THE EFFECTS OF CALCIUM ANTAGONISTS ON BLOOD PRESSURE AND RESPONSES TO α-ADRENOCEPTOR AGONISTS IN HYPERTENSIVE RABBITS

The effects of the calcium antagonists verapamil and nifedipine on mean arterial blood pressure, heart rate and pressor responses to a range of alpha-adrenoceptor agonists were examined in male normotensive New Zealand white rabbits and in rabbits with perinephritis hypertension. Verapamil and nifedipine caused a greater fall in mean arterial pressure in hypertensive compared to normotensive rabbits both when the fall was expressed as an absolute and as a percentage change. Effects on heart rate were similar in normotensive and hypertensive animals. Pressor responses to phenylephrine were attenuated by nifedipine and verapamil in normotensive and hypertensive rabbits. Pressor responses to alphamethyl noradrenaline were also attenuated by nifedipine, but pressor responses to BHT 920 were not significantly altered by either calcium antagonist in normotensive or hypertensive rabbits at the dose used. Thus the calcium antagonists had a greater effect on alpha 1 - than alpha 2-adrenoceptor mediated responses in both normotensive and hypertensive rabbits. Hypertensive animals showed an increased responsiveness to phenylephrine and alphamethyl noradrenaline but not BHT 920 compared to normotensives. This difference remained after treatment with both the calcium antagonists.     

EFFECTS OF 5HT2 RECEPTOR ANTAGONISTS ON RESPONSES TO POTASSIUM DEPOLARIZATION IN RAT ISOLATED AORTA

1. In order to determine whether 5HT₂ receptor antagonists can modify Ca²⁺ uptake via voltage-operated Ca²⁺ channel (VOC) in arterial smooth muscle, a comparative study of the effects of selected Ca²⁺ uptake blockers and 5HT₂ receptor antagonists on K⁺-induced contractions of rat aortic strip was undertaken. 2. The antagonist drugs studied included the Ca²⁺ uptake blockers verapamil, nifedipine, felodipine, diltiazem and cin-narizine, the 5HT₂ receptor antagonists cyproheptadine, ritanserin, mianserin, and ketanserin and the α₁-adrenoceptor antagonist prazosin. 3. With the notable exception of prazosin, each of these compounds diminished K⁺-induced aortic responses. 4. The following order of potencies (mean IC₅₀ values in mol/L) was established: felodipine (7.0 × 10^-11) >nifedipine (4.8 × 10^-9) >verapamil (5.5 × 10^-8) >cyproheptadine (6.2 × 10^-8) > diltiazem (4.1 × 10^-7) >cinnarizine (1.3 × 10^-6) >ritanserin (1.8 × 10^-6) >ketanserin (9.0 × 10^-6) > mianserin (2.0 × 10^-5). 5. The results suggest that antagonists of 5HT₂ receptors can modulate Ca²⁺ uptake via VOC in rat aorta.     

酚苄明衍生物的合成及其生物活性

利用酚苄明结构中氯乙胺基的活性，结合一些钙拮抗剂含乙二胺结构的特征，设计合成了５个酚苄明衍生物。初步药理结果表明，所合成的化合物在１０＾－５ｍｏｌ／Ｌ时对高血钾引起的细胞内钙升高具有一定的抑制作用，体外抑制血小板聚集的作用其ＩＣ５０在１０＾－４￣１０＾－５ｍｏｌ／Ｌ。     

INHIBITION OF BOVINE CEREBRAL CORTEX PROSTAGLANDIN SYNTHETASE BY PHENOXYBENZAMINE AND CYPROHEPTADINE IN VITRO

1. Bovine cerebral cortex (BCC) microsomes were isolated from fresh brain using standard techniques. 2. Two a-adrenoceptor antagonists (phenoxybenzamine and phentolamine) and two anti-serotonin compounds (cyproheptadine and cinanserine) were compared with the anti-inflammatory drugs indomethacin and keptoprofene for inhibition in vitro of prostaglandin (PG) synthetase. 3. Phenoxybenzanine and cyproheptadine inhibited BCC PG synthetase in vitro, but their potency was 1% that of indomethacin and keptoprofene. Phentolamine and cinanserine did not inhibit PG synthetase in concentrations up to ten times the effective concentrations of the other test drugs. 4. It is suggested that the antipyrogenic effect of phenoxybenzamine and cyproheptadine may be due to their inhibitory effect on prostaglandin synthesis.     

