检索结果-内蒙古大学图书馆

Involvement of the N-terminus of Kir6.2 in coupling to the sulphonylurea receptor

JOURNAL OF PHYSIOLOGY-LONDON 1999年第2期518卷 325-336页

作者： Reimann, F Tucker, SJ Proks, P Ashcroft, FM Univ Oxford Physiol Lab Oxford OX1 3PT England

1. ATP-sensitive potassium (K-ATP) channels are. composed of pore-forming Kir6.2 and regulatory SUR subunits. ATP inhibits the channel by interacting with Kir6.2, while sulphonylureas block channel activity by interaction with a high-affinity site on SUR1 and a low-affinity site on Kir6.2. MgADP and diazoxide interact with SUR1 to promote channel activity. 2. We examined the effect of N-terminal deletions of Kir6.2 on the channel open probability, ATP sensitivity and sulphonylurea sensitivity by recording macroscopic currents in membrane patches excised from Xenopus oocytes expressing willd-type or mutant Kir6.2/SUR1. 3. A 14 amino acid N-terminal deletion (Delta N14) did not affect the gating, ATP sensitivity or tolbutamide block of a truncated isoform of Kir6.2, Kir6.2 Delta C26, expressed in the absence of SUR1.. Thus, the N-terminal deletion does not alter the intrinsic properties of Kir6.2. 4. When Kir6.2 Delta N14 was coexpressed with SUR1, the resulting K-ATP channels had a higher open probability (P-o = 0.7) and a lower ATP sensitivity (K-i = 196 mu M) than wild-type (Kir6.2/SUR1) channels (P-o = 0.32, K-1 = 28 mu M). High-affinity tolbutamide block was also abolished. 5. Truncation of five or nine amino acids from the N'-terminus of Kir6.2 also enhanced the open probability, and reduced both the ATP sensitivity and the fraction of high-affinity tolbutamide block, although to a lesser extent than for the Delta N14 deletion. Site-directed mutagenesis suggests that hydrophobic residues in Kir6.2 may be involved in this effect. 6. The reduced ATP sensitivity of Kir6.2 Delta N14 may be explained by the increased P-o. However, when the P-o was decreased (by ATP), tolbutamide was unable to block Kir6.2 Delta N14/SUR1 K719A,K1385M currents, despite the fact that the drug inhibited Kir6.2-C166S/SUR1-K719A,K1385M currents (which in the absence of ATP have a P-o of > 0.8 and are not blocked by tolbutamide). Thus the N-terminus of Kir6.2 may be involved in coupling sul

关键词： ATP结合匣式转运子腺苷二磷酸/药理学腺苷三磷酸/生理学二氮嗪/药理学利尿药电生理学真菌蛋白质类/遗传学真菌蛋白质类/代谢糖基转移酶类降血糖药/药理学离子通道闸门/药物作用离子通道闸门/生理学膜电位/生理学膜蛋白质类诱变定点卵母细胞/药物作用膜片钳术钾通道阻滞剂钾通道/遗传学钾通道/代谢钾通道内向整流受体药物/遗传学受体药物/代谢阻遏蛋白质类/遗传学阻遏蛋白质类/代谢酿酒酵母蛋白质类序列缺失钠氯同向转运体抑制剂/药理学磺酰脲化合物/药理学甲苯磺丁脲/药理学光滑爪蟾动物小鼠

来源：评论

学校读者我要写书评

暂无评论

Hydrochlorothiazide reduces loss of cortical bone in normal postmenopausal women: A randomized controlled trial

引用

AMERICAN JOURNAL OF MEDICINE 2000年第5期109卷 362-370页

作者： Reid, IR Ames, RW Orr-Walker, BJ Clearwater, JM Horne, AM Evans, MC Murray, MAF McNeil, AR Gamble, GD Univ Auckland Dept Med Auckland New Zealand

