野百合碱诱导的肺动脉高压大鼠肺血管5-HT转载体表达增强

目的　研究野百合碱诱导的大鼠肺动脉高压与5 HT转载体基因表达的关系。方法　应用MCT诱导的慢性肺动脉高压大鼠模型,建立离体动脉环5 HT浓度反应曲线;HE染色观察肺动脉构型重建,应用RT PCR检测大鼠肺动脉5 HT转载体mRNA表达。结果　MCT大鼠肺血管对5 HT收缩反应增强,肺肌型小动脉中膜增厚,MCT诱导的肺动脉高压大鼠肺血管5 HT转载体mRNA表达明显增多。5 HT转载体基因表达与肺肌型小动脉中膜增厚有明显相关性。结论　MCT诱导的肺动脉高压大鼠肺血管构型重建及5 HT引起收缩反应增强,伴有5 HT转载体mRNA表达增多;同时5 HT转载体mRNA表达与肺肌型小动脉中膜增厚有明显相关性,提示5 HT转载体可能在肺动脉高压中起重要作用。     

2,6-二甲基-4-(2-氯苯基)-1,4-二氢-3,5-吡啶二羧酸二甲酯的抗5-羟色胺作用在防治野百合碱性大鼠肺动脉高压中的意义

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.     

5—HT3受体拮抗剂

5-羟色胺(5-HT)是人体内分布最广泛的递质之一,对介导其作用的几种类型受体的鉴别,使对5-HT许多作用的分析成为可能。目前已知有4种受体,各有其独特的作用,有的受体还有若干种亚型。5-HT_3受体拮抗剂的开发,与对其在控     

5-羟色胺受体及其激动剂和拮抗剂

近年来,在5-羟色胺(5-HT)的组织分布、生物合成和代谢研究的同时,对其受体研究也取得了重要进展。1986年Bradley等首次提出5-HT受体主要有三种类型,即5-HT_1、5-HT_2和5-HT_3受体。5-HT_1受体进一步分为5-HT_(1A)、5-HT_(1B)、5-HT_(1D)三种亚型。5-HT_2受体分为5-HT_(2A)和5-HT_(2B)两个亚型。5-HT_(1c)受体亚型与5-HT_2受体相似,将在一起讨论。另外,还存在5-HT_(1p)、5-HT_4受体等。这些新的进展使某些疾病的病     

5-羟色胺受体介导迷走交感神经切断犬颈外血管收缩(英文)

One specific example reflecting the completity ofcardiovascular responses induced by serotonin ( 5-hydroxytryptamine; 5-HT) and the progress achieved inthe pharmacological characterization of the receptorsinvolved can be illustrated by the effects of 5-HT on thecanine external carotid artery bed. Within thisframework, it has been shown that the external carotidvasoconstrictor response to 5-HT in the dog is mediatedby '5-HT_1-like' receptors, which being blocked by the5-HT_(1B/1D) receptor antagonist GR127935, resemble 5-HT_(1B/1D)(previously called 5-HT_(1B/1D) ) receptors. It     

5-HT_3受体拮抗剂

5-HT受体起初,根据5-HT引起离体豚鼠回肠收缩的非神经和神经中介机制,将5-HT受体分成“D”型和“M”型,其后,根据[~3H]-5-HT和[~3H]-螺哌隆(3H-Spiperone)与大鼠脑皮质的结合性质,将5-HT受体分成5-HT_1和5-HT_2。5-HT_2结合部位的药理反应与以前认为是由5-HT“D”受体中介的某些反应相关。近来,主要根据放射配体结合的结果,发现在5-HT_1高亲和结合部位显示出异     

氟伐他汀对肺动脉高压大鼠5-羟色胺转载体表达的影响

目的观察氟伐他汀对野百合碱(MCT)所致的肺动脉高压大鼠肺组织5-羟色胺转载体(5-HTT)表达的影响。方法62只大鼠随机分为3组:①M+F组:大鼠首先给予MCT(40 mg/kg)皮下注射和氟伐他汀(1 mg/kg)灌胃,每日各1次,连续2周。第3~6周继续按氟伐他汀初始给药方案灌胃,不再进行MCT皮下注射。②MCT组:实验前2周给予MCT(40 mg/kg)1次/d皮下注射,第3~6周末给予同氟伐他汀等体积的0.9%盐水灌胃;③Saline组:分别于实验前2周及第3~6周给予等体积的盐水皮下注射和灌胃。分别于不同时间点,对大鼠的血流动力学及相关参数和5-HTT的表达情况进行测定。结果MCT组大鼠于实验第2周末即出现显著的肺动脉高压伴5-HTT蛋白水平异常增高,且在观察期间逐渐增高。M+F组大鼠第6周末出现肺动脉压异常增高,但未伴5-HTT表达增高。结论氟伐他汀能有效抑制5-HTT表达上调,该作用可能与其对大鼠肺动脉高压的抑制作用有关。     

