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Relation of preservation of nitric oxide-dependent coronary vasomotor function to plasma vitamin C concentrations in cardiac transplant recipients

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AMERICAN JOURNAL OF CARDIOLOGY 2000年第4期86卷 460-+页

作者： Fang, JC Kinlay, S Hikita, H Suh, JH Piana, RN Selwyn, AP Frei, B Morrow, JD Ganz, P Brigham & Womens Hosp Div Cardiovasc Boston MA 02115 USA Oregon State Univ Linus Pauling Inst Corvallis OR 97331 USA Vanderbilt Univ Dept Med & Pharmacol Nashville TN USA

The contribution of oxidant stress to coronary endothelial dysfunction in cardiac transplant recipients is not known. We found that the plasma vitamin C concentration, but not plasma F-2-isoprostanes, was significantl... 详细信息

关键词：乙酰胆碱/药理学抗氧化剂抗坏血酸/血液抗坏血酸/生理学生物利用度色谱法高压液相冠状血管/药物作用冠状血管/生理学内皮血管/药物作用内皮血管/生理学心脏移植/生理学多元分析一氧化氮/生理学硝酸甘油/药理学手术后期间血管舒张药/药理学血管舒缩系统/药物作用血管舒缩系统/生理学成年人老年人女(雌)性人类男(雄)性中年人

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Altered functional properties of K_ATP channel conferred by a novel splice variant of SUR1

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JOURNAL OF PHYSIOLOGY-LONDON 1999年第2期521卷 337-350页

作者： Sakura, H Trapp, S Liss, B Ashcroft, FM Univ Oxford Physiol Lab Oxford OX1 3PT England

1. ATP-sensitive potassium (K-ATP) channels are composed of pore-forming (Kir6.x) and regulatory sulphonylurea receptor (SURx) subunits. We have isolated a novel SUR variant (SUR1b Delta 33) from a hypothalamic cDNA library. This variant lacked exon 33 and introduced a frameshift that produced a truncated protein lacking the second nucleotide binding domain (NBD2). It was expressed at low levels in hypothalamus, midbrain, heart and the insulin-secreting beta-cell line MIN6. 2. We examined the properties of K-ATP channels composed of Kir6.2 and SUR1b Delta 33 by recording macroscopic currents in membrane patches excised from Xenopus oocytes expressing these subunits. We also investigated the effect of truncating SUR1 at either the start (SUR1bT1) or end (SUR1bT2) of exon 33 on K-ATP channel properties. 3. Kir6.2/SUR1b Delta 33 showed an enhanced open probability (P-o = 0.6 at -60 mV) and a reduced ATP sensitivity (K-i, 88 mu M), when compared with wild-type channels (P-o = 0.3;K-i, 22 mu M). However, Kir6.2/SUR1bT1 and Kir6.2/SUR1bT2 resembled the wild-type channel in their P-o and ATP sensitivity. 4. Neither MgADP, nor the K+ channel opener diazoxide, enhanced Kir6.2/SUR1b Delta 33, Kir6.2/SUR1bT1. or Kir6.2/SUR1bT2 currents, consistent with the idea that these agents require an intact NBD2 for their action. Sulphonylureas blocked K-ATP channels containing any of the three SUR variants, but in excised patches the extent of block was less than that. for the wild-type channel. In intact cells, the extent of sulphonylurea block of Kir6.2/SUR1b Delta 33 was greater than that in excised patches and was comparable to that found for wild-type channels. 5. Our results demonstrate that NBD2 is not essential for functional expression or sulphonylurea block, but is required for K-ATP channel activation by K+ channel openers and nucleotides. Some of the unusual properties of Kir6.2/SUR1b Delta 33 resemble those reported for the K-ATP channel of ventromedial hypothalamic (VMH) n

关键词： ATP结合匣式转运子腺苷二磷酸/药理学腺苷三磷酸/药理学选择性剪接/生理学氨基酸序列叠氮化合物/药理学碱基序列脑化学/遗传学克隆分子二氮嗪/药理学基因缺失降血糖药/药理学离子通道闸门/药物作用离子通道闸门/遗传学小鼠近交C57BL 分子序列数据诱变/生理学卵母细胞/生理学膜片钳术钾通道/遗传学钾通道内向整流 RNA 信使/遗传学大鼠 Wistar 受体药物/遗传学磺酰脲化合物/药理学甲苯磺丁脲/药理学血管舒张药/药理学爪蟾属动物小鼠大鼠

