Sigma和苯环利定受体的配体对电场刺激引起兔耳血管收缩的作用

用生物鉴定法研究苯环利定Ｐｈｅ受体的配体Ｐｈｅ，ＴＣＰ，Ｄｉｚ及σ受体的配体ｄｌ－ＳＫ＆Ｆ－１００４７ ｄｌ－ｐｅｎｔａｚｏｃｉｎｅ，ＤＴＧ在兔耳中动脉的作用。结果表明：Ｐｈｅ受体配体均能剂量依赖地增强电场刺激引起的动脉收缩；而σ受体配体无此作用。右旋的σ受体能抑制Ｐｈｅ的作用；它的异构体却是增强Ｐｈｅ作用。提示：在外周血管上主要存在Ｐｈｅ受体。     

高血压大鼠尾动脉上κ,σ和苯环利定受体激动剂的效应

利用电场刺激引起的大鼠尾动脉收缩模型，研究了κ，σ和苯环利定受体在高血压大鼠上的变化。结果，埃托啡和Ｕ－５０４８８Ｈ在ＳＨＲ上的抑制作用显著高于非高血压大鼠。（＋）－３－ＰＰＰ的结果与上述相反，ＤＴＧ的作用很小，ｐｈｅ，ＴＣＰ和ＭＫ－８０１的增强作用在两者间无显著差别，提示在ＳＨＲ上κ受体的敏感性增高，σ受体相反，Ｐｈｅ受体的敏感性变化减少。     

猪冠状动脉上的苯环利定受体

本采用放射受体结合法研究猪冠状动脉上的苯环立定（Phe)受体，发现猪冠状动脉上存在的Phe特异结合部位，Scatchard分析表明，结合呈单位点，Kd为27．7±6．9nmol.L^-1,Bmax为0．82±0．15pmol/mg protein，取代实验表明Phe及TCP，dextrophan和sinma受体配基d-INN均有取代作用，两类药物取代作用呈量一效关系，本实验结果提示猪冠誊 劝脉上存在的特异结合位点是Phe受体。     

Escape from tension induced by noradrenaline or electrical stimulation in isolated mesenteric arteries

Isolated mesenteric arteries, studied under 25-30 mg resting tension, responded to prolonged noradrenaline or electrical stimulation with a 50-500 mg increase in tension from which they subsequently escaped towards resting tension levels.     

Biphasic relaxation caused by electrical field stimulation of the mesenteric arteries of rats.

Electrical field stimulation (EFS) caused biphasic relaxation, first transient and then sustained, of rat mesenteric arteries precontracted by prostaglandin (PG) F2alpha. The transient relaxation was reduced about 45%, and the sustained relaxation was not observed after endothelium denudation of the arteries. N(omega)-Nitro-L-arginine (L-NOARG) inhibited the biphasic relaxation induced by EFS. At 1 - 100 microM, L-NOARG inhibited the transient relaxation more than the sustained relaxation. Methylene blue inhibited the biphasic relaxation and at 100 microM, L-NOARG abolished the transient relaxation. These results suggest that the transient relaxation mainly involves nitric oxide (NO), whereas the sustained relaxation involves both NO and some other factor(s).     

L-硝基精氨酸对神经刺激所致大鼠肠系膜动脉反应的影响

目的观察大鼠肠系膜动脉对神经刺激引起的反应及其与NO的关系。方法：采用离体去除内皮血管实验方法，测定肠系膜动脉条的等容张力变化。结果：电刺激和化学（烟碱）刺激明显引起大鼠肠系膜动脉收缩，L－硝基精氨酸（L－NA，NO合成抑制剂）明显增强上述收缩反应，此增强作用可被L一精氨酸（NO供体）取消。L－NA对刺激交感神经末梢去甲肾上腺素的释放及对去甲肾上腺素的血管收缩作用均无明显影响。动脉条用哌唑嗪处理并用PGF(2a)部分收缩后，电刺激和烟碱均可引起血管舒张，此舒张效应可被L－NA抑制，该抑制作用又可为L-精氨酸逆转。结论：电刺激和化学（烟碱）刺激引起的动脉舒张效应为NO所致，并提示在大鼠肠系股动脉可能有与NO有关的血管扩张神经存在。     

