冠心病病人淋巴细胞CR1表达及血清sIL—2R水平的变化

目的探讨冠心病病人外周血淋巴细胞补体Ⅰ型受体（ＣＲ１）表达及血清可溶性白细胞介素－２受体（ｓＩＬ－２Ｒ）浓度的变化。②方法采用淋巴细胞花环试验和酶联免疫吸附法（ＥＬＩＳＡ）,检测了７２例冠心病病人和６３例健康人淋巴细胞ＣＲ１花环率（Ｌ－ＣＲ１Ｒ）及血清ｓＩＬ－２Ｒ浓度变化。③结果冠心病病人Ｌ－ＣＲ１Ｒ明显降低,ｓＩＬ－２Ｒ浓度明显增高,与对照组比较差异有极显著性（ｔ＝６．４１４,７．８０６,Ｐ＜０．００１）。冠心病病人Ｌ－ＣＲ１Ｒ与ｓＩＬ－２Ｒ呈负相关（ｒ＝－０．８１５,Ｐ＜０．００１）。不稳定心绞痛（ＵＡ）、急性心肌梗死（ＡＭＩ）和陈旧性心肌梗死（ＯＭＩ）病人Ｌ－ＣＲ１Ｒ和ｓＩＬ－２Ｒ比较,差异亦具有极显著性（Ｆ＝７．８６０,１１．５７９,ｑ＝６．６２７～１０．５５０,Ｐ＜０．００１）,且以ＡＭＩ病人的变化最明显。④结论外周血淋巴细胞ＣＲ１表达和血清ｓＩＬ－２Ｒ浓度异常与冠心病病情变化有密切关系。     

不同生物相容性的透析膜对红细胞免疫功能的影响

目的：了解血液透析病人透析过程中红细胞免疫功能指标的动态改变及不同生物相容性的透析膜对其变化的影响。方法：分别采用铜仿膜（Ｃｕ膜）、聚砜膜（ＰＳ膜）、聚甲基丙烯酸甲酯膜（ＰＭＭＡ膜）,观察了透析过程中不同时相的红细胞免疫功能指标ＲＢＣ－Ｃ３ｂ和ＲＢＣ－ＩＣ的变化。结果：尿毒症病人的 ＲＢＣ－Ｃ３ｂ显著下降, ＲＢＣ－ＩＣ显著增高。透析开始后,早期 ＲＢＣ－Ｃ３ｂ进一步下降,其后逐渐上升;而 ＲＢＣ－ＩＣ早期逐渐增加,其后逐渐稳定。结论：Ｃｕ膜能明显地影响红细胞的免疫功能; Ｐｓ膜次之; ＰＭＭＡ膜对其影响最小。     

Development of receptoral responses in pigmented and albino guinea-pigs (Cavia porcellus)

We describe the postnatal development of the electroretinogram (ERG) receptoral response in the guinea pig. In addition, the time course and nature of maturation was compared between albino and pigmented strains to consider the role that melanogenesis might have in this process. Electroretinograms were collected on groups of albino and pigmented animals from postnatal day (PD) PD1 to PD60. A-wave amplitudes and implicit times were extracted from filtered data (0–75 Hz). Receptoral components were modelled using the delayed gaussian model of Hood and Birch [1] fitted as an ensemble to the raw data. Guinea pigs show saturated amplitudes (Rm_P3) that are 50% of adult values at birth, these mature by PD12. Receptoral delay (t_d) also undergoes some postnatal maturation, while phototransduction gain (log S) is adult-like at birth. Albino animals had significantly (p<0.05) larger Rm_P3 and log S across all ages. Guinea pigs have significant postnatal development in their receptoral response. Maturation of Rm_P3 implies a postnatal increase in rod outer segment length. Whereas the adult values of log S implies a mature phototransduction process at birth. We argue that the likely cause for the larger log S of albino eyes is compatible with theories of increased levels of internal light. Whereas the larger Rm_P3, even after allowing for increased light effectiveness, may reflect a lower ocular resistance in albino eyes due to their lower levels of melanin. Furthermore, decreased Rm_P3 and log S with age is observed in the pigmented group only and is consistent with increased ocular resistance due to melanin development in this strain. This revised version was published online in July 2006 with corrections to the Cover Date.     

