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1.
The ability of antidepressant drugs to increase the concentration of intracellular Ca2+([Ca2+]i) was examined in dispersed brain cells from neonatal rat cortex and hippocampus using the Ca2+ sensitive fluorescent indicator Fura-2. Desipramine (DIM 0.1-1.0 mmol·L-1) increased [Ca2+]i in a concentration-dependent manner. DIM (1.0 mmol·L-1) and fluoxetine (1.0 mmol·L-1) induced [Ca2+]
i increases were not altered by the absence of external Ca2+ or by the presence of nimodipine (10 μmol·L-1). Pretreatment with neomycin (10 mmol·L-1), an inhibitor of inositol 1,4,5-trisphosphate production, significantly inhibited DIM-induced [Ca2+]i increase but could not effectively inhibit fluoxetine-induced [Ca2+]i increase. Pretreatment with dantrolene (0.05 mmol·L-1), an exhaustor of Ca2+ store, inhibited fluoxetineinduced [Ca2+]i increase, suggesting that DIM and fluoxetine provoke intracellular Ca2+ mobilization. In addition, fluoxetine-induced [Ca2+]i increase was about 1.5 times higher than that induced by DIM at the same concentration (0.4 mmol·L-1). Moclobemide, an inhibitor of monoamine oxidase A, did not affect [Ca2+]i. It is concluded that DIM and fluoxetine may be Ca2+ mobilizing agents. 相似文献
i increases were not altered by the absence of external Ca2+ or by the presence of nimodipine (10 μmol·L-1). Pretreatment with neomycin (10 mmol·L-1), an inhibitor of inositol 1,4,5-trisphosphate production, significantly inhibited DIM-induced [Ca2+]i increase but could not effectively inhibit fluoxetine-induced [Ca2+]i increase. Pretreatment with dantrolene (0.05 mmol·L-1), an exhaustor of Ca2+ store, inhibited fluoxetineinduced [Ca2+]i increase, suggesting that DIM and fluoxetine provoke intracellular Ca2+ mobilization. In addition, fluoxetine-induced [Ca2+]i increase was about 1.5 times higher than that induced by DIM at the same concentration (0.4 mmol·L-1). Moclobemide, an inhibitor of monoamine oxidase A, did not affect [Ca2+]i. It is concluded that DIM and fluoxetine may be Ca2+ mobilizing agents. 相似文献
2.
The effect of all trans retinoic acid (ATRA) on changes of DNA synthesis, intracellular free calcium content ([Ca2+]i) and intracellular pH (pHi) of cultured rabbit vascular smooth muscle cells (VSMC) induced by fetal calf serum (FCS) were studied by [3H] thymidine incorporation, Fura-2/AM and BCECF/AM fluorescent probe mark and digital image processing techniques. The results showed that (1) ATRA (0.01, 0.1 and 1.0 μmol·L-1) significantly inhibited 20% FCS-induced VSMC DNA synthesis and its maximal inhibitory rate at 1 μmol·L-1was 90%; (2) incubated with 20% FCS for 5 min, VSMC [Ca2+]i increased and VSMC [H+]i decreased. These effects of FCS were significantly inhibited by ATRA 0.1 μmol·L-1 preincubated for 10 min. The results indicate that ATRA lowering VSMC [Ca2+]i and pHi may be attribute to inhibition of the proliferation of VSMC. 相似文献
3.
三七皂甙Rg1对大鼠实验性血栓形成,血小板聚集率及血小板内游离钙水平的影响 总被引:32,自引:0,他引:32
三七皂甙Rg1可明显降低实验性血栓形成, 并且以剂量依赖方式抑制凝血酶诱导的血小板聚集. 此外, Rg1还可抑制凝血酶诱导的正常血压及肾性高血压大鼠血小板内游离钙([Ca2+]i)升高. 表明Rg1的抗血栓形成和抗血小板聚集作用可能与抑制血小板[Ca2+]i升高有关. 相似文献
4.
