Cerebral metabolism in streptozotocin-diabetic rats: an in vivo magnetic resonance spectroscopy study

Aims/hypothesis. It is increasingly evident that the brain is another site of diabetic end-organ damage. The pathogenesis has not been fully explained, but seems to involve an interplay between aberrant glucose metabolism and vascular changes. Vascular changes, such as deficits in cerebral blood flow, could compromise cerebral energy metabolism. We therefore examined cerebral metabolism in streptozotocin-diabetic rats in vivo by means of localised ³¹P and ¹H magnetic resonance spectroscopy. Methods. Rats were examined 2 weeks and 4 and 8 months after diabetes induction. A non-diabetic group was examined at baseline and after 8 months. Results. In ³¹P spectra the phosphocreatine:ATP, phosphocreatine:inorganic phosphate and ATP:inorganic phosphate ratios and intracellular pH in diabetic rats were similar to controls at all time points. In ¹H spectra a lactate resonance was detected as frequently in controls as in diabetic rats. Compared with baseline and 8-month controls ¹H spectra did, however, show a statistically significant decrease in N-acetylaspartate:total creatine (–14 % and –23 %) and N-acetylaspartate:choline (–21 % and –17 %) ratios after 2 weeks and 8 months of diabetes, respectively. Conclusion/interpretation. No statistically significant alterations in cerebral energy metabolism were observed after up to 8 months of streptozotocin-diabetes. These findings indicate that cerebral blood flow disturbances in diabetic rats do not compromise the energy status of the brain to a level detectable by magnetic resonance spectroscopy. Reductions in N-acetylaspartate levels in the brain of STZ-diabetic rats were shown by ¹H spectroscopy, which could present a marker for early metabolic or functional abnormalities in cerebral neurones in diabetes. [Diabetologia (2001) 44: 346–353] Received: 3 August 2000 and in revised form: 17 October 2000     

Astrocyte volume regulation and ATP and phosphocreatine concentrations after exposure to salicylate,ammonium, and fatty acids

Cellular volume regulation following swelling in hypo-osmotic phosphate-buffered saline (PBS) and ATP and phosphocreatine concentrations of cells incubated in iso-osmotic or hypo-osmotic PBS were measured in primary cultured rat cerebral astrocytes exposed for 30 min to NH₄Cl, salicylate, hexanoate, octanoate, and/or dodecanoate. These compounds have been implicated in the pathogenesis of cerebral edema in Reye's Syndrome. NH₄Cl (0.10–10 raM) had no effect on astrocyte volume regulation or ATP concentration. Salicylate significantly reduced ATP concentrations at 3.0 mM and 10 mM but had no effect on volume regulation. Hexanoate (10 mM and 30 mM) decreased astrocyte ATP content by over 80% while octanoate (10 mM) reduced ATP content by more than 50%. Concentrations of these fatty acids at or below 3.0 mM had no effect on ATP content. Volume regulation was inhibited by 3.0 mM hexanoate and 3.0 mM octanoate but not lower concentrations. Dodecanoate (0.1–3.0 mM) decreased cellular ATP content by 33–51% in iso-osmotic PBS solutions. Phosphocreatine content was reduced by exposure to salicylate or octanoate at concentrations which had no effect on ATP content. These results indicate that astrocyte energy metabolism and volume regulation may be compromised by agents associated with cerebral edema in Reye's Syndrome. Analysis of the dose-dependence of these effects suggests that inhibition of astrocyte energy metabolism is not sufficient to affect volume regulation.     

磷酸肌酸钠在改善老年慢性心力衰竭患者心功能中的应用效果评价

目的 探讨磷酸肌酸钠改善老年慢性心力衰竭患者心功能的疗效.方法 选取我院收治的老年慢性心力衰竭患者并随机分为对照组和观察组.对照组给予传统抗心衰治疗,观察组在对照组基础上给予磷酸肌酸钠治疗,观察比较治疗前后两组患者的心功能及治疗效果.结果 治疗后观察组患者的LVEDD、LVESD、CI、LVEF等心功能指标及BNP和6-MWT均优于对照组,观察组患者的治疗有效率高于对照组,差异有统计学意义（P＜0.05）.结论 磷酸肌酸钠能够显著改善老年慢性心力衰竭患者心功能,并降低患者BNP,临床效果较好.     

