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CHRONIC HYPERHYDRATION AND HEMATOLOGICAL-CHANGES IN TRAINED SUBJECTS DURING PROLONGED RESTRICTION OF MOTOR-ACTIVITY

ACTA ASTRONAUTICA 1995年第4期36卷 231-237页

作者： ZORBAS, YG YAROSHENKO, MN FEDERENKO, YF EUROPEAN INST ENVIRONM CYBERNET HYPOKINET PHYSIOL LABGR-16232 ATHENSGREECE

The objective of this investigation was to evaluate the effect of a daily intake of fluid and salt supplementation (FSS) on the hemoglobin content of endurance trained athletes during hypokinesia (decreased number of steps from 10,000 to 3000 steps per day). The studies were performed on 30 long-distance runners who had a VO2max average of 66 ml kg(-1) min(-1) and were in the age range of 19-24 years. Prior to their exposure to hypokinesia (HK) of 364 days, all volunteers were on an average of 10,000 steps per day. All volunteers were divided into three equal groups: the first group underwent normal ambulatory life (control subjects), the second group was kept under continuous restriction of motor activity (hypokinetic subjects) and the third group was placed under continuous restriction of motor activity and consumed 26 ml water kg(-1) body weight daily and 0.1 g sodium chloride kg(-1) body weight in the form of supplementation (hyperhydrated subjects). For simulation of the hypokinetic effect, the number of steps taken per day by the second and third groups of volunteers was restricted to an average of 3000. During the hypokinetic period we determined reticulocytes (Rt), hemoglobin (Hb), hematocrit (Hct), plasma volume (PV), red blood cell (RBC) mass and VO2max. In hyperhydrated volunteers the content of Hb and Hct decreased significantly, while PV, RBC mass and Rt count increased significantly. In hypokinetic volunteers Hb and Hct increased, while PV, RBC and Rt decreased significantly. It was concluded that chronic hyperhydration may be used to attentuate an increase in the Hb content of physically conditioned subjects during prolonged restriction of motor activity.

关键词：红细胞容量补液疗法血细胞比容血红蛋白类/代谢运动机能减退/血液运动机能减退/药物疗法运动机能减退/代谢氧耗量身体耐力/生理学血浆容量网状细胞计数氯化钠/治疗应用水体重减轻成年人人类男(雄)性

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Artemisinin, an endoperoxide antimalarial, disrupts the hemoglobin catabolism and heme detoxification systems in malarial parasite

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第27期274卷 19383-19388页

作者： Pandey, AV Tekwani, BL Singh, RL Chauhan, VS Int Ctr Genet Engn & Biotechnol Malaria Res Grp New Delhi 110067 India Cent Drug Res Inst Div Biochem Lucknow 226001 Uttar Pradesh India RML Avadh Univ Dept Biochem Faizabad 224001 Uttar Pradesh India

Endoperoxide antimalarials based on the ancient Chinese drug Qinghaosu (artemisinin) are currently our major hope in the fight against drug-resistant malaria. Rational drug design based on artemisinin and its analogues is slow as the mechanism of action of these antimalarials is not clear. Here we report that these drugs, at least in part, exert their effect by interfering with the plasmodial hemoglobin catabolic pathway and inhibition of heme polymerization. In an in vitro experiment we observed inhibition of digestive vacuole proteolytic activity of malarial parasite by artemisinin, These observations were further confirmed by ex vivo experiments showing accumulation of hemoglobin in the parasites treated with artemisinin, suggesting inhibition of hemoglobin degradation. We found artemisinin to be a potent inhibitor of heme polymerization activity mediated by Plasmodium yoelii lysates as well as Plasmodium falciparum histidine-rich protein II. Interaction of artemisinin with the purified malarial hemozoin in vitro resulted in the concentration-dependent breakdown of the malaria pigment. Our results presented here may explain the selective and rapid toxicity of these drugs on mature, hemozoin-containing, stages of malarial parasite. Since artemisinin and its analogues appear to have similar molecular targets as chloroquine despite having different structures, they can potentially bypass the quinoline resistance machinery of the malarial parasite, which causes sublethal accumulation of these drugs in resistant strains.

