Shigeo Kakinoki

Alpha‐1‐Acid Glycoprotein Concentration and the Protein Binding of Disopyramide in Healthy Subjects

Age‐ and gender‐related changes in serum α1‐acid glycoprotein (AAG) concentration and the serum protein binding of disopyramide were examined after intensive medical examination. Based on the clinical chemistry tests over 51 points, 245 subjects were diagnosed as healthy and 71 subjects (22.5%) revealed an abnormal value for at least one item. In the healthy subjects, serum AAG concentration in men was significantly higher than in women (men, 0.78 ± 0.18 mg/mL, mean ± SD; women, 0.67 ± 0.16 mg/mL). In contrast, there were no significant differences in the AAG concentration between age groups for men and women and in the unbound fraction of disopyramide. Gender changes AAG concentration. Age, however, does not change AAG concentration and the protein binding of the basic drug.

Recovery of cardiac norepinephrine concentration and tyrosine hydroxylase activity by the central α2-adrenoceptor agonist guanabenz in rats with aortic constriction

Depletion of cardiac norepinephrine has been reported in cardiac hypertrophy. This depletion causes less support for cardiac output in response to sympathetic nerve activation. The central nervous system is thought to be involved in this abnormality. Correction of this abnormality is expected to restore proper support for the heart. Clipping of the ascending aorta or a sham operation was performed in 10-week-old rats. At 4 weeks after the operation, the left ventricular norepinephrine concentration in clipped rats decreased (p<0.01). The clipped rats and sham-operated rats were treated with either guanabenz (1 mg/kg) or a vehicle for 4 weeks starting from fifth postoperative week. The level of left ventricular norepinephrine increased more in clipped rats treated with guanabenz (469+/-37 ng/g) than in clipped rats treated with a vehicle (325+/-28 ng/g). The norepinephrine concentration in the left ventricle recovered significantly after the treatment with guanabenz (p<0.001). Tyrosine hydroxylase activity in the left ventricle also recovered after treatment with guanabenz (p<0.01). Modulation of sympathetic nerve tone by the alpha2-adrenoceptor agonist restored cardiac norepinephrine concentration and tyrosine hydroxylase activity. This could be a new approach to the treatment of heart failure.

Purification method for α-1-acid glycoprotein with subsequent high-performance liquid chromatographic determination of monosaccharides in plasma of healthy subjects and patients with renal insufficiency

A simple purification method for human plasma α-1-acid glycoprotein (AAG) using an ion-exchange and hydroxyapatite column was developed. The recovery of the method was found to be high. We also improved a determination method for N-acetylneuraminic acid and monosaccharides in the carbohydrate moiety of AAG by using an ion-exchange column and pulse-amperometric detection. By this method, a composition analysis of the carbohydrate moiety of AAG (N-acetylneuraminic acid, fucose, N-acetyl glucosamine, galactose and mannose) was possible with 1.0 ml of plasma. We compared these carbohydrate concentrations in the AAG of patients with renal insufficiency with those of healthy subjects. In the AAG of the patients, the concentrations of N-acetylglucosamine, galactose and mannose were significantly higher than those in the AAG of the healthy subjects.

Malignant Cardiac Pheochromocytoma With Bone Metastases

A 25-year-old man was referred to our hospital because of an abnormal shadow in the mediastinum, detected by gallium scintigraphy, and bone fractures. Three weeks before admission, he experienced severe neck pain while practicing golf at a driving range. The next morning, he was brought to a neurosurgeon by ambulance because the pain had become more severe and he was beginning to lose consciousness. A cervical radiograph showed a C4 compression fracture, and 99mTc bone scintigraphy depicted abnormal shadows in the left frontal bone, C2, C4, Th10, and right 8 rib. Gallium scintigraphy suggested a tumor in the mediastinum (Fig 1⇓). Physical findings at admission, including blood pressure of 110/62 mm Hg, were within …

Effects of short- and long-acting calcium channel blockers on the relationship between blood pressure and physical activity

