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Pharmacological comparison of native mitochondrial K_ATP channels with molecularly defined surface K_ATP channels

MOLECULAR PHARMACOLOGY 2001年第2期59卷 225-230页

作者： Liu, YG Ren, GF O'Rourke, B Marbán, E Seharaseyon, J Johns Hopkins Univ Inst Mol Cardiobiol Baltimore MD 21205 USA Otsuka Amer Pharmaceut Inc Maryland Res Labs Rockville MD USA

Many mammalian cells have two distinct types of ATP-sensitive potassium (K-ATP) channels: the classic ones in the surface membrane (sK(ATP)) and others in the mitochondrial inner membrane (mitoK(ATP)). Cardiac mitoK(ATP) channels play a pivotal role in ischemic preconditioning, and thus represent interesting drug targets. Unfortunately, the molecular structure of mitoK(ATP) channels is unknown, in contrast to sK(ATP) channels, which are composed of a pore-forming subunit (Kir6.1 or Kir6.2) and a sulfonylurea receptor (SUR1, SUR2A, or SUR2B). As a means of probing the molecular makeup of mitoK(ATP) channels, we compared the pharmacology of native cardiac mitoK(ATP) channels with that of molecularly defined sK(ATP) channels expressed heterologously in human embryonic kidney 293 cells. Using mitochondrial oxidation to index mitoK(ATP) channel activity in rabbit ventricular myocytes, we found that pinacidil and diazoxide open mitoK(ATP) channels, but P-1075 does not. On the other hand, 5-hydroxydecanoic acid (5HD), but not HMR-1098, blocks mitoK(ATP) channels. Although pinacidil is a nonselective activator of expressed sK(ATP) channels, diazoxide did not open channels formed by Kir6.1/SUR2A, Kir6.2/SUR2A (known components of cardiac sK(ATP) channels) or Kir6.2/SUR2B. P-1075 activated all the K-ATP channels, except Kir6.1/SUR1 channels. Glybenclamide potently blocked all sK(ATP) channels, but 5HD only blocked channels formed by SUR1/Kir6.1 or Kir6.2 (IC(50)s of 66 and 81 muM, respectively). This potency is similar to that for block of mitoK(ATP) channels (IC50 = 95 muM). In addition, HMR-1098 potently blocked Kir6.2/SUR2A channels (IC50 = 1.5 muM), but was 67 times less potent in blocking Kir6.1/SUR1 channels (IC50 = 100 muM). Our results demonstrate that mitoK(ATP) channels closely resemble Kir6.1/SUR1 sK(ATP) channels in their pharmacological profiles.

关键词： Membrane Proteins Myocardium Potassium Channels Vasodilator Agents Guanidines 膜蛋白质类心肌钾通道血管舒张药 mitochondrial K(ATP) channel Potassium Channels N-cyano-N'-(1,1-dimethylpropyl)-N''-(3-pyridinyl)guanidine Pinacidil KATP Channels Myocardium Vasodilator Agents Guanidines Membrane Proteins

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Control of glutamate and GABA release by nociceptin/orphanin FQ in the rat lateral amygdala

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JOURNAL OF PHYSIOLOGY-LONDON 2001年第3期532卷 701-712页

作者： Meis, S Pape, HC Univ Magdeburg Inst Physiol Fak Med D-39120 Magdeburg Germany

