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Oral vitamin C and endothelial function in smokers: Short-term improvement, but no sustained beneficial effect

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 2000年第6期35卷 1616-1621页

作者： Raitakari, OT Adams, MR McCredie, RJ Griffiths, KA Stocker, R Celermajer, DS Royal Prince Alfred Hosp Dept Cardiol Camperdown NSW 2050 Australia Heart Res Inst Sydney NSW Australia Univ Turku Dept Clin Physiol Turku Finland

OBJECTIVE To test the hypothesis that antioxidant therapy would improve endothelial function in smokers. BACKGROUND Several studies have documented a beneficial effect of short-term oral or parenteral vitamin C on endothelial physiology in subjects with early arterial dysfunction. Possible long-term effects of vitamin C on endothelial function, however, are not known. METHODS We studied the effects of short- and long-term oral vitamin C therapy on endothelial function in 20 healthy young adult smokers (age 36 +/- 6 years, 8 male subjects, 21 +/- 10 pack-years). Each subject was studied at baseline, 2 h after a single dose of 2 g vitamin C and 8 weeks after taking I g vitamin C daily, and after placebo, in a randomized double-blind crossover study. Blood samples were analyzed for plasma ascorbate levels and endothelial function was measured as flow-mediated dilation of the brachial artery, using high resolution ultrasound. Nitroglycerin-mediated dilation (endothelium-independent) was also measured at each visit. RESULTS At baseline, plasma ascorbate level nas low in the smokers (42 +/- 21 mu mol/liter;normal range, 50 to 150 mu mol/liter), increased with vitamin C therapy after 2 h to 120 +/- 54 mu mol/liter (p < 0.001) and remained elevated after eight weeks of supplementation at 92 +/- 32 mu mol/liter (p < 0.001, compared with placebo). Flow-mediated dilation, however, increased at 2 h (from 2.8 +/- 2.0% to 6.3 +/- 2.8%, p < 0.001), but there was no sustained beneficial effect after eight weeks (3.9 +/- 3.2%, p = 0.26). Nitroglycerin-mediated dilation was unchanged throughout. CONCLUSION Oral vitamin C therapy improves endothelial dysfunction in the short term in healthy young smokers, but it has no beneficial long-term effect, despite sustained elevation of plasma ascorbate levels. (C) 2000 by the American College of Cardiology.

关键词：投药口服抗氧化剂/投药和剂量抗坏血酸/投药和剂量交叉研究双盲法内皮血管/药物作用内皮血管/病理生理学随访研究硝酸甘油吸烟/副作用吸烟/病理生理学血管舒张/药物作用血管舒张/生理学血管舒张药青少年成年人人类男(雄)性中年人

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Activation of soluble guanylyl cyclase by the nitrovasodilator 3-morpholinosydnonimine involves formation of S-nitrosoglutathione

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MOLECULAR PHARMACOLOGY 1998年第1期54卷 207-212页

作者： Schrammel, A Pfeiffer, S Schmidt, K Koesling, D Mayer, B Graz Univ Inst Pharmakol & Toxikol A-8010 Graz Austria Free Univ Berlin Inst Pharmakol D-14195 Berlin Germany

Soluble guanylyl cyclase (sGC) is the major physiological target of sydnonimine-based vasodilators such as molsidomine. Decomposition of sydnonimines results in the stoichiometric formation of nitric oxide (NO) and superoxide (O-2(radical anion)) which rapidly react to form peroxynitrite. Inasmuch as sGC is activated by NO but not by peroxynitrite, we investigated the mechanisms underlying sGC activation by 3-morpholinosydnonimine (SIN-1). Stimulation of purified bovine lung sGC by SIN-1 was found to be strongly dependent on glutathione (GSH). By contrast, GSH did not affect sGC activation by NO released from 2,2-diethyl-1-nitroso-oxyhydrazine, indicating that NO/O-2(radical anion) released from SIN-1 converted GSH to an activator of sGC. High performance liquid chromatography identified this product as the thionitrite S-nitrosoglutathione. Further, the reaction product decomposed to release NO upon addition of Cu(NO3)(2) in the presence of GSH. Activation of sGC was antagonized by the Cu(I)-specific chelator neocuproine, whereas the Cu(II)-selective drug cuprizone was less potent. Carbon dioxide (delivered as NaHCO3) antagonized S-nitrosation by peroxynitrite but not by SIN-1. Thus, NO/O-2(radical anion) released from SIN-1 mediates a CO2-insensitive conversion of GSH to S-nitrosoglutathione, a thionitrite that activates sGC via trace metal-catalyzed release of NO. These results may provide novel insights into the molecular mechanism underlying the nitrovasodilator action of SIN-1.