IN VITRO CALCIUM DEPENDENCE OF ARTERIAL SMOOTH MUSCLE IN HUMAN HYPERTENSION

Digital arteries, removed at autopsy from 12 hypertensives and 11 normotensives, have been compared in vitro for the calcium dependence of contractures produced by potassium chloride and noradrenaline, and the potency of verapamil to antagonize contractures to noradrenaline. No significant differences were found between the vessels from the hypertensives and normotensives for the pD2 values or the maximum response to either potassium chloride or noradrenaline in bathing solutions containing 2.5, 1.0, 0.5 or 0 mmol/l calcium chloride. There were also no significant differences between the vessels, from the hypertensive or normotensives, in the pD2 values for the addition of calcium chloride to arteries exposed to potassium chloride or noradrenaline in a calcium free bathing medium, in the ability of verapamil to shift the pD2 values for noradrenaline, nor in the ability of verapamil to reduce the maximum responses to noradrenaline (except at the two highest concentrations of verapamil tested). It is concluded that it is unlikely to be a primary abnormality of the mechanisms regulating calcium ion entry and release in vascular smooth muscle in human hypertension.     

CALCIUM-DEPENDENCY OF THE PRESSOR RESPONSES TO SELECTIVE 5-HYDROXYTRYPTAMINE RECEPTOR AGONISTS IN PITHED RATS

• 1 The pressor responses to six selective 5-HT receptor agonists, quipazine, TMFPP, Org 10155, Ru 24969, 5-methoxytryptamine and 5-methoxy-N,N-dimethyltryptamine, were quantified and tested for calcium dependency following i.v. administration to pithed normotensive rats.
• 2 The pressor responses induced by 5-methoxytryptamine and 5-methoxy-N,N-dimethyltryptamine were not influenced by calcium entry blockade by means of nifedipine.
• 3 The piperazine derivatives quipazine, TMFPP and Org 10155 were full agonists, but the pressor responses to these agonists were sensitive to calcium entry blockade.
• 4 5-Methoxy-N,N-dimethyltryptamine and Ru 24969 were found to be partial agonists.
• 5 It is submitted as a hypothesis that within the present series of 5-HT receptor agonists, a restricted side chain flexibility will enhance the dependency of their pressor responses to extracellular calcium.

     

EFFECTS OF A CONTINUOUS INFUSION OF DOPAMINE ON THE VENTILATORY AND CAROTID BODY RESPONSES TO HYPOXIA IN CATS

1. We investigated how a continuous infusion of dopamine (DA; 5μg/kg per min), which is often used clinically, would affect the ventilation and carotid chemoreceptor neural activity in anaesthetized cats. 2. In anaesthetized, spontaneously breathing cats, tidal volume (Vt) and respiratory frequency (f) were continuously monitored at five levels of inspired oxygen (P10₂= 110,130, 150, 170, 760mmHg) during Da or saline infusion. Vt and f were sampled for 1 min after 3 min exposure to each level of P10₂. Time control study was also performed. 3. DA infusion significantly lowered V_T under both normoxia and hypoxia in seven of eight cats. Respiratory frequency was not affected by DA infusion. Depression of ventilation during post-hypoxic hyperoxia was augmented by DA infusion. Chemodenervntion abolished the ventilatory response to hypoxia and DA did not further affect the ventilatory response to hypoxia. 4. In a second group of artificially ventilated cats, carotid chemoreceptor neural activity was recorded at five levels of arterial oxygen tension. DA infusion significantly depressed carotid chemoreceptor neural activity during normoxia and hypoxia in six of seven cats. 5. These findings suggest that changes in ventilation during low dosage of DA infusion closely correlate with carotid body neural output. A predominant effect of this dosage of DA (5 μg/kg per min) was depression in the ventilatory response to hypoxia due to an inhibition of carotid body neural output.     

