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71.
Kalyuzhin OV Nelyubov MV Kalyuzhina EV Kuzovlev FN Shkalev MV 《Bulletin of experimental biology and medicine》2002,134(3):281-283
Effects of 11 original glycoside derivatives of muramyl dipeptide on the production of interleukin-1 and tumor necrosis factor by mouse peritoneal macrophages were studied. The relationship between macrophage activation evaluated by induction of these cytokines and configuration of glycoside bond and aglycon structure of MDP was revealed. 相似文献
72.
GREGORY V. NIKIFOROVICH ALEXANDER A. GOLBRAIKH MARK D. SHENDEROVICH JURIS BALODIS 《Chemical biology & drug design》1990,36(3):209-218
Models of μ- and δ-receptor-bound backbone conformations of enkephalin cyclic analogues containing Phe4 were determined by comparing geometrical similarity among the previously found low-energy, backbone structures of -enkephalinamide, -enkephalinamide, -enkephalin and -enkephalin. The present μ-receptor-bound conformation resembles a β-I bend in the peptide backbone centred on the Gly3-Phe4 region. Two slightly different models were found for the δ-receptor-bound conformation; both of them are more extended than the μ-receptor-bound conformation and include a γ-turn (or a γ-like turn) on the Gly3 residue. Energetically favourable rotamers of Tyr and Phc side chains were also determined for the μ- and δ-conformations. The present models of μ- and δ-conformations share geometrical similarity with the low-energy structures of Leu-enkephalin and the analogue. 相似文献
73.
S. Gundersen S. Kvinnsland S. Lundgren O. Klepp E. Lund O. Børmer H. Høst 《Breast cancer research and treatment》1990,17(1):45-50
Summary One-hundred and seventy patients with estrogen receptor positive (10 pmol/g protein) advanced breast cancer have been treated in a prospective randomized study either with continuous tamoxifen 30 mg × 1 daily (TAM), or with TAM 30 mg × 1 daily for 8 weeks alternating with medroxyprogesterone acetate 500 mg × 2 daily for 8 weeks (TAM/HD-MPA). The response rate was 62% in the group treated with cyclic TAM/HD-MPA versus 41% in the TAM alone group (p = 0.02). There was no significant difference in duration of remissions or survival. 相似文献
74.
目的:观察大鼠心脏两种负荷状况时环化鸟苷一磷酸(cGMP)对心肌细胞摄取葡萄糖的影响。方法:应用cGMP类似物8-BrcGMP、一氧化氮合酶(NOS)抑制剂L-NAME和NO供体SNAP灌注Wistar大鼠心脏,并用放免法测定组织内cGMP浓度。根据2-^3H标记率计算葡萄糖摄取量。结果:低负荷状况时8-BrcGMP使冠脉血流增加,细胞内糖原浓度升高。高负荷状况时8-BrcGMP使心排出量减少,心肌细胞对葡萄糖摄取减少和使糖原浓度降低。L-NAME降低心肌细胞cGMP逍度,并刺激葡萄糖摄取,而SNAP作用则相反。结论:心肌细胞内cGMP浓度升高,可抑制葡萄糖摄取;而NOS抑制剂L-NAME则能降低cGMP浓度,使心肌细胞葡萄糖摄取增加,糖原分解减少,使缺血心肌功能受到保护。 相似文献
75.
Anita Eckly-Michel Viviane Martin Claire Lugnier 《British journal of pharmacology》1997,122(1):158-164
- The involvement of cyclic AMP-dependent protein kinase (PKA) and cyclic GMP-dependent protein kinase (PKG) in the effects of cyclic AMP-elevating agents on vascular smooth muscle relaxation, cyclic nucleotide dependent-protein kinase activities and ATP-induced calcium signalling ([Ca2+]i) was studied in rat aorta. Cyclic AMP-elevating agents used were a β-adrenoceptor agonist (isoprenaline), a phosphodiesterase 3 (PDE3) inhibitor (SK&F 94120) and a PDE4 inhibitor (rolipram).
