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1.
Leukotriene D4 receptor-mediated hydrolysis of phosphoinositide and mobilization of calcium in sheep tracheal smooth muscle cells 总被引:4,自引:0,他引:4
S Mong J Miller H L Wu S T Crooke 《The Journal of pharmacology and experimental therapeutics》1988,244(2):508-515
A sheep tracheal smooth muscle primary culture cell system was developed to characterize leukotriene D4 (LTD4) receptor-mediated biochemical and pharmacological effects. [3H]LTD4 binding to the enriched plasma membrane receptor was specific, stereoselective and saturable. LTE4 and high affinity receptor antagonists bound to the receptors with a rank-order potency that was expected from previous smooth muscle contraction studies. In the [3H]myoinositol labeled cells, LTD4 and LTE4 induced phosphoinositide hydrolysis. The biosynthesis of [3H]inositol-trisphosphate was rapid and the induction of biosynthesis of [3H]inositol-monophosphate by LTs was stereoselective and specific and was inhibited specifically by a receptor antagonist, SKF 104353. In the fura-2 loaded smooth muscle cells, LTD4 and LTE4 induced transient intracellular Ca++ mobilization. The fura-2/Ca++ transient was stereoselective and specific and was inhibited by receptor antagonist, SKF 104353. These results suggest that the cultured sheep tracheal smooth muscle cells have plasma membrane receptors for LTD4. These receptors were coupled to a phospholipase C that, when activated by agonists, induced hydrolysis of inositol containing phospholipids. The hydrolysis products, e.g. diacylglycerol and inositol-trisphosphate, may serve as intracellular messengers that trigger or contribute to the contractile effect in sheep tracheal smooth muscle. 相似文献
2.
A re-evaluated role for cyclic AMP in uterine relaxation. Differential effect of isoproterenol and forskolin 总被引:1,自引:0,他引:1
L Do Khac A Mokhtari S Harbon 《The Journal of pharmacology and experimental therapeutics》1986,239(1):236-242
Our previous observations suggested that beta adrenergic-mediated relaxation of the rat myometrium could not be ascribed solely to cyclic AMP. The present study examines the relationships between relaxation and cyclic AMP accumulation in the myometrium in response to isoproterenol, forskolin and the combination of both. The diterpene enhanced cyclic AMP generation and potentiated the rises in cyclic AMP due to isoproterenol and prostaglandin (PG) E2. Isoproterenol-induced relaxation of a carbachol-contracted myometrium was associated with modest increments in cyclic AMP (6-12 pmol/mg of protein) in contrast to forskolin whose relaxing effect could be expressed only when associated with large increases in cyclic AMP (80-180 pmol/mg of protein). PGE2, although elevating cyclic AMP to the same extent as isoproterenol, caused contractions which were antagonized by isoproterenol and forskolin, respectively, associated with low and high cyclic AMP concentrations. Both PGE2 and forskolin, by virtue of their stimulatory effect on cyclic AMP generation, enhanced the efficiency of isoproterenol to cause relaxation. Likewise, the greater efficacy of forskolin to relax a PGE2- as opposed to a carbachol-contracted myometrium, was ascribed to its potentiated cyclic AMP response when combined with PGE2. It is proposed that the beta adrenoceptor-linked relaxation results from the concerted effects of both a cyclic AMP-dependent (sensitive to low cyclic AMP) and a cyclic AMP-independent process; the latter is postulated to operate at the membrane level with an ultimate reduction in cytosolic Ca++. On the other hand, cyclic AMP, provided it reached a critical concentration essential to mediate intracellular Ca++ sequestration, would be the sole determinant for forskolin-elicited relaxation. 相似文献
3.