家兔主动脉血管平滑肌细胞内钙动员及小檗胺作用的共聚焦研究 总被引:1,自引:0,他引:1
观察小檗胺 (Ber) 对高钾除极,Bay K8644,5-羟色胺 (5-HT) 及咖啡因升高细胞内钙水平 ([Ca2+]i) 的影响。以Fluo-3/AM负载家兔培养的主动脉平滑肌细胞 (VSMC),共聚焦显微术测定[Ca2+]i,结果以荧光强度(FI)表示. 结果:(1) 在细胞外钙为1.3 mmol·L-1时, VSMC胞浆静息FI明显高于核区, 且不受Ber的影响. (2) Ber 10-100 μmol·L-1预处理可抑制KCl 60 mmol·L-1或Bay K8644 100 μmol·L-1升高的[Ca2+]i,抑制5- HT 1 μmol·L-1升高[Ca2+]i的持续相,但不影响[Ca2+]i的一过性升高。维拉帕米10 μmol·L-1具有相似作用. (3) 在无钙Hanks液中,Ber预处理对咖啡因100 mmol·L-1升高的[Ca2+]i无明显抑制作用。结果表明,Ber可阻断外钙内流,但不抑制内钙释放,这可能与Ber阻断电压依赖性钙通道和受体依赖性钙通道的作用有关. 相似文献
5.
用荧光分光光度法及同位素放射免疫分析法检测丙泊酚(30-300 μmol·L-1)影响大鼠肺动脉平滑肌细胞(PASMC)内游离钙离子浓度([Ca2+]i)与肌醇-1,4,5-三磷酸(IP3)合成作用,以探讨丙泊酚舒张肺动脉平滑肌的作用机理.结果表明,与丙泊酚共同培养72 h,对PASMC [Ca2+]i 基础水平无明显影响,但可浓度依赖性抑制去甲肾上腺素(NE 3 μmol·L-1)引起的[Ca2+]i升高作用;当细胞外液无钙或存在钙通道阻滞剂维拉帕米(30 μmol·L-1)时,丙泊酚抑制NE升高[Ca2+]i作用被增强;丙泊酚还可浓度依赖性抑制NE促进 IP3合成作用. 结果提示丙泊酚舒张血管平滑肌作用与抑制IP3介导的细胞内钙释放密切相关. 相似文献
6.
牛磺酸对培养乳鼠心肌细胞胞浆游离钙浓度的影响 总被引:1,自引:0,他引:1
在培养的单个SD乳鼠心肌细胞,观察了牛磺酸对KCl, 去甲肾上腺素(NE)和毒毛花苷G引起的胞浆游离Ca2+浓度([Ca2+]i)变化的影响. 当细胞外CaCl2浓度为1.3 mmol·L-1时, 牛磺酸10, 20 mmol·L-1不影响心肌细胞静息[Ca2+]i; 但能浓度依赖性地抑制35 mmol·L-1 KCl和1 μmol·L-1毒毛花苷G升高[Ca2+]i的作用.10 μmol·L-1 NE在含Ca2+的缓冲液中能引起双相的[Ca2+]i变化, 即快速升高相和持续升高相.牛磺酸20 mmol·L-1能抑制NE引起的[Ca2+]i持续升高, 而对快速升高相无显著影响. 在无 Ca2+ 的缓冲液中, 牛磺酸不影响NE升高[Ca2+]i的作用. 结果提示牛磺酸可能通过减少心肌细胞电压依赖性Ca2+内流和Na+/Ca2+交换而抑制KCl, NE和毒毛花苷G引起的[Ca2+]i升高. 相似文献
7.
Bcl-2蛋白对环匹阿尼酸诱导CHO细胞凋亡的保护作用 总被引:2,自引:0,他引:2
Hoechst 33258染色和DNA电泳分析揭示了内质网钙泵抑制剂环匹阿尼酸(CPA)呈浓度依赖性地诱导CHO细胞凋亡, 表现出染色体固缩和DNA片断形成的典型特征. Bcl-2的过度表达对CPA诱导的CHO细胞凋亡具有保护作用. 采用Fura-2技术测定细胞内游离钙浓度([Ca2+]i)变化,观察到Bcl-2对CPA触发的细胞Ca2+库Ca2+释放无任何影响. 结果表明Bcl-2蛋白对CPA诱导的CHO细胞凋亡的保护作用不是通过抑制CPA诱导的Ca2+释放,而是作用于[Ca2+]i升高的下游途径. 相似文献
8.