Differential effects of sigma and phencyclidine receptor ligands on learning

Several phencyclidine (PCP) and sigma receptor ligands were examined for their effects on a single trial passive avoidance test in rats. Rats were administered the PCP receptor ligands (+)-5-methyl-10,11-dihydro-5Hdibenzo[a,d]cyclohepten-5,10-im ine maleate (MK-801), PCP, ketamine or the sigma receptor ligands (+)-N-allylnormetazocine ((+)-NANM), (+)-pentazocine, (+)-3-(3-hydroxyphenyl)-N-n-propylpiperidine ((+)-3-PPP) or 1,3-Di(2-[5-3H]tolyl)guanidine (DTG) subcutaneously prior to acquisition of the passive avoidance response, and tested 24 h later for retention. MK-801 (0.1-0.3 mg/kg), PCP (0.54-1.7 mg/kg), ketamine (10.0-17.2 mg/kg) and (+)-N-allylnormetazocine (5.4-10.0 mg/kg) produced significant memory deficits. (+)-Pentazocine (54 mg/kg) and (+)-3-PPP (30 mg/kg) also produced retention deficits, but at significantly higher doses. DTG (0.3-3.0 mg/kg s.c.) had no effect on retention. There was a positive correlation between production of retention deficits and the compounds' PCP receptor binding affinity. The results suggest that the sigma receptor is not involved in learning the passive avoidance response.     

Somatostatin inhibits the release of noradrenaline induced by electrical stimulation of the rat mesenteric artery.

Somatostatin, a peptide with antisecretory and antiproliferative effects, coexists with noradrenaline in sympathetic neurons. Octreotide, a stable somatostatin analogue, prevents hypertension and cardiovascular structural changes induced by prolonged infusion of DPSPX (1,3-dipropyl-8-sulfophenylxanthine, a non-selective adenosine receptor antagonist) in rats. In the present work we investigated the effect of somatostatin and its analogue octreotide on the release of [(3)H]noradrenaline from sympathetic nerves in the rat mesenteric artery. Rat mesenteric arteries were incubated for 60 min with [(3)H]noradrenaline (0.2 microm), mounted in perifusion chambers, washed out for 90 min and electrically stimulated (2 Hz, 5 min, 50 mA). Radioactivity was measured in the tissue and in the perifusion fluid before, during and after stimulation. Both somatostatin and octreotide inhibited tritium release evoked by electrical stimulation of in vitro preparations of rat mesenteric arteries preloaded with [(3)H]noradrenaline. The maximal effects produced by octreotide and somatostatin were a 56 and 70% inhibition of noradrenaline release, respectively. For somatostatin an EC(50)=0. 18 n m (0.01 n m-2.2 n m;n =16) was calculated. When used alone, the somatostatin receptor antagonist, cyclo(7-aminoheptanoyl-Phe- d -Trp-Lys-Thr[BZL]) (CYCAM; 1 microm), had no effect on noradrenaline release induced by electrical stimulation. However, it was able to significantly antagonize the inhibitory effects of octreotide and somatostatin. These results are compatible with a negative modulatory role of somatostatin on sympathetic neurotransmission.     

Effect of tetraethylammonium and verapamil on noradrenaline release induced by field electrical stimulation and potassium from cat cerebral and femoral arteries

Tritium release evoked by field electrical stimulation (FES) or high potassium (K+) from cat cerebral and femoral arteries prelabelled with 3H-noradrenaline was investigated. The release induced by FES and K+ was reduced by Ca2+ suppression and tetrodotoxin (TTX) but not by verapamil in both vessels. Tetraethylammonium (TEA) increased tritium release evoked by FES and K+, when TTX plus TEA were added together radioactivity secretion induced by FES was practically abolished. These results indicate that FES or K+ induce exocytotic noradrenaline release mainly by propagated action potentials and by similar mechanisms in cerebral and femoral arteries.     