Background: Hypercapnia is associated with diaphragm muscle dysfunction that causes a reduction of diaphragmatic force generated for a constant elective myographic activity. No published data are available concerning hypercapnic depression of diaphragmatic contractility during dibutyryl cyclic adenosine monophospate (DBcAMP) administration.Objective: The aim of this study was to assess the effects of DBcAMP on hypercapnic depression of diaphragmatic contractility in pentobarbital-anesthetized dogs.Methods: This experimental study was conducted from July to December 2008 at the Department of Anesthesiology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan. Adult (aged >5 years) mongrel dogs weighing 10 to 15 kg were randomly divided into 3 equal groups. Hypercapnia (80-90 mm Hg) was induced with 10% carbon dioxide added to the inspired gas. When hypercapnia was established, group 1 was infused with low-dose DBcAMP (0.05 mg/kg/min); group 2 was infused with high-dose DBcAMP (0.2 mg/kg/min); and group 3 received placebo (saline). Study drug was administered intravenously for 60 minutes. Diaphragmatic contractility was assessed by transdiaphragmatic pressure (Pdi) at baseline, induction of hypercapnia, and study drug administration.Results: Twenty-one dogs were divided into 3 groups of 7. There were no significant differences observed at baseline. In the presence of hypercapnia, Pdi (mean [SD], cm H2O) at low- (20-Hz) and high-frequency (100-Hz) stimulation was significantly decreased from baseline in each group (all, P = 0.001). In groups 1 and 2, Pdi at both stimuli was significantly increased during DBcAMP administration compared with hypercapnia-induced values (group 1: 20-Hz, 13.5 [2.2] vs 15.0 [2.4], respectively, P = 0.001, 100-Hz, 21.2 [1.6] vs 22.5 [1.6], P = 0.001; group 2: 20-Hz, 13.7 [1.4] vs 19.2 [1.7], P = 0.001, 100-Hz, 21.0 [2.4] vs 27.2 [2.5], P = 0.001). The Pdi at both stimuli during DBcAMP administration was significantly higher in group 2 than in group 1 (20-Hz, 19.2 [1.7] vs 15.0 [2.4], P = 0.001, 100-Hz, 27.2 [2.5] vs 22.5 [1.6], P = 0.003). In group 3, Pdi did not significantly change in regard to either stimulus from hypercapnia-induced values.Conclusion: DBcAMP, in a dose-dependent manner, was associated with improved hypercapnic depression of diaphragmatic contractility in these pentobarbital-anesthetized dogs. 相似文献
4.
T J Torphy C Zheng S M Peterson R R Fiscus G A Rinard S E Mayer 《The Journal of pharmacology and experimental therapeutics》1985,233(2):409-417
Functional antagonism between bronchoconstricting and bronchodilating pathways was examined in canine tracheal smooth muscle. Trachealis strips were contracted with either 0.3 microM (EC55) or 3.0 microM (EC80) methacholine before being relaxed by the cumulative addition of isoproterenol, prostaglandin E2, or forskolin. The EC50 for all three relaxants was increased 10-fold in tissues contracted with 3.0 microM methacholine vs. those contracted with 0.3 microM methacholine. Moreover, contracting tissues with the higher concentration of methacholine reduced the maximum relaxation induced by prostaglandin E2 and isoproterenol. Forskolin produced total relaxation regardless of the concentration of methacholine used and thus was a much more effective bronchodilator than either isoproterenol or prostaglandin E2. The inhibitory effect of methacholine on the relaxant response to these agents was paralleled by a reduction in drug-stimulated cyclic AMP-dependent protein kinase activity. Methacholine reduced the maximum activation of cyclic AMP-dependent protein kinase elicited by isoproterenol, prostaglandin E2 and submaximal concentrations of forskolin, which was a much more powerful enzyme activator than the other two agents. The ability of a maximum concentration of forskolin (30 microM) to activate cyclic AMP-dependent protein kinase was not inhibited by methacholine. Although methacholine also appeared to suppress drug-stimulated cyclic AMP accumulation, the inhibitory effect was only statistically significant in forskolin-treated tissues.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
5.
6.