VASCULAR ENDOTHELIN RESPONSIVENESS AND RECEPTOR CHARACTERISTICS IN VITRO AND EFFECTS OF ENDOTHELIN RECEPTOR BLOCKADE IN VIVO IN CYCLOSPORIN HYPERTENSION

1. The aim of these studies was to determine the role of endothelin in cyclosporin A ([CsA], 10 mg/kg per day, s.c., for 30 days) hypertension in the rat. 2. There were no significant differences in plasma endothelin concentrations, in vitro mesenteric vascular membrane [¹²⁵I]-endothelin-l (ET-1) binding characteristics or myographic vascular responses to endothelin-1 between the CsA and control groups (systolic blood pressure 135 ± 1 vs 127 ± 1 mmHg, respectively, P<0.001). 3. Twenty-four hours after selective endothelin type A receptor blockade in vivo with BQ123, blood pressure in CsA hypertensive rats was lowered to levels of normotensive controls. 4. These results suggest that changes in endothelin synthesis rather than changes in vascular sensitivity and/or ET-1 receptor characteristics may contribute to CsA-induced hypertension.     

EFFECTS OF FIVE NON-STEROIDAL ANTI-INFLAMMATORY DRUGS ON THE RENAL AND SYSTEMIC RESPONSES TO ARACHIDONATE IN CONSCIOUS DOGS

1. The effects of five different non-steroidal anti-inflammatory drugs (NSAID) on the renal blood flow responses to arachidonate were compared. 2. Arachidonate (5-200 micrograms/kg) injected into the renal arteries of conscious dogs caused dose-related renal vasodilatation with no systemic effects. 3. Aspirin (35 mg/kg), phenylbutazone (12 mg/kg) and ibuprofen (25 mg/kg) all markedly reduced arachidonate-induced renal vasodilatation. 4. In contrast, neither indomethacin (3 mg/kg) or its related drug sulindac sulphide (6 mg/kg) significantly reduced arachidonate-induced renal vasodilatation. 5. All NSAID abolished the hypotensive response to intravenous injection of arachidonate (10 mg). 6. Thus, indomethacin and sulindac did not block the effects of renal artery injections of arachidonate but did abolish the systemic effects. Aspirin, phenylbutazone and ibuprofen greatly reduced responses to both renal artery and intravenous arachidonate. 7. Indomethacin and aspirin both reduced the production of prostaglandin E2 and 6-keto-PGF1 alpha by dog renal cortical microsomes in vitro. 8. Thus, indomethacin and sulindac had different effects to other NSAID on arachidonate-induced renal vasodilatation. The results are compatible with the hypothesis that some sites of prostaglandin production in the kidneys of conscious dogs may be relatively resistant to inhibition by indomethacin and sulindac.     

组胺H_2受体激动剂和拮抗剂及抗癌药对正常人造血祖细胞和HL－60白血病细胞生长的作用

采用体外微量克隆培养体系研究了组胺Ｈ＿２受体激动剂４－甲基组胺（４－ＭＨ）和拮抗剂雷尼替叮（ｒａｎｉｔｉｄｉｎｅ）及抗癌药阿糖胞苷分别对正常人外周血粒－巨噬系祖细胞（ＰＢＣＦＵ－ＧＭ）和ＨＬ－６０白血病细胞生长的作用。当４－ＭＨ的浓度为１０￣（－９）～１０￣（－６）ｍｏｌ·Ｌ￣（－１）时，可促进ＰＢＣＦＵ－ＧＭ的增殖，４－ＭＨ的浓度增加至１０￣（－１）ｍｏｌ·Ｌ￣（－１）时则表现为抑制ＰＢＣＦＵ－ＧＭ的增殖。Ｒａｎｉｔｉｄｉｎｅ的浓度为１０￣（－９）～１０￣（－５）ｍｏｌ·Ｌ￣（－１）时，表现出对ＰＢＣＦＵ－ＧＭ增殖的抑制作用，但在１０－６ｍｏｌ·Ｌ￣（－１）剂量时对ＰＢＣＦＵ～ＧＭ的抑制率低于５０％，而在该剂量时对ＨＬ－６０白血病细胞的抑制率已达１００％，具有一定的选择性。抗癌药阿糖胞苷（Ａｒａ－Ｃ）对ＨＬ－６０白血病细胞的抑制作用比对ＰＢＣＦＵ－ＧＭ的抑制作用较强，但两者的ＩＣ＿（５０）值处于同一个数量级。在强化化疗剂量１０￣（－５）ｍｏｌ·Ｌ￣（－１）时，Ａｒａ－Ｃ对ＨＬ－６０白血病细胞和ＰＢＣＦＵ－ＧＭ正常造血祖细胞的抑制率均达１００％。     