PURPOSE: Thiazide diuretics reduce urine calcium excretion and might therefore reduce postmenopausal bone loss. In some, but not all, case-control studies, their use has been associated with a reduced incidence of hip fractures. We studied the effects of hydrochlorothiazide on bone loss in normal postmenopausal women. SUBJECTS AND METHODS: We performed a randomized, double-blind, 2-year trial of the effects of hydrochlorothiazide (50 mg per day) and placebo on bone mineral density in normal postmenopausal women. Participants were not required to have either low bone mineral density or hypertension. Bone mineral density was measured using dual-energy x-ray absorptiometry. RESULTS: One hundred eighty-five women entered the study, of whom 138 completed 2 years of follow-up. In an intention-to-treat analysis, hydrochlorothiazide produced significant benefits on bone mineral density of the total body (between-group difference at 2 years of 0.8%, 95% confidence interval [CI]: 0.3% to 1.3%, P < 0.0001), legs (0.9%, 95% CI: 0.2% to 1.7%, P < 0.0001), mid-forearm (1.2%, 95% CI: 0.2% to 2.2%, P = 0.02), and ultradistal forearm (1.7%, 95% CI: 0.1% to 3.2%, P = 0.04). There was no effect in the lumbar spine (0.5%, 95% CI: -0.5% to 1.6%) or femoral neck (0.2%, 95% CI: 1.3% to 1.7%). The between-group changes tended to be greatest during the first 6 months, except in the mid-forearm where there appeared to be a progressive divergence. An as-treated analysis produced similar results. Urine calcium excretion and indices of bone turnover decreased in the thiazide group, but parathyroid hormone concentrations did not differ between the groups. Treatment was tolerated well. CONCLUSIONS: Hydrochlorothiazide (50 mg per day) slows cortical bone loss in normal postmenopausal women. It may act directly on bone as well as on the renal tubule. The small size of the effect suggests that thiazides may have a role in the prevention of postmenopausal bone loss, but that they are not an appropria

关键词：骨密度/药物作用钙/代谢利尿药双盲法用药计划表股骨颈/代谢氢氯噻嗪/投药和剂量氢氯噻嗪/药理学腰椎/代谢绝经期/代谢骨质疏松绝经后/代谢骨质疏松绝经后/预防和控制参考值钠氯同向转运体抑制剂/投药和剂量钠氯同向转运体抑制剂/药理学时间因素治疗结果老年人女(雌)性人类中年人

来源：评论

学校读者我要写书评

暂无评论

Effects of the potent ampakine CX614 on hippocampal and recombinant AMPA receptors: Interactions with cyclothiazide and GYKI 52466

引用

MOLECULAR PHARMACOLOGY 2000年第4期58卷 802-813页

作者： Arai, AC Kessler, M Rogers, G Lynch, G So Illinois Univ Sch Med Dept Pharmacol Springfield IL 62794 USA Univ Calif Irvine Dept Psychiat Irvine CA 92717 USA Cortex Pharmaceut Inc Irvine CA USA

R,S-alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor up-modulators of the benzamide type ("ampakines") have previously been shown to enhance excitatory synaptic transmission in vivo and in vitro and AMPA receptor currents in excised patches. The present study analyzed the effects of an ampakine (CX614;2H, 3H, 6aH-pyrrolidino[2", 1"-3', 2']1,3-oxazino[6',5'-5,4]benzo[e]1,4-dioxan-10-one) that belongs to a benzoxazine subgroup characterized by greater structural rigidity and higher potency. CX614 enhanced the size (amplitude and duration) of field excitatory postsynaptic potentials in hippocampal slices and autaptically evoked excitatory postsynaptic currents in neuronal cultures with EC50 values of 20 to 40 mu M. The compound blocked desensitization (EC50 = 44 mu M) and slowed deactivation of responses to glutamate by a factor of 8.4 in excised patches. Currents through homomeric, recombinant AMPA receptors were enhanced with EC50 values that did not differ greatly across GluR1-3 flop subunits (19-37 mu M) but revealed slightly lower potency at corresponding flip variants. Competition experiments using modulation of [H-3]fluorowillardiine binding suggested that CX614 and cyclothiazide share a common binding site but cyclothiazide seems to bind to an additional site not recognized by the ampakine. CX614 did not reverse the effect of GYKI 52466 on responses to brief glutamate pulses, which indicates that they act through separate sites, a conclusion that was confirmed in binding experiments. In sum, these results extend prior evidence that ampakines are effective in enhancing synaptic responses, most likely by slowing deactivation, and that their effects are exerted through sites that are only in part shared with other modulators.

