Carrier-mediated processes in blood-brain barrier penetration and neural uptake of paraquat

ELSEVIER, Ishimoto, T; Omori, N; Mutoh, F; Chiba, S, BRAIN RESEARCH, 906(1-2), 152-158, 2001. authorDue to the structural similarity to N-methyl-4-phenyl pyridinium (MPP+), paraquat might induce dopaminergic toxicity in the brain. However, its blood-brain barrier (BBB) penetration has not been well documented. We studied the manner of BBB penetration and neural cell uptake of paraquat using a brain microdialysis technique with the HPLC/UV detection in rats. After subcutaneous administration, paraquat appeared dose-dependently in the dialysate. In contrast, MPP+ could not penetrate the BBB in either control or paraquat pre-treated rats. These data indicated that the penetration of paraquat into the brain would be mediated by a specific carrier process, not resulting from the destruction of the BBB function by paraquat itself or a paraquat radical. To examine whether paraquat was carried across the BBB by a certain amino acid transporter, L-valine or L-lysine was pre-administered as a co-substrate. The pre-treatment of L-valine, which is a high affinity substrate for the neutral amino acid transporter, markedly reduced the BBB penetration of paraquat. When paraquat was administered to the striatum through a microdialysis probe, a significant amount of paraquat was detected in the striatal cells after a sequential 180-min washout with Ringer's solution. This uptake was significantly inhibited by a low Na+ condition, but not by treatment with putrescine, a potent uptake inhibitor of paraquat into lung tissue. These findings indicated that paraquat is possibly taken up into the brain by the neutral amino acid transport system, then transported into striatal, possibly neuronal, cells in a Na+-dependent manner

Antihypertensive Mechanism of Food for Specified Health Use : \u22Eucommia leaf glycoside\u22 and its clinical application

Eucommia is a native Chinese medical herb. The cortex of eucommia has long been used as an antihypertensive medicine. \u22Eucommia leaf glycoside\u22 is a substance extracted from the leaf. A cooling drink has been prepared from the extracts and named \u27Tochu 120\u27. Eucommia leaf glycoside was listed as a food for specified health use in 1997. Its antihypertensive mechanism is thought to involve an agonistic effect on the parasympathetic system based on results of several animal experiments. A double- blind placebo-controlled clinical study of 103 subjects with either high normal blood pressure (BP) or mild hypertension was conducted by means of both casual BP measurement and 24-hour ambulatory BP monitoring. A long-term clinical study was also performed for two years. In these studies, \u27Tochu 120\u27 was found to have mild antihypertensive effects and neither side effects nor adverse effects was observed in either clinical study. These results suggest that \u27Tochu 120\u27, a food for specified health use, is useful for non-pharmacological treatment of mildly hypertensive subjects including those who have high normal BP

A Study on the Application and Effect of \u27Health Formula\u27 to Subjects with Mild Hypertension : Tennis Course for Three Months

Nine mild hypertensives without complications and other severe diseases completed tennis classes which were held twice a week for three months in 1986. Each time they took a 60-minute lecture and a 60-minute tennis training. After 3 month training, their daily activity made remarkable increase in walking distance. %-fat ratio reduced and physical flexibility was improved. From the medical point of view, they showed significant improvement in hemoglobin A1, high density lipoprotein(HDL) cholesterol and respiratory tests such as vital capacity. After 3 month tennis training, post-exercise heart rate did not increase so much. However, subjects did not show significant decrease in blood pressures. Psychologically they felt less anxious about daily life, sports, physical and mental problems including elevated blood pressures. (Journal of Health Science Kyushu University 10 : 59-71, 1988)近郊住民への一般公募によって応募された軽症高血者を対象に講義と実技を組み合わせたテニス教室を週2回,1回90分,3ヵ月問実施した。本教室の開始時,中問時,終了時に身体面,阪学面,心理面,生活面から諸検査を実施した。得られた主な結果は,次のとおりである。1.身体面では皮下脂肪が減少し,立位体前用(柔軟性)が向上した。本教室での1日の平均歩行数は約13,000歩(約7.8Km)でその他の日は約7,500歩(約4.5Km)で３ヵ月の活動量は著しく増加した。ダブルス・ゲーム中の歩行数は1ゲーム約160〜280歩(約96〜168m)であった。テニス教室中の心拍数は,準備運動や歩行・ジョギング中は,個人差がみられた。しかし,ダブルスゲーム中はほぼ130〜150拍/分に増加した。2.医学面では糖代謝・脂質代謝・心機能・呼吸機能に著明な改善効果や機能促進効果が認められた。血圧は教室開始時に既に正常血圧に低下しており連動負荷の血圧値に及ぼす影響は明らかではなかった。3.心理面では日常生活の不安傾向やスポーツ場面の不安傾向は顕著に減少した。また血圧に対する感情的態度や評価的態度が好転し,不安傾向の減少を推察できた。血圧の変化に対する自己評価では5名(55.6%)が低下傾向と、評価した。健康度検査では精神的健康や社会的健康に有意な向上がみられ,健康度の評価は著しく向上した。スポーツ意識や条件では,顕著とはいえないが,スポーツに対する快感情やスポーツの心理的効果,社会的効果,性格の情緒面に好意的態度への変容を推測することができた。4.テニス教室の評価については,指導内容や日常生活での身体面,生活面の変化を肯定的に評価し,活性化に好影響を与えたものと思われる