Relaxant effect of amiloride on canine tracheal smooth muscle 总被引:1,自引:0,他引:1
Amiloride, a K+-sparing diuretic, relaxed canine tracheal smooth muscle strips contracted isometrically with high potassium (KCl), carbachol, serotonin and histamine. This indicated that relaxation was not linked to an interaction with an agonist specific receptor. Amiloride-induced relaxation was also not mediated through the production of relaxant prostaglandins, or by the endogenous release of catecholamines. During potassium contractions, amiloride addition produced a slow monophasic, dose-dependent relaxation (IC50 = 12.3 microM). In carbachol contracted strips, 1 and 10 microM amiloride induced a slow monophasic relaxation. With 35 to 250 microM, an initial rapid phase (IC50 = 75.5 microM) was superimposed onto this slow phase (IC50 = 23.5 microM), producing a biphasic relaxation. The rates of relaxation decreased with increased external [Na+] regardless of stimulus, suggesting possible competitive inhibition of a sodium-dependent process. Exposure caused a rapid decline in tension followed by a recovery phase. Tension maintenance during potassium contraction decreased transiently upon the addition of acid to a much lesser extent. Amiloride (100 microM) depressed tension recovery after acid exposure in both cases. Based on the known actions of this drug, inhibition of the Na+-H+ antiporter appears to be consistent with these data. This suggests amiloride may well belong to a new class of smooth muscle relaxants. 相似文献
7.
Azam MA Yoshioka K Ohkura S Takuwa N Sugimoto N Sato K Takuwa Y 《The Journal of pharmacology and experimental therapeutics》2007,320(2):907-916
We have recently demonstrated in vascular smooth muscle (VSM) that membrane depolarization by high KCl induces Ca(2+)-dependent Rho activation and myosin phosphatase (MLCP) inhibition (Ca(2+)-induced Ca(2+)-sensitization) through the mechanisms involving phosphorylation of myosin-targeting protein 1 (MYPT1) and 17-kDa protein kinase C (PKC)-potentiated inhibitory protein of PP1 (CPI-17). In the present study, we investigated whether and how cAMP affected Ca(2+)-dependent MLCP inhibition by examining the effects of forskolin, cell-permeable dibutyryl cAMP (dbcAMP), and isoproterenol. Forskolin, but not its inactive analog 1,9-dideoxyforskolin, inhibited KCl-induced contraction and the 20-kDa myosin light chain (MLC) phosphorylation without inhibiting Ca(2+) mobilization in rabbit aortic VSM. dbcAMP mimicked these forskolin effects. We recently suggested that Ca(2+)-mediated Rho activation is dependent on class II alpha-isoform of phosphoinositide 3-kinase (PI3K-C2alpha). Forskolin inhibited KCl-induced stimulation of PI3K-C2alpha activity. KCl-induced membrane depolarization stimulated Rho in a manner dependent on a PI3K but not PKC and stimulated phosphorylation of MYPT1 at Thr(850) and CPI-17 at Thr(38) in manners dependent on both PI3K and Rho kinase, but not PKC. Forskolin, dbcAMP, and isoproterenol inhibited KCl-induced Rho activation and phosphorylation of MYPT1 and CPI-17. Consistent with these data, forskolin, isoproterenol, a PI3K inhibitor, or a Rho kinase inhibitor, but not a PKC inhibitor, abolished KCl-induced diphosphorylation of MLC. These observations indicate that cAMP inhibits Ca(2+)-mediated activation of the MLCP-regulating signaling pathway comprising PI3K-C2alpha, Rho, and Rho kinase in a manner independent of Ca(2+) and point to the novel mechanism of the cAMP actions in the regulation of vascular smooth muscle contraction. 相似文献
8.
