Effects of indomethacin, prostaglandins E2 and I2 on the tone of human isolated femoral arteries

Strips of endothelium-denuded femoral arteries from operated patients were set up for isometric recording. Indomethacin (IND, 3 mumol 1(-1] enhanced basal tension of the arteries from 0.13 +/- 0.04 to 0.86 +/- 0.12 mN (P less than 0.001; n = 16) and potentiated the contractile responses of the strips to noradrenaline (NA); EC50 for NA was 1.5 +/- 0.3 mumol 1(-1) (n = 6) in the absence, and 0.4 +/- 0.07 mumol 1(-1) (n = 6) in the presence of IND (P less than 0.01). PGI2 produced dose-related relaxation in IND-treated vessels, its IC50 being 15.0 +/- 1.3 nmol 1(-1). Low concentrations of PGE2 (0.85-8.5 nmol 1(-1] reduced whereas its higher concentrations (28-85 nmol 1(-1] increased smooth muscle tone in the presence of IND. These results indicate that human femoral arteries--unlike femoral arteries of some laboratory animals--are highly sensitive to cyclooxygenase inhibition as well as to PGI2 and PGE2.     

1例吲哚美辛片致神经系统不良反应的病例报道

目的 探讨吲哚美辛临床应用及不良反应。 方法 选取我院2017年1例吲哚美辛片致神经系统不良反应的病例资料进行回顾性分析。 结论 吲哚美辛不良反应多,神经系统不良反应发生率在20%-50%。 随着吲哚美辛应用的日益广泛,其不良反应发生的情况也逐渐增多,在使用过程中临床医生应严把药物适应症及禁忌症,熟知药物不良反应,确保药物使用安全,减少药物不良反应的发生概率。     

Effects of experimental potassium depletion on renal function and urinary prostanoid excretion in normal women during moderate anti-diuresis

Summary. The hypothesis that potassium depletion (KD) might play a role in stimulating the renal synthesis of prostanoids, and that these materials can contribute to hypokalaemic renal dysfunction, has been tested. Healthy women were studied either in normal potassium balance (N, n= 14), or in experimental KD. KD was induced by low dietary potassium intake (10 mmol day^-1) and natriuretic treatment, associated with replacement of net NaCl and water loss. By using different depletive patterns, two groups with estimated cumulative potassium deficits of 160 ± 43 mmol (KD1, n= 8) and 198±22 mmol (KD2, n= 6), respectively, were obtained. Renal function by the clearance (cl.) method and urinary PGE₂, 6-keto-PGF_lä, TxB₂ concentrations by the RIA method were measured during hypotonic polyuria (oral water load) and subsequent moderate antidiuresis induced by the infusion of low-dose lysine-8-vasopressin (LVP). Compared to the N group, only in the KD2 group do glomerular and tubular dysfunctions typical of hypokalaemia and reduced prostanoid excretions (significant for 6-keto-PGF_lä and TxB₂ but not for PGE₂) appear during polyuria besides the significant reductions of plasma potassium concentration, urinary potassium excretion and the significant increase in plasma renin activity. During LVP infusion the urinary prostanoid excretions were all significantly lower in absence of significant differences in urinary flow rate. Concerning its renal effects, LVP lost its ability to reduce the creatinine cl., while expressing a trend towards reduction in fractional chloride excretion. Indomethacin pretreatment restored the LVP effect on creatinine cl. and increased the antichloruretic LVP effect (although not significantly). To the extent that urinary prostanoid excretions reflect their intrarenal synthesis, our data demonstrate that KD inhibits this biosynthesis. A depressed production of prostanoids endowed with vasodilating and chloruretic activity probably played a role in attenuating the renal vascular hyporeactivity and the urinary chloride dispersion induced by KD.     

Intermittent ethanol exposure induces inflammatory brain damage and causes long-term behavioural alterations in adolescent rats