Evidence that multiple P2X purinoceptors are functionally expressed in rat supraoptic neurones

The expression, distribution and function of P2X purinoceptors in the supraoptic nucleus (SON) were investigated by reverse transcription-polymerase chain reaction (RT-PCR), in situ hybridization, and Ca2+-imaging and whole-cell patch-clamp techniques, respectively.RT-PCR analysis of all seven known P2X receptor mRNAs in circular punches of the SON revealed that mRNAs for P2X2, P2X3, P2X4, P2X6 and P2X7 receptors were expressed in the SON, and mRNAs for P2X3, P2X4 and P2X7 were predominant.In situ hybridization histochemistry for P2X3 and P2X4 receptor mRNAs showed that both mRNAs were expressed throughout the SON and in the paraventricular nucleus (PVN).ATP caused an increase in [Ca2+]i in a dose-dependent manner with an ED50 of 1.7 × 10−5m. The effects of ATP were mimicked by ATPγS and 2-methylthio ATP (2MeSATP), but not by AMP, adenosine, UTP or UDP. αβ-Methylene ATP (αβMeATP) and ADP caused a small increase in [Ca2+]i in a subset of SON neurones.The P2X7 agonist 2′- & 3′-O-(4-benzoylbenzoyl)-ATP (BzATP) at 10−4m increased [Ca2+]i, but the potency of BzATP was lower than that of ATP. In contrast, BzATP caused a more prominent [Ca2+]i increase than ATP in non-neuronal cells in the SON.The effects of ATP were abolished by extracellular Ca2+ removal or by the P2 antagonist pyridoxal phosphate-6-azophenyl-2′,4′-disulphonic acid (PPADS), and inhibited by extracellular Na+ replacement or another P2 antagonist, suramin, but were unaffected by the P2X7 antagonist oxidized ATP, and the inhibitor of Ca2+-ATPase in intracellular Ca2+ stores cyclopiazonic acid.Two patterns of desensitization were observed in the [Ca2+]i response to repeated applications of ATP: some neurones showed little or moderate desensitization, while others showed strong desensitization.Whole-cell patch-clamp analysis showed that ATP induced cationic currents with marked inward rectification. The ATP-induced currents exhibited two patterns of desensitization similar to those observed in the [Ca2+]i response.The results suggest that multiple P2X receptors, including P2X3, are functionally expressed in SON neurones, and that activation of these receptors induces cationic currents and Ca2+ entry. Such ionic and Ca2+-signalling mechanisms triggered by ATP may play an important role in the regulation of SON neurosecretory cells

Innovative Criteria for Diagnosing Arterial Hypertension via Blood Pressure Monitoring : The Chronodiagnosis

There is an increasing use of ambulatory blood pressure (BP) monitoring for the clinical diagnosis of arterial hypertension. The BP monitoring is still analyzed with reference to fixed limits. This diagnostic method is highly improved by the use of temporal criteria according to a methodology which is called \u22chronodiagnosis\u22 of arterial hypertension. The chronodiagnostic procedure is structured in three levels, each one providing a specific assessment of BP 24-h pattern. Level 1 analyses the discrete variability of BP raw values. Level 2 estimates the periodic component of BP 24-h pattern which is physiologically arranged to fluctuate with a circadian rhythm. Level 3 computes measures on the BP 24-h pattern as a \u22whole\u22 in order to estimate the Baric Impact produced by the circadian oscillation. According to the chronodiagnostic procedure arterial hypertension can be qualified in its excess and temporal duration. The chronobiometric approach to BP monitoring provides, thus, 1, a more accurate diagnosis; 2. a clinical estimate of the tensiogenic regimen, 3. a clinical classification of arterial hypertension into definite chronopathologic types