关键词：抗疟药/药理学青蒿素类中草药/药理学电泳聚丙烯酰氨凝胶血红素/代谢血红素蛋白类/代谢血红蛋白类/代谢恶性疟原虫/药物作用恶性疟原虫/代谢约氏疟原虫/药物作用约氏疟原虫/代谢前列腺素内过氧化物/代谢倍半萜类/药理学动物男(雄)性小鼠

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EFFECT OF HEAD-UP TILT ON CEREBRAL-CIRCULATION

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ACTA ASTRONAUTICA 1994年第C期33卷 69-76页

作者： YOSHIMOTO, S UENO, T MAYANAGI, Y SEKIGUCHI, C YUMIKURA, S MIYAMOTO, A YAJIMA, K [a]Dept. of Neurosurgery Tokyo Police Hospital Fujimi 2-10-41 Chiyoda-ku Tokyo 102 Japan[b]Dept. of Hygiene School of Med. Nihon University Ohyaguchi-kamimachi 31-1 Itabashi-ku Tokyo 176 Japan[c]National Space Development Agency of Japan Sengen 2-1-1 Tukuba-shi Ibaraki-ken 305 Japan

This study was performed to study the effect of the head up tilt (HUT) on cerebral circulation across the time course (60 degrees HUT for 15 minutes) and across the different angles of HUT (15, 30, 45 60 degrees HUT for 15 minutes). Cerebral circulation was continuously monitored during 15 minutes of HUT by the carotid Doppler flow meter, the transcranial Doppler flow meter, and the near infra-red spectrophotometer. The results show that the cerebral blood flow decreased during HUT and that the cerebral blood volume decreased initially and then gradually increased. And the magnitude of the effect may have the relationship with the angles of the HUT.

关键词：血压/生理学颈动脉/超声检查脑血管循环/生理学超声心动描记术多普勒心率/生理学血红蛋白类/代谢低血压直立性/病理生理学低血压直立性/超声检查激光多普勒流量测定/仪器和设备体位/生理学谱学近红外线倾斜台试验超声检查多普勒经颅女(雌)性人类男(雄)性

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Physiologic responses of cross-linked hemoglobin in endotoxin-treated rats

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ARTIFICIAL CELLS BLOOD SUBSTITUTES AND IMMOBILIZATION BIOTECHNOLOGY 1999年第1期27卷 11-21页

作者： Goff, JM Jackson, MR Taher, M Cutting, MA Alving, BM Krishnamurti, C Walter Reed Army Inst Res Dept Hematol & Vasc Biol Washington DC 20307 USA Walter Reed Army Med Ctr Dept Surg Washington DC 20307 USA

Purified human cross-linked hemoglobin (alpha alpha Hb) as well as recombinant human hemoglobin is undergoing clinical trials in the setting of acute brood loss and perioperative hemodilution. We have previously demonstrated that in rabbits with circulating plasma Hb, such as alpha alpha Hb, infusion of endotoxin (LPS) impairs myocardial contractility which results in hypotension, tissue hypoperfusion and increased mortality. The untoward cardiovascular effects occurring after the combined infusion of LPS and alpha alpha Hb in this model are similar to those reported for other agents that inhibit nitric oxide (NO) availability. To determine if the deleterious effects of alpha alpha Hb and LPS were species specific, we performed similar studies in rats. Anesthetized Sprague-Dawley rats received LPS (4 mg/kg or 40 mg/kg) alone or in combination with alpha alpha Hb (0.7 g/kg). Mean arterial blood pressures (MAP) increased in the group that received alpha alpha Hb alone (105+/-8 to 120+/-7 mm Hg, p=0.2) and a decrease was noted in the groups that received low dose LPS (4 mg/kg, p=0.5) and high dose LPS (40 mg/kg, p=0.016). MAP in rats treated with the LPS at either dose combined with alpha alpha Hb remained unchanged. Levels of urine nitrite, which was measured as a surrogate marker for plasma NO, were significantly decreased at 2 hr in groups that received the combination of alpha alpha Hb and LPS at 4 mg/kg (p=0.022) and 40 mg/kg (p=0.003). No significant decrease was observed in animals treated only with alpha alpha Hb (p=0.21) or LPS (4 mg/kg;p=0.78 and 40 mg/kg;p=0.65). Survival was evaluated during 72 hr in animals that were infused with high dose LPS (40 mg/kg) alone or in combination with alpha alpha Hb and then allowed to recover. The survival of rats treated with LPS alone or the combination was 29% at the end of 24 hr and was 100% for rats receiving only alpha alpha Hb. The data suggest that the toxicity of alpha alpha Hb appears to be a species specific phen

关键词：麻醉血压/药物作用药物协同作用内皮缩血管肽1/血液内毒素类/毒性血红蛋白类/代谢血红蛋白类/药理学低血压/化学诱导低血压/死亡率脂多糖类/药理学一氧化氮/血液亚硝酸盐类/尿大鼠 Sprague-Dawley 动物人类男(雄)性兔大鼠