左旋千金藤啶碱对外周血管多巴胺DA_1和DA_2受体亚型的作用

用家兔离体血管环方法，研究左旋千金藤啶碱（ｌＳＰＤ）对外周血管ＤＡ１和ＤＡ２受体亚型的作用。结果表明，ｌＳＰＤ使ＤＡ１受体激动剂ＦＯＤＡ诱发的肾、肺和肠动脉以及ＤＡ２受体激动剂ＰＢＤＡ诱发的肠和股动脉舒张反应的量效曲线非平行右移，最大反应（Ｅｍａｘ）降低，均呈非竞争性拮抗；ｌＳＰＤ本身还可使肾和肺血管产生轻度的浓度依赖性舒张反应，表现为ＤＡ１受体激动剂的作用特性。提示ｌＳＰＤ为外周血管ＤＡ１和ＤＡ２受体的混合性阻滞剂并兼有ＤＡ１受体部分激动剂的双重作用特性。     

GLUTAMATE-INDUCED CALCIUM LOADS: EFFECTS ON ENERGY METABOLISM AND NEURONAL VIABILITY

1. Glutamate-induced increases in intracellular free Ca²⁺ concentration ([Ca²⁺]i) were recorded from cultured rat hippocampal neurons with single cell microfluorometry. The [Ca²⁺]i increase did not correlate with glutamate-induced cell death, consistent with the idea that Ca²⁺ accumulates in an intracellular store, and that loading this store might be toxic. 2. Glutamate-induced Ca²⁺ loads were buffered by a low-affinity, high-capacity process that was inhibited by the mitochondrial uncoupling agent FCCP and modulated by intracellular Na⁺. 3. Glutamate-induced Ca²⁺ loads also produced an intracellular acidification. The acidification was prevented by the metabolic inhibitor 2-deoxyglucose, mimicked by Ba²⁺, and inhibited by microinjection of ruthenium red. 4. These data are consistent with the hypothesis that mitochondria sequester glutamate-induced Ca²⁺ loads producing a metabolic acidosis; metabolic stress may contribute to glutamate-induced neuronal death.     

RENAL RESPONSES TO ANGIOTENSIN II IN CONSCIOUS DOGS: EFFECTS OF ASPIRIN AND INDOMETHACIN

1. Angiotensin II was infused into the renal artery of unanaesthetized dogs at 0.4 and 2.0 ng/kg per min for 40 min each. 2. Indomethacin (3 mg/kg, and 1 mg/kg per h infusion i.v.) accentuated the angiotensin II-induced falls in glomerular filtration rate, renal blood flow and urine flow rate. Indomethacin did not alter the effects of angiotensin II on Na+ or K+ excretions. 3. Aspirin (35 mg/kg p.o. 2.5 h and 0.5 h prior to experiment) did not significantly change the renal effects of angiotensin II. 4. Both aspirin and indomethacin accentuated renal vasoconstriction during briefer (5 min) angiotensin II infusion. 5. Thus indomethacin and aspirin had markedly different effects on the actions of angiotensin II in the kidney. This suggests that at least one of these drugs has actions which affect angiotensin II-mediated vasoconstriction other than via cyclooxygenase inhibition.     

THE EFFECT OF PHENOXYBENZAMINE AND SARALASIN ON THE ALTERED RENAL BLOOD FLOW DISTRIBUTION IN BABOONS WITH OBSTRUCTIVE JAUNDICE