关键词： Glutathione Guanylate Cyclase Molsidomine Nitroso Compounds Vasodilator Agents 谷胱甘肽鸟苷酰环化酶吗多明亚硝基化合物血管舒张药 3-morpholino-sydnonimine Glutathione Peroxynitrite nitroso compounds Molsidomine Guanylate Cyclase NOBELIUM Vasodilator Agents Soluble Guanylate Cyclase S-Nitrosoglutathione

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Pharmacological stress testing

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SEMINARS IN NUCLEAR MEDICINE 1999年第4期29卷 298-318页

作者： Travin, MI Wexler, JP Montefiore Med Ctr Albert Einstein Coll Med Dept Nucl Med Bronx NY 10467 USA

Pharmacological stress in conjunction with radionuclide myocardial perfusion imaging has become a widely used noninvasive method of assessing patients with known or suspected coronary artery disease. In the United States, over one third of perfusion imaging studies are performed with pharmacological stress. Pharmacological stress agents fall into two categories: coronary vasodilating agents such as dipyridamole and adenosine, and cardiac positive inotropic agents such as dobutamine and arbutamine. For both, in the presence of coronary artery disease (CAD), perfusion image abnormalities result from heterogeneity of coronary blood flow reserve. Vasodilating agents work directly on the coronary vessels to increase blood flow, whereas inotropic agents work indirectly by increasing myocardial work load, which then leads to an increase in coronary blood flow. Both classes of agents have high accuracies for diagnosing coronary artery disease, and they have excellent safety records with acceptably low occurrences of side effects. For dipyridamole planar thallium imaging, pooled analysis yields a sensitivity of 85% and a specificity of 87% for diagnosis of coronary disease, but there is a large variation in reported values depending on various factors, such as the extent of postcatheterization referral bias, the type of imaging (planar versus single photon emission computed tomography [SPECT]), the types of patients being studied (single versus multivessel disease, men versus women), and the imaging agent used (thallium versus one of the technetium-based agents). Diagnostic accuracies for adenosine are similar to those of dipyridamole, with reported overall sensitivities ranging from 83% to 97%, and specificities ranging from 38% to 94%. For dobutamine, pooled analyses yield a sensitivity of 82% and a specificity of 75%. There is some concern that dobutamine may interfere with uptake of technetium-gsm sestamibi, lowering the sensitivity for detection of disease, and thus the

关键词：强心药冠状动脉循环冠心病/诊断显像心脏/诊断显像危险性评估敏感性与特异性体层摄影术发射型计算机单光子血管舒张药女(雌)性人类男(雄)性

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Liposomes containing drug and cyclodextrin prepared by the one-step spray-drying method

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DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY 2000年第12期26卷 1279-1284页

作者： Skalko-Basnet, N Pavelic, Z Becirevic-Lacan, M Univ Zagreb Fac Pharm & Biochem Dept Pharmaceut Zagreb 41000 Croatia

The one-step spray-drying method was applied in the preparation of liposomes containing drug and cyclodextrin (CD). Spray-dried lecithin liposomes, entrapping metronidazole or verapamil alone or together with hydroxypropyl-beta -cyclodextrin (HP beta CD), were characterized for morphology, size distribution, and drug entrapment efficiency. The main factor influencing the liposomal size was the volume of aqueous medium used for hydration of the spray-dried product. No differences in size or entrapment between liposomes prepared by immediate hydration of dried powder or by hydration after 1 year of powder storage at 4 degreesC were observed. All liposomes were tested for their serum stability. The most stable liposomes (still retaining about 10% of the originally entrapped drug even after 24 hr incubation pith serum) were liposomes prepared by the direct spray-drying of the mixture of lipid, drug, and HP beta CD.

关键词： Anti-Infective Agents Metronidazole Vasodilator Agents Verapamil Cyclodextrins 抗感染药甲硝唑血管舒张药维拉帕米

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Interaction potential and tolerability of the coadministration of cilostazol and aspirin

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CLINICAL PHARMACOKINETICS 1999年第2-Sup期37卷 87-93页

作者： Mallikaarjun, S Forbes, WP Bramer, SL Otsuka Amer Pharmaceut Inc Dept Clin Pharmacokinet Pharmacodynam & Metab Rockville MD 20850 USA