Functional antagonism in canine tracheal smooth muscle: inhibition by methacholine of the mechanical and biochemical responses to isoproterenol 总被引:9,自引:0,他引:9
T J Torphy G A Rinard M G Rietow S E Mayer 《The Journal of pharmacology and experimental therapeutics》1983,227(3):694-699
The biochemical basis for the functional interaction between bronchoconstricting and bronchodilating pathways was investigated. Contracting canine trachealis strips with increasing concentrations of methacholine resulted in a progressive shift to the right of isoproterenol concentration-response curves. Thus, the EC50 for the relaxant response to isoproterenol was nearly 500-fold higher in preparations exposed to 3.0 microM methacholine than in tissues exposed to 0.03 microM methacholine. The maximum relaxation produced by isoproterenol was also dependent upon the initial muscarinic cholinergic tone. For example, isoproterenol reversed completely the contraction induced by 0.03 microM methacholine but did not relax trachealis strips contracted with 30 microM methacholine. To identify the molecular mechanism responsible for this functional antagonism, experiments were conducted to determine the effect of methacholine on isoproterenol-stimulated cyclic AMP accumulation and cyclic AMP-dependent protein kinase activation. Methacholine did not alter basal cyclic AMP content but did reduce cyclic AMP accumulation in response to isoproterenol. Furthermore, the ability of isoproterenol to activate cyclic AMP-dependent protein kinase was inhibited by methacholine in a concentration-dependent manner. This inhibition paralleled the decrease in mechanical responsiveness to isoproterenol. These results suggest that muscarinic cholinergic stimulation of canine tracheal smooth muscle functionally antagonizes the relaxant responses to beta adrenergic agonists and that a portion of this antagonism may be due to a suppression of catecholamine-stimulated cyclic AMP accumulation and cyclic AMP-dependent protein kinase activation. 相似文献
9.
Prostacyclin modulates cholesteryl ester hydrolytic activity by its effect on cyclic adenosine monophosphate in rabbit aortic smooth muscle cells. 总被引:7,自引:5,他引:7
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D P Hajjar B B Weksler D J Falcone J M Hefton K Tack-Goldman C R Minick 《The Journal of clinical investigation》1982,70(3):479-488
We tested the hypothesis that prostacyclin (PGI2), 6-keto-prostaglandinF1 alpha(6-keto-PGF1 alpha), and several E series prostaglandins (PG) may affect the activity of cholesteryl ester (CE) hydrolase since our previous experiments indicated that smooth muscle cells (SMC) in neointima of injured rabbit aorta (a) acquire the capacity to produce PGI2 and (b) have increased lysosomal CE hydrolytic (acid cholesteryl ester hydrolase [ACEH])activity. Using cultured SMC from rabbit thoracic aorta, we demonstrated that PGI2, 6-keto-PGF1 alpha, and 6-keto-PGE1 enhanced ACEH activity fourfold. No significant effects on ACEH activity were observed with PGE1 or PGE2. Preincubation of SMC with an inhibitor of adenylate cyclase activity (dideoxyadenosine) abolished the effect of these PG on CE hydrolytic activity. Addition of dibutyryl cAMP to these SMC significantly increased ACEH activity. Although concentrations of PGI2 used significantly increased cAMP levels, proliferation of these SMC was not observed. In related experiments, we determined if the addition of PGI2, 6-keto-PGF1 alpha, or 6-keto-PGE1 to cultured aortic SMC would enhance the egress of unesterified cholesterol and CE from these SMC. A significant loss of total cholesterol from PG-treated SMC was observed at the end of 14 d. Results suggest that increased synthesis of PGI2 by neointimal SMC in the injured aortic wall may, at least in part, explain the changes in CE catabolism and accumulation following injury. These PG may also be important in CE metabolism and accumulation in human arteries. 相似文献
10.