- In rat intact aorta, the relaxant effect induced by isoprenaline (0.01–0.3 μM) was decreased by a specific inhibitor of PKA, H-89, whereas a specific inhibitor of PKG, Rp-8-Br-cyclic GMPS, was without effect. No significant difference in PKA and PKG activity ratios was detected in aortic rings when isoprenaline 10 μM was used. At the same concentration, isoprenaline did not modify ATP-induced changes in [Ca2+]i in smooth muscle cells. Neither H-89 nor Rp-8-Br-cyclic GMPS modified this response. These findings suggest that PKA is only involved in the relaxant effect induced by low concentrations of isoprenaline (0.01–0.3 μM), whereas for higher concentrations, other mechanisms independent of PKA and PKG are involved.
- The relaxant effects induced by SK&F 94120 and rolipram were inhibited by Rp-8-Br-cyclic GMPS with no significant effect of H-89. Neither SK&F 94120, nor rolipram at 30 μM significantly modified the activity ratios of PKA and PKG. Rolipram inhibited the ATP-induced transient increase in [Ca2+]i. This decrease was abolished by Rp-8-Br-cyclic GMPS whereas H-89 had no significant effect. These results suggest that PKG is involved in the vascular effects induced by the inhibitors of PDE3 and PDE4. Moreover, since it was previously shown that PDE3 and PDE4 inhibitors only increased cyclic AMP levels with no change in cyclic GMP level, these data also suggest a cross-activation of PKG by cyclic AMP in rat aorta.
- The combination of 5 μM SK&F 94120 with rolipram markedly potentiated the relaxant effect of rolipram. This relaxation was decreased by H-89 and not significantly modified by Rp-8-Br-cyclic GMPS. Moreover, the association of the two PDE inhibitors significantly increased the activity ratio of PKA without changing the PKG ratio. The present findings show that PKA rather than PKG is involved in this type of vasorelaxation. The differences in the participation of PKA vs PKG observed when inhibitors of PDE3 and PDE4 were used alone or together could be due to differences in the degree of accumulation of cyclic AMP, resulting in the activation of PKA or PKG which are differently localized in the cell.
- These findings support a role for both PKA and PKG in cyclic AMP-mediated relaxation in rat aorta. Their involvement depends on the cellular pathway used to increase the cyclic AMP level.
76.
Hideo Tanaka Yoshizumi Habuchi Taku Yamamoto Manabu Nishio Junichiro Morikawa Manabu Yoshimura 《British journal of pharmacology》1997,122(2):321-329
- The effects of endothelin-1 (ET-1) on sinoatrial (SA) node preparations of the rabbit heart were studied by means of whole-cell clamp techniques.
- ET-1 at 1 nM slowed the spontaneous beating activity and rendered half of the cells quiescent. At a higher concentration of 10 nM, the slowing and cessation of spontaneous activity were accompanied by hyperpolarization.
- In voltage-clamp experiments, ET-1 decreased the basal L-type Ca2+ current (ICa(L)) dose-dependently with a half-maximal inhibitory concentration (EC50) of 0.42 nM and maximal inhibitory response (Emax) of 49.5%. The delayed rectifying K+ current (IK) was also reduced by 33.2±11.1% at 1 nM. In addition, an inwardly rectifying K+ current was activated by ET-1 at higher concentrations (EC50=4.8 nM). These ET-1-induced changes in membrane currents were abolished by BQ485 (0.3 μM), a highly selective ETA receptor antagonist.
- When ICa(L) was inhibited by ET-1 (1 nM), subsequent application of 10 μM ACh showed no additional decrease in ICa(L), suggesting the involvement of cyclic AMP in the effects of ET-1 on ICa(L). In contrast, 1 nM ET-1 further decreased ICa(L) in the presence of 10 μM ACh, suggesting that ET-1 activates some additional mechanism(s) which inhibit ICa(L). The ET-1-induced ICa(L) inhibition was abolished by protein kinase A inhibitory peptide (PKI, 20 μM) or H-89 (5 μM). However, the ICa(L) inhibition was not affected by methylene blue (10 μM), suggesting a minor role for cyclic GMP in the effect of ET-1 under basal conditions.
- ET-1 failed to inhibit ICa(L) when the pipette contained GDPβS (200 μM). However, incubation of the cells with pertussis toxin (PTX, 5 μg ml−1, >6 h) only reduced the ET-1-induced inhibition to 21.5±9.5%, whereas it abolished the inhibitory effect of ACh on ICa(L).