Objective: This study evaluated the effects of repeated oral drug administration with cilostazol alone and with aspirin (acetylsalicylic acid) on platelet aggregation, coagulation and bleeding time as well as the cilostazol-aspirin pharmaco-kinetic interaction in healthy males. Design: This was a randomised, double-blind, placebo-controlled, crossover study. Participants received either cilostazol 100mg or placebo twice a day for 10 days;aspirin 325 mg/day was coadministered for the last 5 days. After a 14-day washout period, participants received the alternative treatment. Study Participants: 12 healthy male volunteers were enrolled. Main Outcome Measures: Difference in bleeding times, platelet aggregation, prothrombin time (PT) and activated partial thromboplastin time (aPTT) between cilostazol with aspirin and cilostazol alone. Noncompartmental pharmacokinetic parameters were determined for each study participant. Results: Cilostazol, with or without aspirin, caused no changes in PT, aPTT or bleeding time. There was a 23 to 35% increase in inhibition of ADP-induced ex vivo platelet aggregation by cilostazol plus aspirin when compared with aspirin alone. There was no additive or synergistic effect on arachidonic acid-induced platelet aggregation. Statistically significant but clinically insignificant increases in the area under the plasma concentration-time curve to the last measurable plasma concentration and trough concentrations of cilostazol and its metabolites (OPC-13015 and OPC-13213) occurred after aspirin coadministration, with no differences observed in the maximum plasma concentration Drug-related adverse events were generally mild, the most frequent being headache. Conclusions: Cilostazol and aspirin coadministration did not cause clinically significant changes in PT, aPTT, bleeding time, platelet aggregation or plasma concentrations of cilostazol and its 2 active metabolites. Cilostazol was generally well tolerated with or without aspirin.

关键词： Anti-Inflammatory Agents Non-Steroidal Aspirin Tetrazoles Vasodilator Agents 消炎药非甾类阿司匹林四唑类血管舒张药

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Brown fat necrosis in the setting of congenital heart disease and prostaglandin E1 use: a case report

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PEDIATRIC RADIOLOGY 1999年第1期29卷 61-63页

作者： Raboi, CA Smith, W Univ Iowa Hosp & Clin Dept Radiol Iowa City IA 52242 USA Henry Ford Hosp Dept Radiol Detroit MI 48202 USA

We report a case of a child with D-transposition of the great arteries treated with prostaglandin E1 (PGE1) who subsequently developed extensive brown fat necrosis, To the best of our knowledge, no previous associatio... 详细信息

关键词： Alprostadil Brown Fat Connective Tissue Diseases Heart Defects Congenital 前列地尔棕色脂肪结缔组织疾病心脏缺损先天性血管舒张药 Necrosis Congenital heart disease solidification Connective Tissue Diseases Congenital Heart Defects Hibernating Gland Alprostadil Fat Necrosis Case Reports

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Tilt methodology in reflex syncope: Emerging evidence

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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 2000年第1期36卷 179-180页

作者： Fitzpatrick, AP Zaidi, A Manchester Royal Infirm Manchester Heart Ctr Manchester M13 9WL Lancs England

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Increased circulating adrenomedullin, a novel vasodilatory peptide, in sepsis

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JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 1996年第4期81卷 1449-1453页

作者： Hirata, Y Mitaka, C Sato, K Nagura, T Tsunoda, Y Amaha, K Marumo, F TOKYO MED & DENT UNIV DEPT INTERNAL MED 2 TOKYO 113 JAPAN TOKYO MED & DENT UNIV INTENS CARE UNIT TOKYO 113 JAPAN SRL INC TOKYO 193 JAPAN

Human adrenomedullin (hAM), a potent vasodilatory peptide originally identified in pheochromocytoma, has been shown to be present in various human tissues and circulate in human plasma. We measured plasma concentrations of immunoreactive hAM in patients with sepsis who had been admitted to intensive care unit (ICU). Plasma hAM concentrations in 12 septic patients upon entering the ICU were extremely elevated (107 +/- 139 fmol/ml: mean +/- SD) compared to those of 16 age-matched normal subjects (7.9 +/- 3 fmol/mL). Among 10 patients with normal renal function, plasma hAM levels either decreased or increased during the hospital course;the former group survived and the latter group succumbed. Two patients with acute renal failure had markedly elevated plasma hAM levels during the early course, which declined rapidly during the recovery course. High performance liquid chromatography of plasma extracts from one patient with acute renal failure revealed a single major component of immunoreactive hAM coeluting with authentic hAM (1-52) during acute and recovery phase. Plasma hAM concentration showed positive correlations with heart rate, right atrial pressure, and serum creatinine concentration, but not with other hemodynamic variables. These data suggest that a marked increase in circulating hAM in sepsis may be caused by its decreased clearance and/or its enhanced synthesis by multiple organ dysfunction, and that increased endogenous hAM may be involved in the mechanism of cardiovascular abnormalities associated with sepsis.

