Yoshinori Miyamoto

Statin Inhibits Hypoxia-Induced Endothelin-1 via accelerated degradation of HIF-1α in Vascular Smooth Muscle Cells

AIMS Endothelin-1 (ET-1) contributes to the pathogenesis of cardiovascular diseases with multiple properties such as vasoconstriction. Human ET-1 gene expression is up-regulated by the transcription factor hypoxia-inducible factor-1 (HIF-1) through hypoxia response element (HRE). Although previous studies suggested that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) alter HIF-1-related gene expression, it remained unclear whether statins modulate HIF-1-mediated ET-1 expression. Therefore, we investigated the effect of fluvastatin on hypoxia-induced human ET-1 expression in vascular smooth muscle cells (VSMC). METHODS AND RESULTS Hypoxia (1% O(2)), compared with the normoxic condition (21% O(2)), significantly induced the expression of preproET-1 mRNA, ET-1 protein, and ET-1 secretion in VSMC. Hypoxia induced a 2.3-fold increase in HRE-dependent ET-1 reporter gene activation. Under concentrations of 1 µmol/L or greater, fluvastatin attenuated the hypoxia-induced ET-1 gene expression through the accelerated ubiquitin/proteasome-dependent degradation of HIF-1α, thus consequently attenuating HIF-1α binding to the HRE of the ET-1 gene. These inhibitory effects of fluvastatin were cancelled by concomitant treatment with mevalonate, farnesyl pyrophosphate, or geranylgeranyl pyrophosphate, but not squalene. CONCLUSION The present study suggests that fluvastatin attenuates HIF-1-dependent ET-1 gene expression in conjunction with the stimulation of HIF-1α ubiquitin/proteasome-dependent degradation via isoprenoid-dependent mechanisms.

Dimenhydrinate effect on cerebral oxygen status and salivary chromogranin-A during cognitive tasks.

To investigate the effects of dimenhydrinate on cerebral oxygen status (COS; cerebral oxygenated hemoglobin concentration changes) and salivary chromogranin-A (CgA) during a cognitive test battery, a double-blind, placebo-controlled, randomized, crossover protocol was used to examine the effect of 50 mg of dimenhydrinate or placebo in 12 subjects. This test battery includes tests of both reaction time and fundamental cognitive ability and was used in the assessment of pilots. Poor cognitive performance was observed in the subjects taking dimenhydrinate. We used two-channel near-infrared spectroscopy to investigate the effects of dimenhydrinate on the COS. With the one exception of shifting attention task in the left forehead, no significant difference was found between dimenhydrinate and placebo during the tasks of the test battery. Under placebo treatment, on the other hand, CgA levels were significantly elevated during cognitive testing when compared with baseline. However, CgA levels were not significantly elevated above baseline following dimenhydrinate. The present study is one of the first to demonstrate that the first-generation antihistamine drugs altered the responses of salivary CgA during cognitive tasks. The changes in salivary CgA secretion, as a result of dimenhydrinate administration, may serve as a sensitive biomarker of a psychological status such as a drug-induced sedation during the performance of a cognitive test battery. Further studies, however, are required to examine the usefulness of this sensitive biomarker in investigation of psychological agents during cognitive tasks.

Urinary Catecholamine Responses in F-15 Pilots: Evaluation of the Stress Induced by Long-Distance Flights

Included in the Cooperative Cope Thunder exercises from Japan to Alaska is one of the longest distance flight missions carried out by Japan Air-Self Defense Force F-15 pilots. The magnitude of the flight stress of these pilots is considered to be quite high. The purpose of this study was to evaluate the flight stress induced by the long-distance flights. The subjects were eight pilots who participated on a volunteer basis. Samples of urine were collected approximately 30 minutes before (preflight) and 20 minutes after (postflight) the flights. The ratios (post-:preflight) of noradrenaline levels were 1.20 +/- 0.09 (Japan-Alaska) and 1.32 +/- 0.12 (Alaska-Japan), and those of adrenaline were 4.03 +/- 1.06 and 3.68 +/- 0.98. These results strongly suggest that psychological stress during the long-distance flights is increased in the fighter pilots.

EFFECTS OF FLIGHT WORKLOAD ON URINARY CATECHOLAMINE RESPONSES IN EXPERIENCED MILITARY PILOTS

This study investigated the flight responses induced by strenuous aerobatic demonstration flight and an air-to-air combat maneuvering flight in experienced pilots. Subjects were 54 military male pilots on a volunteer basis: 8 T-4 pilots (M = 35.8 yr., SD = 4.9), 15 F-4 pilots (M = 32.6 yr., SD = 5.1), 13 F-15 pilots (M = 33.8 yr., SD = 1.0), and 18 F-2 pilots (M = 33.7 yr., SD = 3.9). Samples of urine were collected approximately 30 min. before and 20 min. after the flights. The postflight adrenaline in all pilots was significantly higher than at preflight, while a significant increase in noradrenaline at postflight was not observed. The post-/preflight ratio of adrenaline in all pilots was relatively similar and high. These findings might be regarded as a result of autonomic nervous system response to the flight workload of military pilots. Especially is increment in sympathetic activity considered to play an important part in psychological adaptation to flight.

Decadal electrocardiographic changes between age 40 and 50 in military pilots.

INTRODUCTION Cardiovascular diseases can lead to sudden in-flight incapacitation and long-term disability in aircraft pilots. Electrocardiogram (ECG) has been widely used to screen for these diseases in routine aeromedical examinations. Several ECG changes such as complete left bundle-branch block (CLBBB) and left ventricular hypertrophy (LVH) have been associated with increased likelihood of underlying structural cardiac diseases in addition to the emergence of newly recognized cardiovascular diseases such as Brugada syndrome. Therefore, the purpose of this study was to analyze decadal ECG changes in aircraft pilots between 40 and 50 yr in order to make an appropriate evaluation of these ECG changes. METHODS We analyzed the ECGs from the annual aeromedical examination of age 50 compared to those 40 yr of age in a total of 176 Japan Air Self-Defense Force pilots. RESULTS With regard to decadal changes, we detected 34 new ECG changes (1 of sinus tachycardia, 8 sinus bradycardia, 1 atrial fibrillation, 2 premature atrial contraction, 1 premature ventricular contraction, 2 left axis deviation, 6 first-degree atrioventricular block, 1 CLBBB, 3 complete right bundle-branch block, 2 incomplete right bundle-branch block, 1 right ventricular conduction delay, and 6 LVH). Although the majority of them were concluded to be normal variants, the results of echocardiography in two hypertensive pilots without good control demonstrated abnormalities: one had mild hypertrophic nonobstructive cardiomyopathy and another had heart enlargement. CONCLUSION Thus, this study recommends additional cardiovascular examinations, including echocardiography for hypertensive pilots with ECG changes.