Toshihiko Ishimitsu

Plasma levels of adrenomedullin, a newly identified hypotensive peptide, in patients with hypertension and renal failure.

Adrenomedullin is a potent hypotensive peptide newly discovered in pheochromocytoma tissue by monitoring its elevating activity on platelet cAMP. We measured plasma concentration of adrenomedullin in patients with essential hypertension and chronic renal failure. As compared with normal subjects, plasma adrenomedullin was increased by 26% (P < 0.05) in hypertensives without organ damage and by 45% (P < 0.005) in those with organ damage. The increase in plasma adrenomedullin was more prominent in renal failure than in hypertension. Renal failure patients with plasma creatinine of 1.5-3, 3-6, and > 6 mg/dl had higher plasma adrenomedullin levels than healthy subjects by 78% (P < 0.05), 131% (P < 0.001), and 214% (P < 0.001), respectively. Moreover, adrenomedullin showed intimate correlations with norepinephrine, atrial natriuretic peptide, and cAMP in plasma (r = 0.625, P < 0.001; r = 0.656, P < 0.001; and r = 0.462, P < 0.001; respectively). Thus, plasma adrenomedullin is supposed to increase in association with changes in sympathetic nervous activity and body fluid volume in hypertension and renal failure. Considering its potent vasodilator effect, adrenomedullin may be involved in the defense mechanism preserving the integrity of the cardiovascular system in these disorders.

Relationship Between Left Ventricular Geometry and Natriuretic Peptide Levels in Essential Hypertension

Previous studies have shown that plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are increased in essential hypertension. However, whether left ventricular geometry affects plasma ANP and BNP levels remains unknown. To investigate the effect of left ventricular geometry on plasma ANP and BNP levels in essential hypertension, we measured plasma ANP and BNP levels in 90 patients with essential hypertension. All patients were hospitalized, and fasting blood samples were obtained in the early morning after 30 minutes of bed rest. Plasma ANP and BNP levels were measured by immunoradiometric assay. Hypertensive patients were classified into four groups according to echocardiographic findings that showed normal geometry, concentric remodeling, eccentric hypertrophy, or concentric hypertrophy. Mean plasma ANP and BNP levels in all essential hypertensive patients were higher than those in age-matched normotensive control subjects. Plasma ANP levels in hypertensive patients with concentric remodeling, eccentric hypertrophy, and concentric hypertrophy were higher than in normotensive control subjects, although there were no differences between normotensive subjects and hypertensive patients with normal geometry. Plasma BNP levels tended to be higher in hypertensive patients with normal geometry, concentric remodeling, and eccentric hypertrophy than in normotensive control subjects; however, the differences were not significant. Plasma BNP levels and BNP/ANP ratio were specifically higher in concentric hypertrophy. There were significant correlations between ANP and left ventricular mass index, relative wall thickness, interventricular septal thickness, posterior wall thickness, and mean arterial pressure. Plasma BNP levels significantly correlated with relative wall thickness, interventricular septal thickness, posterior wall thickness, and left ventricular mass index but not with mean arterial pressure. In addition, plasma BNP levels were well correlated with ANP levels, and the slope for the linear regression model was steeper in concentric hypertrophy than in the other four groups. These results show that plasma ANP and BNP levels are increased in essential hypertensive patients with left ventricular hypertrophy. Furthermore, BNP secretion is augmented to a greater extent in concentric hypertrophy. Thus, measurement of plasma ANP and BNP levels may be useful for the detection of concentric left ventricular hypertrophy in patients with essential hypertension.

Relations of plasma high-sensitivity C-reactive protein to traditional cardiovascular risk factors

