Evaluation of the antiobesity effects of an amino acid mixture and conjugated linoleic acid on exercising healthy overweight humans: a randomized, double-blind, placebo-controlled trial.

This single-centre, randomized, double-blind, placebo-controlled trial investigated the effects of administering a mixture of four amino acids (lysine, proline, alanine and arginine) with or without conjugated linoleic acid to healthy overweight humans before and after exercising. Forty-one healthy subjects (body mass index >or= 23 to < 30 kg/m(2)) completed the study following randomization to receive either placebo or one of three test supplements: amino acid mixture 0.76 g/day; amino acid mixture 1.52 g/day; or amino acid mixture 1.52 g/day coadministered with conjugated linoleic acid 1.6 g/day. Each of the study treatments was administered 30 min before and immediately after a period of daily exercise, which was delivered by an exercise expert, for a period of 12 weeks. When compared with the placebo group, several indicators, such as waist and hip circumferences, were found to have significantly decreased in the test supplement groups compared with the placebo. These results suggest that ingestion of these supplements might enhance the fat-burning effects of exercise.

Improvement of accessory symptoms of hypertension by TSUMURA Orengedokuto Extract, a four herbal drugs containing Kampo-Medicine Granules for ethical use: a double-blind, placebo-controlled study.

A double-blind, placebo-controlled study was conducted to evaluate the efficacy, safety, and utility of TSUMURA Orengedokuto Extract Granules for Ethical Use (TJ-15) as a treatment for the accessory symptoms of hypertension. Two capsules of the study drug were administered orally 3 times daily (i.e., before meals) for 8 weeks. Among 265 patients enrolled in the study, 134 were assigned to the TJ-15 group and 131 were assigned to the placebo group, of whom 204 patients (103 in the TJ-15 group and 101 in the placebo group) were included in the efficacy and utility analyze and 251 patients (128 in the TJ-15 group and 123 in the placebo group) were included in the safety analysis. Efficacy was significantly higher in the TJ-15 group based on the total score for the accessory symptoms of hypertensions which was the primary efficacy endpoint (Wilcoxon's rank sum test, p=0.013). When each accessory symptom of hypertension was assessed separately, efficacy was higher for hot flushes and facial suffusion in the TJ-15 group (Wilcoxon's rank sum test, p=0.034, and 0.022, respectively). There were no significant differences between the TJ-15 and the placebo groups with respect to the decrease of blood pressure or the antihypertensive effect. There was also no significant difference between the two groups with regard to the overall safety rating. The utility rating was significantly higher in the TJ-15 group than in the placebo group (Wilcoxon's rank sum test, p=0.016). In conclusion, TJ-15 was superior to placebo with respect to efficacy, safety, and utility for the treatment of accessory symptoms of hypertension.

Increased digitalis-like immunoreactive substances in neonatal plasma measured using fluorescence polarization immunoassay.

OBJECTIVE: To better define the reported increased digitalis-like immunoreactive substances (DLIS) in neonatal plasma, we studied the relation among plasma DLIS level, blank intensity (BLK-I) value at FPIA measurement and plasma total bilirubin level. METHODS: The DLIS levels were measured in 10 neonates with or without jaundice and 10 infants in good health, using fluorescence polarization immunoassay (FPIA) and microparticle enzyme immunoassay (MEIA). BLK-I value and plasma total bilirubin level were also measured simultaneously. RESULTS: In neonates with jaundice, DLIS using FPIA, BLK-I and total bilirubin level were 0.58 +/-0.13 ng/mL, 2598 +/- 408, and 17.98 +/- 1.13 mg/dL, respectively, before phototherapy, and 0.33 +/-0.06 ng/mL, 1886 +/- 237, and 15.16 +/- 2.07 mg/dL after phototherapy. Corresponding values in neonates without jaundice were (DLIS: 0.34 +/-0.04 ng/mL; BLK-I: 1,764 +/- 278; total bilirubin: 10.37 +/- 4.54 mg/dL); in healthy infants (0.12 +/-0.06 ng/mL, 400.7 +/- 4.6 and 0.42 +/- 0.13 mg/dL, respectively) and in healthy volunteers (0.10 +/-0.07 ng/mL, 403.1 +/- 8.4, and 0.58 +/- 0.30 mg/dL, respectively). Using MEIA, DLIS was not detected in 10 neonates, 10 infants and 20 healthy volunteers. CONCLUSIONS: A fluorescent compound related to bilirubin increased the BLK-I value in the measurement of neonatal plasma using FPIA. The fluorescence was not the result of endogenous digitalis-like factors.