Effect of propofol on Na+, K+-ATPase and Ca2+-ATPase activities of cerebral synaptosomes was investigated in rats. It was found that propfol 50 mg·kg-1 ip significantly inhibited Na+, K+-ATPase activity of hippocampal and brain stem′s synaptosomes (P<0.01). Propofol 100 mg·kg-1 ip significantly reduced Na+, K+-ATPase and Ca2+-ATPase activity of cerebrocortical, brain stem′s and hippocampal synaptosomes (P<0.01). It is suggested that the central inhibitory effect of propofol may be related to the inhibition of Na+, K+-ATPase and Ca2+-ATPase activity of cerebral synaptosomes. 相似文献
9.
Radioligand receptor binding assay (RRBA) was used to determine the characteristics of gestrinone binding to estrogen and progestin receptors of the uterine cytosol in rabbits. The results showed that the binding of [3H] progesterone and [3H] estradiol to uterine cytosols was in a concentration-dependent saturation manner, the dissociation constants (Kd) were 0.82 and 0.18 nmol·L-1 by the Scatchard analysis. If the affinities of progesterone and estradiol binding to progestin and estrogen receptors were taken to be 100%, the relative binding affinities of gestrinone were 54.87%, 0.74%, respectively. The results indicated that gestrinone showed a considerably high affinity with progestin receptor, but had only a very poor affinity with estrogen receptor. 相似文献
10.
溶血性磷脂酰胆碱诱导血小板活化及蛋白质酪氨酸激酶和蛋白激酶C的作用 总被引:2,自引:0,他引:2
应用双道血小板聚集仪和荧光分光光度计分别测定溶血性磷脂酰胆碱(LysoPC)诱导的兔洗涤血小板聚集,细胞内钙离子浓度([Ca2+]i),细胞内pH值(pHi)的变化及5-羟色胺(5-HT)的释放,并观察蛋白质酪氨酸激酶(PTK)抑制剂金雀异黄素(Gen)和蛋白激酶C(PKC)抑制剂星形孢菌素(Sta)对其作用的影响. 结果表明:LysoPC(30-300 μmol·L-1)诱导血小板聚集,5- HT释放和[Ca2+]i 升高,均呈现良好的浓度依赖性,100 μmol·L-1以上时伴有pHi的增加;Gen使LysoPC 诱导的聚集浓度效应曲线右移,半效聚集浓度值从(100±23) μmol·L-1增加到(200±42) μmol·L-1,明显抑制 [Ca2+]i 升高和胞浆碱化,对5-HT释放无明显影响;Sta对较低浓度LysoPC 诱导的血小板聚集,5-HT释放, [Ca2+]i 和pHi的增加均有明显抑制作用,但对高浓度LysoPC 诱导的血小板活化无明显影响. 提示:LysoPC通过内Ca2+调节和Na+/H+交换介导血小板聚集和致密颗粒释放;PTK的激活参与了LysoPC诱导的血小板聚集,内Ca2+调节和Na+/H+交换,而在5-HT释放的机理中意义不大;PKC的激活在较低浓度LysoPC 诱导的血小板活化中起重要作用,高浓度LysoPC通过不依赖于PKC的途径激活血小板. 相似文献
11.