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NO-induced modulation of calcium-oscillations in pulmonary vascular smooth muscle

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CELL CALCIUM 2000年第6期27卷 329-338页

作者： Pauvert, O Marthan, R Savineau, JP Univ Bordeaux 2 INSERM E9937 Lab Physiol Cellulaire Resp F-33076 Bordeaux France

The effect of the nitric oxide (NO) donor sodium nitroprusside (SNP) on both [Ca2+](i) and mechanical activity was studied in the rat isolated pulmonary artery (RPA). In freshly isolated myocytes loaded with 1 mu M indo-lace-toxymethyl ester for 30 min, short (40-60 s) application of ATP (100 mu M) or ET-1 (0.1 mu M) induced 3-6 cyclic rises in [Ca2+](i) (Ca-oscillations) of decreasing amplitude. Preincubation of cells with SNP (10-250 mu M) for 10 min had no effect on the resting [Ca2+](i) value, but progressively abolished the oscillations. A similar effect was obtained with 8-bromo-cGMP (100-500 mu M). SNP (0.001-100 mu M) concentration-dependently relaxed ATP (10 mM, n = 4) and ET-1 (0.1 mu M, n = 4)-precontracted RPA. 1H-[1,2,4]oxadiazolol [4,3,-a]quinoxalin-1-one (ODQ, 10 mu M), a potent inhibitor of the cytosolic guanylyl cyclase, fully reversed the effect of SNP on ATP-induced [Ca2+](i) oscillations as well as on ATP-precontracted RPA. In contrast, N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide (H8, 10 mu M), a potent inhibitor of cGMP-dependent protein kinase (PKG), did not alter the effect of SNP Caffeine (5 mM) induced only one transient [Ca2+](i)-increase (n = 24), the amplitude of which was altered neither by SNP nor by 8-bromo-cGMP. Our results show that the relaxing effect of NO in RPA is related, at least in part, to its action on the Ca-signalling pathway. NO interacts with inositol trisphosphate pathway without interacting with the ryanodine-sensitive receptor. Finally, the effect of NO involves an increase in cGMP but appears independent of activation of PKG. (C) 2000 Harcourt Publishers Ltd.

关键词： 8-溴环腺苷一磷酸/药理学腺苷三磷酸/药理学咖啡因/药理学钙/代谢环GMP依赖性蛋白激酶类/拮抗剂和抑制剂内皮缩血管肽1/药理学吲哚类/诊断应用等长收缩吗多明/类似物和衍生物吗多明/药理学肌平滑血管/代谢一氧化氮供体/药理学硝普钠/药理学青霉胺/类似物和衍生物青霉胺/药理学肺动脉/药物作用肺动脉/代谢大鼠 Wistar S-亚硝基-N-乙酰基青霉胺肌浆网/药物作用肌浆网/代谢血管舒张/药物作用血管舒张药/药理学动物男(雄)性大鼠

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Effect of multiple cilostazol doses on single dose lovastatin pharmacokinetics in healthy volunteers

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CLINICAL PHARMACOKINETICS 1999年第2-Sup期37卷 69-77页

作者： Bramer, SL Brisson, J Corey, AE Mallikaarjun, S Otsuka Amer Pharmaceut Inc Dept Clin Pharmacokinet Pharmacodynam & Metab Rockville MD 20850 USA