舍曲林和氟西汀对慢性肺动脉高压模型大鼠的保护作用研究

目的:研究选择性5-羟色胺重吸收抑制剂(SSRI)舍曲林和氟西汀对野百合碱(MCT)诱导的慢性肺动脉高压(PAH)大鼠的保护作用。方法:40只大鼠随机分为对照组、MCT组、MCT+舍曲林(MCT+Ser)组和MCT+氟西汀(MCT+Flu)组,后3组大鼠腹腔注射MCT造模。MCT+Ser组和MCT+Flu组大鼠每天分别给予Ser和Flu,MCT组和对照组大鼠给予相应溶剂。各组大鼠常规饲养3周后检测肺动脉压、右心指数;HE染色法测定并计算非肌型动脉、部分肌型动脉及肌型动脉所占比例,比较各组肺动脉肌化程度;逆转录-聚合酶链反应法测定5-羟色胺转运体(SERT)mRNA表达变化。结果:与对照组比较,MCT组肺动脉压、右心指数、动脉肌化程度及SERTmRNA表达升高;与MCT组比较,MCT+Ser组和MCT+Flu组上述各指标均降低(P<0.05或P<0.01)。结论:Ser和Flu对MCT诱导的PAH具有抑制作用,作用机制可能与抑制SERTmRNA表达有关。     

5-HT受体拮抗剂ketanserin的临床应用

<正> Ketanserin(R41468)是竞争性5-HTS_2受体拮抗剂,能对抗5-HT的外周缩血管作用,是一新型抗高血压药物。 药理作用 5-HT(5-羟色胺,血清素)是一种自体活性物质,对神经系统、心血管系统、平滑肌以及血小板具有广泛的生理和药理作用。5-HT通过受体起作用,其受体有S_1(5-HT_1)和S_2(5-HT_2)两种     

5-HT_(2B)受体阻断剂对心肌肥厚大鼠心肌5-HT含量及5-HT_(2B)受体表达的影响

目的观察5-HT2B受体阻断剂对去甲肾上腺素(norepinephrine,NE)诱导的心肌肥厚大鼠心肌中5-羟色胺(5-hydrotriptamine,5-HT)含量及5-HT2B受体表达的影响。方法雄性SD大鼠24只,随机分为3组,8只/组,分别为对照组、肥厚组、实验组。采用腹腔注射NE(1.5 mg/kg,2次/d,28 d)的方法建立心肌肥厚模型,自第15天起实验组腹腔注射SB204741(5-HT2B受体阻断剂;2 mg/kg,2次/d),连续注射14 d。对照组腹腔注射相同体积的生理盐水(2次/d,28 d)。检测各组左心室重量与体重之比(LVW/BW)、心肌组织中5-HT的含量及5-HT2B受体的表达情况。结果在NE诱导心肌肥厚过程中,应用SB204741干预可显著减轻心肌肥厚的程度,降低心肌组织中5-HT的含量,并抑制5-HT2B受体表达的上调。结论应用5-HT2B受体阻断剂可减轻NE诱导心肌肥厚的程度,降低心肌组织中5-HT的含量,并抑制5-HT2B受体表达的上调。     

5-Hydroxytryptamine receptors mediating vasoconstriction in pulmonary arteries from control and pulmonary hypertensive rats.