为探讨强啡肽(Dyn)镇痛与致瘫的细胞机理,采用Fura-2显微荧光光度技术观测了不同浓度的Dyn A(1-17)对原代培养脊髓神经元单个细胞内游离钙离子浓度([Ca2+]i)的影响. Dyn A 0.1-100 μmol·L-1对基础[Ca2+]i均无影响. Dyn A 0.1和1 μmol·L-1使高钾(50 mmol·L-1)刺激的Ca2+内流峰值反应分别下降94%(n=6)和83%(n=4, P<0.05); Dyn A 10和100 μmol·L-1对高钾刺激反应峰值无明显影响,但所有测试细胞均呈现持续性[Ca2+]i升高;预先给予低浓度的Dyn A (0.1和1 μmol·L-1), 则高浓度Dyn A (10 和100 μmol·L-1)的促进作用明显 减弱甚至消失. 结果表明低浓度和高浓度Dyn A(1-17)对培养脊髓神经元的基础[Ca2+]i无影响,但可分别抑制和促进去极化性钙离子内流,低浓度Dyn A 可对抗高浓度Dyn A 的促进作用. 相似文献
12.
用凝胶电泳和fura-2荧光技术测定[Ca2+]i方法研究咖啡因对低钾诱导的大鼠小脑颗粒神经元凋亡的保护作用与[Ca2+]i升高之间的关系. 将体外培养的小脑颗粒神经元从高钾(25 mmol·L-1 KCl)培养基中转移到低钾(5 mmol·L-1 KCl)培养基中,神经元发生凋亡. 但低钾引起的神经元死亡可被咖啡因(5-20 mmol·L-1)浓度依赖性地保护,且咖啡因的这种作用不受蓝尼定(ryanodine) 敏感钙释放阻断剂蓝尼定和丹曲林(dantrolene)的影响;也不被L-型钙通道阻断剂硝苯地平, 尼莫地平, 维拉帕米和NMDA受体阻断剂地佐环平抑制. 结果说明[Ca2+]i的升高并不是咖啡因对小脑颗粒神经元的保护作用所必需的. 相似文献
13.
The effect of 1-[β-[3-(4-methoxyphenyl)pro- poxy]-4-methoxyphenethyl]-1H-imidazole hydrochloride (SKF 96365) on Ca2+ signaling in Madin Darby canine kidney (MDCK) cells was examined. SKF 96365 at 25–100 μM evoked a robust [Ca2+]i transient in a dose-dependent manner, measured by fura-2 fluorimetry. A concentration of 10 μM SKF 96365 did not have an
effect. The transient consisted of a slow rise, a gradual decay, and a sustained plateau in physiological Ca2+ medium. Removal of extracellular Ca2+ reduced the Ca2+ signals evoked by 50–100 μM SKF 96365 by nearly half in the area under the curve, suggesting that SKF 96365 induced intracellular
Ca2+ release and also extracellular Ca2+ influx. A concentration of 100 μM SKF 96365 caused significant Mn2+ quench of fura-2 fluorescence, which was partly inhibited by La3+ (1 mM) or Gd3+ (0.1 mM), indicating that the SKF 96365-induced Ca2+ influx had two components: one is sensitive to La3+ (1 mM) or Gd3+ (0.1 mM), the other is not. The internal Ca2+ source for the SKF 96365-induced [Ca2+]i transient was the endoplasmic reticulum Ca2+ store because, pretreatment with thapsigargin and cyclopiazonic acid, two inhibitors of the endoplasmic reticulum Ca2+ pump nearly abolished the SKF 96365-induced [Ca2+]i increase in Ca2+-free medium. In contrast, pretreatment with 100 μM SKF 96365 only partly depleted the thapsigargin-sensitive Ca2+ store. Addition of 10 mM Ca2+ induced a significant [Ca2+]i increase after prior incubation with 100 μM SKF 96365 in Ca2+-free medium, demonstrating that SKF 96365 induced capacitative Ca2+ entry. This capacitative Ca2+ entry was about 40% of that induced by 1 μM thapsigargin. Additional to inducing its own capacitative Ca2+ entry, 100 μM SKF 96365 partly inhibited thapsigargin- or uridine trisphos-phate (UTP)-induced capacitative Ca2+ entry. We also investigated the mechanisms underlying the decay of the SKF 96365-induced [Ca2+]i transient. Inhibition of the plasma membrane Ca2+ pump with La3+ or Gd3+, or lowering extracellular Na+ level to 0.35 mM, significantly increased the SKF 96365-induced [Ca2+]i transient. In contrast, the mitochondrial uncoupler carbonylcyanide m-chlorophenylhydrazone had little effect. In Ca2+-free medium, the thapsigargin-induced [Ca2+]i increase was greatly reduced by pretreatment with SKF 96365. Collectively, we have found that besides its well-known inhibitory
action on capacitative Ca2+ entry in many cell types, in MDCK cells SKF 96365 exerted multiple and complex effects on Ca2+ signaling. It induced a considerable increase in [Ca2+]i by releasing Ca2+ from the endoplasmic reticulum store followed by capacitative Ca2+ entry. It also caused a direct Ca2+ entry. The decay of the SKF 96365 response was significantly governed by efflux via the plasma membrane Ca2+ pump or Na+/Ca2+ exchange. Sequestration by mitochondria or the endoplasmic reticulum played a minor role. We caution use of SKF 96365 as
an inhibitor of capacitative Ca2+ entry.
