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.

Effect of beta-blocker on left ventricular function and natriuretic peptides in patients with chronic heart failure treated with angiotensin-converting enzyme inhibitor.

To evaluate whether or not beta-blockers can improve the condition of patients with heart failure treated with a combination of diuretics, digitalis and angiotensin-converting enzyme inhibitor (ACEI), 52 patients with chronic heart failure who have been treated with ACEI for more than 6 months were enrolled. They were divided into 2 groups: 26 patients continued the same therapy another 6 months or more (group A), and 26 patients were given oral metoprolol for 6 months or more, in addition to the ACEI (group B). Echocardiographic parameters and atrial and brain natriuretic peptides (ANP, BNP) were measured. The left ventricular dimensions at end-diastole and end-systole were significantly decreased and fractional shortening was significantly increased in group B after 6 months' treatment with the beta-blocker, but these parameters remained unchanged in group A. Plasma levels of both ANP and BNP were significantly decreased in group B, but remained unchanged in group A. These results indicate that concomitant beta-blocker therapy can improve left ventricular function and attenuate plasma ANP and BNP levels in patients with chronic heart failure treated with ACEI.

[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.

Morphologic and histologic characterization of cardiac myxomas by magnetic resonance imaging.

The purpose of this study was to assess the role of ECG-gated spin-echo (SE) magnetic resonance (MR) images, cine MR images, and gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA)-enhanced MR images for the morphologic and histologic diagnosis of atrial myxomas. Four patients with left atrial myxoma were imaged with a 1.5-T MR imager. The T1-weighted images and the cine MR images were obtained before injection of Gd-DTPA. After the injection of Gd-DTPA, the T1-weighted images were obtained again. Gd-DTPA-enhanced images of the myxomas were histologically compared with the extracted specimens. The tumors were represented more clearly on the cine MR images as low-intensity areas than on the SE images as high-intensity areas. On post-Gd-DTPA images, the 2 tumors were homogeneously enhanced and the other 2 were inhomogeneously enhanced. The locus of enhancement on post-Gd-DTPA images fitted with histologic myxoma or inflammation, and the unenhanced region reflected the necrosis or cystic changes in the specimens, respectively. The morphologic diagnosis of cardiac myxomas by MRI first should be done with SE images, and when the images are unclear, the cine MR images must be supplemented to depict the tumor clearly. Moreover, Gd-DTPA-enhanced MRI could elucidate histologic characteristics in myxomas.

Cardiovascular effect of oral calcium supplementation: echocardiographic study in patients with essential hypertension.

Oral calcium (Ca) supplementation mildly reduces blood pressure. The authors studied the effects of Ca supplementation on the cardiovascular system in patients with mild to moderate essential hypertension. Twelve patients aged forty-nine to seventy years (7 men and 5 women, mean age with 60.3 +/- 7.2 years) participated. The investigators orally administered Ca (1.0 g/day for one week) under hospitalization, adding to a dietary intake of Ca (0.6 g/day). Left ventricular function and systemic arterial compliance were evaluated by M-mode and pulsed Doppler echocardiographies before and after seven days of Ca supplementation. Left ventricular contractility and afterload were not changed. Preload indicated by end-diastolic volume was significantly decreased after Ca supplementation (109.6 +/- 8.5 vs 107.3 +/- 8.2 mL, P < 0.05). Myocardial relaxation evaluated by IIa-mitral valve opening time (87.7 +/- 6.7 vs 82.1 +/- 6.2 ms, P < 0.01) and maximum descending rate of the left ventricular posterior wall (10.6 +/- 1.0 vs 12.4 +/- 1.0 cm/s, P < 0.01), and atrioventricular net compliance assessed by the descending slope of rapid filling flow in the left ventricular inflow tract (2.63 +/- 0.24 vs 2.26 +/- 0.17 m/s2, P <0.05), as well as systemic arterial compliance (2.05 +/- 0.20 vs 2.73 +/- 0.26 mL/mmHg, P < 0.01) were significantly improved by Ca supplementation. Oral Ca supplementation improved the disturbed left ventricular diastolic function and systemic arterial compliance.

Molecular cloning and gene mapping of human basic and acidic calponins.

The nucleotide and deduced amino acid sequences of human basic and acidic calponins were determined. The basic calponin cDNA from human aorta (1496 bp) contained a single open reading frame (ORF) which encodes 297 amino acids (33,169 Da). The acidic calponin cDNA from human kidney (1607 bp) contained a single ORF which encodes 329 amino acids (36,412 Da). Basic calponin mRNA was expressed in only smooth muscle tissues, but acidic calponin mRNA was expressed in non-smooth muscle tissues as well as smooth muscle tissues. Fluorescent in situ hybridization revealed that basic and acidic calponin genes localize in 19p13.1-13.2 and 1p21-22 of human chromosomes, respectively.