1. We investigated 5-hydroxytryptamine (5-HT)-receptor mediated vasoconstriction in the main, first branch and resistance pulmonary arteries removed from control and pulmonary hypertensive rats. Contractile responses to 5-HT, 5-carboxamidotryptamine (5-CT, non-selective 5-HT1 agonist), and sumatriptan (5-HT1D-like receptor agonist) were studied. The effects of methiothepin (non-selective 5-HT1 + 2-receptor antagonist) and ketanserin (5-HT2A receptor antagonist) and GR55562 (a novel selective 5-HT1D receptor antagonist) on 5-HT-mediated responses were also studied. Basal levels of adenosine 3':5'-cyclic monophosphate ([cyclic AMP]i) and guanosine 3':5'-cyclic monophosphate ([cyclic GMP]i) were determined and we assessed the degree of inherent tone in the vessels under study. 2. 5-HT was most potent in the resistance arteries. pEC50 values were 5.6 +/- 0.1, 5.3 +/- 0.1, 5.0 +/- 0.2 in the resistance arteries, pulmonary branch and main pulmonary artery, respectively (n = at least 5 from 5 animals). The sensitivity to, and maximum response of, 5-HT was increased in all the arteries removed from the chronic hypoxic (CH) rats. In CH rats the pEC50 values were 5.9 +/- 0.2, 6.3 +/- 0.2, 6.4 +/- 0.2 and the increase in the maximum response was 35%, 51% and 41% in the resistance arteries, pulmonary branch and main pulmonary artery, respectively. Sumatriptan did not contract any vessel from the control rats whilst 5-CT did contract the resistance arteries. In the CH rats, however, they both contracted the resistance arteries (responses to sumatriptan were small) (pEC50: 5-CT; 5.4 +/- 0.2) and the pulmonary artery branches (pEC50: sumatriptan, 5.4 +/- 0.2; 5-CT, 5.4 +/- 0.2). 5-CT also caused a contraction in the main pulmonary artery (pEC50: 6.0 +/- 0.3). 3. Ketanserin (1 nM-1 microM) caused a competitive antagonism of the 5-HT response in all vessels tested. In control rats, the estimated pKb values for ketanserin in resistance arteries, pulmonary branches and main pulmonary artery were 8.3, 7.8 and 9.2, respectively. Methiothepin (1 nM-1 microM) inhibited responses to 5-HT in the first branch (estimated pKb value: 7.8) and main pulmonary artery. In CH rats, the estimated pKb values for ketanserin in resistance arteries, pulmonary branches and main pulmonary artery were 7.7, 8.3 and 9.6, respectively. Methiothepin also inhibited contractions to 5-HT in the pulmonary artery branch and main pulmonary artery with estimated pKb values of 7 and 9.5, respectively. In control animals, GR55562 had no effect on responses to 5-HT in any of the vessels tested. In the CH rats the estimated pKb values for GR55562 were 6.5, 7.8 and 7.0 in the pulmonary resistance arteries, first branch and main pulmonary artery, respectively. 4. Large pulmonary arteries from controls demonstrated inherent tone and this was increased three fold in the CH rats. The resistance arteries from controls demonstrated little inherent tone though this was enhanced in those from the CH rats. 5. [Cyclic AMP]i was 259 +/- 23 pmol mg-1 protein in the pulmonary artery branches removed from control rats and decreased to 192 +/- 11 pml mg-1 protein in the CH rats (P < 0.01, n = 8). [Cyclic GMP]i also decreased in the pulmonary artery branches (from 550 +/- 15, control to 462 +/- 31 pmol mg-1 protein in CH vessels, n = 8, P < 0.01) and in the main pulmonary arteries (from 566 +/- 33, control to 370 +/- 25 pmol mg-1 protein in CH vessels, n = 8, P < 0.001). No changes in either [cyclic AMP]i or [cyclic GMP]i were observed in the resistance arteries. 6. The results suggest that the increased vasoconstrictor response to 5-HT in CH rat pulmonary arteries is due to an increase in 5-HT2A-receptor mediated contraction combined with an increase in r5-HT1B-like receptor-mediated contraction. An increase in vascular tone and decreased levels of [cyclic GMP]i in the large pulmonary arteries may contribute to the observed increase in activity of r5-HT1B-like receptor     

SL65.0472 blocks 5-hydroxytryptamine-induced vasoconstriction in a dog hindlimb ischemia model