In Vivo Induced Malignant Hyperthermia in Pigs. I. Physiological and Biochemical Changes and the Influence of Dantrolene Sodium

The effects of an induced malignant hyperthermia (MH) crisis have been studied in the intact pig. Both physiological and biochemical changes in skeletal muscle were studied. MH was induced with 3% halothane plus a bolus injection of succinylcholine. In the prechallenge period a significant difference was observed in the concentration of certain muscle metabolites, comparing the MH-susceptible (MH+) with the non-susceptible (MH^-) pigs. A lower level was measured for phosphocreatine (PCr), inosine monophosphate (IMP) and an increased level of lactate and creatine (Cr) in the susceptible pigs (MH+). The challenge caused a significant reduction of the level of PCr and adenosine in MH+ pigs, compared to the prechallenge period. After administration of dantrolene sodium, a significant decrease was measured in the level of lactate, compared to the prechallenge period as well as during the challenge. In contrast, in the control pigs no significant changes were observed in muscle metabolites, either after induction of MH or after the administration of dantrolene sodium. Enzyme activity determinations of muscle adenylate kinase and adenosine monophosphate (AMP)- deaminase did not show any difference in activity either before or during the MH crisis or after treatment with dantrolene sodium. The earliest physiological change during an induced MH crisis in our study was thrapid increase of the end-tidal CO₂. Within 5 min after MH induction, end-tidal CO₂ was doubled. It is concluded that the monitoring of the end-tidal CO2 is essential to diagnose MH at a very early stage.     

磷酸肌酸钠治疗扩张型心肌病心功能不全的疗效观察

目的：观察磷酸肌酸钠治疗扩张型心肌病伴心功能不全患者的疗效。方法：将103例扩张型心肌病心功能不全的患者随机为两组,对照组给予血管紧张素转换酶抑制剂或血管紧张素II受体拮抗剂,利尿剂,β受体阻滞剂（无禁忌证）,强心剂,血管扩张剂等基础抗心衰治疗,试药组在此基础上给予磷酸肌酸钠。观察治疗前和治疗后患者的心功能分级、左室收缩功能相关参数的变化,并观察药物不良反应。结果：两组患者经治疗后临床症状均有好转,但是试药组心悸、呼吸困难、水肿等改善率,脑钠尿肽水平的下降、左室射血分数的增加显著优于对照组（P〈0.05）。结论：磷酸肌酸钠可以安全、有效地改善扩张型心肌病心功能不全患者的临床症状和心功能指标。     

磷酸肌酸对阿霉素致大鼠心肌损伤的保护作用及其抗细胞凋亡的实验研究

目的通过建立大鼠阿霉素心肌损伤模型,观察磷酸肌酸对阿霉素心肌损伤的保护作用,并研究磷酸肌酸抑制心肌细胞凋亡的机制。方法采用随机分组的方法将40只SD大鼠分为4组。（1）对照组：腹腔注射生理盐水每日一次;（2）阿霉素组：隔日一次腹腔注射阿霉素建立阿霉素心肌损伤模型。（3）阿霉素＋磷酸肌酸钠组（小剂量）：隔日一次腹腔注射磷酸肌酸钠（200mg/kg）,30min后注射阿霉素。（4）阿霉素＋磷酸肌酸钠组（大剂量）：隔日1次腹腔注射磷酸肌酸钠（300mg/kg）,30min后注射阿霉素。用药结束后测定各组大鼠血清、心肌组织中丙二醛（MDA）含量、超氧化物歧化酶（SOD）活性、过氧化氢酶（CAT）活性,血清中肌酸激酶（CK）、肌酸激酶同工酶（CK-MB）含量变化。取心肌组织HE染色,观察大鼠心肌病理形态学变化。免疫组织化学染色方法检测各组心肌组织中BAX、BCL-2蛋白表达情况。结果两组加入磷酸肌酸钠大鼠脂质过氧化产物MDA含量减少,心肌抗氧化酶SOD及CAT活性增加,血清中CK、CK-MB含量减少,与阿霉素组比较有统计学意义（P〈0.05）。免疫组化结果显示,磷酸肌酸钠组大鼠心肌促凋亡蛋白BAX表达减弱,抗凋亡蛋白BCL-2表达增强,且与阿霉素组比较有意义（P〈0.05）。给予不同剂量磷酸肌酸钠的两组大鼠,各项检测指标未见差异（P〈0.05）。结论磷酸肌酸通过增强抗氧化酶系统的功能,降低阿霉素引起的氧化应激损伤,抑制自由基引起的心肌细胞凋亡,起到保护心脏功能的作用。     

Graded effects of oxygen and respiratory inhibitors on cell metabolism and spontaneous contractions in smooth muscle of the rat portal vein