Calcium channel blockers are widely used as antihypertensive drugs. However, there is some controversy as to how they should be used. Our first aim was to clarify how the dihydropyridine calcium channel blocker, benidipine, affects the quantitative relationship between blood pressure (BP) and physical activity. The second aim was to determine whether there is a relationship between systolic blood pressure (SBP) and physical activity in patients with hypertension when treating with a short-acting (nifedipine) or long-acting (benidipine) calcium channel blocker. In Study 1, ambulatory BP and physical activity were measured simultaneously in 27 patients with hypertension before and after 6 months with benidipine. In Study 2, ambulatory BP and physical activity were measured simultaneously in 16 patients with hypertension before (placebo) and after 6 weeks of crossover treatment with nifedipine and benidipine. In Study 1, there was no difference in the SBP change caused by physical activity between the pre- and posttreatment periods. In Study 2, SBP was significantly related to physical activity in the placebo (16/16) and benidipine (16/16) groups but not in the nifedipine (12/16) group. The lowest BP during day-time and nighttime in the nifedipine group were significantly lower than those in the benidipine group. Plasma renin activity (ng/mL/h) was significantly higher in the nifedipine group (1.20+/-1.05) than in the placebo (0.57+/-0.59) and benidipine (0.75+/-0.78) groups. These findings indicate that nifedipine might interfere with the adaptation mechanism of BP changed by physical activity and that the activated renin-angiotensin system might cause cardiac events.

Rationale and design of the Japanese Heart Failure Outpatients Disease Management and Cardiac Evaluation (J-HOMECARE)

BACKGROUND Although many studies have demonstrated the efficacy of disease management programs on mortality, morbidity, quality of life (QOL), and medical cost in patients with heart failure (HF), no study has focused on psychological status as an outcome of disease management. In addition, very little information is available on the effectiveness of disease management programs in other areas than the USA and Europe. METHODS The Japanese Heart Failure Outpatients Disease Management and Cardiac Evaluation (J-HOMECARE) is a randomized controlled trial in which 156 patients hospitalized with HF will be randomized into usual care or a home-based disease management arm receiving comprehensive advice and counseling by visiting nurses during the initial 2 months and telephone follow-up for the following 4 months after discharge. This study evaluates depression and anxiety (Hospital Anxiety and Depression Scale), mortality, readmission due to HF, and QOL (Short Form-8). Data are collected during index hospitalization and then 2, 6, and 12 months after discharge. This study started in December 2007, and the final results are expected in 2011. CONCLUSION The J-HOMECARE will provide important information on the efficacy of disease management for psychological status as well as the effective components of disease management for patients with HF. (ClinicalTrials.gov number, NCT01284400).

Excretions of urinary albumin and various proteins increase in hypertension

Aims. Hypertension causes proteinuria and is an important factor in the progress of renal dysfunction. Increases in various proteins in urine are caused by malfunction of the glomerulus and the renal tubules. In the present study, the effects of hypertension on urinary excretion levels of various proteins were investigated to show the tubular cell malfunction in hypertensive patients. Methods and subjects. The subjects included 55 non‐diabetic hypertensive patients without previous treatment and 42 normotensive individuals without microalbuminuria. Total urinary protein/creatinine ratio was measured, and urinary proteins were analyzed by sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS–PAGE). Findings. Total urinary protein/creatinine ratio was higher in hypertensive patients than in normotensive individuals (122.0±11.0 vs. 60.6±3.1 mg/gCr; p<0.001). SDS–PAGE resolved 15 protein fractions from the urine of both groups. Thirteen fractions were more intensely stained in samples from the hypertensive than from the normotensive. Two fractions did not differ between the groups. Hypertension increased the urinary excretion of various proteins including proteins of less than 40 kDa, called tubular proteins, in addition to albumin. Conclusions. Hypertension differently influenced the excretion of each urinary protein fraction. Tubular malfunction should be considered in hypertensive patients in addition to glomerular malfunction.