Adolescent brain development seems to be important for the maturation of brain structures and behaviour. Intermittent binge ethanol drinking is common among adolescents, and this type of drinking can induce brain damage. Because we have demonstrated that chronic ethanol treatment induces inflammatory processes in the brain, we investigate whether intermittent ethanol intoxication enhances cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in adolescent rats, and whether these mediators induce brain damage and cause permanent cognitive dysfunctions. Adolescent rats were exposed to ethanol (3.0 g/kg) for two consecutive days at 48-h intervals over 14 days. Levels of COX-2, iNOS and cell death were assessed in the neocortex, hippocampus and cerebellum 24 h after the final ethanol administration. The following day or 20 days after the final injection (adult stage), animals were tested for different behavioural tests (conditional discrimination learning, rotarod, object recognition, beam-walking performance) to assess cognitive and motor functions. Our results show that intermittent ethanol intoxication upregulates COX-2 and iNOS levels, and increases cell death in the neocortex, hippocampus and cerebellum. Furthermore, animals treated with ethanol during adolescence exhibited behavioural deficits that were evident at the end of ethanol treatments and at the adult stage. Administration of indomethacin, a COX-2 inhibitor, abolishes the induction of COX-2 and iNOS expression and cell death, preventing ethanol-induced behavioural deficits. These findings indicate that binge pattern exposure to ethanol during adolescence induces brain damage by inflammatory processes and causes long-lasting neurobehavioural consequences. Accordingly, administering indomethacin protects against ethanol-induced brain damage and prevents detrimental ethanol effects on cognitive and motor processes.     

The effects of desensitization of capsaicin-sensitive afferent neurons on the microcirculation in the stomach in rats depend on the blood glucocorticoid hormone level

The effects of densensitization of capsaicin-sensitive afferent neurons on the microcirculation in the stomach were studied before and after administration of indomethacin at an ulcerogenic dose in adrenalectomized rats receiving and not receiving replacement therapy with corticosterone and in sham-operated animals. Measures of the microcirculation consisted of blood flow rates in microvessels in the submucous layer of the stomach and the diameter and permeability of microvessels in the mucosa. Desensitization of capsaicin-sensitive afferent neurons was performed by administration of capsaicin at a dose of 100 mg/kg for two weeks and adrenalectomy one week before the experiment. Blood flow rates in microvessels and microvessel diameters were assessed in non-anesthetized rats by direct video recording methods using a special optical system with a contact dark-field epiobjective. Administration of indomethacin at an ulcerogenic dose led to decreases in blood flow rate in microvessels in the submucous layer, dilation of superficial microvessels in the mucosa of the stomach, and an increase in their permeability. Desensitization of capsaicin-sensitive neurons potentiated indomethacin-induced impairments to the microcirculation in the submucous layer and the mucosa of the stomach. These effects of densensitization were significantly enhanced in conditions of glucocorticoid hormone deficiency. Thus, glucocorticoid hormones have favorable effects on the gastric microcirculation in rats with desensitization of capsaicin-sensitive afferent neurons. Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 94, No. 6, pp. 700–709, June, 2008.     

Heat shock preconditioning modulates proliferation and apoptosis after superficial injury in isolated guinea pig gastric mucosa via an eicosanoid and protein synthesis-dependent mechanism

AIM: In restitution after superficial injury of the gastric mucosa, the epithelial continuity is restored by cellular migration. We have shown that heat shock preconditioning inhibits restitution after superficial injury. This study investigates the effect of heat shock preconditioning on tissue proliferation and apoptosis. EXPERIMENTAL DESIGN: Paired guinea pig gastric mucosae were mounted and perfused in Ussing chambers (37 degrees C). After heat shock preconditioning (42 degrees C) (30 min) and normothermic recovery (37 degrees C) (150 min) or normothermic perfusion, a superficial injury was induced by luminal exposure to 1.25 mol/L NaCl (5 min) followed by a 3 h restitution. During perfusion, the mucosa was exposed to 30 micromol/L arachidonic acid (AA) to enhance heat shock response, to 50 micromol/L quercetin (Q) to inhibit the metabolism of arachidonic acid via lipoxygenases, to 50 micromol/L indomethacin (In) to inhibit the metabolism of arachidonic acid via cyclo-oxygenases, or to 150 micromol/L cycloheximide (CHX) to inhibit de novo protein synthesis. After the experiment the mucosa was prepared for immunohistochemical analysis of the expression of Mib-1 proliferation antigen and pro-apoptotic protein Bax. RESULTS: Heat shock decreased Mib-1/Bax ratio and this effect was maintained after superficial injury and exposure to Q, to AA+CHX or to In+CHX. Exposure to CHX, to AA, to In+Q, to In+AA, In+AA+Q or to In+AA+CHX, however, blocked the effect of heat shock preconditioning. The decreasing effect of heat shock preconditioning on Mib-1/Bax ratio could be reversed by exposure to AA+Q or to In. CONCLUSION: The heat-preconditioning-induced effects on the mucosa are reversible and sensitive to exogenous pharmacological modulation. Heat shock preconditioning inhibits proliferation of superficially injured isolated gastric mucosa by a mechanism involving eicosanoid pathways and de novo protein synthesis.     