复发性单纯疱疹性角膜炎患者血清IL-2及SIL-2R水平的研究

目的研究复发性单纯疱疹性角膜炎患者血清白细胞介素-2（IL－2）及其可溶性白细胞介素-2受体（SIL－2R）水平。方法本文测定了30例复发性单纯疱疹性角膜炎患者（实验组）和25例健康人（对照组）血清白细胞介素－2（IL－2）及其可溶性白细胞介素－2受体（SIL－2R）的水平。结果对照组IL－2的水平为5．41±1．45mg·L－1,实验组IL－2R水平为2．80±1.47mg·L-1,2组比较t＝2．90,P＜0．01,说明复发性单纯疱疹性角膜炎患者血清IL－2水平较对照组明显降低。对照组SIL－2R水平为90．86±17．90mg·L－1,实验组SIL－2R水平为171·46±19.30mg·L－1,2组比较t＝5．17,P＜0．01。复发性单纯疱疹性角膜炎患者血清SlL－2R水平较对照组显著升高。结论复发性单纯疱疹性角膜炎患者体内免疫功能紊乱,血清IL－2活性降低、SlL－2R水平升高可能是其原因之一,这也为免疫治疗提供了一定依据。     

NMDA receptor antagonism, but not AMPA receptor antagonism attenuates induced ischaemic tolerance in the gerbil hippocampus

Recent studies have shown that a brief ‘pre-conditioning' ischaemic insult reduces the hippocampal cell death caused by a subsequent more severe test insult. In the present studies, we have examined the effects of the non-competitive NMDA receptor antagonist ((5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine, MK-801) a competitive NMDA receptor antagonist, LY202157, AMPA receptor antagonist ((3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)]decahydroisoquinoline-3-carboxylic acid, LY293558), a non-competitive AMPA receptor antagonist ((−)-1-(4-amino-phenyl)-4-methyl-7,8-methylenedioxy-4,5-dihydro-3-acetyl-2,3-benzodiazepine, LY300164), and a mixed NMDA/AMPA receptor antagonist, LY246492, in a gerbil model of ischaemic tolerance. Ischaemic tolerance was induced by subjecting gerbils to a 2-min ‘pre-conditioning' ischaemia (bilateral carotid occlusion) 2 days prior to a 3-min test ischaemia. The effects of MK-801 (2 mg/kg i.p.), LY293558 (20 mg/kg i.p., followed by 4×10 mg/kg at 3 h intervals), LY300164 (4×10 mg/kg i.p. at 1 h intervals), LY246492 (40 mg/kg i.p., followed by 4×20 mg/kg i.p. at 3 h intervals) and LY202157 (30 mg/kg i.p., followed by 4×15 mg/kg i.p. at 2 h intervals) were then examined in this model. Initial dosing commenced 30 min prior to the 2-min ‘pre-conditioning' ischaemia. Results indicated that a 2-min ‘pre-conditioning' ischaemia produced ischaemic tolerance in all cases. The non-competitive NMDA receptor antagonist, MK-801, produced a significant (P<0.01) reduction in the induced tolerance, while the competitive NMDA receptor antagonist, LY202157, also attenuated (P<0.05) the induction of tolerance. In contrast, two AMPA receptor antagonists (LY293558 and LY300164) and a mixed NMDA/AMPA receptor antagonist (LY246492) had no effect on the induction of tolerance. These results suggest that NMDA receptor activation, but not AMPA receptor activation is involved in the phenomenon of ischaemic tolerance.     

Identification of an amino acid residue important for binding of methiothepin and sumatriptan to the human 5-HT(1B) receptor.

