胞内钙释放在胃泌素引起胃平滑肌细胞收缩中的作用

本研究用大鼠游离的胃平滑肌细胞,观察五肽胃泌素（G5）对胃平滑肌细胞的收编作用及胃泌索引起胃平滑肌细胞收缩时胞内游离钙释放作用。结果表明：（1）G5能够引起胃体、胃窦、幽门平滑肌细胞收缩,并对胃窦作用最强。在G54×10－8～16×10－8mol／L剂量范围内,呈剂量依赖性。（2）丙谷胺或抗胃泌素血清可以阻断G5对胃肌细胞的收缩反应,而阿托品则不影响G5的作用。（3）G5与乙酸胆碱对平滑肌细胞收缩有相加作用。（4）胞内钙释放阻断剂TMB-8可抑制G5对胃肌细胞的收缩作用。（5）G5作用于胃窦平滑肌细胞后胞内游离Ca2 显著上升。上述结果提示：胃泌素通过特异性受体引起胃平滑肌细胞收缩,其收缩作用通过胞内Ca2 释放介导。     

胃动素和胃泌素引起大鼠胃窦平滑肌细胞收缩的信号转导通路

应用大鼠游离胃窦平滑肌细胞,观察胃动素和胃泌素对胃窦平滑肌细胞收缩作用的胞内信号转导通路。结果显示：⑴胃动素和胃泌素对胃窦平滑肌细胞均有收缩作用;⑵Ｇａｉ－３抗体可抑制胃动素和胃泌素加强胃窦平滑肌细胞的收缩,胃动素、胃泌明显增加Ｇａｉ－３抗体与「＾３５Ｓ」ＣＴＰγＳ的结合;⑶磷脂酶抑制剂Ｕ－７３１２２、三磷酸肌醇受体拮抗剂肝素可抑制胃坳素和胃泌素引起的胃窦平滑肌细胞的收缩。结果表明：胃坳素和胃泌表     

RU486对兔输卵管平滑肌的收缩效应

应用肌肉机械－电换能器和Ｇｉｌｓｏｎ生理记录仪,观察ＲＵ４８６对假孕４ｄ兔离体输卵管平滑肌的收缩效应。结果显示：（１）ＲＵ４８６可直接作用输卵管平滑肌,使其收缩频率增加,而未明显改变收缩张力及振幅,与在体肌内注射ＲＵ４８６观察到的结果相似;（２）ＲＵ４８６部分抑制ｃａ~（２＋）诱发的平滑肌收缩活动,它还与Ｖｅｒａｐａｍｉｌ诱发的抑制效应有协同作用,与ＮＥ诱发的收缩张力有拮抗作用,而对Ｆｏｒｓｋｏｌｉｎ诱发的效应未产生任何影响。以上结果表明,ＲＵ４８６对输卵管平滑肌的作用似乎是改变细胞内游离Ｃａ（２＋）的结果,可能干扰Ｃａ（２＋）的流入、或／和内质网Ｃａ（２＋）释放以及Ｃａ（２＋）－Ｉｐ３信息传递机制。     

SNP抑制5-HT诱导的胞内游离钙浓度升高和内钙释放

用Ｆｕｒａ － ２／ＡＭ 荧光测量技术研究了５ － 羟色胺（５－ ＨＴ） 诱导的大鼠尾动脉平滑肌细胞胞内钙升高和一氧化氮（ＮＯ） 的抑制效应。实验表明, 胞外０ｍ ｍｏｌ／ Ｌ Ｃａ２ ＋ 时胞内静息［Ｃａ２ ＋ ］ ｉ 为２０ ．２±８ ．６ｎｍｏｌ／Ｌ（ｎ ＝ ８） 。１０μｍｏｌ／Ｌ ５－ ＨＴ 可诱导出胞内钙库释放引起的瞬态［Ｃａ２ ＋］ｉ 升高,其峰值达２４５ ．７ ±７１．６ｎｍｏｌ／ Ｌ（ｎ ＝ ６） 。１０ － ７ ｍｏｌ／Ｌ 硝普钠（ＳＮＰ） 可抑制５－ ＨＴ 诱导的［Ｃａ２ ＋］ｉ 升高,其峰值浓度降为７５．１±３５ ．９ｎｍｏｌ／Ｌ（ｎ ＝ ５） 。当细胞浴液含２．５ｍ ｍｏｌ／Ｌ Ｃａ２ ＋ 时,静息［Ｃａ２ ＋］ｉ为１１２ ．８ ±１０ ．３ｎｍｏｌ／ Ｌ（ｎ ＝ ５） , 这时１０μｍｏｌ／ Ｌ ５ － ＨＴ 可诱导［Ｃａ２ ＋ ］ ｉ 的峰值为２５２ ．３ ±８０ ．６ｎｍｏｌ／Ｌ（ｎ ＝ ４） ,以及其后平台浓度为１４３ ．０ ±３７ ．６ｎｍｏｌ／Ｌ（ｎ ＝ ４） ,略大于［Ｃａ２ ＋］ｉ 为１１２．８ ±１０ ．３ｎｍｏｌ／Ｌ 的静息浓度,为外钙内流引起。１０ － ７ ｍｏｌ／Ｌ ＳＮＰ 也可抑制５－ ＨＴ 诱导［Ｃａ２ ＋ ］ｉ 平台相浓度。平台浓度由１４３ ±４７     