1. Using the ¹³³xenon (¹³³Xe) washout technique, renal cortical perfusion was measured in fourteen baboons before and 1 and 2 weeks after ligation of the common bile duct. 2. In the 1-week group (seven animals), ligation of the common bile duct caused no significant changes in cortical perfusion in comparison with preligation values. 3. Intrarenal infusion of the angiotensin II blocking agent, saralasin, at a rate of 0.1 mmol/min caused no change in cortical perfusion in the 1-week group. However, an infusion of 0.3 mmol/min of the α-adrenoreceptor blocking agent, phenoxybenzamine, caused significant increases in outer cortical flow over control (P < 0.05) and 1-week values (P < 0.05). 4. In the 2-week group (seven animals), ligation of the common bile duct caused a non-significant decrease in outer cortical flow and a significant decrease in the percentage distribution of radioactivity distributed to the outer cortex (P < 0.001). 5. A 0.1 mmol/min intrarenal infusion of saralasin had no effect on outer cortical flow in the 2 week group, but significantly raised the percentage distribution of flow to the outer cortex (P < 0.001) over the 2-week value. An intrarenal infusion of 0.3 mmol/min phenoxybenzamine in the 2-week group significantly increased outer cortical flow levels over the 2-week (P < 0.001) and control (P < 0.05) values. The percentage distribution to the outer cortex was also significantly raised (P < 0.001) over the 2-week values. 6. There was a significant correlation between the changes in outer cortical blood flow induced by phenoxybenzamine at 1 and 2 weeks and the percentage increases in total serum bilirubin (r= 0.802, P < 0.001) and cholesterol (r= 0.668, P < 0.01) plasma levels over baseline values. 7. These results demonstrate that in baboons with experimentally-induced obstructive jaundice there is increased activity of the renal a-adrenoreceptors, and when renal cortical vasoconstruction is present, the renin-angiotensin system may also be activated and contributes to the cortical vasoconstriction.     

大鼠蛛网膜下腔联合注射kappa受体激动剂和NMDA受体拮抗剂协同镇痛

以大鼠热辐射甩尾潜伏期为测痛指标，蛛网膜下腔（ｉｔ）联合注射非镇痛剂量的ｋａｐｐａ阿片受体激动剂强啡肽（ｄｙｎｏｒｐｈｉｎ，Ｄｙｎ）Ａ－（１－１３）５ｎｍｏｌ或Ｕ５０４８８Ｈ（ｔｒａｎｓ－（±）－３，４－ｄｉｃｈｌｏｒｏ－Ｎ－ｍｅｔｈｙｌ－［２－（１－ｐｙｒｒｏｌｉｄｉｎｙｌ）－ｃｙｃｌｏｈｅｘｙｌ］－ｂｅｎｚｅｎｅａｃｅｔａｍｉｄｅ）１００ｎｍｏｌ和Ｎ－ｍｅｔｈｙｌ－Ｄ－ａｓｐａｒｔａｔｅ（ＮＭＤＡ）受体拮抗剂ＤＬ－２－ａｍｉｎｏ－５－ｐｈｏｓｐｈｏｎｏｖａｌｅｒｉｃａｃｉｄ（ＡＰｖ）１０ｎｍｏｌ或ｋｙｎｕｒｅｎｉｃａｃｉｄ（ＫＹＮ）５０ｎｍｏｌ有显著的协同镇痛效应，其效应与ＮＭＤＡ受体拮抗剂呈一定量效关系。Ｋａｐｐａ阿片受体特异性拮抗剂ｎｏｒ－ｂｉｎａｌｔｏｒｐｈｉ－ｍｉｎｅ（ｎｏｒ－ＢＮＩ）１５ｎｍｏｌｉｔ可完全翻转ＤｙｎＡ－（１－１３）５ｎｍｏｌ和ＡＰｖ１０ｎｍｏｌ及Ｕ５０４８８Ｈ１００ｎｍｏｌ和ＫＹＮ５０ｎｍｏｌ的协同镇痛。说明协同作用是通过ｋａｐｐａ受体和谷氨酸能神经元之间的相互作用实现的。     

丁基苯酞对低糖低氧引起神经细胞内钙升高的作用

目的:探讨抗脑缺血新药丁基苯酞(NBP) 对脑缺血过程中细胞内游离钙升高的影响及其作用机制。方法:采用低糖低氧损伤胎鼠或新生鼠神经细胞以模拟脑缺血,用Fura-2/AM 作荧光指示剂,观察手性丁基苯酞对神经细胞内游离钙升高的抑制作用,并用内钙释放剂thapsigargin,外源性谷氨酸,高K+ 及钙离子载体A23187 作工具药,对其作用环节进行分析。结果:d-,l-,dl-丁基苯酞能完全抑制低糖低氧造成的神经细胞内钙升高。手性NBP能降低thapsigargin 引起的内质网钙库释放,d-NBP 还对谷氨酸引起的内钙升高表现出抑制作用。结论:丁基苯酞抑制低糖低氧条件下神经细胞内钙升高的作用环节主要是抑制细胞内钙库的释放。     