关键词：丙氨酸/类似物和衍生物丙氨酸/化学丙氨酸/药理学抗焦虑药/药理学苯二氮|艹卓|类苯噻二嗪/药理学细胞培养的利尿药药物相互作用电生理学兴奋性氨基酸拮抗剂/药理学兴奋性突触后电位/药物作用海马/药物作用海马/代谢恶嗪类/药理学嘧啶酮类大鼠 Sprague-Dawley 受体 AMPA/药物作用受体 AMPA/代谢受体 AMPA/生理学重组蛋白质类/药物作用重组蛋白质类/代谢钠氯同向转运体抑制剂/药理学氚尿嘧啶动物人类男(雄)性大鼠

来源：评论

学校读者我要写书评

暂无评论

Pharmacological and histochemical distinctions between molecularly defined sarcolemmal K_ATP channels and native cardiac mitochondrial K_ATP channels

引用

MOLECULAR PHARMACOLOGY 1999年第6期55卷 1000-1005页

作者： Hu, H Sato, T Seharaseyon, J Liu, YG Johns, DC O'Rourke, B Marbán, E Johns Hopkins Univ Sch Med Dept Med Sect Mol & Cellular Cardiol Baltimore MD 21205 USA

A variety of direct and indirect techniques have revealed the existence of ATP-sensitive potassium (K-ATP) channels in the inner membranes of mitochondria. The molecular identity of these mitochondrial K-ATP, (mitoK(ATP)) channels remains unclear. We used a pharmacological approach to distinguish mitoK(ATP) channels from classical, molecularly defined cardiac sarcolemmal K-ATP (surfaceK(ATP)) channels encoded by the sulfonylurea receptor SUR2A and the pore-forming subunit K(lr)6.2. SUR2A and K(ir)6.2 were expressed in human embryonic kidney (HEK)293 cells, and their activities were measured by patch-clamp recordings of membrane current. SurfaceK(ATP) channels are activated potently by 100 mu M pinacidil but only weakly by 100 mu M diazoxide;in addition, they are blocked by 10 mu M glibenclamide, but are insensitive to 500 mu M 5-hydroxydecanoate. This pharmacology, which was confirmed with patch-clamp recordings in intact rabbit: ventricular myocytes, contrasts with that of mitoK(ATP) channels as indexed by flavoprotein oxidation. MitoK(ATP) channels in myocytes are activated equally by 100 mu M diazoxide and 100 mu M pinacidil. In contrast to its lack of effect on surfaceK(ATP) channels, 5-hydroxydecanoate is an effective blocker of mitoK(ATP) channels. Glibenclamide's effects on mitoK(ATP) channels are difficult to assess, because it independently activates flavoprotein fluorescence, consistent with a previously described primary uncoupling effect. Confocal imaging of the subcellular distribution of expressed fluorescent K(ir)6.2 in HEK cells and in myocytes revealed no targeting of mitochondrial membranes. The differences in drug sensitivity and subcellular localization indicate that mitoK(ATP) channels are distinct from surface K-ATP channels at a molecular level.

关键词：细胞培养的癸酸类/药理学二氮嗪/药理学利尿药电生理学黄素蛋白类/代谢格列本脲/药理学羟酸类/药理学膜电位/药物作用线粒体心脏/化学线粒体心脏/药物作用线粒体心脏/代谢心肌/代谢钾通道阻滞剂钾通道/激动剂钾通道/化学钾通道/代谢钾通道内向整流肌膜/化学肌膜/药物作用肌膜/代谢钠氯同向转运体抑制剂/药理学亚细胞部分动物人类小鼠兔

来源：评论

学校读者我要写书评

暂无评论

Thiazides and bone

引用

AMERICAN JOURNAL OF MEDICINE 2000年第5期109卷 429-430页

作者： Sebastian, A Univ Calif San Francisco Moffitt Hosp 1202 San Francisco CA 94143 USA Gen Clin Res Ctr San Francisco CA USA

During the past decade, the use of thiazide diuretics in the treatment of essential hypertension has decreased, despite their established antihypertensive efficacy, positive benefit in coronary heart disease, and low cost, and widespread recommendations for their use. That decrease may be, in part, the result of concern about their effects on lipid and carbohydrate metabolism, and, especially, by the promotion of newer classes of antihypertensive medications. However, thiazides have antihypertensive efficacy and cardiovascular benefit in doses below those that produce potentially adverse metabolic effects.