Augmentation of baroreceptor reflex function by oral calcium supplementation in essential hypertension.

1. We studied the effect of oral calcium supplementation (1.0 g/day) for 1 week on baroreceptor reflex function and the lability of blood pressure in association with the changes in autonomic nervous activity in 14 hospitalized patients with mild to moderate essential hypertension (nine males and five females, mean age of 56 +/- 11.2 (s.d.) years). 2. Baroreceptor reflex sensitivity (BRS) was determined by the change in R-R intervals in response to the pressor response induced by phenylephrine injection. We measured coefficient of variation of R-R interval (CVR-R) and urinary excretion of catecholamines to evaluate the mechanism of change in BRS. We also used coefficient of variation of blood pressure (CVBP) and error of single cosinor analysis as parameters for lability of 24-h blood pressure. 3. The means of 24-h systolic and diastolic blood pressures showed no significant changes after calcium supplementation for 1 week. BRS and CVR-R were significantly increased by calcium supplementation. Daily excretions of norepinephrine and epinephrine corrected by creatinine were unchanged. Both CVBP and error of 24-h systolic blood pressure showed a significant decrease after calcium treatment. 4. These results indicate that oral calcium supplementation augments baroreceptor reflex function, in part through an enhancement of parasympathetic nervous activity, resulting in reduction of the lability of blood pressure in patients with mild to moderate essential hypertension.

Augmentation of the renal tubular dopaminergic activity by oral calcium supplementation in patients with essential hypertension.

We studied the effect of oral calcium supplementation on renal tubular dopaminergic activity in patients with mild to moderate essential hypertension. Fifteen patients aged 45 to 68 years (nine men and six women, mean age 59 +/- 7 [SD]) participated in the study. We orally administered calcium (1.0 g per day for 1 week) during hospitalization. The change in 24-h blood pressure (BP), measured by ambulatory BP monitoring, and excretions of electrolytes and catecholamines were investigated before and after 1 week of oral calcium supplementation. The mean values of 24-h systolic and diastolic BP showed no significant changes by calcium loading. Daily urinary excretion of free dopamine, sodium clearance (CNa), fractional excretion of sodium (FENa), and urinary volume were significantly increased by oral calcium supplementation. Urinary excretions of epinephrine and norepinephrine and creatinine clearance showed no significant changes by oral calcium treatment. CNa and FENa showed significant correlations with urinary excretion of free dopamine. These results suggest that oral calcium supplementation induces natriuresis partly through augmentation of renal tubular dopaminergic activity.

Renal and extra-renal renin gene expression in spontaneously hypertensive rats.

To study the effect of antihypertensive therapy on the regulation of renin gene expression, the levels of tissue renin messenger RNA (mRNA) were measured after treatment with a calcium channel blocker (manidipine hydrochloride 3 mg/kg/day) or an angiotensin-converting enzyme inhibitor (delapril hydrochloride 30 mg/kg/day), administered orally for 1 week, in spontaneously hypertensive rats (SHR). Male SHR, aged 15 weeks old, were used in this study (n = 5 per group). Control rats were administered the vehicle alone. Tissue total RNA was isolated from kidney, adrenal gland, heart, and brain tissue, and tissue RNA was reverse-transcribed to complementary DNA (cDNA), which was specifically amplified by polymerase chain reaction with labeled-primers for the rat renin gene. The radioactivity of the cDNA products was measured directly. Although delapril increased plasma renin activity (PRA) about 5-fold compared with the control group, manidipine did not change PRA. The kidney renin mRNA content was increased about 6-fold by treatment with delapril. Manidipine and delapril significantly decreased the renin mRNA content in the heart (p < 0.01 and p < 0.05, respectively). The level of renin mRNA in the adrenal gland and brain tissues was not significantly changed by treatment with either drug. These results suggest that tissue renin gene expression in SHR is regulated by a tissue-specific process independent of the circulating renin-angiotensin system.

The role of hypothalamic glutathione in hypertensive animals.

The role of brain glutathione metabolism in hypertensive animals was studied. In spontaneously hypertensive rats (SHR) from prehypertension to established hypertension, the content of oxidized glutathione (GSSG) and the ratio of GSSG to GSH in the hypothalamus were significantly (p less than 0.05) higher than those in age-matched normotensive Wistar Kyoto rats (WKY). Hypothalamic glutathione reductase (GR) activities in prehypertensive and established hypertensive SHR were significantly (p less than 0.05) lower than those in WKY. DOCA-salt hypertensive rats (DSR) also had a significantly (p less than 0.05) higher content of GSSG and GSSG/GSH ratio and a significantly (p less than 0.05) lower GR activity in the hypothalamus than the normotensive control. There were no significant differences in these values in the brain stem between hypertensive and normotensive rats. These results suggest that the increased GSSG/GSH ratio due to reduced activity of GR in the hypothalamus may have an important role in the development of hypertension in SHR and DSR.