1. The actions of the heptadecapeptide termed nociceptin or orphanin FQ (N/OFQ) and the recently discovered putative precursor product nocistatin were examined on synaptic transmission in putative projection cells of the rat lateral amygdala using the whole-cell patch-clamp technique. 2. N/OFQ decreased evoked non-NMDA receptor-mediated excitatory postsynaptic current (EPSC) amplitudes in a concentration-dependent manner, with a half-maximal inhibitory effect elicited by 21.8 +/- 7.5 nM and a Hill coefficient of 0.8 +/- 0.2 (n = 22). Responses were maximally suppressed to 70.3 +/- 1.7% of the control value. The effect of N/OFQ was prevented by 1 muM [Phe(1)psi (CH2-NH)Gly(2)]NC(1-3)NH2 (Phe psiN/OFQ), a substance known as an antagonist/partial agonist of the ORL receptor. 3. GABA(A) receptor-mediated inhibitory postsynaptic currents (IPSCs) elicited through intra amygdaloid stimulation were reduced to 48.0 +/- 6.8% by 1 muM N/OFQ (n = 5). 4. Nocistatin had no measurable effect on evoked synaptic currents or membrane properties of recorded neurons. 5. N/BFQ reduced the frequency of spontaneous miniature EPSCs and IPSCs to 74.0 +/- 2.6% and 84.4 +/- 1.1%, respectively, without affecting the amplitudes. 6. The present findings indicate that N/OFQ, but not nocistatin, inhibits the release of glutamate and GABA in the lateral amygdala, presumably by acting on presynaptic release sites. These mechanisms may add to the role of N/OFQ in reducing stress vulnerability as recently proposed On the basis of behavioural and genetic approaches.

关键词： Amygdala GABA Glutamic Acid Opioid Peptides Vasodilator Agents 谷氨酸阿片样肽类血管舒张药 Opioid Peptides controlling value Amygdala gamma-Aminobutyric Acid Glutamates nocistatin Basolateral Nuclear Complex Hill coefficient Vasodilator Agents nociceptin Glutamic Acid

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Evidence supporting abnormalities in nitric oxide synthase function induced by nitroglycerin in humans

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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 2001年第4期38卷 1096-1101页

作者： Gori, T Mak, SS Kelly, S Parker, JD Mt Sinai Hosp Div Cardiol Dept Med Toronto ON M5G 1X5 Canada Univ Toronto Cardiovasc Collaborat Program Toronto ON Canada

OBJECTIVES We studied the effects of nitroglycerin (GTN) therapy on die response to endothelium-dependent and independent vasoactive agents in the forearm circulation of healthy subjects. BACKGROUND Recent evidence suggests that therapy with GTN may induce specific changes in endothelial cell function, including increased superoxide anion production and sensitivity to vasoconstrictors. Additionally, continuous GTN therapy worsens endothelial function in the coronary circulation of patients with ischemic heart disease. METHODS Forearm blood flow was measured with venous occlusion, mercury-in-silastic strain gauge plethysmography. RESULTS Sixteen male volunteers (26 +/- 6 years) were randomized to no therapy (control) or GTN, 0.6 mg/h/24 h, for six days in an investigator-blind, parallel-design study. The flow responses to brachial artery infusions of acetylcholine ([Ach] 7.5, 15.0, 30.0 mug/min), N-monomethyl-L-arginine (L-NMMA) (1, 2, 4 mu mol/min) and sodium nitroprusside (SNP) (0.8, 1.6, 3.2 mug/min) were recorded. The vasodilator responses to Ach were blunted in the GTN group as compared with the control group (p < 0.05). The vasoconstrictor responses to L-NMMA were also blunted in the GTN group (p < 0.001). In the GTN group, paradoxical vasodilation was observed in response to the lowest infused concentration of L-NMMA. The vasodilator responses to SNP did not differ. between groups. CONCLUSIONS The response to Ach confirms the hypothiesis that continuous GTN causes endothelial dysfunction. The responses to L-NMMA suggest that GTN therapy causes abnormalities in nitric oxide synthase (NOS) function;the vasodilation observed at the lowest infused concentration of L-NMMA in the GTN group also suggests that continuous GTN therapy is associated with a NOS-mediated production of a vasoconstrictor. (C) 2001 by the American College of Cardiology.

关键词： Nitric-Oxide Synthase Nitroglycerin Vasoconstriction Vasodilation Vasodilator Agents 一氧化氮合酶硝酸甘油血管收缩血管舒张血管舒张药 Vasoconstriction Vasoconstrictor Agents Nitric Oxide Synthase Intra-Arterial Infusions Vasodilator Agents Vasodilation omega-N-Methylarginine Global Transportation Net-work（GTN)

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Differential effects of pentaerythritol tetranitrate and nitroglycerin on the development of tolerance and evidence of lipid peroxidation: A human in vivo study

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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 2001年第3期38卷 854-859页

