Different Effects of Palmitoyl-L-carnitine and Palmitoyl-CoA on Mitochondrial Function in Rat Ventricular Myocytes

Although mitochondrial oxidative catabolism of fatty acid (FA) is a major energy source for the adult mammalian heart, cardiac lipotoxity resulting from elevated serum FA and enhanced FA use has been implicated in the pathogenesis of heart failure. To investigate the effects of the intermediates of FA metabolism, palmitoyl-L-carnitine (Pal-car) and palmitoyl-CoA (Pal-CoA), on mitochondrial function, we measured membrane potential(Δψm), opening of the mitochondrial permeability transition pore (mPTP) and the production of reactive oxygen species (ROS) in saponin-treated rat ventricular myocytes with a laser scanning confocal microscope. Our results revealed that: 1) lower concentrations of Pal-car (1 and 5μM) caused a slight hyperpolarization of Δψm (TMRE intensity increased to 115.5 ± 5.4 % and 110.7±1.6 % of the baseline, respectively. p<0.05) but did not open mPTP, 2) a higher concentration of Pal-car (10μM) depolarized Δψm (TMRE intensity decreased to 61.9 ± 12.2 % of the baseline, p<0.01) and opened mPTP (calcein intensity decreased to 70.7 ± 2.8% of the baseline, p<0.01), 3) Pal-CoA depolarized Δψm without opening mPTP, and 4) only the higher concentration of Pal-car (10μM) increased ROS generation (DCF intensity increased to 3.4 ± 0.3 fold of the baseline). We concluded that excessive exogenous intermediates of long chain saturated FA may disturb mitochondrial function in different ways between Pal-car and Pal-CoA. The distinct mechanisms of the deteriorating effects of long chain FA on mitochondrial function are important for our understanding of the development of cardiac diseases in systemic metabolic disorders.浜松医科大学学位論文　医博第517号(平成２０年１０月１７日

Vasodilator Stress Impairs the Left Ventricular Function Obtained With Gated Single-Photon Emission Computed Tomography in Patients With Known or Suspected Coronary Artery Disease

Background: Transient ischemic dilatation (TID) and post-stress dysfunction of the left ventricle (LV) are important markers of severe coronary artery disease (CAD). To clarify the effects of stressor type on TID and post-stress LV dysfunction, changes in LV measurements were compared between patients with exercise- or vasodilator-induced stress. Methods and Results: The 689 patients referred for technetium-99m tetrofosmin myocardial perfusion imaging were included. Patients were stressed with either a vasodilator (n=236) or exercise (n=453). LV measurements were obtained with ECG-gated SPECT. LV end-diastolic and end-systolic volume indexes (LVEDVI, LVESVI) increased and LV ejection fraction (LVEF) decreased after stress in the vasodilator-stress group. Vasodilator-stress and the summed difference score (SDS) were independent variables that decreased LVEF after stress. Even in patients without reversible defects, vasodilator-stress impaired LV function. There were no differences in the stress-to-rest ratios of LVEDVI (rEDV) and LVESVI (rESV) among patients with normal myocardial perfusion, fixed defects and reversible defects in the vasodilator-stress group, whereas in the exercise-stress group, rESV was significantly higher in the patients with reversible defects than in those without reversible defects. Within the vasodilator-stress group, neither rEDV nor rESV correlated with the SDS. Conclusions: Vasodilator-stress by itself decreases LVEF after stress. TID should be carefully interpreted when vasodilator-stress is used to detect severe CAD

Waist to height ratio is an independent predictor for the incidence of chronic kidney disease.

Obesity is a risk factor for chronic kidney disease (CKD) and cardiovascular disease. The association between waist to height ratio (WheiR) and CKD is unclear. This study evaluated the association between WheiR and CKD.In this longitudinal cohort study, 4841 Japanese workers (3686 males, 1155 females) 18 to 67 years of age in 2008 were followed up until 2011. CKD was defined as an estimated glomerular filtration rate of <60 mL/min/1.73 m² (by the Modification of Diet in Renal Disease equation for Japanese) or dipstick proteinuria (≥1+). Cox proportional hazards models were used to examine the relationship between WheiR and development of CKD.A total of 384 (7.9%) participants (300 men and 84 women) were found to have new CKD. The incidence of CKD was 13.7, 24.2, 37.9 and 43.7 per 1000 person-years of follow-up in the lowest, second, third and highest quartiles of WheiR, respectively. After adjustment for potential confounders, the adjusted hazard ratios (95% confidence interval) for CKD were 1.00 (reference), 1.23 (0.85, 1.78), 1.59 (1.11, 2.26) and 1.62 (1.13, 2.32) through the quartiles of WheiR, respectively. WheiR had a significant predictive value for the incidence of both proteinuria and low estimated glomerular filtration rate. After subdivision according to gender, the relationship between WheiR and the incidence of CKD was statistically significant in the unadjusted model. However, after adjusting for potential confounders, WheiR was significantly associated with the incidence of CKD in females, whereas it was not significant in males.WheiR, which is commonly used as an index of central obesity, is associated with CKD. There was a significant gender difference in the relationship between CKD and WheiR

Transient Laterality of Cerebral Oxygenation Changes in Response to Head-of-Bed Manipulation in Acute Ischemic Stroke