Objective: To assess the effects of cilostazol on lovastatin pharmacokinetics. Design: This was a single-centre, open-label, multiple dose, sequential treatment study. Participants received single oral doses of lovastatin 80mg on days 1, 7 and 9, as well as oral cilostazol 100mg twice daily on days 2 to 8, followed by a single oral 150mg cilostazol dose on day 9. Study Participants: 15 healthy, nonsmoking male or female volunteers (aged 18 to 60 years) were enrolled, and 12 completed the study. Main Outcome Measures: Pharmacokinetic parameters were calculated using plasma concentrations of lovastatin and its beta-hydroxy metabolite and of cilostazol and its metabolites. Differences in the pharmacokinetics of each drug when given alone or in combination were assessed by analysis of variance. Results: The maximum observed plasma concentration (C-max) of lovastatin or its metabolite did not differ significantly when lovastatin was given alone and when it was given with 100mg of cilostazol. The mean ratios of the area under the plasma concentration-time curve from zero to the time of the last measurable concentration (AUC(t)) for lovastatin coadministered with 100mg of cilostazol to that with lovastatin given alone were 1.6 for lovastatin and 1.7 for its metabolite. With 150mg of cilostazol, lovastatin Cmax did not change, whereas Cmax of the metabolite increased 2.2-fold. The mean AUC(t) ratios for lovastatin given with 150mg cilostazol/lovastatin given alone were 1.6 and 2.0 for lovastatin and its metabolite, respectively. All increases in lovastatin and metabolite AUC were statistically significant, except for the 1.6-fold increase in lovastatin AUC with 150mg of cilostazol. Maximum steady-state plasma drug concentration (C(ss)max) and AUC during a dosage interval (AUC(tau)) for cilostazol 100mg twice daily decreased 14 and 15%, respectively, upon lovastatin coadministration. Conclusions: Lovastatin and metabolite exposure is increased only by up to 2-fold when cilos

关键词：方差分析抗胆固醇血症药/血液抗胆固醇血症药/代谢抗胆固醇血症药/药代动力学曲线下面积色谱法高压液相剂量效应关系药物用药计划表药物相互作用半衰期肠吸收/药物作用洛伐他汀/血液洛伐他汀/代谢洛伐他汀/药代动力学参考值四唑类/投药和剂量四唑类/血液四唑类/药代动力学四唑类/药理学血管舒张药/投药和剂量血管舒张药/血液血管舒张药/药代动力学血管舒张药/药理学成年人女(雌)性人类男(雄)性中年人

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Hemodynamic and electrophysiologic effects of acute chocolate ingestion in young adults

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AMERICAN JOURNAL OF CARDIOLOGY 1999年第3期84卷 370-+页

作者： Baron, AM Donnerstein, RL Samson, RA Baron, JA Padnick, JN Goldberg, SJ Univ Arizona Coll Med Ctr Heart Tucson AZ 85724 USA Steele Mem Childrens Res Ctr Dept Pediat Diamond Res Lab Tucson AZ USA

The purpose of this study was to determine the hemodynamic and electrophysiologic effects of acute chocolate, and hence theobromine, ingestion on the hearts of young adults. Theobromine was not found to have any cardi... 详细信息

关键词：可可树交叉研究双盲法超声心动描记术多普勒心电描记术/药物作用心脏传导系统/药物作用可可碱/投药和剂量可可碱/药理学血管舒张药/投药和剂量血管舒张药/药理学成年人女(雌)性人类男(雄)性

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Characterization of the ATP-sensitive potassium channels (K_ATP) expressed in guinea pig bladder smooth muscle cells

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第1期289卷 551-558页

作者： Gopalakrishnan, M Whiteaker, KL Molinari, EJ Davis-Taber, R Scott, VES Shieh, CC Buckner, SA Milicic, I Cain, JC Postl, S Sullivan, JP Brioni, JD Abbott Labs Div Pharmaceut Prod Neurol & Urol Dis Res Abbott Pk IL 60064 USA