缓激肽对大鼠背根神经节分离神经元ATP激活电流的调制作用

在新鲜分离大鼠背根神经节（ＤＲＧ）的５６个细胞标本上,应用全细胞膜片箝技术进行记录。胞外加缓激肽（ＢＫ,１０＾－６￣１０＾－４ｍｏｌ／Ｌ）引坊的ＤＲＧ细胞膜反应结果如下：（１）７１．４％的细胞为内向电流,其电流反应的幅值具有明显的浓度信赖性;（２）１２．５％的细胞为外向电流;（３）１６．１％的细胞未引起可检测的膜反应,单独给予ＡＴＰ（１０＾－６￣１０＾－３ｍｏｌ／Ｌ）在大多数受栓细胞（５４／５６）     

福建产圆斑蝰蛇毒中性磷脂酶A2的降压作用与机理

福建产圆斑蝰蛇毒中性磷脂酶Ａ２（ＰＬＡ２－３）对麻醉Ｗｉｓｔａｒ大鼠、猫和家兔均产生急性降压效应,并具快速耐受性。该降压作用能被吲哚美辛取消。应用放射免疫法测定血浆前列环素（其稳定产物６－ｋｅｔｏ－ＰＧＦｌａ）含量,与给药前相比,降压高峰时血浆６－ｋｅｔｏ－ＰＧＦＩｌａ含量增高。离体入胃网膜动脉条实验观察到,ＰＬＡ２－３呈剂量依赖性降低入胃网膜动脉条静息张力;对预先用去甲肾上腺素或５－羟色胺收缩的人胃网膜动脉条也具松弛作用。结果表明该ＰＬＡ２降压机制与前列环素（ＰＧＩ２）的释放和外周血管扩张有关。     

Ghrelin、GHRP-6以及胃动素对大鼠胃肠运动影响研究

目的:探究ghrelin、GHRP-6以及胃动素对大鼠胃肠运动的影响。方法:在体实验观察ghrelin、GHRP-6及胃动素对大鼠胃排空及小肠推进的影响,离体实验观察ghrelin、GHRP-6及胃动素对大鼠电场刺激引起胃窦胃底平滑肌舒缩反应的影响,RT-PCR观察ghrelin mRNA在胃的表达。结果:在体研究发现ghrelin及GHRP-6能够促进胃排空及小肠推进,胃动素对胃排空及小肠推进无影响。离体研究发现,ghrelin 1μM能够抑制胃底平滑肌4-8Hz开电刺激下的舒张反应,并增强胃底平滑肌1-8Hz及胃窦平滑肌4-16Hz断电刺激下的收缩反应;GHRP-6 1μM能够抑制胃底平滑肌4-8Hz开电刺激下的舒张反应,并增强胃底平滑肌1-2Hz、8-16Hz及胃窦平滑肌4-8Hz断电刺激下的收缩反应;L-NAME增强ghrelin、GHRP-6诱导的胃底和胃窦平滑肌条舒缩作用。大鼠胃窦及胃底分布有ghrelin受体mRNA。结论:ghrelin和GHRP-6能够加快胃排空促进小肠推进,该效应可能是通过迷走神经通路及胆碱能兴奋产生的。     