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Oxidative cross-linking of ApoB100 and hemoglobin results in low density lipoprotein modification in blood -: Relevance to atherogenesis caused by hemodialysis

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第27期274卷 18916-18924页

作者： Ziouzenkova, O Asatryan, L Akmal, M Tetta, C Wratten, ML Loseto-Wich, G Jürgens, G Heinecke, J Sevanian, A Univ So Calif Sch Pharm Dept Mol Pharmacol & Toxicol Los Angeles CA 90033 USA Univ So Calif Div Nephrol Los Angeles CA 90033 USA Bellco SPA Clin & Lab Res Dept I-41037 Mirandola Italy Washington Univ Sch Med St Louis MO 63110 USA Karl Franzens Univ Graz A-8010 Graz Austria

Human blood contains a form of minimally modified low density lipoprotein (LDL), termed LDL-, whose origin remains unknown. Exploring the mechanism of formation, we found that LDL- can be produced in plasma in the absence of oxygen following LDL incubation with oxidized hemoglobin species. A high degree of apolipoprotein B100 modification results from covalent association of hemoglobin with LDL involving dityrosine formation but not due to the malonaldehyde epitope formation. This was evidenced by the cross-reactivity of oxidized LDL with antibodies against hemoglobin that was accompanied by a 60-fold increase in dityrosine levels. In this study we found significantly higher LDL- levels in the blood of hemodialysis patients, perhaps contributing 60 their greatly increased risk of atherosclerosis. The mechanism of LDL- formation was studied during ex vivo blood circulation using a model system resembling clinical hemodialysis in terms of the induction of inflammatory responses. This circulation increased free hemoglobin and LDL- levels compared with non-circulated blood without appreciable lipid peroxidation, Pronounced increases in LDL- were found also during circulation of plasma supplemented with nanomolar hemoglobin levels. The increase in dityrosine content and presence of heme in LDL after blood circulation suggest that LDL is modified, in part, by hemoglobin-LDL conjugates containing heme, Thus, hemoglobin-mediated reactions leading to LDL oxidation in plasma can account for high LDL- levels in hemodialysis patients.

关键词：载脂蛋白B100 载脂蛋白B类/血液动脉硬化/病因学色谱法高压液相血红蛋白类/代谢肾功能衰竭慢性/血液肾功能衰竭慢性/并发症肾功能衰竭慢性/治疗脂质过氧化作用脂蛋白类 LDL/血液丙二醛/代谢肾透析/副作用成年人老年人老年人 80以上女(雌)性人类男(雄)性中年人

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Improvement of Staphylococcus aureus-V8-protease hydrolysis of bovine haemoglobin by its adsorption on to a solid phase in the presence of SDS:: peptide mapping and obtention of two haemopoietic peptides

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BIOTECHNOLOGY AND APPLIED BIOCHEMISTRY 2000年第2期31卷 127-134页

作者： Vercaigne-Marko, D Kosciarz, E Nedjar-Arroume, N Guillochon, D Univ Lille 1 Inst Technol A Lab Technol Subst Nat F-59653 Villeneuve Dascq France

Hydrolysis of bovine haemoglobin by the V8 protease from Staphylococcus aureus (EC 3.4.21.19) was studied in the presence of sos in a homogeneous-phase and in a solid-phase system. In both cases, hydrolyses were performed at 37 degrees C, in 50 mM phosphate buffer, pH 6.0, containing 0.1% SDS. Solid-phase hydrolyses were carried out with haemoglobin adsorbed on a negatively charged hydrophobic support, namely Amberlyst 15Wet (Rohm and Haas). The, peptides were isolated from the hydrolysates by reverse-phase HPLC and analysed for their amino acid composition on a Waters Pico-Tag column, confirmed by second-order derivative spectrometry or by MS. A peptide map of the hydrolysates was drawn up, and numerous new cleavages in haemoglobin chains were observed, especially after Asp. This study showed that SDS permitted a dramatic improvement in the hydrolysis of whole haemoglobin by vs protease in both homogeneous-phase and solid phase systems after adsorption of haemoglobin on to an anionic support. Moreover, in the heterogeneous phase, all the theoretical cleavage sites of V8 protease, Asp as well as Glu bonds, were hydrolyeed, except for four sites which were resistant owing to strong interactions with the support. These results led to us obtain two haemopoietic peptides, namely peptide alpha (Leu(76)- Pro-Gly-Ala-Leu-Seu-Glu(82)) and peptide beta (Lys(94)-Leu-His-Val-Asp-Pro-Glu(100)). These active peptides have never before been prepared from bovine haemoglobin, and they may have great potentialities in biotechnology.