Received: 21 September 1998 / Accepted: 2 December 1998 相似文献
14.
阿克他利对佐剂性关节炎大鼠腹腔巨噬细胞分泌IL-1和T淋巴细胞亚群的影响 总被引:1,自引:0,他引:1
Effects of actarit on production of interleukin-1(IL-1)by peritoneal macrophages from adjuvant arthritis(AA) rats ex vivo and the ratio of subpopulation of T lymphocytes in AA rats ex vivo and the production of hydrogen peroxide (H2O2)by peritoneal macrophages of mice in vitro were studied. The results showed that IL-1 synthesis from the adherent peritoneal macrophages induced with lipopolysaccharide (8 mg·L-1) in AA rats in vivo were inhibited by actarit; the ratio of L3T4+/Lyt-2+ was lowered after administrating actarit; and H2O2 release of the peritoneal macrophages of mice was reduced in dose-dependent manner. The data suggest that the therapeutic effects of actarit on AA rats be related to inhibition of production of IL-1 and reduction of H2O2 release and lowered rat io of L3T4+/Lyt-2+ T-lymophocyte. 相似文献
15.
三氟拉嗪对大鼠脑突触体内Ca2+水平和Ca2+, Mg2+-ATP酶活性的作用 总被引:1,自引:0,他引:1
黄秀兰薛春生 《中国药理学与毒理学杂志》1996,3(3):204-206
用Quin 2法测得大鼠脑突触体内静息游离Ca2+浓度([Ca2+]i)为85±13 μmol·g-1 protein. 三氟拉嗪(TFP) 1, 5和10 μmol·L-1对静息突触体[Ca2+]i无明显影响, 但能以剂量依赖方式增高65 mmol·L-1 KCl所致突触体[Ca2+]i升高, 从192±58 μmol·g-1 protein分别达到233±63, 431±99和661±173 μmol·g-1 protein. TFP 5,10和50 μmol·L-1分别使突触体Ca2+, Mg2+-ATP酶活性降低31%, 41%和45%; 使Mg2+-ATP#FK酶活性降低30%, 36%和39%, 提示TFP可能是通过抑制钙调素, 进而抑制Ca2+, Mg2+-ATP酶活性, 使突触体[Ca2+]i升高, 促进神经末梢释放递质. 相似文献
16.