Site-directed mutagenesis of the human 5-HT_1B receptor was performed to investigate the role of the amino acid residues cysteine 326 and tryptophan 327 in transmembrane region VI and aspartic acid 352 in transmembrane region VII in ligand binding. Binding studies were performed with the antagonist radioligand [³H]GR125743 on mutant and wild-type receptors stably expressed in Chinese hamster ovary cells (CHO)-K1 cells. Substitution of tryptophan 327 by alanine resulted in decreased affinities of all ligands tested. The most prominent changes in affinity were observed for the antagonist methiothepin and the antimigraine drug sumatriptan, which were reduced approximately 300- and 60-fold, respectively. Nevertheless, the affinity of 5-HT remained the same. Replacement of the aspartic acid 352 by alanine reduced high-affinity binding of 5-HT. Substitution of cysteine 326 by alanine had minor effects on ligand binding. Some of these results agree with the results from mutagenesis studies of the corresponding amino acids in other receptors. However, some notable differences also emerge showing that functional roles of individual amino acid residues must be tested experimentally in each receptor subtype.     

In vitro antiplatelet profile of FR171113, a novel non-peptide thrombin receptor antagonist

We have examined the potency of several adenosine receptor antagonists at adenosine A₁ and A_2A receptors using quantitative autoradiography and have compared the results with those of previous studies using the same radioligands in membrane preparations. The agonists [³H]cyclohexyladenosine and [³H]2-[p-(2-carbonylethyl)-phenylethylamino]-5′-N-ethylcarboxamido adenosine ([³H]CGS 21680) were used as radioligands for the two receptors. The results show that 1,3-dipropyl-8-cyclopentyl xanthine (DPCPX) is almost 1000-fold and 8-chloro-4-cyclohexyl-amino-1-(trifluoromethyl)[1,2,4]triazolo[4,3-a] quinoxaline (CP-68,247) about 300-fold more potent at adenosine A₁ receptors in cortex and striatum than at striatal adenosine A_2A receptors. Conversely, 5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo [1,5-c]pyrimidine (SCH 58261) is approximately 1000-fold and 4-(2-[7-amino-2-(2-furyl) [1,2,4]-triazolo[2,3-a][1,3,5]triazin-5-yl amino]ethyl)phenol (ZM 241,385) about 400-fold more potent at adenosine A_2A than at A₁ receptors. Caffeine and its metabolites did not show any selectivity. Other studied antagonists were non-selective or showed a modest (20- to 40-fold) adenosine A_2A receptor selectivity. Thus, only a few of the antagonists show such high selectivity that it is not offset by differences in drug distribution and levels of receptor subtype expression.     

Naloxone reverses disinhibitory/aggressive behavior in 5,7-DHT-lesioned rats; involvement of GABA(A) receptor blockade?

Effective medical treatment for impulsive aggression and several impulse control disorders is needed. Disinhibited, impulsive behavior of e.g. murderers, arsonists, suicidal patients, and patients suffering from antisocial personality or substance abuse disorders has been associated with signs of a deficiency in brain serotonin (5-HT) systems. Depletion of brain 5-HT consistently produces disinhibition and aggression also in experimental animals. The present series of experiments using a modified Vogel’s conflict test indicates that the disinhibitory behavior of 5-HT-lesioned rats can be reversed by the commonly used opiate receptor antagonist naloxone at doses (0.1–5.0 mg/kg, s.c.) that do not significantly affect behavior in sham-lesioned controls. Moreover, this effect of naloxone, which resembles that previously observed after administration of negative modulators of γ-aminobutyric acid_A (GABA_A)/benzodiazepine receptor complexes, was reversed by a low inert dose (2.0 mg/kg, i.p.) of amobarbital. Furthermore, both naloxone (5.0 mg/kg, s.c.) and Ro 15-4513 (1.0 mg/kg, p.o.; a partial inverse agonist at benzodiazepine receptors) significantly decreased the number of attacks and the time spent in aggressive acts in 5,7-DHT-lesioned male residents. These results taken together with previous behavioral and neurochemical data suggest that the behavioral effects of naloxone observed here may involve an antagonistic action at brain γ-aminobutyric acid_A (GABA_A)/benzodiazepine receptor complexes. Thus, naloxone, its stable analogue naltrexone or other weak negative modulators of brain GABA_A/benzodiazepine receptor complexes may represent a new pharmacological principle for the treatment of impulse control disorders.     