慢性低氧性肺动脉高压鼠原代培养肺动脉平滑肌细胞内钙的检定

用共聚焦激光扫描显微镜观察经Ｆｌｕｏ－３／ＡＭ负荷的慢性低氧性肺动脉高压（ＨＰＨ）大鼠原代培养的肺动脉平滑肌细胞（ＰＡＳＭＣ）的形态与内游离Ｃａ２＋浓度的动态变化。结果表明：原代培养的（ＨＰＨ）大鼠的ＰＡＳＭＣ与正常大鼠相比,①细胞内游离Ｃａ２＋浓度增加,但其收缩性减弱;②随培养日数增加,咖啡因（Ｃａｆｅｉｎ）所致的细胞内储钙池－肌浆网的Ｃａ２＋释放作用逐渐减弱,直至消失;③血管紧张素Ⅱ（ＡＴ－Ⅱ）升高细胞内钙作用明显增强;④部分呈大红色细胞对多种缩血管物质敏感性增强。结果提示,ＨＰＨ大鼠的ＰＡＳＭＣ的内钙明显增加,其调节机制处于紊乱状态。     

EDRF对PE引起的大鼠主动脉缩血管效应的作用

本文研究ＥＤＲＦ（ｅｎｄｏｔｈｅｌｉｕｍ－ｄｅｒｉｖｅｄｒｅｌａｘｉｎｇｆａｃｔｏｒ,ＥＤＲＦ）对ＰＥ（ｐｈｅｎｙｌｅｐｈｒｉｎｅ）引起的大鼠主动脉收缩反应的影响。内皮完整和去内皮的大鼠主动脉环悬挂于器官浴槽中,测定血管的张力和收缩速度的变化。所有的实验在消炎痛（ｉｎｄｏｍｅｔｈａｃｉｎ,１０μｍｏｌ／Ｌ）存在下进行。用美兰（ｍｅｔｈｙｌｅｎｅｂｌｕｅ,ＭＢ,１０μｍｏｌ／Ｌ）或左旋硝基精氨酸（ＮＧ－ｎｉｔｒｏ－Ｌ－ａｒｇｉｎｉｎｅ,Ｌ－ＮＮＡ,３０μｍｏｌ／Ｌ）处理内皮完整的大鼠主动脉环,ＰＥ的剂量－收缩张力曲线明显左移,ＥＣ３０值均降低５倍,最大反应比率分别为１．６±０．４和１．６±０．５。在去内皮的大鼠主动脉环中,经ＭＢ和Ｌ－ＮＮＡ处理后,仍可见ＥＣ３０下降３倍,最大反应比率均为１．０±０．２。后者可能与血管平滑肌产生少量ＥＤＲＦ有关。我们的结果提示ＰＥ对血管的收缩反应也受血管内皮和平滑肌产生的ＥＤＲＦ的调控     

表皮生长因子对离体大鼠肺动脉及肺动脉平滑肌细胞作用的研究

本研究着重探讨表皮生长因子（ＥＧＦ）对大鼠肺动脉的收缩作用及对肺动脉平滑肌细胞分裂增殖的影响。浓度为１×１０－９－１×１０－７ｍｏｌ／Ｌ的ＥＧＦ可引起大鼠肺动脉剂量依赖性收缩（ｒ＝０．９６８,Ｐ＜０,００１）,其Ｅｍａｘ为１００．６ｍｇ,ＥＣ５０为１１．９６ｎｍｏｌ／Ｌ。在同时存在０．５％胎牛血清（ＦＣＳ）时,ＥＧＦ能促进平滑肌细胞的３Ｈ－ＴｄＲ参入率,该作用与剂量呈正相关（ｒ＝０．８２３,Ｐ＜０．０５）,其ＥＣ５０为６．５×１Ｏ－１２ｍｏｌ／Ｌ。１×１０－９ｍｏｌ／Ｌ的ＥＧＦ＋０．５％ＦＣＳ能产生与１０％ＦＣＳ相当的促细胞分裂增殖能力（在培养的第１,３,５,７天,二者促分裂增殖能力相差不明显,Ｐ均＞０．０５,第９天时,前者大于后者,Ｐ＜０．０５）。１×１０－９ｍｏｌ／ＬＥＧＦ单独存在时对平滑肌细胞未显示出明显的致分裂活性。上述作用提示ＥＣＦ在某些肺血管病变如缺氧性肺动脉高压中可能有一定意义。     

Direct contractile effect of motilin on isolated smooth muscle cells of guinea pig small intestine.