ATP-sensitive K+ (K-ATP) channels play an important role in the regulation of smooth muscle membrane potential. To investigate the properties of K-ATP channels in guinea pig urinary bladder smooth muscle cells, fluorescence-based assays were carried out with the membrane potential-sensitive probe bis-(1,3-dibutylbarbituric acid)trimethine oxonol [DiBAC(4)(3)]. The prototypical channel openers, including pinacidil, (-)-cromakalim, and diazoxide, elicited concentration-dependent decreases in membrane potential that were attenuated by glyburide. Similar responses were evoked by a reduction in intracellular ATP levels by metabolic inhibition. The observed rank order potency (EC50) for evoking membrane potential changes by potassium channel openers, P1075 (53 nM) similar to Bay X 9228 > (-)-cromakalim similar to ZD6169 similar to pinacidil > Bay X 9227 similar to ZM244085 > diazoxide (59 mu M), showed a good correlation with that of bladder smooth muscle relaxation, as assessed by isolated tissue bath studies. The maximal efficacies of (-)-cromakalim, pinacidil, Bay X 9228, and ZD6169 were comparable with the response achieved by the reference activator P1075. Whole cell currents in bladder smooth muscle cells were increased in both inward and outward directions by P1075 and were reversed by glyburide to control levels. The molecular composition assessed by reverse transcriptase-polymerase chain reaction analysis using subunit-specific primers revealed the presence of mRNA for inward rectifying potassium channel (K(IR)6.2) and sulfonylurea receptors (SUR)2B and SUR1. The subunit profile together with pharmacological properties suggests that the K-ATP channel in bladder smooth muscle cells could be composed of SUR2B associated with a single inward rectifier, K(IR)6.2. In summary, these studies have characterized the pharmacological profile using fluorescent imaging plate reader-based membrane potential techniques and provide evidence for the molecular identity of K-ATP ch

关键词：腺苷三磷酸/生理学细胞培养的荧光胍类/代谢膜电位/药物作用肌松弛/药物作用肌平滑/代谢膜片钳术钾通道/生物合成钾通道/药物作用钾通道/代谢吡啶类/代谢 RNA 信使/分析 RNA 信使/生物合成放射配体测定逆转录聚合酶链反应膀胱/代谢血管舒张药/药理学动物豚鼠

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Short-term oral estrogen replacement therapy does not augment endothelium-independent myocardial perfusion in postmenopausal women

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AMERICAN HEART JOURNAL 2001年第4期142卷 641-647页

作者： Peterson, LR Eyster, D Dávila-Román, VG Stephens, ALP Schechtman, KB Herrero, P Gropler, RJ Washington Univ Sch Med Div Cardiovasc Dept Med St Louis MO 63110 USA Washington Univ Sch Med Div Geriatr & Gerontol St Louis MO USA Washington Univ Sch Med Dept Obstet & Gynecol St Louis MO USA Washington Univ Sch Med Dept Radiol St Louis MO 63110 USA Washington Univ Sch Med Div Biostat St Louis MO 63110 USA

Objectives Th. purpose of this study was to determine the effect of usual-dose estrogen replacement therapy (ERT) on myocardial perfusion and myocardial perfusion reserve (MPR) (evoked by an endothelium-independent vasodilator) in healthy postmenopausal women. Postmenopausal women have a decreased myocardial perfusion reserve compared with younger women. Estrogen infusions are known to enhance endothelium-dependent vasodilation of the epicardial coronary arteries in postmenopausal women, but whether ERT also enhances endothelium-independent myocardial perfusion and perfusion reserve is unclear. Methods In 2.4 healthy postmenopausal women who were not taking ERT, myocardial perfusion at rest, perfusion during the infusion of adenosine (a primarily endothelium-independent vasodilator), and MPR were determined by positron-emission tomography (PET) and oxygen 15-labeled water. The women were then randomly assigned in a double-blind fashion to receive either 0.625 mg of oral conjugated estrogens (Premarin) or placebo per day for 4 to 6 weeks, after which they underwent a repeat cardiac PET study. Results There was no statistical difference between those assigned to ERT and those assigned to placebo in the measurement of myocardial perfusion at rest (1.21 +/- 0.31 vs 1.16 +/- 0.18 mL/g/min, respectively) in response to adenosine (2.66 +/- 0.96 vs 3.3 +/- 0.45 mL/g/min) or MPR (2.24 +/- 0.83 vs 2.88 +/- 0.64 mL/g/min) after 4 to 6 weeks of oral ERT. There was also no difference between the groups in any of the myocardial perfusion measurements after correction for the rate-pressure product. Conclusions Short-term oral ERT does not affect myocardial perfusion at rest in response to adenosine or MPR in healthy postmenopausal women. Thus potential beneficial effects of ERT on vasomotor function may be limited to enhancement of endothelium-dependent vasodilative mechanisms affecting conduit vessels.

