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Effects of the flavoprotein inhibitor, diphenyleneiodonium sulfate, on ex vivo organic nitrate tolerance in the rat

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期293卷 569-577页

作者： Ratz, JD McGuire, JJ Anderson, DJ Bennett, BM Queens Univ Fac Hlth Sci Dept Pharmacol & Toxicol Kingston ON K7L 3N6 Canada

The flavoprotein inhibitor, diphenyleneiodonium (DPI), inhibits the action of glyceryl trinitrate (GTN) and the D-enantiomer of isoidide dinitrate (IIDN), but not the L-enantiomer (L-IIDN), in isolated rat aorta via inhibition of the bioactivation of these prodrugs. Paradoxically, a vascular NAD(P)H oxidase, which also is inhibited by DPI, has been proposed to generate superoxide that quenches nitric oxide (NO) produced during GTN biotransformation, and increased oxidase levels are proposed to contribute to the phenomenon of organic nitrate tolerance. We examined the effect of DPI on isolated rat aorta using an in vivo model of organic nitrate tolerance. The EC50 values for GTN-, D-IIDN-, and L-IIDN-induced relaxation of aorta from GTN- tolerant rats were increased 4.5- to 7.5-fold. Treatment of blood vessels with DPI (0.3 mu M) increased the EC50 values for GTN and D-IIDN by the same magnitude in control and tolerant aortae, a result that would not be predicted if DPI and GTN tolerance affected common targets. The expression of NADPH-cytochrome P450 reductase (CPR) during in vivo tolerance was assessed by NADPH-dependent cytochrome c reductase activity of aortic microsomes, immunoblotting, and Northern analysis. By all three determinants, CPR expression was unchanged in aorta from GTN- tolerant rats. Superoxide dismutase-inhibitable NADPH-dependent cytochrome c reductase activity (a measure of superoxide generation) of tolerant rat aortic microsomes was not different from that of controls. Superoxide dismutase-inhibitable NADH-dependent cytochrome c reductase activity was detected only in microsomes from tolerant animals. DPI caused a modest increase in the sensitivity for relaxation by the NO donor DEA NONOate to an equal extent in tolerant and nontolerant tissues, whereas the superoxide scavenger, 4,5-dihydroxy-1,3-benzene disulfonic acid (Tiron), had no effect on the sensitivity for relaxation by GTN. These results would not be expected if tolerance-induced incr

关键词：主动脉胸/药物作用生物转化印迹法 RNA 药物耐受性酶抑制剂/药理学黄素蛋白类/拮抗剂和抑制剂谷胱甘肽/类似物和衍生物谷胱甘肽/药理学异山梨酯硝酸/拮抗剂和抑制剂异山梨酯硝酸/代谢异山梨酯硝酸/药理学微粒体/药物作用微粒体/代谢肌平滑血管/药物作用 NADPH高铁血红素蛋白还原酶/代谢硝酸盐类/拮抗剂和抑制剂硝酸盐类/代谢硝酸盐类/药理学一氧化氮供体/药理学一氧化氮合酶/拮抗剂和抑制剂硝酸甘油/拮抗剂和抑制剂硝酸甘油/代谢硝酸甘油/药理学亚硝基化合物/药理学鎓类化合物/药理学药物前体/代谢药物前体/药理学大鼠 Sprague-Dawley S-亚硝基谷胱甘肽立体异构现象超氧化物类/代谢血管舒张药/拮抗剂和抑制剂血管舒张药/代谢血管舒张药/药理学动物男(雄)性大鼠

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Nociceptin/orphanin FQ metabolism and bioactive metabolites

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PEPTIDES 2000年第7期21卷 919-922页

作者： Terenius, L Sandin, J Sakurada, T Karolinska Inst Karolinska Hosp Dept Clin Neurosci Expt Alcohol & Drug Addict S-17176 Stockholm Sweden Daiichi Coll Pharmaceut Sci Dept Biochem Minami Ku Fukuoka 8158511 Japan

Thr endogenous ligand for the orphan NOR receptor (earlier named ORL1) was recently discovered. This ligand, nociceptin/orphanin FQ is involved in a number of pharmacological actions in the CNS, including modulation of pain and cognition. However, its specific physiological role remains to be determined. Two major pathways of metabolism have been identified;the action of aminopeptidase(s) that prominently occurs in plasma, and endopeptidase activity that successively generates the N-terminal 1-13 and 1-9 fragments. Both pathways result in fragments that are inactive at the NOR receptor. However, short N-terminal fragments appear to be active in blocking the release of substance P from primary afferent C-fiber terminals in the dorsal spinal cord. The same endopeptidase(s) may also be involved in the fragmentation of dynorphin A since the inhibitor profile is similar. Enzyme activity is upregulated by morphine using either peptide as substrate that may lead to pharmacological interactions. (C) 2000 Elsevier Science Inc. All rights reserved.