Background: Cerebral oxygenation monitoring provides important information for optimizing individualized management in patients with acute ischemic stroke (AIS). Although changes in cerebral oxygenation are known to occur in response to head-of-bed (HOB) elevation within 72 h after onset, changes in cerebral oxygenation during stroke recovery are unclear. We compared changes in total- (tHb), oxygenated- (HbO2), and deoxygenated-hemoglobin (deoxyHb) concentrations in response to HOB manipulation between the timeframes within 72 h and 7&ndash;10 days after AIS onset. Methods: We measured forehead &Delta;tHb, &Delta;HbO2, and &Delta;deoxyHb in response to HOB elevation (30&deg;) within 72 h (first measurement) and 7&ndash;10 days (second measurement) after AIS onset using time-resolved near-infrared spectroscopy. Results: We enrolled 30 participants (mean age 72.8 &plusmn; 11.3 years; 13 women) with a first AIS. There were no significant differences in &Delta;tHb, &Delta;HbO2, or &Delta;deoxyHb measurements on the infarct or contra-infarct side. At the first measurement, &Delta;tHb, &Delta;HbO2, and &Delta;deoxyHb measured on the contra-infarct side did not correlate with those measured on the infarct side: &Delta;tHb (r = 0.114, p = 0.539); &Delta;HbO2 (r = 0.143, p = 0.440); &Delta;deoxyHb (r = 0.227, p = 0.221). Notably, at the second measurement, correlation coefficients of &Delta;tHb and &Delta;HbO2 between the contra-infarct and infarct sides were statistically significant: &Delta;tHb (r = 0.491, p = 0.008); &Delta;HbO2 (r = 0.479, p = 0.010); &Delta;deoxyHb (r = 0.358, p = 0.054). Conclusion: Although changes in cerebral oxygenation in response to HOB elevation had a laterality difference between hemispheres within 72 h of AIS onset, the difference had decreased, at least partially, 7&ndash;10 days after AIS onset

Calcium Release from Endoplasmic Reticulum Involves Calmodulin-Mediated NADPH Oxidase-Derived Reactive Oxygen Species Production in Endothelial Cells

Background: Previous studies demonstrated that calcium/calmodulin (Ca2+/CaM) activates nicotinamide adenine dinucleotide phosphate oxidases (NOX). In endothelial cells, the elevation of intracellular Ca2+ level consists of two components: Ca2+ mobilization from the endoplasmic reticulum (ER) and the subsequent store-operated Ca2+ entry. However, little is known about which component of Ca2+ increase is required to activate NOX in endothelial cells. Here, we investigated the mechanism that regulates NOX-derived reactive oxygen species (ROS) production via a Ca2+/CaM-dependent pathway. Methods: We measured ROS production using a fluorescent indicator in endothelial cells and performed phosphorylation assays. Results: Bradykinin (BK) increased NOX-derived cytosolic ROS. When cells were exposed to BK with either a nominal Ca2+-free or 1 mM of extracellular Ca2+ concentration modified Tyrode&#8217;s solution, no difference in BK-induced ROS production was observed; however, chelating of cytosolic Ca2+ by BAPTA/AM or the depletion of ER Ca2+ contents by thapsigargin eliminated BK-induced ROS production. BK-induced ROS production was inhibited by a CaM inhibitor; however, a Ca2+/CaM-dependent protein kinase II (CaMKII) inhibitor did not affect BK-induced ROS production. Furthermore, BK stimulation did not increase phosphorylation of NOX2, NOX4, and NOX5. Conclusions: BK-induced NOX-derived ROS production was mediated via a Ca2+/CaM-dependent pathway; however, it was independent from NOX phosphorylation. This was strictly regulated by ER Ca2+ contents

Effect of co-administered inducer or inhibitor on omeprazole pharmacokinetics based on CYP2C19 genotype

Polymorphisms of cytochrome P450 (CYP) enzymes can affect enzymatic activity, drug metabolism and drug interactions. Although the potential for drug interactions is especially important when co-administering drugs with strong inductive or inhibitory potential towards drug-metabolizing enzymes, the relationship between CYP genotypes and the extent of the inductive or inhibitory effects remain poorly understood. We investigated the effects of rifampicin (inductive) and fluvoxamine (inhibitory) on metabolism of omeprazole and CYP2C19 enzymatic activity in 19 healthy Japanese subjects. Pharmacokinetic analyses of the CYP2C19 probe drug, omeprazole, were performed before and after rifampicin or fluvoxamine administration. The allele frequencies of the CYP2C19*1, CYP2C19*2 and CYP2C19*3 genotypes were 65.8%, 26.3% and 7.9%, respectively. Subjects with the CYP2C19*1 allele displayed higher levels of omeprazole metabolism than those without the CYP2C19*1 allele. Rifampicin increased omeprazole metabolism in all subjects irrespective of genotype, which suggested that CYP2C19 enzymatic activity was induced by rifampicin administration for all genotypes. Conversely, while fluvoxamine reduced omeprazole metabolism in subjects carrying the CYP2C19*1 allele, it had no impact on omeprazole pharmacokinetics in subjects without this allele. The genotyping of CYP2C19 may be useful for predicting drug interactions with metabolic inhibitors. Keywords: Cytochrome P450 2C19, Drug interaction, Fluvoxamine, Omeprazole, Rifampici