J F Tomera 《The Journal of burn care & rehabilitation》1991,12(6):485-497
This study examines the nature of skeletal muscle weakness (dysfunction) that is exhibited by patients who have incurred large-size body surface area burns (greater than 30%). It uses the mouse model of scald-burn injury in which groups of mice with varying burn sizes (i.e., 20%, 30%, and 50%) and time-matched controls were evaluated on postburn day 21. The primary purpose of this work was to evaluate secondary messenger cascades in gastrocnemius muscle relative to increasing burn size. Muscles that were distantly located to the actual site of burn injury were used for twitch analyses to measure active tension. The second messengers, adenosine 3':5' cyclic monophosphate (cAMP), inositol, 1,4,5-trisphosphate (IP3) and Ca2+, were measured with radioisotopes. The results of this study indicate that perturbations in the cAMP-IP3 cascade may be responsible for increasing myoplasmic Ca2+, which leads to dysfunction. The long-term goal of this work is to aid in the alleviation of chronic skeletal muscle dysfunction that leads to sustained debilitation and prolonged rehabilitation in patients with burns. 相似文献
11.
目的:观察靶肌肉注射外源性环磷酸腺苷对大鼠坐骨神经再生的治疗作用。方法:实验于2004-10/2005-03在华中科技大学同济医学院协和医院骨科实验室完成。选择健康雄性Wistar大鼠48只,制备大鼠左侧坐骨神经挤压伤模型。实验动物随机数字表法分为3组,每组16只,高剂量组:腓肠肌内注射0.2mL环磷酸腺苷1mg。低剂量组:腓肠肌内注射注射0.2mL环磷酸腺苷0.1mg。对照组:腓肠肌内注射0.2mL生理盐水。术后每日给药1次,共4周。术后4,8周时检测左侧小腿三头肌湿质量。术后8周时检测坐骨神经运动神经传导速度、小腿三头肌复合肌肉动作电位波幅、潜伏期及形态学观察神经再生情况。结果:纳入动物48只,均进入结果分析。①术后4,8周时高剂量组和低剂量组大鼠左小腿三头肌湿质量显著高于对照组[术后4周分别为(1.70±0.58),(1.26±0.71),(0.91±0.24)g;术后8周分别为(2.26±0.62),(1.65±0.16),(1.24±0.37)g],且高剂量组明显高于低剂量组,差异有显著性意义(P<0.01)。②术后8周高剂量组和低剂量组坐骨神经运动神经传导速度、小腿三头肌复合肌肉动作电位波幅、潜伏期及有髓神经纤维计数、髓鞘厚度、轴突直径均高于对照组[运动神经传导速度分别为(33.54±2.65),(26.96±4.12),(19.83±2.74)m/s;复合肌肉动作电位波幅分别为(2.435±1.257),(1.867±0.566),(1.218±0.647)mV;复合肌肉动作电位潜伏期分别为(2.946±0.658),(4.537±0.932),(5.825±1.043)ms;有髓神经纤维计数分别为(1693±201),(1357±185),(876±124)个;髓鞘厚度分别为(1.149±0.138),(0.924±0.086),(0.633±0.105)μm;轴突直径分别为(1.045±0.150),(0.794±0.095),(0.512±0.138)μm],且高剂量组显著高于低剂量组,差异有显著性意义(P<0.01)。结论:靶肌肉注射环磷酸腺苷可促进周围神再生,高剂量环磷酸腺苷对神经再生具有更好的促进作用。 相似文献
12.