軽症高血圧に対する健康処方の適用と効果に対する研究(第2報) : 3ヵ月間のテニス教室について

Nine mild hypertensives without complications and other severe diseases completed tennis classes which were held twice a week for three months in 1986. Each time they took a 60-minute lecture and a 60-minute tennis training. After 3 month training, their daily activity made remarkable increase in walking distance. %-fat ratio reduced and physical flexibility was improved. From the medical point of view, they showed significant improvement in hemoglobin A1, high density lipoprotein(HDL) cholesterol and respiratory tests such as vital capacity. After 3 month tennis training, post-exercise heart rate did not increase so much. However, subjects did not show significant decrease in blood pressures. Psychologically they felt less anxious about daily life, sports, physical and mental problems including elevated blood pressures. (Journal of Health Science Kyushu University 10 : 59-71, 1988)近郊住民への一般公募によって応募された軽症高血者を対象に講義と実技を組み合わせたテニス教室を週2回,1回90分,3ヵ月問実施した。本教室の開始時,中問時,終了時に身体面,阪学面,心理面,生活面から諸検査を実施した。得られた主な結果は,次のとおりである。1.身体面では皮下脂肪が減少し,立位体前用(柔軟性)が向上した。本教室での1日の平均歩行数は約13,000歩(約7.8Km)でその他の日は約7,500歩(約4.5Km)で３ヵ月の活動量は著しく増加した。ダブルス・ゲーム中の歩行数は1ゲーム約160〜280歩(約96〜168m)であった。テニス教室中の心拍数は,準備運動や歩行・ジョギング中は,個人差がみられた。しかし,ダブルスゲーム中はほぼ130〜150拍/分に増加した。2.医学面では糖代謝・脂質代謝・心機能・呼吸機能に著明な改善効果や機能促進効果が認められた。血圧は教室開始時に既に正常血圧に低下しており連動負荷の血圧値に及ぼす影響は明らかではなかった。3.心理面では日常生活の不安傾向やスポーツ場面の不安傾向は顕著に減少した。また血圧に対する感情的態度や評価的態度が好転し,不安傾向の減少を推察できた。血圧の変化に対する自己評価では5名(55.6%)が低下傾向と、評価した。健康度検査では精神的健康や社会的健康に有意な向上がみられ,健康度の評価は著しく向上した。スポーツ意識や条件では,顕著とはいえないが,スポーツに対する快感情やスポーツの心理的効果,社会的効果,性格の情緒面に好意的態度への変容を推測することができた。4.テニス教室の評価については,指導内容や日常生活での身体面,生活面の変化を肯定的に評価し,活性化に好影響を与えたものと思われる

Differences in Glucose Metabolism and Renin-angiotensin-aldosterone System between Normotensive and Borderline -hypertensive Male Students : 2. from the Responses to 75 g Fructose Ingestion

This study is aimed to investigate the effects of blood pressure in glucose metabolism and renin- angiotensin-aldosterone system in the young Japanese. Thirteen clinically healthy male students (21.61± 2.3 yo, normotensive;NT, n=5, borderline hypertensive;BHT, n=8) voluntarily participated in the study. They collected urine and were taken blood, before and 1, 2, 3 hours after taking 225ml solution of 75 gram fructose. Plasma renin activity and aldosterone concentration were higher in BHT than NT. Serum glucose and glucagon concentrations were higher after fructose ingestion in BHT, suggesting their endogenous glucose production from fructose. Serum lipase concentration was lower in BHT. These results showed that even slight elevation of blood pressure influenced glucose and lipid metabolism

Studies on Sodium Transport in Human Red Blood Cells.

Na-influx in red cells was measured in normotensive and borderline hypertensive subjects using the Mahoney\u27s method. In normotensives, Na-influx was higher in males than in females, and also in offspring of hypertensives than in those without familial predisposition of hypertension, compared between age-matched groups. Influence of age on Na-influx was unclear in both sex groups. In male subjects, Na-influx showed higher values in 14 borderline hypertensives than in 12 normotensives, and also higher in 9 women with high normal blood pressure (Hi-BP) than in 12 women with low normal blood pressure (Lo-BP). To test the effect of Na and K intake on Nainflux, Hi-BP and Lo-BP groups were given 200-220 mEq of Na and 40-50 mEq of K one by one, in addition to a normal intake of 100-120 mEq Na and 40-50 mEq K per day. Na load significantly increased Na-influx in Hi-BP group, but did not in Lo-BP group. On the other hand K load insignificantly decreased Na-influx in Lo-BP group, but unchanged in Hi-Bp group. In young men, Na-influx from 21 borderline hypertensives was statistically significantly increased after one-hour upright position, whereas that from 12 normotensives unchanged. Responsibility of Na-influx to upright position was not significantly correlated with blood pressure in either group. In order to investigate the mechanism of changes in Na-influx, variables other than blood pressure should be taken into account. Six healthy women, 22 years of age, stayed in RISM (Rational Intensive Self Measurement) rooms, Kyushu University for 3 days seasonally. Four-hourly blood sampling revealed circadian variation of Na-influx. Its peak appeared at around midnight. No report has been made on circadian rhythm of Na-influx. Its detection and explanation remain to be resolved. When we assess Na transport in cell membrane, conditions such as sampling time, position and Na intake should be considered