作者： Jurt, U Gori, T Ravandi, A Babaei, S Zeman, P Parker, JD Mt Sinai Hosp Dept Med Div Cardiol Toronto ON M5G 1X5 Canada Univ Hlth network Toronto ON Canada Cardiovasc Collaborat Program Toronto ON Canada Univ Toronto Banting & Best Dept Med Res Dept Lab Med & Pathobiol Toronto ON M5S 1A1 Canada

OBJECTIVES We investigated the development of nitrate tolerance after continuous exposure to nitroglycerin (GTN) as compared with pentaerythritol tetranitrate (PETN) in humans. BACKGROUND Sustained therapy with GTN causes tolerance and has been associated with increased production of free oxygen radicals by the endothelium. Pentaerythritol tetranitrate is an organic nitrate that has been used in the therapy of angina. There have been no investigations concerning the development of tolerance to PETN in humans. Animal investigations suggested that continuous therapy with PETN does not cause increased free radical production or hemodynamic tolerance. METHODS We randomized 30 healthy volunteers to continuous GTN (0.6 mg/h/24 h), long-acting PETN (60 mg orally three times a day) or no treatment (control group) for seven days. We studied systemic blood pressure responses and venous volume responses to GTN with strain-gauge plethysmography. The levels of cytotoxic aldehydes and isoprostanes were measured as markers of free radical-mediated lipid peroxidation. RESULTS Tolerance, as demonstrated by blood pressure and forearm plethysmography, developed in the GTN group and was absent in the PETN group (p < 0.05). Therapy with GTN was associated with a significant increase in plasma markers of lipid peroxidation. This response was not observed in those treated with PETN (isoprostanes: control: 38 +/- 5;GTN: 59 +/- 6;PETN: 38 +/- 3 mug/ml;p < 0.005). CONCLUSIONS Treatment with PETN does not cause tolerance and is not associated with evidence of increased free radical production. (C) 2001 by the American College of Cardiology

关键词： Lipid Peroxidation Nitroglycerin Pentaerythritol Tetranitrate Vasodilator Agents 脂质过氧化作用硝酸甘油戊四硝酯血管舒张药 Reactive Oxygen Species differential effect Pentaerythritol Tetranitrate Global Transportation Net-work（GTN) Vasodilator Agents Lipid Peroxidation Isoprostanes

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内皮素-1对离体动脉的收缩作用及舒张药物的对抗效应

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中华手外科杂志 2001年第1期17卷 34-35页

作者：王涛顾玉东沈忆文上海复旦大学附属华山医院手外科 200040 上海复旦大学法医教研室

目的　研究内皮素 1(Endothelin 1,ET 1)收缩血管的特性及显微血管外科常用舒张药物的对抗效应。方法　采用离体血管舒缩功能的实验技术比较ET 1与去甲肾上腺素 (noradrenaline ,NE)对离体动脉张力的影响 ,同时检测舒张药物对ET 1... 详细信息

目的　研究内皮素 1(Endothelin 1,ET 1)收缩血管的特性及显微血管外科常用舒张药物的对抗效应。方法　采用离体血管舒缩功能的实验技术比较ET 1与去甲肾上腺素 (noradrenaline ,NE)对离体动脉张力的影响 ,同时检测舒张药物对ET 1收缩血管的拮抗作用。结果　ET 1使离体大鼠颈总动脉环产生浓度依赖性的恒定收缩 ,ET 1与NE的半数有效浓度 (medianeffectiveconcentration ,EC50 )分别为 1.8× 10 -9mol/L和 3 .4× 10 -8mol/L ,NE的EC50 值为ET 1的 18.9倍。血管舒张药如利多卡因、硝苯啶、罂粟硷、硝普钠、山莨菪硷 ,能有效对抗ET 1的缩血管作用。其中以硝普钠最强 ,利多卡因与山莨菪硷较弱。结论　ET 1对离体动脉具有强大而持久的收缩效应。血管舒张药可以减弱ET 1的缩血管作用。

关键词：内皮缩血管肽-1 血管收缩血管舒张药药物拮抗作用

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心血通治疗糖尿病肾病疗效观察(附41例报告)

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河北医科大学学报 2001年第3期22卷 168-169页