靶肌肉注射环磷酸腺苷对周围神经再生的作用 总被引:2,自引:0,他引:2
目的:观察靶肌肉注射外源性环磷酸腺苷对大鼠坐骨神经再生的治疗作用。
方法:实验于2004-10/2005-03在华中科技大学同济医学院协和医院骨科实验室完成。选择健康雄性Wistar大鼠48只。制备大鼠左侧坐骨神经挤压伤模型。实验动物随机数字表法分为3组,每组16只,高剂量组:腓肠肌内注射0.2mL环磷酸腺苷1mg。低剂量组:腓肠肌内注射注射0.2mL环磷酸腺苷0.1mg。对照组:腓肠肌内注射0.2mL生理盐水。术后每日给药1次,共4周。术后4,8周时检测左侧小腿三头肌湿质量。术后8周时检测坐骨神经运动神经传导速度、小腿三头肌复合肌肉动作电位波幅、潜伏期及形态学观察神经再生情况。
结果:纳入动物48只,均进入结果分析。①术后4,8周时高剂量组和低剂量组大鼠左小腿三头肌湿质量显著高于对照组[术后4周分别为(1.70&;#177;0.58),(1.26&;#177;0.71),(0.91&;#177;0.24)g;术后8周分别为(2.26&;#177;0.62),(1.65&;#177;0.16),(1.24&;#177;0.37)g],且高剂量组明显高于低剂量组,差异有显著性意义(P〈0.01)。②术后8周高剂量组和低剂量组坐骨神经运动神经传导速度、小腿三头肌复合肌肉动作电位波幅、潜伏期及有髓神经纤维计数、髓鞘厚度、轴突直径均高于对照组[运动神经传导速度分别为(33.54&;#177;2.65),(26.96&;#177;4.12),(19.83&;#177;2.74)m/s;复合肌肉动作电位波幅分别为(2.435&;#177;1.257),(1.867&;#177;0.566),(1.218&;#177;0.647)mV;复合肌肉动作电位潜伏期分别为(2.946&;#177;0.658),(4.537&;#177;0.932),(5.825&;#177;1.043)ms;有髓神经纤维计数分别为(1693&;#177;201),(1357&;#177;185),(876&;#177;124)个;髓鞘厚度分别为(1.149&;#177;0.138),(0.924&;#177;0.086),(0.633&;#177;0.105)min;轴突直径分别为(1.045&;#177;0.150),(0.794&;#177;0.095),(0.512&;#177;0.138)μm],且高剂量组显著高于低剂量组,差异有显著性意义(P〈0.01)。
结论:靶肌肉注射环磷酸腺苷可促进周围神再生,高剂量环磷酸腺苷对神经再生具有更好的促进作用。 相似文献
13.
Effect of atropine on the hyperresponsiveness of ragweed-sensitized canine tracheal smooth muscle 总被引:1,自引:0,他引:1
R W Mitchell L A Antonissen W Kepron E A Kroeger N L Stephens 《The Journal of pharmacology and experimental therapeutics》1986,236(3):803-809
The present studies were undertaken to obtain histamine (HIST) dose-response curves for tracheal smooth muscle (TSM) from an actively ragweed-sensitized canine model of asthma and to compare these results with 1) HIST dose-response data from littermate control dogs, 2) initially nonsensitized TSM passively sensitized (in vitro) to ragweed and 3) the dose-response curve to an agonist that opens primarily voltage-sensitive calcium channels, i.e., K+. Actively ragweed-sensitized TSM was significantly hyperreactive (upward shift of the dose-response curve) to HIST (1.882 kg of force produced normalized to cross-sectional area-kg/cm2 +/- 0.087 S.E. vs. littermate controls 1.151 +/- 0.253) and hypersensitive as indicated by the leftward shift in the median effective dose or ED50 (1.86 X 10(-6) +/- 0.24 vs. 5.54 X 10(-6) +/- 1.35 M). Passively sensitized TSM (using serum from ragweed-sensitized dogs) also showed a hyperreactivity to HIST when compared to control TSM incubated with control serum (1.204 +/- 0.127 vs. 0.825 +/- 0.081 kg/cm2). No significant difference was found in the ED50 values, indicating similar sensitivities. Atropine (10(-7) M) reduced the hypersensitivity of actively sensitized TSM significantly toward control values; however, the hyperreactivity persisted. Atropine did not affect responses to HIST in control TSM. Ragweed actively sensitized TSMs were also hyperreactive and hypersensitive to K+ when compared to littermate control TSM. Atropine abolished both the hyperreactivity and hypersensitivity to K+ but had no effect on the dose-response curve of control TSM to K+.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
14.
