRPC6 activation and promoting endothelial healing could improve the outcomes for patients undergoing cardiovascular interventions. 相似文献
14.
15.
Bone is a target tissue of progestins, but the mechanisms by which they act are still unclear. We examined the early (5-60 s) effects of progesterone and progesterone covalently bound to BSA (P-CMO BSA), which does not enter the cell, on the cytosolic free Ca(2+) concentration ([Ca(2+)]i) and the formation of inositol 1,4,5 trisphosphate (InsP3) and diacylglycerol (DAG) in confluent female and male rat osteoblasts. P-CMO BSA like free progesterone increased [Ca(2+)]i via Ca(2+) influx through L-type Ca(2+) channels and Ca(2+) mobilization from the endoplasmic reticulum. Both progestins increased InsP(3) and DAG formation within 10 s, and the increase was blocked by phospholipase C inhibitors (neomycin and U-73122). Progesterone and P-CMO BSA mobilized calcium from the endoplasmic reticulum via the activation of a phospholipase C linked to a pertussis toxin-insensitive G-protein in both osteoblast types, and this process was controlled by protein kinase C. Neither progestin had any effect on cAMP formation in male and female osteoblasts. The membrane effects were not blocked by a progesterone nuclear antagonist. They were independent of the concentration of nuclear receptors and not linked to gender. Thus, progesterone appears to act in female and male rat osteoblasts via unconventional cell-surface receptors which belong to the class of membrane receptors coupled to phospholipase C via a pertussis toxin-insensitive G-protein. The bifurcating pathways leading to the formation of InsP(3) and DAG may provide a certain flexibility in controlling cell responses, both by their nature and by their rates of formation and degradation. 相似文献
16.
A. Faletti M. A. Chaud M. A. F. Gimeno A. L. Gimeno 《Prostaglandins, leukotrienes, and essential fatty acids》1988,34(3)
The effects of morphine on the constancy of spontaneous contractions (isometric developed TENSION = IDT and contractile FREQUENCY = CF), in uterine strips isolated from ovariectomized rats and the influence of naloxone, were explored. The inotropic responses to added prostaglandins (PGs) E2 and F2α and the influences of morphine and of morphine in the presence of naloxone on PG actions, were also determined. Moreover, the synthesis and outputs of PGs E and F from uteri and the effects of morphine alone and of morphine plus naloxone, were studied. Morphine (10−6 M) significantly depressed uterine constancy of IDT during the first hours following delivery, but its action on CF did not differ from controls. Naloxone, neither at 10−8 M nor at 10−6 M, altered the negative inotropoic influence of morphine on IDT. Exogenous PGs E2 and F2α, stimulated uterine inotropism in a concentration-dependent fashion. Morphine altered dose-response curves for exogenous PGE2, evoking a parallel surmountable shift to the right, but did not affect the inotropic action of added PGF2α. This antagonistic effect of the opioid was not altered by preincubation with naloxone. Basal synthesis and outputs of PGs E and F in uteri from ovariectomized rats were significantly depressed by morphine (10−6 M) but not altered by incubating tissues with morphine in presence of naloxone. Results are discussed in terms of a presumptive dual action of morphine on uterine motility, i.e., antagonizing PGE2 receptors and inhibiting the synthesis of some PGs by the uterus. These influences of morphine do not appear to be subserved by the activation of μ opioid receptors. Moreover, the possibility that endogenous opioids could play a relevant role modulating uterine PG influences, is also discussed. 相似文献
17.
Ten natural progestins were evaluated for their capacity to inhibit the motility of rat's uterus. Progestins with their ring A reduced in the 5β position were significantly more potent than Δ4-3 keto and 5α reduced progestins. These last progestins were ineffective to inhibit uterine motility excepting 3α-hydroxy-5α-pregnan-20-one which was slightly less effective than progesterone. The potency of the progestins to inhibit uterine motility was related to their capacity to induce membrane stabilization. The data indicates that 5β, but not 5α reduction of progesterone, may be important for regulating myometrial activity. 相似文献
18.