We examined the direct effect of motilin on longitudinal and circular smooth muscle cells isolated from the guinea pig small intestine. In addition, the effects of 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxy-benzoate hydrochloride (TMB-8, an inhibitor of intracellular Ca(2+)-release), verapamil (a voltage-dependent Ca(2+)-channel blocker), and removal of extracellular Ca2+ were investigated to evaluate the role of intracellular Ca2+ stores and extracellular Ca2+ on the muscle contraction induced by motilin. The effects of atropine (a muscarinic receptor antagonist), spantide (a substance P receptor antagonist) and loxiglumide (a CCK-receptor antagonist) were also examined to determine whether the motilin-induced contraction was independent of those receptors. Motilin induced a contraction of the longitudinal and circular smooth muscle cells in a dose-dependent manner with the maximal effect attained after 30 seconds of incubation. The ED50 values were 0.3 nM and 0.05 nM, respectively. TMB-8 suppressed completely the motilin-induced contraction of both types of smooth muscle cells. Verapamil had only a slight suppressive effect. Removal of extracellular Ca2+ did not have any significant influence on motilin-induced contraction. The contractile response to motilin was not affected by atropine, spantide or loxiglumide. Our findings showed that:1) motilin has a direct contractile effect on both longitudinal and circular smooth muscle cells; 2) this contractile effect is not evoked via muscarinic, substance P or CCK receptors, and 3) the intracellular release of Ca2+ plays an important role in the contractile response to motilin on both types of smooth muscle cells.     

辣椒素对离体大鼠胃平滑肌收缩性的影响

目的:考察辣椒素对离体大鼠胃平滑肌收缩性的影响。方法:本研究以大鼠的离体胃平滑肌条为模型,首先考察在正常钙克氏液、高钙克氏液和低钙克氏液中辣椒素对胃平滑肌收缩作用的影响。然后正常克氏液中,分别观察辣椒素对乙酰胆碱、新斯的明、阿托品分别存在下的胃平滑肌收缩性的影响。结果:辣椒素在2.5μmol/L-40μmol/L浓度范围内可剂量依赖性显著抑制高钙溶液(Ca2 终浓度5μmol/L)引起的大鼠胃平滑肌强烈收缩,在5μmol/L-40μmol/L浓度范围内可显著抑制正常克氏液中大鼠胃平滑肌条的运动,且具有明显剂量依赖性,在10μmol/L-40μmol/L浓度范围内可显著抑制低钙克氏液中大鼠胃平滑肌条的运动,且具有剂量依赖性。辣椒素(10μmol/L)可拮抗乙酰胆碱和新斯的明引起的收缩作用(P<0.01)。辣椒素(10μmol/L)的作用与阿托品具有相加作用(P<0.01)。结论:辣椒素对胃平滑肌的收缩具有明显的抑制作用。     

Calcium-independent tacrine-induced relaxation of rat gastric corpus smooth muscles

Tacrine, a non-competitive reversible acetylcholinesterase and butyrylcholineserase inhibitor, caused a concentration-dependent tonic contraction of gastric smooth muscle preparations in the concentration range 1 x 10(-7) mol/L - 1 x 10(-5) mol/L, whereas concentrations higher than 2 x 10(-5) mol/L induced a biphasic effect; a short-time contraction was followed by a prolonged relaxation. To shed some light on the mechanism underlying this untypical relaxation, the amplitude of mechanical reactions caused by tacrine were compared with those of tacrine in the presence of atropine, ipratropium, metrifonate, TTX, nifedipine, D-600, caffeine, apamin, and charybdotoxin. The results obtained revealed that the relaxation was neither cholinergic in nature, nor mediated by the influence of the drug on intramural neuronal structures. It was not influenced by processes inducing changes in cytosolic Ca2+ levels. This assumption was confirmed by experiments with permeabilized muscle preparations that were pre-contracted in a solution with pCa 5.5. Tacrine relaxed the smooth muscles in spite of the constant intracellular Ca2+ concentration resulting from the permeabilization. These findings argue that tacrine at concentrations higher than 2 x 10(-5) mol/L has a desensitizing effect on the contractile apparatus of gastric corpus smooth muscle preparations towards Ca2+.     