The basis for the hypoxic relaxation of spontaneous activity in the rat portal vein was investigated by comparing responses to oxygen and the respiratory chain inhibitors amobarbital and cyanide. With the inhibitors, 0₂ consumption (J_O2) is uniformly decreased throughout the cell mass, and thus O₂ gradients in the tissue are avoided. Hence the effects are not to be attributed to all-or-none inhibition in anoxic regions, a possibility that might complicate the interpretation of responses to hypoxia. With stepwise reduction in P_Q2 (96 to o % O₂ in N₂ + 4 % CO₂) or increasing concentration of inhibitor (0–5 mmol), J_O2, decreased with a concomitant reduction in mean contractile activity (p?) and increase in lactate production (J L_A). The calculated ATP production (J ATP) was linearly related to p? for p? > 10% of the control value in 96% O₂, with the same slope for hypoxia and both inhibitors. In this range the reduced J_ATP with can largely be attributed to decreased metabolic demand of contraction, as evident from a comparison with the responses to hypoxia of portal veins relaxed in nominally Ca²⁺-free medium. With reduced P_O2 or increased amobarbital concentration the tissue content of phosphocreatine decreased, whereas ATP remained constant for p? gt; 10% of control. Similar responses to hypoxia and respiratory inhibition demonstrate graded effects on metabolism and contractility in the vascular smooth muscle cells, correlating with reported vasodilatory effects of these interventions in vivo.     

Power output and muscle metabolism during and following recovery from 10 and 20 s of maximal sprint exercise in humans

On two separate days eight male subjects performed a 10- or 20-s cycle ergometer sprint (randomized order) followed, after 2 min of recovery, by a 30-s sprint. Muscle biopsies were obtained from the vastus lateralis at rest, immediately after the first sprint and after the 2 min of recovery on both occasions.The anaerobic ATP turnover during the initial 10 s of sprint 1 was 129 ± 12 mmol kg dry weight^?1 and decreased to 63 ± 10 mmol kg dry weight^?1 between the 10th and 20th s of sprint 1. This was a result of a 300% decrease in the rate of phosphocreatine breakdown and a 35% decrease in the glycolytic rate. Despite this 51% reduction in anaerobic ATP turnover, the mean power between 10 and 20 s of sprint 1 was reduced by only 28%. During the same period, oxygen uptake increased from 1.30 ± 0.15 to 2.40 ± 0.23 L min^?1, which partially compensated for the decreased anaerobic metabolism. Muscle pH decreased from 7.06 ± 0.02 at rest to 6.94 ± 0.02 after 10 s and 6.82 ± 0.03 after 20 s of sprinting (for all changes P < 0.01). Muscle pH did not change following a 2-min recovery period after both the 10- and 20-s sprints, but phosphocreatine was resynthesized to 86 ± 3 and 76 ± 3% of the resting value, respectively (n.s. 10- vs. 20-s sprint). Following 2 min of recovery after the 10-s sprint subjects were able to reproduce peak but not mean power. Restoration of both mean and peak power following the 20-s sprint was 88% of sprint 1, and was lower compared with that after the 10-s sprint (P < 0.01). Total work during the second 30-s sprint after the 10- and the 20-s sprint was 19.3 ± 0.6 and 17.8 ± 0.5 kJ, respectively (P < 0.01). As oxygen uptake was the same during the 30-s sprints (2.95 ± 0.15 and 3.02 ± 0.16 L min^?1), and [Phosphocreatine] before the sprint was similar, the lower work may be related to a reduced glycolytic ATP regeneration as a result of the higher muscle acidosis.     

Cerebral energy reserves of mice during seizures induced by 3-mercaptopropionic acid

Convulsions were induced in mice by the intraperitoneal injection of 3-mercaptopropionic acid. Energy metabolism of the cerebral cortex was studied during the first clonic seizure and during the recovery period (10 and 30 min after the end of convulsions). At the onset of a seizure the content of phosphocreatine, adenosine triphosphate, glucose and glycogen decreased and the level of lactate, adenosine di- and monophosphate increased; the ‘energy charge potential’ of the adenine nucleotide pool was diminished. The calculated extra energy expenditure during seizure was about 40 μequiv. ~ P g^?1.min^?1. Ten minutes after the end of convulsions normal values of phosphocreatine, adenylates and energy charge potential were attained, the content of glucose was increased, while lactate and glycogen levels were partly restored. Lactate content returned to control values after 30 min of recovery, whereas glycogen did not reach its control level until 1 h after the end of convulsions. Na-phenobarbital in a non-anaesthetic dose not only prevented clinical manifestation of 3-mercaptopropionic acid-induced seizures, but also all changes of brain metabolite levels accompanying the convulsions.These observations are discussed and compared with those obtained previously in studies on seizures induced by homocysteine and methionine sulphoximine, i.e. other sulphur-containing convulsants; the changes in brain energy metabolism during seizures induced by 3-mercaptopropionic acid are similar to those observed during homocysteine-induced seizures and differ substantially from changes accompanying convulsions induced by methionine sulphoximine.