关键词：腺苷/药理学冠状动脉循环/药物作用冠状动脉循环/生理学冠状血管/药物作用冠状血管/放射性核素显像雌激素替代疗法/方法雌激素类共扼(USP)/药理学心脏/放射性核素显像氧放射性同位素/诊断应用绝经后期体层摄影术发射型计算机/统计学和数值数据血管舒张药/药理学水/诊断应用成年人女(雌)性人类

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Effects of supraspinal orphanin FQ/nociceptin

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PEPTIDES 2000年第7期21卷 1037-1045页

作者： Grisel, JE Mogil, JS Furman Univ Dept Psychol Greenville SC 29613 USA Univ Illinois Dept Psychol Champaign IL 61820 USA Univ Illinois Program Neurosci Champaign IL 61820 USA

The first reported behavioral action of the endogenous ligand for the "orphan" opioid receptor was a seemingly paradoxical increased sensitivity to nociception (i.e, hyperalgesia) after supraspinal injection into the cerebral ventricles of mice. In the continuing absence of an appropriate in vivo receptor antagonist, studies attempting to define the role of orphanin FQ/nociceptin (OFQ/N) in pain modulation and other behaviors have also featured central injection of peptide. This article reviews the findings of such studies. There appears to be concordance around the observation of anti-opioid actions of supraspinally injected OFQ/N, whereas the observations of hyperalgesia and/or analgesia are much less clear. A portion of the discrepant data may be explained in terms of methodological issues, stress-induced analgesia accompanying experimental protocols, and genotypic variation among subjects. Clarification of OFQ/N's role in nociception, as with other putative biologic functions, will probably depend upon the availability of a selective receptor antagonist. (C) 2000 Elsevier Science Inc. All rights reserved.

关键词：镇痛药/药理学基因型小鼠基因敲除阿片样肽类/投药和剂量阿片样肽类/拮抗剂和抑制剂阿片样肽类/遗传学阿片样肽类/药理学肽类/化学肽类/药理学表型血管舒张药/投药和剂量血管舒张药/拮抗剂和抑制剂血管舒张药/药理学动物小鼠大鼠

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Vascular actions of brain natriuretic peptide: Modulation by atherosclerosis and neutral endopeptidase inhibition

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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 2000年第3期35卷 796-801页

作者： Schirger, JA Grantham, JA Kullo, IJ Jougasaki, M Wennberg, PW Chen, HH Lisy, O Miller, V Simari, RD Burnett, JC Mayo Clin & Mayo Fdn Cardiorenal Res Lab Div Cardiovasc Dis Dept Internal Med Rochester MN 55905 USA Mayo Clin & Mayo Fdn Div Cardiovasc Dis Dept Physiol Rochester MN 55905 USA Mayo Clin & Mayo Fdn Div Cardiovasc Dis Dept Biochem & Mol Biol Rochester MN 55905 USA Mayo Clin & Mayo Fdn Div Cardiovasc Surg Dept Biochem & Mol Biol Rochester MN 55905 USA Mayo Clin & Mayo Fdn Div Cardiovasc Surg Dept Physiol Rochester MN 55905 USA Mayo Clin & Mayo Fdn Div Cardiovasc Surg Dept Internal Med Rochester MN 55905 USA

OBJECTIVES We sought to define the vascular actions of the cardiac hormone brain natriuretic peptide (BNP) on cellular proliferation and cyclic guanosine monophosphate (cGMP) in human aortic vascular smooth muscle cells (HAVSMCs). Secondly, we investigated BNP and acetylcholine (ACh) vasorelaxations in aortic rings from normal and atherosclerotic rabbits in the presence and absence of long-term oral inhibition of neutral endopeptidase (NEP). BACKGROUND The vascular actions of BNP are not well defined, despite the presence of its receptor in vascular smooth muscle and the upregulation of NEP, the ectoenzyme that degrades BNP, in the vascular wall in atherosclerosis. METHODS HAVSMCs stimulated with fetal calf serum (FCS) were pulsed with bromodeoxyuridine (BrdU) with and without BNP. The HAVSMCs were incubated in the presence and absence of BNP to assess cGMP. Vasorelaxations to BNP and ACh were assessed in rings in normal and atherosclerotic rabbits in the presence and absence of long-term oral inhibition of NEP, together with assessment of atheroma formation. RESULTS FCS-stimulated BrdU uptake in HAVSMCs was suppressed with BNP. BNP potentiated cGMP in HAVSMCs. BNP resulted in potent vasorelaxation in normal isolated aortic rings, which were impaired in atherosclerotic versus normal rabbits and preserved with NEP inhibition, which also decreased atheroma formation. Relaxations to ACh, which were also impaired in atherosclerosis, were preserved with inhibition of NEP. CONCLUSIONS We conclude that BNP potently inhibits vascular smooth muscle cell proliferation and potentiates the generation of cGMP. BNP potently relaxes the normal rabbit aorta, and this response is impaired in atherosclerosis but preserved with inhibition of NEP, together with a reduction in atheroma formation and preservation of relaxations to ACh. (C) 2000 by the American College of Cardiology.