关键词： Peptides Septicemia Vasodilator Agents 肽类败血病血管舒张药

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Usefulness of Coronary Fractional Flow Reserve Measurements in Guiding Clinical Decisions in Intermediate or Equivocal Left Main Coronary Stenoses

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AMERICAN JOURNAL OF CARDIOLOGY 2009年第7期103卷 943-949页

作者： Courtis, Javier Rodes-Cabau, Josep Larose, Eric Potvin, Jean-Michel Dery, Jean-Pierre De Larochelliere, Robert Cote, Melanie Cousterousse, Olivier Nguyen, Can M. Proulx, Guy Rinfret, Stephane Bertrand, Olivier F. Laval Hosp Quebec Heart Inst Intervent Cardiol Labs Quebec City PQ Canada

The objectives of this study were to evaluate the usefulness of fractional flow reserve (FFR) measurements to guide the clinical decision in patients with intermediate left main coronary artery (LMCA) stenosis and to determine the predictors of major adverse cardiac events (MACE)-cardiac death, myocardial infarction, coronary revascularization-in such cases;142 consecutive patients with intermediate LMCA stenosis (mean percent diameter stenosis 42 +/- 13%) were included. All patients underwent FFR measurement after intracoronary administration of adenosine at a dose >= 30 mu g. The clinical decisions were based on FFR as follows: coronary revascularization was recommended if FFR was <0.75, medical treatment if FFR was >0.80, and individualized decision based on additional clinical data if FFR was between 0.75 and 0.80. Mean FFR was 0.81 +/- 0.09 after the administration of 176 +/- 99 mu g of adenosine. Based on FFR results, 60 patients (42%) underwent coronary revascularization, and 82 patients (58%) received medical treatment. At 14 +/- 11 months follow-up, the incidence of MACE related to the LMCA stenosis was 13% in the medical treatment group and 7% in the revascularization group (p = 0.27). The incidence of cardiac death or myocardial infarction was 6% in the medical treatment group and 7% in the revascularization group (p = 0.70). In the medical treatment group, with MACE had received a lower dose of intracoronary adenosine (86 +/- 57 vs 167 +/- 102 mu g;odds ratio 1.39 for each decrease of 30 mu g of intracoronary adenosine, 95% confidence interval 1.02 to 1.89) and more frequently had diabetes (55% vs 21%;odds ratio 4.40, 95% confidence interval 1.17 to 16.42). In conclusion, FFR measurement is helpful in guiding the decision whether to revascularize patients with intermediate LMCA stenosis. However, patients with diabetes remain at higher risk, and higher doses than previously recommended of intracoronary adenosine might have to be used in the evaluation of

关键词： Adenosine Blood Pressure Coronary Angiography Coronary Circulation Coronary Stenosis Coronary Vessels Diagnosis Differential Electrocardiography Female Humans Injections Intra-Arterial Male Middle Aged Myocardial Revascularization Regional Blood Flow Vasodilator Agents 腺苷血压冠状血管造影术冠状动脉循环冠状血管诊断鉴别心电描记术注射动脉内心肌血管重建术局部血流血管舒张药

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Antihypertensive, vasodilator and antioxidant effects of a vinifera grape skin extract

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JOURNAL OF PHARMACY AND PHARMACOLOGY 2002年第11期54卷 1515-1520页

作者： de Moura, RS Viana, FSC Souza, MAV Kovary, K Guedes, DC Oliveira, EPB Rubenich, LMS Carvalho, LCRM Oliveira, RM Tano, T Correia, MLG Univ Estado Rio de Janeiro Dept Farmacol IBRAGCB Av 28 Setembro87 BR-20551030 Rio De Janeiro Brazil Univ Estado Rio de Janeiro Dept Biochem IBRAGCB BR-20551030 Rio De Janeiro Brazil

Cumulative evidence suggests that moderate wine consumption exerts a cardioprotective effect. We investigated the occurrence of an antihypertensive effect of an alcohol-free hydroalcoholic grape skin extract (GSE) obtained from skins of a vinifera grape (Vitis labrusca) in experimental rodent hypertension models. The vasodilator effect of GSE (polyphenols concentration 55.5 mg g(-1)) was also assessed in the isolated mesenteric vascular bed of Wistar rats and the antioxidant effect was studied on lipid peroxidation of hepatic microsomes. Oral administration of GSE significantly reduced systolic, mean and diastolic arterial pressure in Wistar rats with desoxycorticosterone acetate-salt and N-G-nitro-L-arginine methyl ester (L-NAME) induced experimental hypertension. In the rat isolated mesenteric vascular bed pre-contracted with norepinephrine, bolus injections of GSE induced endothelium-dependent vasodilatation that was substantially inhibited by L-NAME, but not by indometacin, tetraethylammonium or glibenclamide. Lipid peroxidation of hepatic microsomes estimated as malondialdehyde production was concentration-dependently inhibited by GSE. In conclusion, the anti hypertensive effect of GSE might be owing to a combination of vasodilator and antioxidant actions of GSE. These findings also suggest that the beneficial effect of moderate red wine consumption could be owing to an anti hypertensive action induced by compounds occurring in the skin of vinifera grapes.

关键词： Antihypertensive Agents Antioxidants Hypertension Phytotherapy Plant Extracts 抗高血压药抗氧化药高血压植物提取物血管舒张药

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