作者：周红王瑞英于秀军河北医科大学第二医院内分泌科石家庄050000

糖尿病肾病是糖尿病严重的微血管并发症，对糖尿病肾病患者除采用降血糖、降血压治疗外，选择一种能改善微循环，降低尿蛋白的药物尤为重要。本文观察41例2型糖尿病肾病患者应用心血通治疗前后尿白蛋白的变化，现报告如下。

关键词：糖尿病肾病心血通低蛋白血症血管舒张药药物疗法治疗疗效

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胎粪吸入综合征的研究进展

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国外医学（儿科学分册） 2001年第6期28卷 324-326页

作者：龙小雅浙江大学湖滨校区附属儿童医院浙江杭州310006

胎粪吸入综合征可引起多种严重的并发症，是足月新生儿发病及死亡的重要原因。缺氧，中性粒细胞的活化、聚集、黏附等多种机制与胎粪吸入引起的肺损伤有关．地塞米松，血管扩张剂如一氧化氮、三磷酸腺苷，肺泡表面活性物质及机械通气是... 详细信息

胎粪吸入综合征可引起多种严重的并发症，是足月新生儿发病及死亡的重要原因。缺氧，中性粒细胞的活化、聚集、黏附等多种机制与胎粪吸入引起的肺损伤有关．地塞米松，血管扩张剂如一氧化氮、三磷酸腺苷，肺泡表面活性物质及机械通气是有效的治疗手段。

关键词：胎囊吸入综合征药物疗法地塞米松血管舒张药治疗

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液中干燥法制备盐酸丁咯地尔微囊及其缓释性研究

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沈阳药科大学学报 2001年第4期18卷 253-255页

作者：翟光喜臧恒昌山东大学药学院山东济南250012 山东大学实验药厂山东济南250012

用液中干燥法制备盐酸丁咯地尔微囊 ,正交实验设计优选制备工艺 ,以光学显微镜观察其形态及大小分布 ,体外溶出试验研究其缓释性。结果表明所得微囊颗粒圆整 ,粒径在 10 0～ 80 0 μm,载药量为 5 8 8% ,8h释放百分率为 87 6 %。

关键词：盐酸丁咯地尔微囊正交设计缓释性液中干燥法血管舒张药

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Topical alprostadil in the treatment of female sexual arousal disorder: A pilot study

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JOURNAL OF SEX & MARITAL THERAPY 2001年第5期27卷 531-540页

作者： Islam, A Mitchel, J Rosen, R Phillips, N Ayers, C Ferguson, D Yeager, J Target Hlth Inc New York NY 10165 USA Univ Med & Dent New Jersey Robert Wood Johnson Med Sch Ctr Sexual & Marital Hlth Piscataway NJ 08854 USA NexMed Inc Robbinsville NJ USA

This study evaluated the efficacy and safety of three doses of topical alprostadil* USP (prostoglandin E-1) cream in 8 patients with Female Sexual Arousal Disorder (FSAD). Each patient tvas administered a single intravaginal dose of placebo followed by, escalating intravaginal doses of the active drug at 2-week intervals, Alprostadils effectiveness in enhancing subjective and physiological arousal during visual sexual stimulation was supported by patient ratings and physician assessments of vaginal erythema and transudate volume. Photoplethysmography measurement of vaginal pulse amplitude was not able to demonstrate treatment sensitivity in the present study. Adverse events included mild cases of vaginal itching and burning. The data support further investigation of the use of alprostadil for FSAD.

关键词： Alprostadil Sexual Dysfunctions Psychological Vasodilator Agents 前列地尔血管舒张药

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The effect of sodium nitroprusside on the chronic allograft damage in a rat model of renal transplantation

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TRANSPLANTATION PROCEEDINGS 2001年第1-2期33卷 853-853页

作者： Soots, A Krogerus, L Lautenschlager, I Ahonen, J Univ Helsinki Cent Hosp Dept Surg Transplant UnitRes Lab FIN-00130 Helsinki Finland Univ Helsinki Cent Hosp Dept Pathol FIN-00130 Helsinki Finland Univ Helsinki Cent Hosp Dept Virol FIN-00130 Helsinki Finland

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