关键词：氨基酸序列氨肽酶类/血液脑/代谢细胞系细胞培养的强啡肽类/代谢配体分子序列数据阿片样肽类/血液阿片样肽类/化学阿片样肽类/代谢肽类/代谢蛋白质前体/代谢受体阿片样/代谢脊髓/代谢肿瘤细胞培养的血管舒张药/血液血管舒张药/化学血管舒张药/代谢动物人类小鼠大鼠

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Inhibition of CYP2D6 by quinidine and its effects on the metabolism of cilostazol

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CLINICAL PHARMACOKINETICS 1999年第2-Sup期37卷 41-51页

作者： Bramer, SL Suri, A Otsuka Amer Pharmaceut Inc Dept Clin Pharmacokinet Pharmacodynam & Metab Rockville MD 20850 USA

Objective: In vitro results are inconclusive as to whether cilostazol is metabolised by cytochrome P450 isoenzyme 2D6 (CYP2D6). The goals of this study were (1) to assure the dose of quinidine and timing relative to cilostazol used in this study were adequate to cause inhibition of CYP2D6, (2) to evaluate carryover effects of quinidine administration, and (3) to evaluate the effect of CYP2D6 deficiency and administration of quinidine (a CYP2D6 inhibitor) on the pharmacokinetics of a single 100mg oral dose of cilostazol. Design: This study was conducted as a single-centre, open-label, randomised sequence, 2-period, crossover pharmacokinetic trial. Water alone (treatment without quinidine) or two 200mg oral doses of quinidine sulfate with water were administered 25 hours and 1 hour prior to a single 100mg dose of cilostazol in period 1. Study participants were crossed over to opposite treatment in period 2. Metoprolol 25mg, used as a positive control, was administered 1 hour after quinidine sulfate with water or using water alone to assess the magnitude of CYP2D6 inhibition by quinidine. Study Participants: 22 healthy nonsmoking Caucasian (14 male and 8 female) volunteers participated in the study. Main Outcome Measures: Serial blood and urine samples were collected at predose and after cilostazol administration to characterise cilostazol and its metabolite pharmacokinetics. Additional plasma samples were taken to assess the pharmacokinetics of quinidine. Urine samples were collected to measure metoprolol and hydroxymetoprolol. Results: Administration of metoprolol with quinidine caused a significant (p < 0.001) decrease in the urinary 4-hydroxymetoprolol/metoprolol ratio compared with administration of metoprolol alone (42-fold decrease, 0.065 vs 2.707). Hence, quinidine effectively converted extensive metabolisers of CYP2D6 to poor metabolisers of CYP2D6. The 21-day washout period was adequate to have complete recovery from quinidine inhibition of CYP2D6. The analys

关键词：投药口服肾上腺素能β受体拮抗剂/代谢肾上腺素能β受体拮抗剂/尿方差分析曲线下面积交叉研究细胞色素P450CYP2D6/拮抗剂和抑制剂药物相互作用酶抑制剂/药代动力学酶抑制剂/药理学半衰期代谢清除率美托洛尔/代谢美托洛尔/尿奎尼丁/药代动力学奎尼丁/药理学四唑类/投药和剂量四唑类/代谢四唑类/药代动力学血管舒张药/投药和剂量血管舒张药/代谢血管舒张药/药代动力学成年人女(雌)性人类男(雄)性中年人

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Enalapril and losartan augment endogenous nitric oxide release in Takayasu's arteritis - A case report

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ANGIOLOGY 2000年第1期51卷 69-75页

作者： Marsen, TA Sukau, G Pollok, M Baldamus, CA Univ Cologne Klin Innere Med 4 D-50924 Cologne Lindenthal Germany

Prognosis in Takayasu's arteritis is limited owing to renovascular hypertension. The authors report a patient with Takayasu's arteritis,who had been unilaterally nephrectomized and presented with malignant hypertension due to renal artery stenosis. Hypertension was refractory to conventional antihypertensive treatment, and stenosis was not accessible by interventional angioplasty. Initiation of enalapril and losartan therapy was successful in improving blood pressure without deterioration of renal function due to ischemic failure. Antihypertensive treatment resulted in dramatically stimulated endogenous nitric oxide (NO) synthesis, while elevated plasma endothelin-l levels were unchanged. Renovascular hypertension in Takayasu's arteritis is associated with an imbalance of vasoconstrictor peptide endothelin-l and vasodilator peptide NO. Successful treatment of hypertension by enalapril or losartan results in improved endogenous NO synthesis, which putatively counterbalances excessive vasoconstrictor actions and may retard the progression of renal failure.

关键词：血管紧张素转换酶抑制药/治疗应用抗高血压药/治疗应用依那普利/治疗应用内皮缩血管肽1/血液高血压肾血管性/药物疗法高血压肾血管性/病因学洛沙坦/治疗应用肾切除术一氧化氮/代谢预后肾动脉梗阻/病因学血管收缩药/血液血管舒张药/代谢女(雌)性人类中年人

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Trimetazidine:: a novel protective role via maintenance of Na⁺ /K⁺-ATPase activity?

