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Endothelin receptor antagonism does not prevent the development of in vivo glyceryl trinitrate tolerance in the rat

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期295卷 578-585页

作者： Ratz, JD Fraser, AB Rees-Milton, KJ Adams, MA Bennett, BM Queens Univ Fac Hlth Sci Dept Pharmacol & Toxicol Kingston ON K7L 3N6 Canada

There is evidence that increased endothelial production of endothelin-1 (ET-1) may contribute to glyceryl trinitrate (GTN) tolerance. We used the competitive ETA receptor antagonist ZD2574 to determine whether chronic ETA receptor blockade affected the biochemical and functional responses to GTN during the development of GTN tolerance in vivo. Tolerance induced using transdermal GTN patches resulted in a 5.3 +/- 1.2-fold increase in the EC50 value for GTN relaxation in isolated aorta from GTN-tolerant rats. Coadministration of ZD2574 (100 mg kg(-1) t.i.d. for 3 days) during tolerance induction had no effect on GTN-induced relaxation. This dose of ZD2574 markedly blunted the pressor response to ET-1, indicating effective blockade of ETA receptors, and also abolished the initial transient depressor response to ET-1, indicating that blockade of endothelial ETB receptors also occurred using this dosage regimen for ZD2574. Consistent with the relaxation data, coadministration of ZD2574 had no effect on the decrease in GTN-induced cGMP accumulation or on the decrease in GTN biotransformation that occurred in aortae from GTN-tolerant animals. Radioimmunoassay data indicated that the GTN tolerance induction protocol caused a 2.3 +/- 0.4-fold and a 2.2 +/- 0.5-fold increase in total tissue ET-1 levels in tolerant aorta and vena cava, respectively. These data suggest that chronic inhibition of ET receptors by ZD2574 was not sufficient to prevent or diminish the tolerance-inducing effects of GTN, and that the increase in ET-1 levels observed in tolerant tissues may occur as a consequence of the vascular changes that occur during chronic GTN exposure.

关键词：主动脉胸/药物作用主动脉胸/代谢主动脉胸/生理学结合竞争性生物转化血压/药物作用环GMP/代谢药物耐受性/生理学内皮缩血管肽1/拮抗剂和抑制剂内皮缩血管肽1/代谢内皮缩血管肽1/生理学肌收缩/药物作用肌松弛/药物作用硝酸甘油/药代动力学硝酸甘油/药理学吡嗪类/药理学大鼠 Sprague-Dawley 受体内皮素A 受体内皮缩血管肽/拮抗剂和抑制剂受体内皮缩血管肽/代谢磺胺类/药理学血管舒张药/药代动力学血管舒张药/药理学动物男(雄)性大鼠

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Elevated airway GSH resynthesis confers protection to Clara cells from naphthalene injury in mice made tolerant by repeated exposures

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期294卷 516-523页

作者： West, JAA Buckpitt, AR Plopper, CG Univ Calif Davis Sch Vet Med Dept Anat Physiol & Cell Biol Davis CA 95616 USA Univ Calif Davis Sch Vet Med Dept Mol Biosci Davis CA 95616 USA

Repeated exposures to Clara cell cytotoxicants, such as naphthalene (NA), render target cell populations resistant to further acute injury. Previous studies suggest that alterations in bioactivation enzymes in target sites (bronchioles) of tolerant mice are insufficient to account for the marked reduction in susceptibility. Mice were made tolerant by seven daily injections of NA. GSH in the terminal airways was 2.7-fold greater in tolerant mice than in vehicle controls and a NA (300 mg/kg) challenge dose did not produce injury. Tolerant mice, allowed to recuperate for 96 h after the seventh NA injection, were again susceptible to NA injury, and terminal airway GSH levels had declined to control levels. To determine whether alterations in GSH resynthesis account for tolerance, the activity of gamma-glutamylcysteine synthetase (gamma-GCS) was measured or mice were treated with a combination of buthionine sulfoximine (BSO), a gamma-GCS inhibitor, and NA. gamma-GCS activity was elevated in resistant airways of tolerant mice. Tolerant mice treated with both BSO and NA appeared as susceptible to injury as NA-challenged controls. We conclude that GSH is critical for Clara cell resistance to NA injury in tolerant mice because: 1) GSH levels in target airways from NA-tolerant animals are elevated;2) after a 96-h recuperation period, tolerant mice had lower GSH levels and are again susceptible to NA injury;3) alterations in the activity of gamma-GCS correspond with changes in susceptibility to NA injury;and 4) inhibition of gamma-GCS with BSO increases susceptibility to NA injury in tolerant mice.