关键词：吸附氨基酸序列生物技术血红蛋白类/化学血红蛋白类/遗传学血红蛋白类/代谢水解作用分子序列数据肽碎片/化学肽碎片/分离和提纯肽谱丝氨酸内肽酶类/代谢十二烷硫酸钠葡萄球菌金黄色/酶学动物牛

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Polymerization of diaspirin cross-linked hemoglobin (DCLHb) with water-soluble, nonimmunogenic polyamide cross-linking agents

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BIOCONJUGATE CHEMISTRY 1999年第6期10卷 1013-1020页

作者： Hai, TT Pereira, DE Nelson, DJ Srnak, A Catarello, J Baxter Healthcare Corp Corp Res & Tech Serv Round Lake IL 60073 USA

Diaspirin cross-linked hemoglobin (DCLHb), a human hemoglobin that is intramolecularly cross-linked between the a chains (lysine 99(alpha 1)-lysine 99(alpha 2)), was polymerized with a number of water-soluble, nonimmunogenic polyamide cross-linking agents. The degree of polymerization and the oxygen-carrying capacity depended upon the polyamide reagent, the starting concentration of DCLHb, the molar ratio of the polyamide reagent to DCLHb used, the reaction pH, and whether oxy- or deoxy-DCLHb was used in the polymerization reaction.

关键词：阿司匹林/类似物和衍生物阿司匹林/化学阿司匹林/代谢交联试剂血红蛋白类/化学血红蛋白类/代谢氢离子浓度指示剂和试剂分子量尼龙/化学氧/代谢氧合血红蛋白/化学聚合物/化学溶解度水人类

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Synthesis and physicochemical characterization of a series of hemoglobin-based oxygen carriers: Objective comparison between cellular and acellular types

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BIOCONJUGATE CHEMISTRY 2000年第1期11卷 56-64页

作者： Sakai, H Yuasa, M Onuma, H Takeoka, S Tsuchida, E Waseda Univ Adv Res Inst Sci & Engn Dept Polymer Chem Tokyo 1698555 Japan

A series of hemoglobin (Hb)-based O-2 carriers, acellular and cellular types, were synthesized and their physicochemical characteristics were compared. The acellular type includes intramolecularly cross-linked Hb (XLHb), polyoxyethylene (POE)-conjugated pyridoxalated Hb (POE-PLP-Hb), hydroxyethylstarch-conjugated Hb (HES-XLHb), and glutaraldehyde-polymerized XLHb (Poly-XLHb). The cellular type is Hb-vesicles (HbV) of which the surface is modified with POE (POE-HbV). Their particle diameters are 7 +/- 2, 22 +/- 2, 47 +/- 17, 68 +/- 24, and 224 +/- 76 nm, respectively, thus all the materials penetrate across membrane filters with 0.4 mu m pore size, though only the POE-HbV cannot penetrate across the filter with 0.2 mu m pore size. These characteristics of permeability are important to consider-an optimal particle size in microcirculation in vivo. POE-PLP-Hb ([Hb] = 5 g/dL) showed viscosity of 6.1 cP at 332 s(-1) and colloid osmotic pressure (COP) of 70.2 Torr, which are beyond the physiological conditions (human blood, viscosity = 3-4 cP, COP = ca. 25 Torr). XLHb and Poly-XLHb showed viscosities of 1.0 and 1.5 cp, respectively, which are significantly lower than that of blood. COP of POE-HbV is regulated to 20 Torr in 5% human serum albumin (HSA). HES-XLHb and POE-HbV/HSA showed comparable viscosity with human blood. Microscopic observation of human red blood cells (RBC) after mixing blood with POE-PLP-Hb or HES-XLHb disclosed aggregates of RBC, a kind of sludge, indicating a strong interaction with RBC, which is anticipated to modify peripheral blood flow in vivo. On the other hand, XLHb and POE-HbV showed no rouleaux or aggregates of RBC. The acellular Hbs (P-50 = 14-32 Torr) have their specific O-2 affinities determined by their structures, while that;of the cellular POE-HbV is regulated by coencapsulating an appropriate amount of an allosteric effector (e.g., P-50 = 18, 32 Torr). These differences in physicochemical characteristics between the acellular and cellu

关键词：血液代用品/化学合成血液代用品/化学血液代用品/代谢血液代用品/药理学胶剂/化学红细胞聚集/药物作用红细胞/药物作用戊二醛/血液戊二醛/化学血红蛋白类/化学合成血红蛋白类/化学血红蛋白类/代谢血红蛋白类/药理学羟乙基淀粉/化学合成羟乙基淀粉/化学羟乙基淀粉/代谢分子量渗透压氧/投药和剂量氧/血液氧/化学粒子大小聚乙烯二醇类/化学合成聚乙烯二醇类/化学聚乙烯二醇类/代谢黏度人类