Variations of circulating C-reactive protein (CRP) levels are supposed to reflect chronic inflammatory process of the cardiovascular system. In particular, it has been reported that high-sensitivity CRP (hsCRP) is a promising marker of coronary heart disease. In the present study, we assessed the relationship between hsCRP and classic cardiovascular risk factors, such as age, blood pressure, smoking habit and serum lipids. Plasma hsCRP was measured by ELISA in 908 subjects, aged 30-79 years, who entered our health-check program. Plasma hsCRP level was 0.54+/-0.02 mg/l in 566 subjects without any disease currently treated. The level was significantly higher in patients treated for hypertension (0.74+/-0.06 mg/l, P=0.002), diabetes mellitus (0.77+/-0.09 mg/l, P=0.016) or coronary artery disease (0.99+/-0.16 mg/l, P=0.008) than in subjects without diseases. In a simple regression analyses of the 566 subjects without diseases, plasma hsCRP positively correlated with male gender, smoking, body mass index, systolic blood pressure, white blood cell count, blood hemoglobin, fasting blood glucose, serum gamma-GTP, uric acid and triglycerides, and inversely correlated with serum albumin and HDL-cholesterol. In multiple regression analysis, white blood cell count (r=0.276, P<0.001), body mass index (r=0.246, P<0.001), age (r=0.122, P=0.001) and smoking (r=0.112, P=0.009) showed independent correlations with plasma hsCRP. It is suggested that variation of circulating hsCRP, even within normal range, is involved in the interrelation of cardiovascular risk factors, such as age, smoking, obesity, high blood pressure and dyslipidemia, which are supposed to promote atherosclerosis and ultimately provoke cardiovascular diseases, such as coronary artery disease.

Effects of Smoking Cessation on Blood Pressure and Heart Rate Variability in Habitual Smokers

We investigated the effects of 1-week of smoking cessation on ambulatory blood pressure, heart rate, and heart rate variability in 39 normotensive male habitual smokers (mean+/-SEM, 32.5+/-1.0 years). The ambulatory blood pressure, heart rate, and ECG R-R intervals were measured during a 24-hour period with a portable recorder (TM-2425) on the last day of 1-week smoking and nonsmoking periods. The order of the 2 periods was randomized. In the smoking period, the subjects were instructed to smoke cigarettes according to their usual smoking patterns. A power-spectral analysis of R-R intervals was performed to obtain the low-frequency (LF) and high-frequency (HF) components. The percentage of differences between adjacent normal R-R intervals >50 milliseconds (pNN50) was used as a time-domain measure of heart rate variability. The 24-hour ambulatory blood pressure was significantly lower in the nonsmoking period than in the smoking period, by 3.5+/-1.1 mm Hg systole [P<0. 01] and by 1.9+/-0.7 mm Hg diastole [P<0.05], whereas the nighttime blood pressure did not differ significantly between the 2 periods. The 24-hour heart rate was significantly lower in the nonsmoking period than in the smoking period, by 7.3+/-1.0 beats/min (P<0.0001). The pNN50 and the 24-hour HF component were significantly higher in the nonsmoking period than in the smoking period (P<0.0001 for each). The plasma norepinephrine and epinephrine concentrations were significantly lower in the nonsmoking period than in the smoking period (P<0.05 for each). These results demonstrate the substantial and immediate benefits of smoking cessation on these cardiovascular indices.

Clinical studies on the sites of production and clearance of circulating adrenomedullin in human subjects.

Adrenomedullin is a novel hypotensive peptide, newly discovered in pheochromocytoma. Because immunoreactive adrenomedullin is present in human plasma, adrenomedullin may play a role in regulating blood pressure. A recent report showed that human adrenomedullin mRNA is expressed not only in pheochromocytoma but also in the normal adrenal medulla, kidney, lung, and ventricle. However, whether or not these organs actually release adrenomedullin into the circulation remains unknown. To investigate the sites of production and degradation of adrenomedullin in human subjects, we obtained blood samples from various sites and measured immunoreactive adrenomedullin concentrations. In study 1, blood samples were obtained from the infrarenal inferior vena cava, suprarenal inferior vena cava, superior vena cava, right atrium, right ventricle, pulmonary artery, pulmonary capillary, left ventricle, and aorta during cardiac catheterization in 15 patients with ischemic heart disease (67 +/- 10 years). In study 2, blood samples were taken from the infrarenal inferior vena cava, suprarenal inferior vena cava, right and left renal veins, and left adrenal vein in 5 hypertensive patients (42 +/- 14 years) suspected of having renovascular hypertension. In study 3, peripheral venous blood samples were obtained in 2 patients (males, 45 and 36 years old) with pheochromocytoma at rest and during hypertensive attacks. Plasma adrenomedullin concentrations were measured by a newly developed radioimmunoassay. In study 1, there were no significant differences in plasma adrenomedullin concentrations in various sites of the right-side circulation. There was no step-up of plasma adrenomedullin levels in the coronary sinus. However, the plasma concentration of adrenomedullin in aorta was slightly but significantly lower than in pulmonary artery.(ABSTRACT TRUNCATED AT 250 WORDS)

Urinary liver-type fatty acid binding protein as a useful biomarker in chronic kidney disease.