关键词：支气管/细胞学支气管/药物作用支气管/代谢丁硫氨酸硫酸亚胺/药理学催化作用用药计划表药物耐受性/生理学酶抑制剂/药理学谷氨酸-半胱氨酸连接酶/拮抗剂和抑制剂谷氨酸-半胱氨酸连接酶/代谢谷胱甘肽/拮抗剂和抑制剂谷胱甘肽/生物合成谷胱甘肽/生理学动力学萘类/毒性动物男(雄)性小鼠

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Chronic exposure to ethanol alters GABA_A receptor-mediated responses of layer II pyramidal cells in adult rat piriform cortex

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JOURNAL OF NEUROPHYSIOLOGY 2000年第1期84卷 247-254页

作者： Signore, AP Yeh, HH Univ Connecticut Ctr Hlth Program Neurosci Farmington CT 06030 USA Univ Connecticut Ctr Hlth Dept Pharmacol Farmington CT 06030 USA

This study examined the effect of chronic exposure to ethanol on gamma-aminobutyric acid type-A (GABA(A)) receptor-mediated responses of layer II pyramidal neurons of the piriform cortex. Slices containing the piriform cortex were derived from pair-fed adult rats maintained on ethanol-supplemented or control liquid diet for 30 days. Responses of identified layer II pyramidal neurons to exogenously applied GABA were monitored by whole-cell patch-clamp recording. Chronic exposure to ethanol resulted in a rightward shift in the EC50 of GABA and a decrease in the amplitude of maximal GABA response. GABA-induced responses were modulated by acutely applied ethanol (10-100 mM) in both chronic ethanol-treated and control groups. No significant difference was found in the average change in GABA response, suggesting that tolerance to acute ethanol exposure did not develop. When the modulatory responses of individual cells were classified and grouped as either being attenuating, potentiating, or having no effect, the incidence of potentiation in the ethanol-treated group was significantly higher. Consistent with the absence of tolerance to acute ethanol, cross-tolerance to diazepam was not observed following 30 days of treatment with ethanol. These results are discussed in light of regionally specific effects of chronic ethanol treatment on GABA(A) receptor-mediated responses of layer II piriform cortical neurons.

关键词：年龄因素慢性酒精中毒/病理生理学荷包牡丹碱/药理学中枢神经系统抑制药/药理学大脑皮质/细胞学大脑皮质/药物作用大脑皮质/生理学地西泮/药理学药物耐受性/生理学乙醇/药理学 GABA拮抗剂/药理学 GABA调节剂/药理学锥体细胞/化学锥体细胞/药物作用锥体细胞/生理学大鼠 Sprague-Dawley 受体 GABA-A/生理学 γ氨基丁酸/生理学动物男(雄)性大鼠

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A locus and mechanism of action for associative morphine tolerance

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NATURE NEUROSCIENCE 2000年第1期3卷 47-53页

作者： Mitchell, JM Basbaum, AI Fields, HL Univ Calif San Francisco Dept Physiol San Francisco CA 94143 USA Univ Calif San Francisco Dept Anat San Francisco CA 94143 USA Univ Calif San Francisco Dept Neurol San Francisco CA 94143 USA

Repeated administration of an opioid in the presence of specific environmental cues can induce tolerance specific to that setting (associative tolerance). Prolonged or repeated administration of an opioid without consistent contextual pairing yields non-associative tolerance. Here we demonstrate that cholecystokinin acting at the cholecystokinin-B receptor is required for associative but not nonassociative morphine tolerance. Morphine given in the morphine-associated context increased Fos-like immunoreactivity in the lateral amygdala and hippocampal area CA1. Microinjection of the cholecystokinin B antagonist L-365,260 into the amygdala blocked associative tolerance. These results indicate that cholecystokinin acting in the amygdala is necessary for associative tolerance to morphine's analgesic effect.

关键词：杏仁核/代谢杏仁核/生理学地伐西匹/药理学药物耐受性/生理学海马/代谢海马/生理学激素拮抗药/药理学免疫组织化学微量注射吗啡/药理学麻醉品/药理学神经元/代谢癌基因蛋白质v-fos/代谢大鼠 Sprague-Dawley 受体胆囊收缩素A 受体胆囊收缩素B 动物男(雄)性大鼠

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Absence of cross-tolerance and the situational specificity of tolerance

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PALLIATIVE MEDICINE 2000年第1期14卷 75-77页

作者： Siegel, S Kim, JA McMaster Univ Dept Psychol Hamilton ON Canada

Suggests that the disruption of tolerance in a patient who showed tolerance to morphine but no tolerance to fentanyl is a demonstration of the situational specificity of tolerance. Factors modulating morphine toleranc... 详细信息

关键词：投药皮肤镇痛药阿片类/投药和剂量镇痛药阿片类/药理学药物耐受性/生理学芬太尼/药理学吗啡/药理学人类

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