关键词：钾/投药和剂量钠氯同向转运体抑制剂/药理学钠氯同向转运体抑制剂/治疗应用

来源：评论

学校读者我要写书评

暂无评论

Mechanism of differential effects of antihypertensive agents on serum lipids

引用

Current Hypertension Reports 2000年第4期2卷 370-377页

作者： Brook, Robert D. Division of Hypertension 3918 Taubman Center University of Michigan Ann Arbor MI 48104 1500 E. Medical Center Drive United States

Essential hypertension is frequently associated with the metabolic abnormalities of insulin resistance and dyslipidemia. This prevalent clustering of multiple cardiovascular risk factors may help explain the less-than-expected improvement in coronary heart disease mortality provided by simple blood pressure reduction alone. Many antihypertensive medications effectively reduce blood pressure while providing no benefit or even causing a detrimental effect on the associated metabolic abnormalities. (3-Blockers and diuretics tend to negatively affect both glucose tolerance and plasma lipids. Calcium channel blockers, angiotensin converting enzyme inhibitors, and angiotensin II receptor blockers are most often found to be metabolically neutral. a-Blockers provide the most favorable metabolic effects of antihypertensive agents by improving both insulin sensitivity and dyslipidemia. The multiple physiologic mechanisms by which blood pressure medications alter plasma lipids are discussed in detail. The effects of antihypertensive medications on postprandial lipid metabolism and the associated postprandial lipemia-induced endothelial dysfunction deserve special attention. Copyright © 2000 by Current Science Inc.

关键词：肾上腺素能β受体拮抗剂/药理学抗高血压药/药理学自主神经系统/药物作用苯噻二嗪钙通道阻滞药/治疗应用利尿药胰岛素/代谢脂类/血液脂蛋白类/血液微循环/药物作用饭后期间钠氯同向转运体抑制剂/药理学人类

来源：评论

学校读者我要写书评

暂无评论

Old antihypertensive agents-diuretics and β-blockers: Do we know how and in whom they lower blood pressure?

引用

Current Hypertension Reports 1999年第4期1.0卷 296-304页

作者： Sica, Domenic A. MCV Station Medical College of Virginia of Virginia Commonwealth University Richmond VA 23298-0160 Box 980160 United States

Morbidity and mortality data that increasingly favor the use of diuretics and β-blockers continue to accumulate. Nonetheless, the use of these agentsóparticularly diureticsóis viewed as a dated practice. The issue of which antihypertensive drug to use will remain complex and confusing as the marketing juggernauts of the pharmaceutical industry vigorously promote drug classes such as angiotensinconverting enzyme inhibitors, angiotensin-receptor antagonists, and calcium-channel blockers. A pharmacologic middle ground will probably be reached in the form of fixed-dose combination therapy. Diuretics and b-blockers are mechanistically rational when combined with numerous other drugs;thus, the issue of which drug should be used to begin treatment will be settled by a truce, albeit an uneasy one, favoring the increased use of fixed-dose combination antihypertensive therapy. Copyright © 1999 by Current Science Inc.

关键词：肾上腺素能β受体拮抗剂/药理学抗高血压药/药理学苯噻二嗪血压/药物作用心排血量/药物作用利尿药/药理学钠氯同向转运体抑制剂/药理学血管阻力/药物作用人类

来源：评论

学校读者我要写书评

暂无评论

Clinical limitation of bone-specific alkaline phosphatase assays

引用

ANNALS OF CLINICAL BIOCHEMISTRY 2001年第5期38卷 572-572页

作者： Wu, F Orr-Walker, B Reid, IR Univ Auckland Dept Med Auckland New Zealand

来源：评论

学校读者我要写书评

暂无评论

建议与咨询留下您的常用邮箱和电话号码，以便我们向您反馈解决方案和替代方法

时间限定

文献类型

馆藏选择

核心期刊

语言

文献类型

帮助

文字说明：

检索规则说明：

检索范例：

分类表

所选分类

限定检索结果

文献类型

馆藏范围

日期分布

学科分类号

主题

机构

作者

语言

请选择保存的检索档案：

请选择收藏分类：

通借通还

建议与咨询 留下您的常用邮箱和电话号码，以便我们向您反馈解决方案和替代方法

时间限定

文献类型

馆藏选择

核心期刊

语言

文献类型

帮助

文字说明：

检索规则说明：

检索范例：

分类表

所选分类

限定检索结果

文献类型

馆藏范围

日期分布

学科分类号

主题

机构

作者

语言

请选择保存的检索档案： 新增检索档案 确定 取消

请选择收藏分类： 新增自定义分类 确定 取消

通借通还

建议与咨询留下您的常用邮箱和电话号码，以便我们向您反馈解决方案和替代方法

请选择保存的检索档案：

请选择收藏分类：