Bombesin-induced changes in membrane potential-dependent phasic contractions of cat gastric muscle

Electrical and contractile activities of smooth muscle strips isolated from the circular muscle layer of cat gastric antrum were studied using the sucrose gap technique. Bombesin (10(-8) mol/l) depolarized the gastric muscle; this was accompanied by an increase in the strip tone, in the plateau action potential frequency and in both the frequency and the amplitude of the spike potentials as well as by a shortening of the plateau action potential duration. Both the frequency and the amplitude of the phasic contractions increased thereafter. The changes in the frequency of the plateau action potentials and contractions were not influenced either by antagonists of cholinergic and adrenergic receptors or by TTX. In the presence of the Ca antagonists D600 (10(-6) mol/l) and nifedipine (10(-7) mol/l) or in Ca-free medium containing EGTA the effect of bombesin on the frequency of the plateau action potentials and phasic contractions remained unchanged; however, spike potentials were not observed and no increase in the amplitude of phasic contractions occurred. UV-light inactivation of nifedipine restored the typical bombesin effect on the electrical and contractile activities of the gastric smooth muscle. The present data suggest that the effect of bombesin on the frequency of both plateau action potentials and phasic contractions is not linked with Ca2+ influx.     

Effect of different calcium modulators on motilin-induced contractions of the rabbit duodenum. Comparison with acetylcholine

Motilin and acetylcholine (ACh) have a direct contractile effect on rabbit small intestinal smooth muscle. To explore the role of calcium influx in these contractions, we studied the effect of extracellular calcium concentration and of calcium antagonists on the response of longitudinal muscle preparations from rabbit duodenum. Motilin- (10(-7) M) and ACh- (10(-4) M)-induced contractions were abolished in Ca2+-depleted medium. ACh (10(-4) M) or motilin (10(-8) and 10(-7) M) increased the contractile response to added Ca2+ to 130 +/- 6%, 129 +/- 10% and 145 +/- 5% of the maximal response to Ca2+ added alone (10 mM in a cumulative concentration response curve). The sensitivity to Ca2+ was greater in the presence of ACh and motilin (EC50 = 1.0 and 1.1 mM Ca2+) than in the absence of any agonist (1.7 mM). In cumulative concentration response (CCR) curves for motilin and ACh, pD2'-values were 7.0 and 6.6 for diltiazem, 8.4 and 7.8 for verapamil (two calcium entry blockers), 5.6 and 5.2 for TMB-8 (an inhibitor of intracellular calcium), 5.3 and 5.2 for TFP (a calmodulin-antagonist). All CCR-curves showed metactoid-like action of the antagonistic drugs. We conclude that ACh and motilin cause calcium to enter the smooth muscle cell. They are probably operating via separate channels, and use a mechanism which differs from K+-induced influx. Intracellular calcium stores appear to play a minor role in these contractions.     

Stretch-induced calcium release in smooth muscle

Smooth muscle cells undergo substantial increases in length, passively stretching during increases in intraluminal pressure in vessels and hollow organs. Active contractile responses to counteract increased transmural pressure were first described almost a century ago (Bayliss, 1902) and several mechanisms have been advanced to explain this phenomenon. We report here that elongation of smooth muscle cells results in ryanodine receptor-mediated Ca(2+) release in individual myocytes. Mechanical elongation of isolated, single urinary bladder myocytes to approximately 120% of slack length (DeltaL = 20) evoked Ca(2+) release from intracellular stores in the form of single Ca(2+) sparks and propagated Ca(2+) waves. Ca(2+) release was not due to calcium-induced calcium release, as release was observed in Ca(2+)-free extracellular solution and when free Ca(2+) ions in the cytosol were strongly buffered to prevent increases in [Ca(2+)](i). Stretch-induced calcium release (SICR) was not affected by inhibition of InsP(3)R-mediated Ca(2+) release, but was completely blocked by ryanodine. Release occurred in the absence of previously reported stretch-activated currents; however, SICR evoked calcium-activated chloride currents in the form of transient inward currents, suggesting a regulatory mechanism for the generation of spontaneous currents in smooth muscle. SICR was also observed in individual myocytes during stretch of intact urinary bladder smooth muscle segments. Thus, longitudinal stretch of smooth muscle cells induces Ca(2+) release through gating of RYR. SICR may be an important component of the physiological response to increases in luminal pressure in smooth muscle tissues.     