- Intracellular perfusion of 8-bromo cyclicAMP (8-Br cyclicAMP, 500 μM) attenuated, but did not abolish the inhibitory effect of ET-1 on ICa(L). This 8-Br cyclicAMP-resistant component (17.5±14.4%, n=20) was not affected by combined application of 8-Br cyclicAMP with 8-bromo cyclicGMP (500 μM), ryanodine (1 μM) or phorbol-12-myristate-13-acetate (TPA; 50 nM).
- In summary, ET-1 exerts negative chronotropic effects on the SA node via ETA-receptors. ET-1 inhibits both ICa(L) and IK, and increases background K+ current. The inhibition of ICa(L) by ET-1 is mainly due to reduction of the cyclicAMP levels via PTX-sensitive G protein, but some other mechanism(s) also seems to be operative.
77.
Satoko Takizawa Hiroshi Ozaki Hideaki Karaki 《European journal of pharmacology》1997,330(2-3):143-150
Stimulation of vascular smooth muscle by bacterial lipopolysaccharide has been shown to produce interleukin-1β and to induce vasodilation in septic shock. To understand the mechanisms of interleukin-1β-induced relaxation, we examined the effects of interleukin-1β on contractility and cyclic GMP contents of vascular smooth muscle. After treatment of the rat aorta with interleukin-1β (20 ng/ml) for 6 h, the cyclic GMP content increased and the contraction induced by phenylephrine (1 μM) was partially inhibited. An inhibitor of nitric oxide (NO) synthase, NG-monomethyl-
-arginine (
-NMMA, 100 μM), prevented the inhibitory effect of interleukin-1β. After treatment with interleukin-1β for 24 h, the phenylephrine-induced contraction was inhibited more strongly. Neither
-NMMA (100 μM) nor aminoguanidine (100 μM) reversed the inhibition, whereas methylene blue (10 μM) partially reversed the inhibition. After treatment with interleukin-1β for 12 or 24 h, the cyclic GMP content increased but to a level lower than that obtained with a 6-h treatment. The effects of sodium nitroprusside (1 μM) to inhibit the phenylephrine-induced contraction and to increase the cyclic GMP content were markedly suppressed by the 24-h interleukin-1β treatment. In contrast, the 24-h interleukin-1β treatment did not change the ability of 8-bromo-cGMP to relax the phenylephrine-stimulated aorta. Addition of
-NMMA (1 mM) during the 24 h treatment prevented NO production and preserved the sodium nitroprusside-induced cGMP generation by interleukin-1β. The 24 h interleukin-1β treatment increased the threshold concentration of KCl needed to induce contraction without changing the maximum contraction. In the presence of 25.4 mM KCl or the non-selective K+ channel inhibitor, tetraethylammonium, the inhibitory effect of the 24-h interleukin-1β treatment on phenylephrine-induced contraction was restored. These results suggest that interleukin-1β inhibits vascular smooth muscle contraction by a time-dependent, dual mechanism. After a 6-h treatment with interleukin-1β, the NO/cyclic GMP system is activated. After a 24-h interleukin-1β treatment, in contrast, the NO/cyclic GMP system may be desensitized and the contraction of vascular smooth muscle is inhibited by another mechanism, possibly membrane hyperpolarization. 相似文献
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78.
Jacqui Cooper Stephen J Hill Stephen P H Alexander 《British journal of pharmacology》1997,122(3):546-550
- Cyclic AMP generation by adenosine analogues was examined in human embryonic kidney (HEK 293) cells by use of a [3H]-adenine pre-labelling methodology.
- Adenosine analogues showed the following rank order of potency (pD2 value): 5′-N-ethylcarboxamidoadenosine (NECA, 5.24)>2-chloroadenosine (4.41) ⩾ adenosine (4.19)=N6-(2-(4-aminophenyl)-ethylamino)adenosine (APNEA, 4.11). The A2A-selective agonist failed to elicit a significant stimulation of cyclic AMP generation at concentrations below 30 μ CGS21680M.
- Of these agents, NECA was observed to exhibit the greatest intrinsic activity, while in comparison maximal responses to adenosine (76±8% NECA response), 2-chloroadenosine (70±6%) and APNEA (40±3%) were significantly reduced.