Pharmacokinetics and pharmacodynamics of candesartan cilexetil in patients with normal to severely impaired renal function

Objective: We studied the pharmacokinetics and pharmacodynamics of single and multiple doses of candesartan cilexetil 8 mg per day in hypertensive patients with different degrees of renal function impairment. Candesartan is an angiotensin II subtype 1 (AT1) receptor antagonist that is administered orally as candesartan cilexetil which is converted in the active compound. Methods: Twenty-three patients were included, divided into groups according to creatinine clearance (cr cl. group A >60 nl · min⁻¹ · 1.73 m⁻², group B 30–60 ml · min⁻¹ · 1.73 m⁻² and group C 15–30 ml · min⁻¹ · 1.73 m⁻²). Results: Trough serum concentrations of candesartan were higher in group C compared with group A. The values did not increase after multiple dosing, indicating absence of accumulation. There was a significant negative correlation between the area under the concentration-time curve extrapolated to time infinity (AUC_inf) and the glomerular filtration rate (GFR) indicating a lower renal clearance of candesartan in patients with impaired renal function. The onset of haemodynamic and hormonal effects was gradual. During the single-dose study blood pressure as well as plasma renin activity (PRA) and angiotensin II were unchanged at peak. At day 5 of the multiple-dose study blood pressure was lower and both PRA and angiotensin II were higher compared with baseline. Conclusion: Although serum trough levels increased during repeated administration and half-life was higher in patients with impaired renal function, candesartan cilexetil at a dose of 8 mg per day does not lead to drug accumulation in these patients. This dose is effective in lowering blood pressure and appears to be suitable for patients with renal function impairment. Received: 3 August 1998 / Accepted in revised form: 19 October 1998     

Ionic effects on human recombinant P2X7 receptor function

The actions of monovalent and divalent ions on the P2X₇ receptor have been assessed by measuring their effect on responses to the P2 receptor agonist, 2’- and 3’-O-(4-benzoyl-benzoyl)-ATP (DbATP), in HEK293 cells expressing the human recombinant P2X₇ receptor. In these cells, DbATP increased the cellular accumulation of the DNA binding, fluorescent dye, YO-PRO-1. The potency of DbATP to elicit this effect was decreased by both calcium and magnesium ions. In addition, when the pH was increased above 8 or reduced below 6.5, the potency of DbATP was less than obtained at pH 7.5. Monovalent ions also affected the P2X₇ receptor such that the potency of DbATP was 19-fold higher in NaCl-free buffer containing 280 mM sucrose (pEC₅₀=6.48) than in 140 mM NaCl containing buffer (pEC₅₀=5.19). Monovalent cations differentially affected the potency of DbATP. Thus, when the chloride concentration was maintained at 140 mM, pEC₅₀ values for DbATP were 6.14, 5.87 and 5.19 when the counter cation was 140 mM choline, potassium or sodium, respectively. Monovalent anions also differentially affected the potency of DbATP and in the presence of 140 mM sodium ions, pEC₅₀ values for DbATP were 6.14, 6.07, 5.19 and 4.53, respectively, when the counter anion was 140 mM aspartate, glutamate, chloride or iodide. The inhibitory effect of monovalent anions on P2X₇ receptor function was also observed in electrophysiological studies. Thus in sodium glutamate containing buffer the potency of DbATP (pEC₅₀=5.55) was approximately 22-fold higher than in NaCl containing buffer (pEC₅₀=4.20). This study has demonstrated that P2X₇ receptor function can be markedly affected by a wide range of ions and that physiological concentrations of sodium and chloride ions, as well as divalent cations, contribute to the low potency of ATP as an agonist at this receptor. Received: 27 July 1998 / Accepted: 18 November 1998