Les «nouvelles» algies de la face

Résumé  L’algie vasculaire de la face et la névralgie du trijumeau sont des céphalées facilement individualisables par, un interrogatoire rigoureux. Mais il existe des entités intermédiaires individualisées plus récemment: ce sont les nouvelles algies faciales, souvent dénommées algies faciales atypiques, comprenant les hémicranies paroxystiques chroniques et épisodiques, le syndrome SUNCT (short lasting unilateral nevralgia with conjonctival injection and tearing) et l’Hemicrania Continua. Ces nouvelles algies faciales sont caractérisées par l’unilatéralité de la douleur, le plus souvent orbitaire out temporale, l’existence de sympt?mes neourovégétatifs associés à la douleur., ce qui fait soulever l’hypothèse physiopathologique d’une activation trigemino-parasympathique (boucle réflexe entre nerf trijumeau et contingent paraysympathique du nerf facial). Les hémicranies paroxystiques se rapprochent de l’algie vasculaire de la face, mais il s’agit d’une affection à prédominance féminine pour laquelle les crises sont plus fréquentes et plus brèves. Le syndrome SUNCT se caractérise par des crises d’allure plus névralgiques bien que non systématisées à une des trois branches du nerf trijumeau. Enfin, l’Hemicrania Continua, la plus rare des céphalées dysautonomiques, comporte, comme son nom l’indique une douleur d’évolution continue. En raison de l’existence de quelques cas ayant révélé un élément lésionnel sous-jacent, une imagerie encéphalique doit être réalisée de principe. Rares, elles sont pourtant importantes à reconna?tre car pour certaines d’entre elles, il existe des thérapeutiques spécifiques efficaces: les hémicranies paroxystiques et l’Hemicrania Continua sont caractérisées par leur sensibilité à l’indométhacine.

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Summary  Though Cluster Headache, Trigeminal nevralgia are well-known, some dysautonomic headaches are rare, and more recently described: these headaches with autonomic features are chronic and episodic paroxysmal hemicrania, SUNCT syndrome (short lasting unilateral nevralgiform headache nevralgia with conjonctival injection and tearing) and Hemicrania Continua. These headaches are characterised by the unilaterality of the pain, temporal or orbital, and by the associated autonomic features. The pathophysiology of these disorders may be linked with a connection between the trigeminal nerve and the facial para sympathetic outflow. Episodic paroxysmal hemicrania are characterized by frequent short lasting attacks of pain, ressembling to cluster headache, but with more frequent and briefer attacks. The SUNCT syndrome is rare and the pain is nevralgiform, even if not systematised. At last in hemicrania continua there is a continue pain. Secondary Paroxystic Hemicrania, SUNCT syndromes, and Hemicrania Continua have been reported, that’s why investigations are required to identify or exclude treatable underlying causes. Despite their low frequency, they must be recognized because of their possible selective response to treatment: Paroxysmal Hemicrania and Hemicrania Continua are absolutely responsive to indomethacine.

     

Nonsteroidal anti‐inflammatory drugs stimulate spermidine/spermine acetyltransferase and deplete polyamine content in colon cancer cells

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit colonic tumourigenesis and have an established usefulness in cancer prevention. Because polyamines are essential for neoplastic cell growth, the aim of this study was to evaluate the effect of NSAIDs (indomethacin, a nonselective COX-1 and COX-2 inhibitor) on polyamine metabolism in colon cancer cells. METHODS: Both cell counting and thymidine incorporation into cellular DNA were used to assess colon cancer cell growth. Activities of polyamine-metabolising enzymes, polyamine content (HPLC) and ODC and c-myc protein expression (Western blot) were measured in colon cancer cells treated with indomethacin during logarithmic phase of proliferation. RESULTS: Indomethacin impaired growth of human colon cancer cells (Caco-2 and HCT-116). As a result, ornithine decarboxylase activity and c-myc protein expression were decreased. Treatment with indomethacin induced intracellular oxidant formation in colon cancer cells significantly increased the spermidine/spermine-acetyltrasferase activity (SSAT) and enhanced polyamine acetylation and efflux from colon cancer cells. Impairment of cell growth by indomethacin could not be reversed by exogenous polyamines. CONCLUSION: Taken together, our results suggest that NSAIDs affect polyamine metabolism in colon cancer cells by inducing SSAT activity, and that polyamine depletion in NSAID-treated colon cancer cells is mainly due to enhanced polyamine acetylation and irreversible depletion of intracellular polyamine pools.