Comparison of the actions of phencyclidine and sigma ligands on CA1 hippocampal pyramidal neurons in the rat

To compare the actions of prototypic drugs which are selective for phencyclidine and sigma receptors, the electrophysiological effects of phencyclidine (PCP),3-[3-hydroxyphenyl]-N-(1-propyl)piperidine [+)3-PPP), and 1,3-di(2-tolyl)guanidine (DTG) on CA1 hippocampal pyramidal neurons were examined. A wide range of concentrations of drug was tested to differentiate specific, receptor-mediated effects from nonselective, anesthetic-like actions. At relatively large concentrations (0.1-1 mM), each compound reversibly increased the threshold of action potentials driven by Schaffer collaterals, the duration of action potentials and membrane resistance. The low potencies and rank order of potency suggested that phencyclidine, (+)3-PPP, and DTG were not acting through either high affinity sigma or phencyclidine receptors. These compounds did have receptor-mediated effects at smaller concentrations. Since none of the compounds affected evoked excitatory or inhibitory postsynaptic potentials (EPSP or IPSP) or driven action potentials at subanesthetic concentrations (less than 100 microM), no evidence was found to support the hypothesis that the actions of phencyclidine result from enhanced release of transmitter, caused by the inhibition of a presynaptic potassium conductance. As observed in other neurons, phencyclidine blocked excitations in CA1 pyramidal cells mediated by N-methyl-D-aspartic acid (NMDA) at behaviorally relevant concentrations (1-10 microM). However, (+)3-PPP (1 microM-1 mM) enhanced the pyramidal cell response to NMDA. Alone, DTG did not effect the NMDA-induced response but did inhibit the enhancement induced by (+)3-PPP. The agonist and antagonist actions of the sigma-selective ligands, (+)3-PPP and DTG, suggests that they modify NMDA-induced responses by acting at the sigma receptor.     

Binding affinity and antimuscarinic activity of sigma and phencyclidine receptor ligands.

The characterization of the sigma receptor has been hampered by the lack of a functional bioassay system. Drugs that bind to sigma receptors have been reported to inhibit carbachol-induced phosphatidylinositol turnover in rat brain; however, these drugs might directly affect muscarinic acetylcholine receptors. The purpose of the present study was to determine the affinity for muscarinic receptors and the antimuscarinic activity of sigma and phencyclidine receptor ligands. All of the drugs tested inhibited the binding of [3H]N-methylscopolamine to guinea pig cerebral cortical membranes with KI values in the micromolar range and also inhibited carbachol-induced contractions in the guinea pig ileum. These results demonstrate that these compounds have substantial antimuscarinic activity which might limit the use of the inhibition of carbachol-induced phosphatidylinositol turnover as a functional assay system for studying sigma ligands. Furthermore, this antimuscarinic activity must be considered when evaluating the effects of these compounds after in vivo administration.     

Endothelium modulates vasoconstrictor response to prostaglandin I2 in rat mesenteric resistance arteries: interaction between EP1 and TP receptors

Background and purpose:

Prostacyclin (PGI₂) is usually described as an endothelium-derived vasodilator, but it can also induce vasoconstriction. We studied the vasomotor responses to PGI₂ in resistance arteries and the role of thromboxane (TP) and prostaglandin E₂ (EP) receptors in this effect.

Experimental approach:

Mesenteric resistance arteries were obtained from Sprague-Dawley rats. Vasomotion to PGI₂ was studied in segments of these arteries with and without endothelium and in presence of the nitric oxide (NO) synthase inhibitor N^G-nitro-L-arginine methyl ester (L-NAME), the potassium channel blockers apamin plus charybdotoxin, the non-selective EP receptor antagonist AH6809, the selective TP receptor antagonist SQ29548 or the EP₁ receptor antagonist SC19220. PGI₂-induced NO release was analysed in the absence or presence of SQ29548, AH6809 or SC19220.

Key results:

PGI₂ caused contractions in arterial segments that were increased by endothelium removal, L-NAME or L-NAME plus apamin plus charybdotoxin and abolished by SQ29548. In segments with endothelium, AH6809 or SC19220 almost abolished the contractions to PGI₂; this effect was prevented by L-NAME, L-NAME plus apamin plus charybdotoxin or by endothelium removal. PGI₂ induced NO release that was inhibited by the prostacyclin receptor (IP receptor) antagonist, RO1138452, and increased by SQ29548, SC19220 and AH6809. The increase in NO release induced by these separate drugs was inhibited by RO1138452.

Conclusions and implications:

PGI₂ activated the TP receptor in mesenteric resistance arteries and produced vasoconstriction, which the endothelium modulated through TP and EP₁ receptors. PGI₂ also released endothelium-derived hyperpolarizing factor and, through IP receptor activation, induced NO release, which in turn, was antagonized by TP and EP₁ receptor activation.