- Antagonists of the NECA-evoked cyclic AMP generation showed the rank order of apparent affinity (apparent pA2 value): CGS 15943 (7.79)=XAC (7.74)>DPCPX (7.01)=PD115199 (6.93)=8FB-PTP (6.80)>KF 17837 (5.98)>3-propylxanthine (5.13).
- Agarose gel electrophoresis of the products of the polymerase chain reaction, with cDNA generated from HEK 293 cell total RNA showed virtually identical patterns and nucleotide sizes in comparison with the vector for the full length human brain A2B adenosine receptor.
- We concluded that HEK 293 cells express an endogenous adenosine receptor coupled to cyclic AMP generation which is of the A2B subtype.
79.
Kubota Toshiro; Kamada Shusaku; Taguchi Makoto; Aso Takeshi 《Human reproduction (Oxford, England)》1994,9(11):2118-2122
The present study was undertaken to investigate the effectsof transforming growth factor (TGF)-1 on ovarian steroidogenesisin immature or moderately mature porcine granulosa cells invitro. TGF-1 (0.0110 ng/ml) significantly attenuatedprogesterone release from the basal and follicle stimulatinghormone-stimulated porcine granulosa cells, and significantlyincreased DNA synthesis. TGF-1 also significantly increasedthe extracellular accumulation of cyclic AMP, but did not changethe production of inositol phosphate or the intracellular calciumconcentration in these cells. Thus, TGF-1 appears to have adirect effect on porcine granulosa cell function, regulatingthe differential synthesis of progesterone mainly via the intracellularsignal transduction of the cyclic AMPprotein kinase Apathway. This growth factor may play a physiologically significantrole in controlling differentiation of immature and moderatelymature porcine granulosa cells via an autocrine/paracrine mechanism. 相似文献
80.
Anne-Ulrike Trendelenburg Klaus Starke Norbert Limberger 《Naunyn-Schmiedeberg's archives of pharmacology》1994,350(5):473-481
2-Adrenoceptors modulating the release of dopamine were identified and characterized in slices of the head of the rabbit caudate nucleus. Release of endogenous dopamine was measured by fast cyclic voltammetry as the increase in the extracellular concentration of dopamine elicited by electrical stimulation. The electrochemical signal was identified as dopamine by means of the oxidation potential, the voltammogram and the fact that the signal was not changed by desipramine, which inhibits the high affinity uptake of noradrenaline, but was greatly increased by nomifensine, which in addition inhibits the high affinity uptake of dopamine.Stimulation by 6 pulses/100 Hz increased the extracellular concentration of dopamine by about 85 nM. The selective 2-adrenoceptor agonist 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK 14,304) reduced this release with an EC50 of 173 nM and by maximally 75%. The 2-adrenoceptor agonists clonidine and oxymetazoline only tended to cause a decrease. Six drugs, including oxymetazoline, were tested as antagonists against UK 14,304. Their order of antagonist potency (pKD values in brackets) was rauwolscine (8.0) > oxymetazoline (7.5) > 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane (WB 4101; 7.3) > phentolamine (7.1) > corynanthine (5.1) prazosin (< 6). Given alone, the antagonists did not change the release of dopamine elicited by 6 pulses/100 Hz, and the same was true for the dopamine receptor antagonist sulpiride. When caudate slices were stimulated by 10 pulses/1 Hz, sulpiride increased the release of dopamine. Desipramine and rauwolscine, in contrast, again caused no change.It is concluded that dopaminergic axons in the rabbit caudate nucleus possess release-inhibiting 2-adrenoceptors. The antagonist affinities indicate that they belong to the 2A subtype. In this, they agree with all presynaptic 2-autoreceptors studied so far in rabbits as well as with the 2-heteroreceptors modulating the release of serotonin in rabbit brain cortex, suggesting that at least the majority of presynaptic 2-adrenoceptors in the rabbit are 2A. The agonist sensitivity of the caudate presynaptic 2-adrenoceptors is low in comparison with cerebrocortical presynaptic 2-autoreceptors, possibly due to absence of a receptor reserve.
Correspondence to: N. Limberger at the above address 相似文献