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Changes in the functional properties of bovine hemoglobin induced by covalent modification with polyethylene glycol

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ARTIFICIAL CELLS BLOOD SUBSTITUTES AND IMMOBILIZATION BIOTECHNOLOGY 1999年第3期27卷 185-202页

作者： Shorr, RGL Kwong, S Gilbert, C Benesch, RE Enzon Inc Piscataway NJ 08854 USA Columbia Univ Coll Phys & Surg Dept Biochem & Mol Biophys New York NY 10032 USA

Polyethylene glycol conjugation to proteins and peptides (PEGylation) has been shown to promote increased retention time in the circulation as well as to blunt immune or allergic reactions. PEGylated bovine hemoglobin (PEG-Hb) is being explored in human clinical trials as an oxygen delivering agent for the sensitization of solid tumors to radiation therapy. In this study the functional properties of PEG-Hb were compared to those of bovine hemoglobin (Hb), the mutant human hemoglobin Rothchild and bovine hemoglobin crosslinked between the beta chains. The rate of heme transfer from Hb to serum albumin at pH 9.0 was greatly increased by PEGylation, suggesting destabilization of the heme-globin linkage and of the bonds between alpha beta dimers. Measurement of oxygen binding equilibrium showed that the oxygen affinity of Hb became unusually dependent on temperature and Hb concentration after PEGylation. Evidence is presented to suggest that PEGylation of lysine beta-81 at the entrance to the central cavity of the Hb tetramer might be responsible for these observations. The alterations of the functional properties of Hb induced by PEGylation are consistent with the beneficial effects of PEG-Hb in exchange transfusion and radiation sensitization models of human conditions.

关键词：血液代用品/化学血液代用品/代谢药物稳定性血红素/代谢血红蛋白类/分析血红蛋白类/化学血红蛋白类/代谢氧/代谢聚乙烯二醇类/分析聚乙烯二醇类/化学聚乙烯二醇类/代谢血清白蛋白/代谢血清白蛋白牛/代谢温度动物牛人类

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The ability of polyethylene glycol conjugated bovine hemoglobin (PEG-Hb) to adequately deliver oxygen in both exchange transfusion and top-loaded rat models

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ARTIFICIAL CELLS BLOOD SUBSTITUTES AND IMMOBILIZATION BIOTECHNOLOGY 1999年第2期27卷 93-107页

作者： Conover, CD Linberg, R Shum, KL Shorr, RGL Enzon Inc Formulat Toxicol Dept Piscataway NJ 08854 USA

The purpose of this study was to determine whether a six gram percent (g%) solution of the hemoglobin based oxygen carrier, polyethylene glycol conjugated bovine hemoglobin (PEG-Hb) could adequately deliver oxygen in both partial exchange transfusion and top-loaded rat models. This study measured tissue oxygen tension, circulatory retention and cardiovascular effects following both 30% exchange transfusion and 20 to 25 mL/kg top-loaded infusions of PEG-Hb. Oxygen delivery to rat tissues was determined using an oxygen dependant phosphorescence quenching method (Oxyspot(TM)). Telemetric intravascular blood pressure probes monitored heart rate and mean arterial pressure. In both models, six g% PEG-Hb (P-50 - 15 torr) was shown to oxygenate tissue better than stroma-free bovine Hb (P-50 - 26 torr), cross-linked bovine Hb (P-50 - 48 torr) or simple plasma expanders. The mean circulatory half life of PEG-Hb was 15.0 +/- 2.3 hours and 17.4 +/- 1.6 hours for exchange transfusion and 25 mL/kg top-loaded rat models, respectively. Mean arterial pressure (MAP) in PEG-Hb treated rats was insignificantly different from sham controls undergoing a 30% exchange transfusion or following a top-loaded infusion. In conclusion, the PEG conjugated form of bovine Hb with its relatively long vascular persistence may possess characteristics that facilitate tissue oxygenation in the rat.

关键词：血压血液代用品/投药和剂量血液代用品/代谢血液代用品/药代动力学心率血红蛋白类/投药和剂量血红蛋白类/代谢血红蛋白类/药代动力学注射静脉内肾/代谢氧/代谢聚乙烯二醇类/投药和剂量聚乙烯二醇类/代谢聚乙烯二醇类/药代动力学大鼠 Sprague-Dawley 脾/代谢动物牛女(雌)性大鼠

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