分岐鎖アミノ酸は心臓悪液質を伴ったラット心不全モデルの病態を改善する

京都大学0048新制・課程博士博士(医学)甲第19601号医博第4108号新制||医||1014(附属図書館)32637京都大学大学院医学研究科医学専攻(主査)教授 岩井 一宏, 教授 柳田 素子, 教授 山下 潤学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA

Cardiac effects of acute administration of a protonophore in a rat model

[Objectives]Excessive use of uncoupling agents, previously used as weight loss agents, has led to the increase in body temperature and death. The aim of the present study was to evaluate the acute cardiac effects of mitochondrial protonophore in a rat model at a high dose, and its specific influence on cardiac substrate uptake. [Methods]Eight‐week‐old male Sprague–Dawley rats were intraperitoneally injected with the protonophore carbonyl cyanide m‐chloro phenyl hydrazone (CCCP; 4 mg/kg) or vehicle (dimethyl sulfoxide). Blood pressure, heart rate (HR) and systolic function were recorded. Substrate uptake was monitored by radioactive tracers. [Key findings]Compared to the control group, the respiratory rate and body temperature increased, the left ventricle was dilated, and systolic function transiently deteriorated in the CCCP group. There was no difference in blood pressure and HR between the two groups. In cardiac substrate uptake, glucose uptake showed a 95% increase (P < 0.05), and fatty acid uptake showed a 52% decrease (P < 0.05) in CCCP‐administered group. [Conclusions]The deleterious effects on cardiac function and the changes in substrate uptake were observed when administered with the protonophore at a high dose

The metabolic profile of a rat model of chronic kidney disease

[Background]The kidney is always subjected to high metabolic demand. The aim of this study was to characterize metabolic profiles of a rat model of chronic kidney disease (CKD) with cardiorenal syndrome (CRS) induced by prolonged hypertension. [Methods]We used inbred male Dahl salt-sensitive (DS) rats fed an 8% NaCl diet from six weeks of age (high-salt; HS group) or a 0.3% NaCl diet as controls (low-salt; LS group). We analyzed function, pathology, metabolome, and the gene expression related to energy metabolism of the kidney. [Results]DS rats with a high-salt diet showed hypertension at 11 weeks of age and elevated serum levels of creatinine and blood urea nitrogen with heart failure at 21 weeks of age. The fibrotic area in the kidneys increased at 21 weeks of age. In addition, gene expression related to mitochondrial function was largely decreased. The levels of citrate and isocitrate increased and the gene expression of alpha-ketoglutaratedehydrogenase and succinyl-CoA synthetase decreased; these are enzymes that metabolize citrate and isocitrate, respectively. In addition, the levels of succinate and acetyl Co-A, both of which are metabolites of the tricarboxylic acid (TCA) cycle, decreased. [Conclusions]DS rats fed a high-salt diet were deemed a suitable model of CKD with CRS. Gene expression and metabolites related to energy metabolism and mitochondria in the kidney significantly changed in DS rats with hypertension in accordance with the progression of renal injury

¹²⁵I-9MPA signals and correlation with ^99mTc-MIBI signals.

<p>(A) In DS rats fed an HS diet (n = 26), the signals for ¹²⁵I-9MPA, an indicator of the activity of mitochondrial β-oxidation, decreased compared with those in DS rats fed an LS diet (n = 10). *<i>P</i> < 0.05 versus LS. (B) ¹²⁵I-9MPA signals positively correlated with ^99mTc-MIBI signals (r = 0.74, <i>P</i> < 0.0001, n = 36).</p