Rustenbeck I Leupolt L Kowalewski R Hasselblatt A 《Naunyn-Schmiedeberg's archives of pharmacology》1999,359(3):235-242
Imidazolines are regarded as a pharmacological group of insulin secretagogues with one uniform mechanism of action, namely
closure of ATP-dependent K+ channels (KATP channels) and, in consequence, depolarization of the plasma membrane, Ca2+ influx and stimulation of secretion. This assumption was investigated by measuring insulin secretion from perifused pancreatic
islets in response to three imidazoline compounds and comparing the characteristics of secretion with changes in membrane
potential and cytosolic Ca2+ concentration [Ca2+]i of single β-cells. Phentolamine (32 μM) stimulated insulin secretion from perifused mouse islets in the presence of stimulatory
(10 mM and 30 mM) and substimulatory (5 mM) glucose concentrations and even in the absence of glucose. Idazoxan in concentrations
up to 500 μM was virtually ineffective in the presence of 5 mM glucose. At 10 mM glucose, there was a moderate but significant
increase of secretion by idazoxan, 20 μM being nearly as effective as 100 μM. The effect of phentolamine was of slow onset
and irreversible in the time frame of the experiments, while the effect of idazoxan was of fast onset and reversible. Alinidine
also stimulated secretion in the presence of 10 mM glucose with fast and reversible kinetics, but in contrast to idazoxan,
100 μM was clearly more effective than 20 μM. These heterogeneous characteristics of secretion were reflected by changes of
[Ca2+]i: the increase of [Ca2+]i by phentolamine was slow and only partially reversible, whereas idazoxan led to a smaller, but faster and reversible response.
The increase of [Ca2+]i by phentolamine and idazoxan was abolished by the Ca2+ channel blocker D 600. Surprisingly, all three compounds depolarized the β-cell plasma membrane from a resting potential
of –71 mV to about –36 mV. Again, the effect of phentolamine was slow and that of idazoxan and alinidine fast. Thus, the characteristics
of phentolamine-induced secretion appear to be attributable to the consequences of KATP channel closure. It is unclear, however, why all three test compounds achieved the same degree of depolarization in spite
of their known different efficiency to close KATP channels. Apparently, there are additional mechanisms involved in the action of idazoxan and alinidine, which may contribute
to the obvious differences in the characteristics of secretion.
Received: 2 October 1998 / Accepted: 21 December 1998 相似文献
17.
A synthetic seleno-organic compound, α-methyl-4-(3-oxo-2H-1,2-benzoisoselenazol-2-yl) benzeneacetic acid (MBBA) inhibited the lipid peroxidation of rat liver microsome induced by cysteine/Fe2+ and NADPH/Fe2+, the IC50 (95% confidence limits) values were 12.2(3.8-39.6) and 7.1(2.5-20.3) μmol·L-1 respectively. Furthermore, it showed a glutathione peroxidase like activity in vitro. However MBBA (2-100 μmol·L-1) had no direct inhibition on the production of superoxide anions (O-2) and hydroxy radical. Our data suggest that MBBA is a novel inhibitor of lipid peroxidation. Its antioxidant effect may be attributed to glutathione peroxidase like activity. The direct free radical quenching activity of MBBA is ruled out. 相似文献
18.
采用免疫组化,图像分析,细胞培养和细胞内游离钙离子浓度([Ca2+]i)测定等方法研究2,6- 二甲基-4-(2-氯苯基)-1,4-二氢-3,5-吡啶二羧酸二甲酯(DCDDP)防治野百合碱(MCT)所致肺动脉高压的作用机理. 结果发现每天ip DCDDP 5-500 μg ·kg-1 1次, 连续28 d, 能够明显地减少MCT(60 mg·kg-1 sc)引起的大鼠肺组织中5-HT相对含量及其受体阳性细胞数目增多,对5-HT引起的肺动脉平滑肌细胞增生,收缩及其[Ca2+]i增高都有显著的抑制作用. 结果提示,抑制肺组织中5-HT含量及其受体数目的增加, 对抗5-HT引起的血管平滑肌细胞增生及收缩, 可能是DCDDP防治MCT性肺动脉高压的重要机理之一. 相似文献
19.