M Masuo T Shimada T Kitazawa 《The Journal of pharmacology and experimental therapeutics》1992,260(3):1300-1308
The mechanism of inhibitory effects of azelastine, an antiallergic and antiasthmatic agent, on depolarization- and alpha-1 adrenergic agonist-induced contractions of intact smooth muscle was studied. The effects of azelastine on membrane currents were determined in isolated guinea pig ileum smooth muscle cells with the whole-cell clamp technique; the effects on contraction were evaluated in receptor- and G-protein-coupled, alpha-toxin-permeabilized rabbit femoral artery and portal vein smooth muscle strips. Azelastine (1-20 microM), like dihydropyridines, inhibited spontaneous rhythmic and high K(+)-induced contractions, mainly through inhibition of the voltage-dependent (L-type) Ca++ current. The tonic component of high K+ contractions was inhibited more than the phasic component, correlating to voltage-dependent inhibition of Ca++ current by the drug. Azelastine (IC50 of 0.25 microM), a known histamine blocker, also reversibly inhibited alpha-1 agonist-induced contractions in the presence and absence of extracellular Ca++. Both major pathways of pharmacomechanical coupling, agonist-induced Ca++ release from the sarcoplasmic reticulum and Ca++ sensitization of the regulatory/contractile apparatus were blocked by the same concentration of drug in permeabilized as in intact muscle. Inositol 1,4,5-trisphosphate-induced Ca++ release and guanosine 5'-O-(tau-thiotriphosphate)-induced Ca++ sensitization, however, were not inhibited. Azelastine at high (greater than 10 microM) concentrations reversibly inhibited Ca(++)-activated contraction, more potently at lower Ca++ concentration and in phasic smooth muscle, but inhibited neither adenosine 5'-O-(tau-thiotriphosphate)-induced, Ca(++)-independent nor phorbol ester-induced contractions. These results indicate that azelastine is a genuine Ca++ antagonist that inhibits voltage-gated Ca++ inward current and agonist-induced Ca++ release and Ca++ sensitization. 相似文献
15.
J Y Blay D Branellec E Robinet B Dugas F Gay S Chouaïb 《The Journal of clinical investigation》1990,85(6):1909-1913
In previous studies, IL-4 has been reported to interfere with IL-2-driven generation of lymphokine-activated killer (LAK) activity. In this investigation, we have demonstrated that IL-4 inhibited the IL-2-induced differentiation of large granular lymphocytes (LGL) into LAK effectors by a mechanism involving, at least in part, an increase in LGL intracellular cAMP levels. In contrast, with its capacity to induce cAMP accumulation in resting LGL, IL-4 had a very negligible effect on LAK activity induction, and cAMP levels increase in LGL that had been preincubated with IL-2. Furthermore, the inhibitory effect of IL-4 on LAK activity generation also correlated with a marked decrease in N-CBZ-L-lysine thiobenzylester esterase activity, with an inhibition of tumor necrosis factor (TNF) mRNA expression and TNF production by IL-2-stimulated LGL. These results strongly suggest that complex signaling processes could be ascribed to the dual activities of cytokines and their interplay in LAK promotion. 相似文献
16.
Effects of atrial natriuretic factor on cyclic guanosine monophosphate and cyclic adenosine monophosphate accumulation in microdissected nephron segments from rats.
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Atrial natriuretic factor (ANF) (1 microM) markedly increased cyclic guanosine monophosphate (cGMP) content in microdissected glomeruli (35-fold) and in microdissected inner medullary collecting ducts (IMCD) (20-fold). ANF caused little or no increase in cGMP content in other nephron segments. The threshold concentration for increased cGMP accumulation by ANF was 0.1-1 nM in IMCD, which is in the range reported for rat plasma. Sodium nitroprusside (1 mM), which selectively stimulates soluble guanylate cyclase, increased cGMP content in glomeruli but not in IMCD. ANF did not alter cAMP accumulation in the absence or presence of vasopressin (AVP) or parathyroid hormone (PTH) in outer and inner medullary tubule suspensions, or in microdissected proximal convoluted tubules (PCT), medullary thick ascending limbs (MAL) or IMCD. These data are compatible with the hypothesis that cGMP is a second messenger for a physiologic action of ANF in the inner medullary collecting duct. ANF apparently activates membrane-bound guanylate cyclase in this segment. 相似文献
17.