We have studied the ability of SL65.0472 (7-fluoro-2-oxo-4-[2-[4-(thieno[3,2-c]pyridin-4-yl)piperazin-1-yl]ethyl]-1,2-dihydroquinoline-1-acetamide), a 5-hydroxytryptamine (5-HT) 5-HT1B/5-HT2A receptor antagonist, to antagonise the vasoconstrictor effects of 5-HT and sumatriptan in a canine model of hindlimb ischemia. Dogs underwent right external iliac artery ligation and right superficial femoral artery excision, resulting in decreased perfusion (-31%, P<0.05) in the right hindlimb. Following pretreatment with L-NAME, phentolamine and propranolol, intra-aortic injection of 5-HT markedly reduced blood flow to the right ischemic hindlimb (-50 +/- 2%, P<0,05). 5-HT induced vasoconstriction was significantly inhibited (-66%, P<0.05) by SL65.0472 (300 microg/kg i.v.), but unaffected by ketanserin (300 microg/kg i.v.), a 5-HT2A receptor antagonist. SL65.0472 also blocked sumatriptan-induced vasoconstriction in ischemic and normally perfused hindlimbs. Thus, SL65.0472 is an effective antagonist of 5-HT-receptor mediated hindlimb vasoconstriction.     

Vasoconstrictor responses to 5-hydroxytryptamine in the autoperfused hindquarters of spontaneously hypertensive rats

In this work we studied the responses and receptors involved in the effects of intra-arterial 5-hydroxytryptamine (5-HT) in the in situ autoperfused hindquarters of spontaneously hypertensive rats (SHR). Intra-arterial administration of the highest doses (50-1,000 ng/kg) produced a vasoconstrictor effect that was inhibited by ritanserin (a selective 5-HT2 receptor antagonist), SB 206553 (a selective 5-HT(2B/2C) receptor antagonist) and spiperone (a nonspecific 5-HT(1/2A) receptor antagonist), and was mimicked by alpha-methyl-5-HT (a selective 5-HT2 receptor agonist) and m-CPP (a selective 5-HT2C receptor agonist), but not by the intra-arterial administration of BW 723C86, a selective 5HT2B receptor agonist. SB 206553 and spiperone inhibited alpha-methyl-5HT-induced vasoconstriction in the hindquarters of SHR. Our data suggest that the vasoconstrictor response induced by 5-HT in the autoperfused hindquarters of SHR is mainly mediated by the activation of 5-HT2A and 5-HT2C receptors.     

SB_(224289)对5-HT诱导的肺动脉平滑肌细胞增殖的影响

目的研究 5 HT1B受体拮抗剂SB2 2 42 89对 5 HT诱导的肺动脉平滑肌细胞增殖的影响 ,探讨肺血管构型重建的 5 HT1B受体机制。方法分离培养大鼠肺动脉平滑肌细胞 ,用MTT法和3 H TdR掺入法检测细胞增殖和DNA合成。结果SB2 2 42 89能剂量依赖地抑制 5 HT诱导的肺动脉平滑肌细胞增殖。SB2 2 42 89能剂量依赖地抑制 5 HT诱导的肺动脉平滑肌细胞的DNA合成 ,SB2 2 42 89能阻断 5 HT对肺动脉平滑肌细胞的促有丝分裂作用。结论SB2 2 42 89能抑制 5 HT引起的肺动脉平滑肌细胞的增殖。5 HT1B受体在 5 HT诱导的肺动脉平滑肌细胞增殖中有重要作用。     

5—羟色胺增强去甲肾上腺素诱导的肥厚心肌L—型钙电流

目的:研究5-羟色胺(5-HT)对去甲肾上腺素(NE)诱导的大鼠肥厚心肌L-型钙电流(I_(Ca))的影响.方法:大鼠腹腔注射NE建立心肌肥厚模型;酶解分离单个心室肌细胞;全细胞膜片箝记录I_(Ca).结果:(1)腹腔注射NE第15天,大鼠左心室与体重比增加31.8％(2)肥厚心肌细胞I_(Ca)与正常心肌细胞相比,明显增加0mV时分别为4.5pA/pF±0.5pA/pF和3.5pA/pF±0.3pA/pF(P<0.01).(3)5-HT可显著增加肥厚和正常心肌细胞I_(Ca),并使最大激活电流从0mV降低至-10mV;此外,5-HT增加I_(Ca)作用在肥厚心肌细胞更为显著.(4)稳态激活和失活实验发现,5-HT对稳态激活曲线无显著影响,而影响稳态失活曲线,使半失活电压从-39.5mV±1.8mV升高至-27.8mV±1.7mV(P<0.05),而不改变钙通道电压依赖性(斜率因子k无显著变化).结论:5-HT通过改变L-型钙通道稳态失活特征而显著增加I_(Ca),此作用在肥厚心肌细胞更显著,提示在肥厚心肌5-HT更易于诱导心律失常发生.     