DIFFERENTIAL BLOCKING EFFECTS OF PRAZOSIN AND YOHIMBINE ON PRESSOR RESPONSES TO NEURONALLY RELEASED AND EXOGENOUSLY ADMINISTERED NORADRENALINE IN THE PITHED RAT

The effects of prazosin and yohimbine on pressor responses to sympathetic nerve stimulation and intravenous injections of noradrenaline, phenylephrine and clonidine were examined in pithed rats to determine the postjunctional location of alpha 2-adrenoceptors in the vascular smooth muscle. Prazosin antagonized the pressor responses to phenylephrine and to sympathetic nerve stimulation more effectively than the responses to noradrenaline and to clonidine. Yohimbine antagonized the pressor responses to noradrenaline and to clonidine more effectively than the responses to sympathetic nerve stimulation and to phenylephrine. These results suggest that alpha 2-adrenoceptors as well as alpha 1-adrenoceptors produce vasoconstriction in the rat vasculature and support the hypothesis that alpha 1-adrenoceptors are predominantly located within the neuroeffector junction in contrast to an extrajunctional location of alpha 2-adrenoceptors.     

过氧化氢诱导牛主动脉内皮细胞损伤和胞内Ca2+升高及钙拮抗剂的抑制作用

为探讨缺氧/缺血过程中自由基损伤与钙超载的关系,观察了过氧化氢(H₂O₂)诱导培养牛主动脉内皮细胞(BAEC)的损伤和胞内游离钙([Ca²⁺]i)的变化。结果表明,H₂O₂可剂量、时间依赖地诱导BAEC活性下降(MTT值下降),脂质过氧化产物丙二醛(MDA)生成显著增加,同时伴有[Ca²⁺]i迅速显著升高。钙拮抗剂硝苯地平可剂量依赖地抑制H₂O₂引起的[Ca²⁺]i升高;同时能显著升高BAEC的MTT值,降低MDA生成,有效对抗H₂O₂诱导的BAEC损伤。提示,H₂O₂诱导内皮损伤可能与升高[Ca²⁺]i有关,Ca²⁺超载可能是活性氧致损伤的途径之一。钙拮抗剂对活性氧损伤具有一定保护作用。     

EFFECTS OF HISTAMINE RECEPTOR ANTAGONISM ON ADRENALINE-INDUCED CHANGES IN BLOOD PRESSURE IN INTACT DOGS

This study was designed to test the hypothesis that histamine may contribute to the vasodepressor response which occurs in response to physiologic increments in adrenaline concentration in intact animals. Accordingly, following a control period of 30 min, adrenaline was infused intravenously for 45 min at a rate of 250 ng/kg per min in 14 anaesthetized dogs (Group I). A second group of eight dogs received an identical adrenaline infusion following complete H1- and H2-histamine receptor antagonism with tripelennamine plus cimetidine (Group II). A time control group of experiments, in which no drugs were infused, as well as groups receiving adrenaline plus either tripelennamine or cimetidine, were also performed. In Group I, adrenaline infusion increased heart rate and reduced mean arterial blood pressure by 10 mmHg (P less than 0.01). Following combined H1- and H2-histamine receptor antagonism (Group II), adrenaline infusion failed to reduce mean arterial blood pressure. However, mean arterial blood pressure was reduced significantly in the groups receiving adrenaline plus only one of the histamine receptor blocking agents. Since only the combined histamine receptor blockade completely eliminated the vasodepressor response to adrenaline, the data suggest that histamine may play a physiological role in the vasodepressor response to circulating adrenaline in the intact animal, and that both H1- and H2-histamine receptors may be involved.     

增加运动对单纯性肥胖者周血红细胞胰岛素受体的影响

观察增加运动对单纯性肥胖者血浆胰岛素水平、红细胞胰岛素受体（Ｑ１、Ｑ２）及亲和常数（Ｋ１、Ｋ２）的影响发现：单纯性肥胖者运动前存在明显的高胰岛素血症，其红细胞膜上胰岛素受体的四个参数均较正常组减低（Ｐ＜０．０５）。增加运动２４周后Ｑ１、Ｑ２、Ｋ２均出现有意义增加。提示单纯性肥胖者的高胰岛素血症可能由于胰岛素受体数量及亲和能力改变所致，增加运动量有助于改善胰岛素抵抗。