Excitatory and inhibitory actions of isoprostanes in human and canine airway smooth muscle 总被引:8,自引:0,他引:8
Janssen LJ Premji M Netherton S Catalli A Cox G Keshavjee S Crankshaw DJ 《The Journal of pharmacology and experimental therapeutics》2000,295(2):506-511
Isoprostanes are generated nonenzymatically during free radical-mediated lipid peroxidation, and are used clinically and experimentally as markers of oxidative stress. However, their biological effects are poorly understood. We examined the effects of seven different 8-isoprostanes in human and canine airway smooth muscles. In large order airways (carina) of the human, several isoprostanes evoked powerful contractions, with 8-iso-prostaglandin (PG) E(2), 8-iso-PGF(1 alpha), and 8-iso-PGF(2 alpha) being the most efficacious (and with logEC(50) values of 7.0, 5.9, and 6.2 microM, respectively). These contractions were sensitive to the prostanoid TP receptor antagonist ICI 192,605 (0.1-1 microM), but not the EP prostanoid receptor antagonist AH-6809 (50 microM), or the leukotriene receptor antagonists monteleukast or ICI 198,615 (both 1 microM). Qualitatively similar results were obtained in small order human airways (<2 mm o.d.), except that the isoprostanes were generally slightly less potent. None of the isoprostanes had any marked excitatory effect in canine airways. In carbachol-preconstricted tissues (pretreated with ICI 192,605 to block any potential contraction), several isoprostanes completely relaxed canine airways: 8-iso-PGE(1), 8-iso-PGE(2), and 8-iso-PGF(3 alpha) were the most potent, with logIC(50) values of 6.9, 6.9, and 5.7, respectively. Only 8-iso-PGF(3 alpha) relaxed human airways (logIC(50) = 4.9). Our results show that several 8-isoprostanes are highly biologically active in human and canine airways, evoking both excitatory and/or inhibitory effects, and that these effects are compound, species, and tissue dependent. 相似文献
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Characterization of neuromedin U effects in canine smooth muscle 总被引:2,自引:0,他引:2
Westfall TD McCafferty GP Pullen M Gruver S Sulpizio AC Aiyar VN Disa J Contino LC Mannan IJ Hieble JP 《The Journal of pharmacology and experimental therapeutics》2002,301(3):987-992
Two endogenous receptors for the potent smooth muscle-stimulating peptide neuromedin U (NmU) have recently been identified and cloned. Pharmacological, binding, and expression studies were conducted in an attempt to determine the receptor(s) involved in the smooth muscle-stimulating effects of NmU. The NmU peptides caused a concentration-dependent contraction of canine isolated urinary bladder. NmU did not have this same effect in the urinary bladder from rat, guinea pig, rabbit, mouse, or ferret. Although NmU had no effect on canine uterus it did cause contraction of canine stomach, ileum, and colon. As well as causing contraction of canine bladder in vitro, NmU administered systemically resulted in a significant increase in urinary bladder pressure in vivo. High-affinity binding sites for NmU were identified in canine bladder. The four NmU peptides porcine NmU-8, rat NmU-23, human NmU-25, and porcine NmU-25 displaced (125)I-NmU-25 binding with similar K(i) values (0.08-0.24 nM). A different binding profile was revealed in human embryonic kidney-293 cells transiently expressed with the canine NmU-2 receptor where porcine NmU-8 (K(i) = 147.06 nM) was much less potent than the other NmU peptides. Using TaqMan, expression of NmU-1 was detected in human urinary bladder, small intestine, colon, and uterus. Expression of NmU-2 was much lower or absent in these human tissues and undetectable in canine bladder and stomach. The results of this study reveal significant species differences in the activity of NmU. The contractile activity in human and canine smooth muscle seems to be mediated by the recently cloned NmU-1 receptor. 相似文献