Hypertension in a patient with Gitelman's syndrome.

Gitelman's syndrome is an autosomal recessive disorder characterized by sodium wasting and hypotension. A middle-aged woman was diagnosed with Gitelman's syndrome because of typical clinical manifestations in the youth and homozygous mutations of 18-base-pair insertion in exon 6 of thiazide-sensitive NaCl-cotransporter gene. It was unusual that she showed hypertension with advancing age. Her serum potassium levels remained low at around 3.5 mEq/l despite potassium supplementation. This case demonstrates that hypertension could result in spite of the extremely decreased sodium reabsorption in Gitelman's syndrome and that essential hypertension is genetically heterogeneous, and abnormality of all genes may not be necessarily required to cause blood pressure rise.

Metabolic effects of long-term treatments with nifedipine-retard and captopril in young hypertensive patients.

The objective of this study was to clarify potential differences in the metabolism of glucose and lipids in a long-term treatment (for 5 years) for hypertension among nifedipine-retard and captopril in young, nonobese hypertensive men (HT). In 78 previously untreated HT who were given nifedipine-retard and in 81 HT given captopril, blood pressure (BP), pulse rate, blood glucose, and plasma insulin levels were measured every 30 min for 2 h after 75 g oral glucose ingestion, every year for 5 years. Twenty-six age- and body mass index (BMI)-matched normotensive men (NT) were measured for the same variables for 5 years. They were also measured for total cholesterol, triglyceride levels, and lipids fractions after an overnight fast, every year for 5 years without any kinds of lipid lowering agents. At 1 year after treatment with nifedipine-retard or captopril, BP decreased significantly, and the reductions in BP did not differ between HT treated with nifedipine-retard and captopril. In the entry period, fasting insulin (P < .05), the area under the curve (AUC) of insulin (P < .01), AUC of blood glucose (P < .05) after 75 g oral glucose ingestion, fasting total cholesterol (P < .05), and triglyceride levels (P < .05) in HT were significantly greater than those in NT. In HT treated with captopril, AUC of insulin (P < .01), AUC of blood glucose (P < .05), and total cholesterol (P < .05) decreased significantly after 1 year of treatment for HT, and triglyceride (P < .05) decreased significantly after the 2 year treatment. Although in HT treated with nifedipine-retard, AUC of insulin (P < .01) and AUC of blood glucose levels (P < .05) decreased significantly after 1 year of treatment, triglyceride and total cholesterol levels did not decrease throughout the 5 years. These results indicate that captopril has ameliorative effects in hyperinsulinemia or reduced insulin sensitivity, hypercholesterolemia, and hypertriglyceridemia starting at 1 year after the treatment for HT, whereas nifedipine-retard has an ameliorative effect in the metabolism of glucose but not in the metabolism of lipids. Therefore, ACE inhibitor has additional ameliorative effects on insulin sensitivity to the vasodilatory action.

[Guidelines on treatment of hypertension in the elderly, 1995--a tentative plan for comprehensive research projects on aging and health-- Members of the Research Group for "Guidelines on Treatment of Hypertension in the Elderly", Comprehensive Research Projects on Aging and Health, the Ministry of Health and Welfare of Japan].