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CARDIOVASCULAR RESEARCH 2000年第4期47卷 637-639页

作者： Cross, HR Duke Univ Med Ctr Dept Pathol Durham NC 27710 USA

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Increased expression of adrenomedullin mRNA in the tissues of intraocular and orbital tumors

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AMERICAN JOURNAL OF OPHTHALMOLOGY 2000年第4期129卷 555-556页

作者： Udono, T Totsune, K Takahashi, K Abe, T Sato, M Shibahara, S Tamai, M Tohoku Univ Sch Med Dept Mol Biol & Appl Physiol Aoba Ku Sendai Miyagi 9808575 Japan Tohoku Univ Sch Med Dept Ophthalmol Aoba Ku Sendai Miyagi 9808575 Japan Tohoku Univ Sch Med Dept Internal Med 2 Aoba Ku Sendai Miyagi 9808575 Japan

PURPOSE: To explore the possible involvement of ade renomedullin in the pathophysiology of intraocular and orbital tumors. METHODS: Competitive reverse transcription-polymerase chain reaction was used to determine adrenomedullin mRNA levels in the tissues from 40 consecutive patients (40 eyes) undergoing vitrectomy, orbital tissue biopsy, or enucleation for various ocular diseases, including intraocular (n = 4) and orbital (n = 3) tumors, proliferative vitreoretinopathy (n = 8), proliferative diabetic retinopathy (n = 8), age related macular degeneration (n = 4), preretinal macular fibrosis (n = 9), and acute retinal necrosis (n = 4). RESULTS: Adrenomedullin mRNA levels in the tissues obtained from patients with intraocular or orbital tumors were significantly higher than those of patients with proliferative vitreoretinopathy (P < .05), proliferative diabetic retinopathy (P < .05), preretinal macular fibrosis (P < .005), and acute retinal necrosis (P < .01). CONCLUSION: Adrenomedullin may play a role in the pathophysiology of intraocular and orbital tumors. (Am J Ophthalmol 2000;129:555-556. (C) 2000 by Elsevier Science Inc. All rights reserved.).

关键词：肾上腺髓质素脉络膜肿瘤/遗传学脉络膜肿瘤/代谢脉络膜肿瘤/病理生理学基因表达眶肿瘤/遗传学眶肿瘤/代谢眶肿瘤/病理生理学肽类/遗传学肽类/代谢 RNA 信使/生物合成视网膜疾病/遗传学视网膜疾病/代谢视网膜疾病/病理生理学逆转录聚合酶链反应血管舒张药/代谢女(雌)性人类男(雄)性中年人

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Glyceryl trinitrate-induced vasodilation is inhibited by ultraviolet irradiation despite enhanced nitric oxide generation: Evidence for formation of a nitric oxide conjugate

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第2期289卷 895-900页

作者： Hussain, AS Crispino, NH McLaughlin, BE Brien, JF Marks, GS Nakatsu, K Queens Univ Fac Hlth Sci Dept Pharmacol & Toxicol Kingston ON K7L 3N6 Canada

Our objective was to determine whether a stabilized form of nitric oxide (NO) such as an S-nitrosothiol, rather than NO itself, is the vasoactive metabolite produced when glyceryl trinitrate (GTN) interacts with vascular smooth muscle. In a control study, NO formation was measured by a chemiluminescence-headspace gas method during the incubation of a prototype S-nitrosothiol, namely, S-nitroso-N-acetylpenicillamine (SNAP), in Krebs' solution. NO formation from SNAP was increased when the incubation was carried out in the presence of UV light, indicating that homolytic photolysis of the S-nitrosothiol had occurred. When GTN was incubated with bovine pulmonary artery (BPA) in the absence of UV light, NO was not measurable until 5 min of incubation. By contrast, in the presence of UV light, NO was measurable as early as 0.5 min, and by 5 min, it was higher than that observed in the absence of UV light. BPA rings were relaxed with SNAP and GTN in the absence of UV light, and EC50 values of 0.24 +/- 0.28 mu M and 10 +/- 6 nM, respectively, were observed. In the presence of UV light, the vasodilator response of BPA to SNAP and GTN was attenuated, and EC50 values of 2.7 +/- 3.0 mu M and 49 +/- 23 nM, respectively, were observed. Our results are consistent with the idea that GTN biotransformation by vascular smooth muscle results in the production of a stabilized form of NO, possibly an S-nitrosothiol, and that degradation of this metabolite by UV light results in NO formation accompanied by decreased vasodilation.

关键词：肺动脉/药物作用肺动脉/代谢 S-亚硝基-N-乙酰基青霉胺紫外线血管舒张/药物作用血管舒张/辐射效应血管舒张药/代谢血管舒张药/药理学

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