m-CPP, a 5-HT2C receptor agonist that modifies the perfusion pressure of the hindquarter vascular bed of anesthetized rat

In the present work we studied the actions of the intra-arterial administration of meta-chlorophenylpiperazine (m-CPP - a 5-HT(2C) receptor agonist) in the hindquarters of the anesthetized rat. The lowest doses used (0.001, 0.01, 0.1, 0.25 and 0.5 microg/kg) induced vasodilatation whereas the highest doses produced vasoconstriction (1, 6.25, 12.5 and 25 microg/kg). Both vasodilatation and vasoconstriction were inhibited by the 5-HT(1,2 )receptor antagonist methiothepin, whereas the 5-HT(2 )receptor antagonist ritanserin blocked only the vasoconstrictor responses. 1-[4-(1-Adamantanecarboxamido)butyl]-4-(2-methoxyphenyl)piperazine (a 5-HT(1A) receptor antagonist) and ICI 118,551 (a beta(2)-receptor antagonist) failed to modify the vasodilator responses of m-CPP. Both BRL 15572 (a 5-HT(1D) receptor antagonist) and GR 55562 (a 5-HT(1B) receptor antagonist) only partially inhibited this action. Our data reveal that m-CPP induces the 5-HT(1 )and/or non-specific vasodilator effect and 5-HT(2) vasoconstrictor effects in the hindquarter vascular bed of the rat.     

Vasoconstriction in human isolated middle meningeal arteries: determining the contribution of 5-HT1B- and 5-HT1F-receptor activation

AIMS: Sumatriptan is a 5-HT1B/1D-receptor agonist which also has affinity for 5-HT1F-receptors. The vasoconstrictor effects of sumatriptan are thought to be 5-HT1B-receptor mediated and these receptors have been shown to be expressed in human cranial blood vessels. However, in the same tissue mRNA coding for 5-HT1F-receptors has also been identified and this study addresses the possibility of whether 5-HT1F-receptor activation contributes to vasoconstriction. METHODS: The ability of two selective 5-HT1B/1D-receptor antagonists (GR125,743 and GR127,935) with no affinity for 5-HT1F-receptors, to inhibit sumatriptan evoked contractions in human isolated middle meningeal artery was investigated. Using a series of 5-HT1B/1D-receptor agonists (sumatriptan, zolmitriptan, CP122,288, L-741,519 and L-741,604), some with high affinity for 5-HTIF-receptors and the non-selective 5-HT-receptor agonists 5-HT and 5-CT, we compared the vasoconstrictor potency of these drugs in human isolated middle meningeal artery with their affinities at cloned human 5-HT1B-, 5-HT1D-and 5-HT1F-receptors expressed in CHO cell lines. RESULTS: GR125,743 antagonized sumatriptan evoked contractions in a competitive manner (apparent pA2 9.1) and GR127,935 antagonized sumatriptan-induced responses in a non-competitive manner (reducing the maximum contraction to 27%). There was a significant correlation between vasoconstrictor potency and 5-HT1B-receptor affinity (r=0.93, P=0.002) but not with 5-HT1D- or 5-HT1F-receptor affinity (r=0.74, P=0.06; r= 0.31, P= 0.49, respectively). CONCLUSIONS: These experiments show that in human middle meningeal artery vasoconstriction to sumatriptan-like agents is 5-HT1B-receptor mediated with little if any contribution from 5-HT1F-receptor activation.     

The serotonin receptor and transporter as potential therapeutic targets for pulmonary hypertension

Pulmonary hypertension (PHT) results from compromised pulmonary vasoconstriction and vascular remodeling. Serotonin (5-hydroxytryptamine/5-HT) is one of the important vasomotor agents, and its importance in the pathogenesis of PHT is currently being investigated. In most mammalian species, PHT can result from numerous serotonergic drugs, demonstrating that various 5-HT receptor subtypes and the 5-HT transporter (5-HTT) contribute to PHT. Both are therefore potential therapeutic targets for the treatment of the disorder. This review describes current awareness of the roles of 5-HT, the 5-HT receptor and the 5-HTT in PHT.