We propose the following guidelines for treatment of hypertension in the elderly. 1. Indications for Treatment. 1) Age: Lifestyle modification is recommended for patients aged 85 years and older. Antihypertensive therapy should be limited to patients in whom the merit of the treatment is obvious. 2) Blood pressure: Systolic BP > 160 mmHg, diastolic BP > 90 approximately 10 mmHg. Systolic BP < age + 100 mmHg for those aged 70 years and older. Patients with mild hypertension (140-160/ 90-95 mmHg) associated with cardiovascular disease should be considered for antihypertensive drug therapy. 2. Goal of Therapy for BP: The goal BP in elderly patients is higher than that in younger patients (BP reduction of 10-20 mmHg for systolic BP and 5-10 mmHg for diastolic BP). In general, 140-160/< 90 mmHg is recommended as the goal. However, lowering the BP below 150/85 should be done with caution. 3. Rate of Lowering BP: Start with half the usual dose, observe at the same dose for at least four weeks, and reach the target BP over two months. Increasing the dose of antihypertensive drugs should be done very slowly. 4. Lifestyle Modification: 1) Dietary modification: (1) Reduction of sodium intake is highly effective in elderly patients due to their high salt-sensitivity. NaCl intake of less than 10 g/day is recommended. Serum Na+ should be occasionally measured. (2) Potassium supplementation is recommended, but with caution in patients with renal insufficiency. (3) Sufficient intake of calcium and magnesium is recommended. (4) Reduce saturated fatty acids. Intake of fish is recommended. (2) Regular physical activity: Recommended exercise for patients aged 60 years and older: peak heart rate 110/minute, for 30-40 minutes a day, 3-5 days a week. (3) Weight reduction. (4) Moderation of alcohol intake, smoking cessation. 5. Pharmacologic Treatment: 1) Initial drug therapy. First choice: Long-acting (once or twice a day) Ca antagonists or ACE inhibitors. Second choice: Thiazide diuretics (combined with potassium-sparing diuretic). 2) Combination therapy. (1) For patients without complications, either of the following is recommended. i) Ca antagoinst + ACE inhibitor, ii) ACE inhibitor + Ca antagonist (or low-dose diuretics), iii) diuretic + Ca antagonist (or ACE inhibitor), iv) beta-blockers, alpha 1-blockers, alpha + beta blockers can be used according to the patho-physiological state of the patient. (2) For patients with complications. Drug(s) should be selected according to each complication. 3) Relatively contraindicated drugs. beta-Blockers and alpha 1-blockers are relatively contraindicated in elderly patients with hypertension in Japan. Centrally acting agents such as reserpine, methyldopa and clonidine are also relatively contraindicated beta-Blockers are contraindicated in patients with congestive heart failure, arteriosclerosis obliterans, chronic obstructive pulmonary disease, diabetes mellitus (or glucose intolerance), or bradycardia. These conditions are often present in elderly subjects. Elderly subjects are susceptible to alpha 1-blocker-induced orthostatic hypotension, since their baroreceptor reflex is diminished. Orthostatic hypotension may cause falls and bone fractures in the elderly.

Fat-soluble vitamins in cord blood and colostrum in the south of China.

Certain diseases have been associated with micronutrient deficiencies in China, and nutritional assessments have become important means of preventing such diseases. In the present study, fat-soluble vitamins including vitamins A, D, E, K, and beta-carotene in the cord blood and colostrum of Chinese subjects in Guilin, China, were assayed and compared with those of Japanese subjects in Osaka, Japan. These vitamins were analyzed by high-performance liquid chromatography. Vitamin A and E levels in the cord blood and colostrum of the Chinese group showed almost the same values as those of the Japanese group. There was also no significant difference in vitamin D level in cord blood between the two groups, while significantly lower levels of beta-carotene and cryptoxanthin, and a higher level of PIVKA-II (protein induced in vitamin K absence) in cord blood were observed in the Chinese group. These findings pointed to a restricted intake of green-yellow vegetables in the Chinese group and an increased risk of hemorrhagic disease in newborn of that group is suggested.

Participation of a proton-cotransporter, MCT1, in the intestinal transport of monocarboxylic acids.

A molecular mechanism for the intestinal monocarboxylic acid transport was characterized by using a proton/monocarboxylate transporter, MCT1, in Chinese hamster ovary (CHO) cells, first found by Garcia et al. (Cell, 76, 865-873, 1994). Northern blotting analysis showed that MCT1-isomers exist in the rat and rabbit intestinal enterocytes and Caco-2 cells. The expression of [14C]lactic acid uptake by Xenopus laevis oocytes injected with rabbit intestinal mRNA was reduced by hybridizing the mRNA with a MCT1 cDNA of CHO cells before microinjection used as the antisense DNA. [14C]Lactic acid uptake by CHO cells was pH dependent, saturable, stereospecific, and reduced in the presence of acetic acid, benzoic acid, S- and R-ibuprofen, S- and R-mandelic acid, nicotinic acid, pravastatin, propionic acid and valproic acid. In addition, several monocarboxylic acids were transported in pH-dependent and saturable manners. These results suggest that the intestinal MCT1-related protein contributes to a carrier-mediated absorption for organic weak acid compounds.

Comparative effects of monatepil, a novel calcium antagonist with alpha 1-adrenergic-blocking activity, and nitrendipine on lipoprotein and carbohydrate metabolism in patients with hypertension.