Effects of the Aldosterone Antagonist Spironolactone on Ventricular Arrhythmias and Serum Electrolyte Levels in Congestive Heart Failure

SummaryThe effects of spironolactone 75 mg/day on heart failure and arrhythmia were evaluated in patients with chronic heart failure who had been maintained on a loop diuretic (furosemide) for 4 weeks or more. The effects on heart failure, indicated by improvement in subjective symptoms and clinical signs, were observed. While the frequencies of premature ventricular contraction measured by the two Holier monitorings at the pretreatment period did not differ significantly from each other, each of two Holier monitorings performed after treatment was initiated showed a tendency towards lower frequency compared with the two pretreatment measurements. Serum potassium levels were increased after treatment, but remained within the normal range throughout the treatment period. In the present study, we found that the aldosterone antagonist spironolactone improved the condition of patients with chronic heart failure [i.e. subjective symptoms and clinical signs improved, cardiothoracic ratio and echocardiographic parameters (left ventricular end-diastolic and -systolic dimensions and percentage of fractional shortening) significantly improved (p < 0.05), and New York Heart Association class also improved] treated with a loop diuretic, without inducing an imbalance in serum electrolyte levels. Furthermore, changes after spironolactone treatment in plasma renin activity, plasma aldosterone, plasma angiotensin II and human atrial natriuretic peptide were compared between the total evaluable patients and evaluable subpatients for occurrence of premature ventricular contractions. In the total evaluable patients, levels of the above first three parameters were increased, while human atrial natriuretic peptide decreased significantly. Similar results were obtained in those evaluable for occurrence of premature ventricular contractions. It was concluded that the abovementioned action of spironolactone possibly influenced ventricular arrhythmia associated with heart failure, contributing to an ameliorating tendency in arrhythmia.

Carvedilol improves uptake-1 in patients with systolic congestive heart failure.

Background The sympathetic nervous system (SNS) of the whole body, including cardiac sympathetic nerves, is activated in patients with severe congestive systolic heart failure (CHF). Carvedilol can improve clinical status in such patients. This study aimed to determine how carvedilol acts on the SNS to improve CHF. Methods and Results Ten subjects (New York Heart Association criteria III) were treated using carvedilol at 2.5 mg/d for 1 week. Before and after treatment, subjects walked on a treadmill for 6 minutes, and plasma concentrations of carvedilol, norepinephrine, and 3,4-dihydroxyphenyl glycol were measured. After treatment, norepinephrine was decreased at rest (3.2 ± 0.3 pmole/mL to 2.1 ± 0.4 pmole/mL, P < 0.05), while standing (5.4 ± 1.2 to 3.3 ± 0.7 pmole/mL, P < 0.01) and during exercise (6.5 ± 1.3 pmole/mL to 5.1 ± 1.1 pmole/mL, P < 0.05). Regression lines for percentage changes in norepinephrine and 3,4-dihydroxyphenyl glycol were compared before and after treatment, showing steeper slopes after treatment (P < 0.05). Plasma carvedilol concentrations (1.8 ± 0.3 ng/mL) did not reach &bgr;-adrenoceptor–blocking levels of effect. Conclusions Carvedilol is considered to improve function of uptake-1 for the whole-body SNS, including the cardiac SNS, and does not seem to block adrenoceptors at such low doses in CHF patients. However, both effects seem to work at high doses in clinical settings.

Effects of doxazosin on orthostatic blood pressure in hypertensive patients with and without diabetes mellitus

Abstract Alpha 1 -blockers are thought to cause the orthostatic hypotension frequently observed in patients with hypertension. We studied the degree to which doxazosin reduced the blood pressure in hypertensive patients with diabetes mellitus (HDM [+]) and without diabetes mellitus (HDM [−]), when they were placed in a standing position. Seven HDM (−) patients and eight HDM(+) patients were included in this study. After diagnosis, a blood pressure—monitoring system for ambulatory patients was attached to each patient. Blood pressure was measured, first with patients in a supine position and again 2 and 4 minutes after standing. The same procedure was performed on each patient after 12 weeks of doxazosin treatment. The mean dose of doxazosin was 2.1 ± 1.5 mg for HDM(−) patients and 2.4 ± 2.5 mg for HDM(+) patients. Treatment with doxazosin resulted in a significant sitting blood pressure reduction as measured by the ordinary cuff method. Doxazosin caused no statistically significant orthostatic systolic blood pressure reduction at 2 minutes after standing for HDM(−) patients (15 ± 5 mm Hg [control] vs 16 ± 4 mm Hg [treatment]) and for HDM(+) patients (7 ± 15 mm Hg [control] vs 8 ± 14 [treatment]), respectively). We concluded doxazosin did not have a statistically significant effect on the orthostatic blood pressure reduction for both HDM(−) patients and HDM(+) patients with respect to the doses used.