Shigeru Tatsumi Y. Itoh Yojiro Ukai Kiyoshi Kimura 《Naunyn-Schmiedeberg's archives of pharmacology》1998,358(2):191-196
The substance 4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy) pyrimidine hydrochloride (NS-7) has been developed recently
as a cerebroprotective compound with Na+ and Ca2+ channel blocking action. In the present study, the effect of NS-7 in an in vitro model of hypoxic injury was examined and
the possible involvement of Na+ and Ca2+ channels in the hypoxic injury subsequently determined. When slices of rat cerebral cortex were exposed to hypoxia/glucose
deprivation followed by reoxygenation and restoration of the glucose supply, marked leakage of lactate dehydrogenase (LDH)
occurred 3–6 h after reoxygenation. This hypoxia/reoxygenation-induced injury was blocked almost completely by the removal
of extracellular Ca2+ or by chelating intracellular Ca2+ with 1,2-bis(o-aminophenoxy)ethane-N,N,N’,N’-tetraacetic acid tetra(acetoxymethyl)ester (BAPTA/AM). In addition, combined treatment with the N-type Ca2+ channel blocker ω-conotoxin GVIA and the P/Q-type Ca2+ channel blocker ω-agatoxin IVA significantly reduced LDH leakage, although neither of these Ca2+ channel blockers alone, nor nimodipine, an L-type Ca2+ channel blocker, was effective. On the other hand, several Na+ channel blockers, including tetrodotoxin, local anaesthetics and antiepileptics, significantly reduced the hypoxic injury.
NS-7 (3–30 μM) concentration-dependently inhibited LDH leakage caused by hypoxia/reoxygenation, but had no influence on the
reduction of tissue ATP content and energy charge during hypoxia and glucose deprivation. It is suggested that blockade of
Na+ and Ca2+ channels is implicated in the cerebroprotective action of NS-7.
Received: 10 March 1998 / Accepted: 19 April 1998 相似文献
20.
D. W. P. Hay Mark A. Luttmann Roseanna M. Muccitelli Roy G. Goldie 《Naunyn-Schmiedeberg's archives of pharmacology》1999,359(5):404-410
Tension and phosphatidyl inositol (PI) turnover experiments were conducted to investigate the receptors and signal transduction
pathways responsible for contractions elicited by endothelin (ET) ligands in human bronchus. Nicardipine (1 μM), the L-type
calcium channel inhibitor, or incubation in Ca2+-free medium, produced marked inhibition of contractions to the ETB receptor-selective agonist, sarafotoxin S6c, and especially those induced by KCl. In contrast, Ca2+-free medium was without appreciable effect against contraction produced by endothelin-1 (ET-1), the non-selective ETA and ETB receptor agonist. In Ca2+-free medium, ryanodine (10 μM), which inhibits intracellular calcium mobilization, reduced sarafotoxin S6c- and ET-1-induced
responses, but was without effect on responses to KCl. Similarly, nickel chloride (Ni2+; 1 mM) caused marked inhibition of contractions induced by sarafotoxin S6c or ET-1, but had no significant effect on KCl
concentration-response curves. The mixed ETA/ETB receptor antagonist SB 209670 (3 μM) inhibited responses to sarafotoxin S6c and ET-1 such that concentration-response curves
were shifted rightward, at the 30% maximum response level, by 10.0- and 3.8-fold, respectively, whereas BQ-123 (3 μM), the
ETA receptor antagonist, was without effect on responses induced by either agonist. ET-1 (1 nM–0.3 μM) caused a concentration-dependent
stimulation of PI turnover, whereas sarafotoxin S6c (0.3 nM–0.1 μM) induced only small and variable increases, except at the
highest concentration. The increase in PI turnover evoked by ET-1 was inhibited by SB 209670 (3 μM), and also by BQ-123 (3
μM). This is consistent with linkage of ETA receptors to activation of inositol phosphate generation in human bronchial smooth muscle cells. Collectively, the data suggest
that differences exist in the relative contributions of intracellular and extracellular Ca2+ mobilization mechanisms elicited by ETA and ETB receptor activation. Thus, sarafotoxin S6c-induced, ETB receptor-mediated contraction in human bronchial smooth muscle appears to be dependent, in part, upon extracellular Ca2+, although a significant component of the response was also mediated by intracellular Ca2+ release, including from ryanodine-sensitive stores. ETA receptor-mediated contraction of human airway smooth muscle was activated largely via the release of intracellular Ca2+.
Received: 21 July 1998 / Accepted: 26 January 1999 相似文献