The effects of monatepil, a new calcium antagonist with alpha 1-blocking activity, and nitrendipine on lipoprotein and carbohydrate metabolism in 86 patients with mild-to-moderate hypertension were examined in a randomized, open-label, multicenter (32 hospitals) study. Thirty-nine patients treated with monatepil and 33 patients treated with nitrendipine completed the 12-week study. Monatepil and nitrendipine each significantly decreased both systolic and diastolic blood pressure. Changes in heart rate were not seen in either group. Monatepil administration significantly decreased total cholesterol, low density lipoprotein (LDL) cholesterol, the LDL cholesterol to high density lipoprotein (HDL) cholesterol ratio, apolipoprotein (Apo) B levels, and HbA1c levels, whereas no changes in these measurements were observed in nitrendipine-treated patients. Monatepil also significantly decreased lipoprotein(a) levels, but there were no significant changes in HDL cholesterol, Apo-AI, or Apo-E levels. After nitrendipine treatment, the C peptide concentration decreased significantly, although no significant changes were observed in fasting blood glucose or immunoreactive insulin levels. On the basis of these results, it can be concluded that monatepil belongs to a new class of antihypertensive calcium antagonist with favorable carbohydrate metabolism and lipid-lowering activity, although the clinical importance of these findings has not been established.

Novel in vitro gene transfer method for study of local modulators in vascular smooth muscle cells.

Although many in vitro gene transfer methods already exist, such as calcium phosphate precipitation, electroporation, or cationic liposomes, these methods cause significant cell injury and cell death. The study of the biology of endogenous autocrine-paracrine vasoactive systems such as the renin-angiotensin system in vascular cells is limited by the lack of a suitable gene transfer method with high efficiency of transfection and expression that will permit cell biology studies. Recently, the Sendai virus (hemagglutinating virus of Japan, HVJ)-liposome-mediated gene transfer method has been shown to be an efficient and nontoxic method of gene transfer. In this study, we characterized the efficiency and suitability of the HVJ method for vascular biology research. Using SV40 T-antigen complementary DNA (cDNA), we initially compared the efficiency of the HVJ method and lipofection for transfection of cultured vascular smooth muscle cells (VSMCs). We observed that after 35 minutes of incubation, the HVJ method exhibited a 10-fold higher efficiency of transfection than lipofection. We used this method to study vascular angiotensin converting enzyme (ACE) expression in cultured VSMCs and cultured rat carotid arteries in vitro. The HVJ method of transfection of human ACE cDNA into VSMCs and COS cells was significantly more efficient than lipofection. Using this method, we demonstrated that transfection of ACE cDNA resulted in increased DNA synthesis, which was inhibited by the specific angiotensin II receptor antagonist DuP 753 (10(-6) M).(ABSTRACT TRUNCATED AT 250 WORDS)

Role of tissue renin angiotensin system in two-kidney, one-clip hypertensive rats.

To investigate the molecular pathology of two-kidney, one-clip (2K-1C) rats, we examined the gene expressions of the renin-angiotensin system (RAS) and angiotensin II (ANG II) concentration in various tissues in the early (4 wk) and chronic (16 wk) phases of hypertension. Four weeks after clipping, the brain renin mRNA level was lower in 2K-1C rats than in control rats (P < 0.05). On the other hand, the levels of brain and renal angiotensinogen mRNA were not significantly different in the two groups. The brain and adrenal ANG II concentrations were significantly higher in 2K-1C rats than in control rats. Sixteen weeks after clipping, there was no significant difference in the brain renin mRNA levels in the two groups, and renal and brain angiotensinogen mRNA levels were normal. Moreover, the ANG II concentrations in the adrenals and brain (except the cortex) of 2K-1C rats were not significantly higher than those in control rats. These results show a differential pattern of tissue RAS gene expression in rats during the development of 2K-1C hypertension, which is regulated in a tissue-specific manner. Furthermore, the data suggest that brain ANG II may be affected by circulating ANG II, but not by the brain renin angiotensin system, and may regulate brain renin, probably by negative feedback through its own receptor.

Adverse reactions to lipiodol ultra fluid: report of an accidental case.

A 25-year-old Japanese woman experienced pulmonary edema, shock, encephalopathy and silent pancreatitis after hysterosalpingography using lipiodol ultra fluid, because the contrast media flowed directly into the blood stream from endometrium injured by several curettages for termination of pregnancy. Total iodine concentrations in plasma and urine decreased exponentially and their half-life was 16.12 and 13.04 days, respectively. Clear correlations were observed between the iodine concentration in plasma and the amelioration of both electroencephalogram and neuropsychic abnormalities. Adverse reactions of oil-soluble contrast media are also discussed.

Blood pressure response to dietary calcium intervention in humans.