Svend Maigaard Axel Forman Karl-Erik Andersson 《Prostaglandins & other lipid mediators》1985,30(4):599-607
Tubal segments of the ascending uterine arteries and of intramyometrial arteries were obtained from 18 women who underwent hysterectomy at various phases of the menstrual cycle. Ring preparations of the vessels were mounted in organ baths and isometric tension was recorded. In extramyometrial arteries (outer diameter 2–3 mm) prostaglandin (PG) F2α most potently, but also PGE2 caused concentration-related contractions. In contrast, the contractant effects of both PGs on intramyometrial arteries (outer diameter 0.5–0.6 mm) were negligible. Both extra- and intramyometrial vessels were relaxed to a moderate degree (10–25%) by low concentrations of PGF2α and PGE2. No significant differences between the responses to vasopressin and noradrenaline were found between the vessel preparations. Thus human uterine arteries seem to change their responses to PGF2α and PGE2 as they enter the myometrium and decrease in diameter, and the results raise doubt about the view that direct vasoconstrictor effects of these PGs contribute to the regulation of myometrial blood flow. Such effects of vasopressin and noradrenaline cannot be excluded. 相似文献
19.
J.J. Knickerbocker W.W. Thatcher F.W. Bazer D.H. Barron R.M. Roberts 《Prostaglandins & other lipid mediators》1986,31(4)
The effect of bovine conceptus secretory proteins (CSP) on uterine prostaglandin (PG)-F2α production was evaluated in dairy cattle following injection of estradiol-17β. Intrauterine injections of dialyzed serum proteins (Control, n=5) or CSP (n=5) were administered from days 15 through 18 post-estrus. Following intrauterine treatments on day 18, all cows were injected with E2 (3 mg) to stimulate uterine PGF2α production. Plasma concentrations of progesterone (P4) and 15-keto-13,14-dihydro-PGF2α (PGFM) were determined by RIA. The PGFM responses following E2 challenge were decreased (p<0.01) for cows receiving CSP versus serum proteins into the uterine lumen. Individual PGFM, P4 and cycle length responses are discussed. Data suggest that proteins secreted by the bovine conceptus suppress uterine PGF2α production during pregnancy recognition in the cow. 相似文献
20.
Dong-Mei Zhang Yong Li Wai San Cheang Chi Wai Lau Shun-Ming Lin Qian-Lan Zhang Nan Yao Ying Wang Xin Wu Yu Huang Wen-Cai Ye 《PloS one》2012,7(10)
Cajaninstilbene acid (CSA) is a major active component present in the leaves of Cajanus cajan (L.) Millsp. The present study explores the underlying cellular mechanisms for CSA-induced relaxation in rat renal arteries. Vascular reactivity was examined in arterial rings that were suspended in a Multi Myograph System and the expression of signaling proteins was assessed by Western blotting method. CSA (0.1–10 µM) produced relaxations in rings pre-contracted by phenylephrine, serotonin, 9, 11-dideoxy-9α, 11α-epoxymethanoprostaglandin F2α (U46619), and 60 mM KCl. CSA-induced relaxations did not show difference between genders and were unaffected by endothelium denudation, nor by treatment with NG-nitro-L-arginine methyl ester, indomethacin, ICI-182780, tetraethylammonium ion, BaCl2, glibenclamide, 4-aminopyridine or propranolol. CSA reduced contraction induced by CaCl2 (0.01–5 mM) in Ca2+-free 60 mM KCl solution and by 30 nM (−)-Bay K8644 in 15 mM KCl solution. CSA inhibited 60 mM KCl-induced Ca2+ influx in smooth muscle of renal arteries. In addition, CSA inhibited contraction evoked by phorbol 12-myristate 13-acetate (PMA, protein kinase C agonist) in Ca2+-free Krebs solution. Moreover, CSA reduced the U46619- and PMA-induced phosphorylation of myosin light chain (MLC) at Ser19 and myosin phosphatase target subunit 1 (MYPT1) at Thr853 which was associated with vasoconstriction. CSA also lowered the phosphorylation of protein kinase C (PKCδ) at Thr505. In summary, the present results suggest that CSA relaxes renal arteries in vitro via multiple cellular mechanisms involving partial inhibition of calcium entry via nifedipine-sensitive calcium channels, protein kinase C and Rho kinase. 相似文献