关键词：乙酰胆碱/药理学主动脉/药物作用主动脉/酶学主动脉/病理学动脉硬化/酶学动脉硬化/病理学动脉硬化/病理生理学细胞分裂/药物作用细胞培养的肌平滑血管/药物作用肌平滑血管/酶学肌平滑血管/病理学利钠肽脑/药理学脑啡肽酶/代谢苯福林/药理学血管收缩药/药理学血管舒张/药物作用血管舒张药/药理学动物人类男(雄)性兔

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Sodium nitroprusside increases human skeletal muscle blood flow, but does not change flow distribution or glucose uptake

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JOURNAL OF PHYSIOLOGY-LONDON 1999年第3期521卷 729-737页

作者： Pitkänen, OP Laine, H Kemppainen, J Eronen, E Alanen, A Raitakari, M Kirvelä, O Ruotsalainen, U Knuuti, J Koivisto, VA Nuutila, P Univ Turku Turku PET Ctr FIN-20520 Turku Finland Univ Turku Dept Med FIN-20520 Turku Finland Univ Turku Dept Diagnost Radiol FIN-20520 Turku Finland Univ Turku Dept Anesthesiol FIN-20520 Turku Finland Univ Helsinki FIN-00290 Helsinki Finland

1. The role of blood flow as a determinant of skeletal muscle glucose uptake is at present controversial and results of previous studies are confounded by possible direct effects of vasoactive agents on glucose uptake. Since increase in muscle blood flow can be due to increased flow velocity or recruitment of new capillaries, or both, it would be ideal to determine whether the vasoactive agent affects flow distribution or only increases the mean flow. 2. In the present study blood flow, flow distribution and glucose uptake were measured simultaneously in both legs of 10 healthy men (aged 29 +/- 1 years, body mass index 24 +/- 1 kg m(-2)) using positron emission tomography (PET) combined with [O-15]H2O and [F-18]fluoro-2-deoxy-D-glucose (FDG). The role of blood flow in muscle glucose uptake was studied by increasing blood flow in one leg with sodium nitroprusside (SNP) and measuring glucose uptake simultaneously in both legs during euglycaemic hyperinsulinaemia (insulin infusion 6 pmol kg(-1) min(-1)). 3. SNP infusion increased skeletal muscle blood flow by 86% (P < 0.01), but skeletal muscle flow distribution and insulin-stimulated glucose uptake (61.4 +/- 7.5 vs. 67.0 +/- 7.5 mu mol kg(-1) min(-1) control vs. SNP infused leg, not significant), as well as flow distribution between different tissues of the femoral region, remained unchanged. The effect of SNP infusion on blood flow and distribution were unchanged during infusion of physiological levels of insulin (duration, 150 min). 4. Despite a significant increase in mean blood flow induced by an intra-arterial infusion of SNP, glucose uptake and flow distribution remained unchanged in resting muscles of healthy subjects. These findings suggest that SNP, an endothelium-independent vasodilator, increases non-nutritive, but not nutritive flow or capillary recruitment.

关键词：氟脱氧葡萄糖F18/诊断应用葡萄糖/代谢葡萄糖/药代动力学降血糖药/药理学胰岛素/药理学腿/血液供给肌骨骼/血液供给肌骨骼/药物作用肌骨骼/代谢硝普钠/药理学放射性药物/诊断应用局部血流/药物作用组织分布体层摄影术发射型计算机血管舒张药/药理学成年人人类男(雄)性

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