Epidemiological and experimental studies have suggested that dietary calcium deficiency may lead to the development of hypertension. This article reviews findings in human trials on calcium intervention with special reference to the responses of blood pressure and biochemical variables. Calcium supplementation consistently resulted in decreased blood pressure in a subset of hypertensive and normotensive subjects, but led to increased blood pressure in some hypertensive patients. The variable blood pressure responses to calcium supplementation could not be predicted on the basis of routine biochemical parameters and appeared to be due to differences in the backgrounds of the subjects and/or the design and size of the trials. It is concluded that further studies are required on the hypotensive effect of calcium supplementation.

Comparison of the production of cyclic AMP in response to parathyroid hormone in fibroblasts from aged subjects and young subjects: lack of an age-dependent decrease.

An age-dependent effect on the ability to produce cyclic AMP in response to parathyroid hormone (PTH) stimulation was examined using culture skin fibroblasts from both young and elderly female subjects. The mean values of both absolute and comparative production of intracellular cyclic AMP due to various concentrations of PTH administration did not differ between the two age groups, although the mean serum PTH level was significantly higher in the elderly subjects. These results indicate that the decreased response of the target organ to PTH in aged subjects can be explained mainly by the decreased number of intact cells rather than a decreased response of individual cells to PTH.

Hypotensive effect of long-term oral calcium supplementation in elderly patients with essential hypertension.

Calcium gluconate (22.4 g/day; 2 g/day as Ca) was administered orally for 8 weeks to eight hospitalized elderly patients with essential hypertension in order to confirm the hypotensive effect of oral calcium supplementation and to clarify its hypotensive mechanism by analyzing changes in hormonal factors. After 2 weeks of calcium supplementation, both systolic and diastolic pressures decreased significantly and remained decreased for the duration of the study. An elevation of plasma PGE2 correlated with blood pressure reduction was observed at 2 weeks. Plasma norepinephrine decreased significantly from 4 weeks. Plasma parathyroid hormone decreased significantly from 4 weeks, and 1,25-dihydroxyvitamin D (1,25-[OH]2D) decreased significantly at 8 weeks. The reduction of plasma 1,25-(OH)2D correlated with blood pressure decrease at 8 weeks. The present study indicates that the mechanism of its hypotensive effect is multifactorial and may be different during different phases of calcium supplementation. The suppression of plasma 1,25-(OH)2D following reduction of parathyroid hormone may be involved in the hypotensive effect in the chronic phase of calcium supplementation. Enhancement of PGE2 production in the early phase and suppression of sympathetic nervous activity in the chronic phase may also be factors in blood pressure reduction.

Hypotensive mechanism of potassium supplementation in salt-loaded patients with essential hypertension.

To investigate the hypotensive mechanism of potassium supplementation, blood pressure responses and hormonal changes were measured during KCl supplementation in salt-loaded patients with essential hypertension. Ten patients with essential hypertension were placed on low sodium intake, high sodium intake, and high sodium intake with KCl supplementation. Blood pressure increased during NaCl loading and decreased during KCl supplementation. The levels of urinary sodium and fractional sodium excretion increased after KCl supplementation. Reduction in blood pressure after KCl supplementation was correlated with an increase in blood pressure after NaCl supplementation, i.e., potassium sensitivity and sodium sensitivity were correlated. Plasma PGE2 and norepinephrine increased after KCl loading. Increases in plasma PGE2 were correlated with a reduction of blood pressure by KCl. These results indicate that natriuresis and hypotensive action of KCl are associated with increased PGE2 production, and the sympathetic nerve activity suggests a compensatory increase for the decrease in blood pressure.

A new orally active hypotensive peptide, N-(dibenzyloxyphosphinoyl)-L-alanyl-L-prolyl-L-proline (PAPP).

The antihypertensive effects and mechanisms of a newly developed orally active tripeptide, N-(dibenzyloxyphosphinoyl)-L-alanyl-L-prolyl-L-proline (PAPP), were investigated. When PAPP (1-30 mg/kg orally) was administered to spontaneously hypertensive rats (SHR), systolic blood pressure (SBP) reached a maximum reduction after 8 h and this effect lasted over 24 h. In two-kidney, one clip hypertensive rats (2KIC rats) and DOCA-salt hypertensive rats, PAPP also reduced SBP. In normotensive Wistar rats, however, PAPP did not have a hypotensive effect. PAPP showed low toxicity in Sprague-Dawley rats. The depressor response to bradykinin (BK) was potentiated, but the pressor response to angiotensin I (ANG I) was not inhibited by PAPP. PAPP significantly relaxed isolated SHR aortic strips treated with KC or norepinephrine. Angiotensin converting enzyme (ACE) inhibition by PAPP was relatively low in vivo and in vitro.