Direct inhibitory effect of calcitonin gene-related peptide and atrial natriuretic peptide on gastric smooth muscle cells via different mechanisms.

Smooth muscle cells isolated from the gastric muscle layers of the guinea pig were used to determine whether calcitonin gene-related peptide (CGRP) and atrial natriuretic peptide (ANP) can inhibit the contractile response produced by 10(-6) M carbachol by exerting a direct action on muscle cells. In addition, the inhibitory effect of 2', 5'-dideoxyadenosine, an inhibitor of adenylate cyclase, on the CGRP-induced or ANP-induced relaxation of gastric smooth muscle cells were examined. CGRP and ANP inhibited the contractile response produced by carbachol in a dose-dependent manner, and the values of IC50 were 3 nM and 2 nM, respectively. 2',5'-dideoxyadenosine significantly inhibited the relaxation produced by CGRP. On the other hand, 2',5'-dideoxyadenosine did not have any significant effect on the relaxation produced by ANP. These results demonstrate the difference between intracellular mechanism responsible for gastric smooth muscle relaxation by CGRP and the mechanism responsible for muscle relaxation by ANP, and strongly suggest that the action of CGRP is mediated by adenosine 3',5'-cyclic monophosphate.     

Relationship between extra and intracellular sources of calcium and the contractile effect of thiopental in rat aorta

To evaluate the relationship between the vasocontractile effect of thiopental and the extra and intracellular sources of Ca2+, we analyzed both the contractile effect of the barbiturate on rat aortic rings and its ability to modify the intracellular calcium concentration in cultured rat aorta smooth muscle cells. Thiopental (10-310 microg/mL) contracted aortic rings only in the presence of extracellular Ca2+, and this effect was not blocked by verapamil or diltiazem. On the contrary, Ca2+ (0.1-3.1 mM) evoked contractions only when thiopental (100 microg/mL) was present. Although in calcium-free solution thiopental (100 microg/mL) did not contract aortic rings, it abolished the contractile effect of either phenylephrine (10(-6) M) or caffeine (10 mM). Finally, thiopental augmented the intracellular calcium concentration in cultured smooth muscle cells incubated either in the presence or absence of calcium. In conclusion, thiopental's vasocontractile effect depends on extracellular calcium influx, which is independent of L-calcium channels. The increase in intracellular Ca2+ concentration elicited by thiopental in Ca2+-free solution and its ability to block the effect of phenylephrine and caffeine suggest that this barbiturate can deplete intracellular pools of calcium. Therefore, the calcium entry pathway associated with the contractile effect of thiopental may correspond to the capacitative calcium entry model.     

Ghrelin对豚鼠胃窦平滑肌细胞钙离子浓度的影响及与NO关系研究

目的:探讨Ghrelin对豚鼠胃窦平滑肌细胞内钙离子浓度的影响及其与一氧化氮(NO)的关系。方法:采用荧光免疫组化检测胃窦平滑肌细胞ghrelin受体(GHS-R)的表达;应用钙离子(Ca2+)指示剂Fluo-3/AM作为细胞内Ca2+的荧光探针,对负载培养的平滑肌细胞应用激光共聚焦显微镜技术,检测不同浓度ghrelin对平滑肌细胞内Ca2+荧光强度(FI)的影响,以及ghrelin受体阻断剂D-Lys3-GHRP-6、NO供体硝普钠(SNP),一氧化氮合酶(NOS)抑制剂N-硝基左旋精氨酸甲酯(L-NAME)对ghrelin调控Ca2+荧光强度的影响。结果:(1)豚鼠胃窦平滑肌细胞呈GHS-R免疫反应阳性表达.(2)随着ghrelin浓度升高(10-11,10-10,10-9,10-8,10-7mol/L),平滑肌细胞内Ca2+荧光强度逐渐升高,组间峰值(分别为54.7±11.5,58.1±5.7,64.8±6.6,84.9±7.1,95.7±10.5)和峰高(分别为1.8±0.3,2.1±0.8,5.3±1.3,28.9±4.2,37.6±3.7)均存在显著差异(P<0.05-0.01),即呈明显剂量依赖...