Background: We reported that urinary L-FABP reflected the progression of chronic kidney disease (CKD). This study is aimed to evaluate the clinical significance of urinary liver type fatty acid binding protein (L-FABP) as a biomarker for monitoring CKD. Methods: Urinary L-FABP was measured using human L-FABP ELISA kit (CMIC.Co., Ltd., Tokyo, Japan). The relations between urinary L-FABP and clinical parameters were evaluated in non-diabetic CKD (n = 48) for a year. In order to evaluate the influence of serum L-FABP derived from liver upon urinary L-FABP, both serum and urinary L-FABP were simultaneously measured in patients with CKD (n = 73). Results: For monitoring CKD, the cut-off value in urinary L-FABP was determined as 17.4 μg/g.cr. by using a receiver operating characteristics (ROC) curve. Renal function deteriorated significantly more in patients with ‘high’ urinary L-FABP (n = 36) than in those with ‘low’ L-FABP (n = 12). The decrease in creatinine clearance was accompanied by an increase in urinary L-FABP, but not in urinary protein. Serum L-FABP in patients with CKD was not correlated with urinary L-FABP. Conclusion: Urinary excretion of L-FABP increases with the deterioration of renal function. Serum L-FABP did not influence on urinary L-FABP. Urinary L-FABP may be a useful clinical biomarker for monitoring CKD.

Seasonal variations in office, home and 24 h ambulatory blood pressure in patients with essential hypertension

Objective To study the influence of seasons on blood pressure in ordinary circumstances. Design and methods We examined seasonal variations of home and 24 h ambulatory and office blood pressures in outpatients with essential hypertension. Office, home and ambulatory blood pressures of 50 outpatients with essential hypertension were recorded in 1993. The subjects were 26 women and 24 men, aged 59.3 ± 1.1 years (mean ± SEM). Office blood pressure was measured monthly by physicians. Home blood pressure was measured every day by the patients in the morning and evening. Ambulatory blood pressure was recorded every 30min in summer and in winter. The order of ambulatory blood pressure monitoring was randomized. The daytime and night-time blood pressures were calculated according to the true waking and sleeping times of the individual patients. Results Both office and home blood pressures showed significant seasonal variations. The winter-summer differences in office and home blood pressures were 4.7 ± 1.3/3.3 + 0.9 and 5.9 ± 1.1/2.7 + 0.6 mmHg, respectively. They were not influenced by the presence of antihypertensive agents. The winter-summer difference was also significant for daytime ambulatory blood pressure (3.5 ± 1.4/2.5 + 0.8 mmHg), but not for night-time ambulatory blood pressure (-2.9 + 1.7/-1.2 ± 1.0 mmHg) or average 24 h blood pressure (1.5 + 1.3/1.2 + 0.7 mmHg). There were no significant differences in the waking and sleeping times between the two seasons. Conclusions Office, home and daytime ambulatory blood pressure levels were higher in winter than they were in summer in patients with essential hypertension. However, the seasonal variations in average 24 h blood pressure may be small because of the lack of changes in night-time blood pressure.

Clinical Significance of Urinary Liver-Type Fatty Acid Binding Protein in Diabetic Nephropathy of Type 2 Diabetic Patients

OBJECTIVE Urinary liver-type fatty acid–binding protein (L-FABP) is a promising indicator of tubular but not glomerular damage. The aim of this study was to evaluate the clinical usefulness of urinary L-FABP as a prognostic biomarker in impaired diabetic nephropathy in type 2 diabetes. RESEARCH DESIGN AND METHODS This investigation involved a cross-sectional and longitudinal analysis of the relationship between urinary L-FABP levels and progressive nephropathy. Urinary L-FABP was measured with enzyme-linked immunosorbent assay. In the cross-sectional analysis, the association of urinary L-FABP, with the severity of diabetic nephropathy, was investigated in 140 patients with type 2 diabetes and in 412 healthy control subjects. Of the patients in the former study, 104 have been followed for 4 years. The progression of diabetic nephropathy was defined as progressive albuminuria, end-stage renal disease, or induction of hemodialysis. RESULTS Urinary L-FABP levels were progressively increased in subjects with normo-, micro-, or macroalbuminuria and further increased in patients with end-stage renal disease. In the longitudinal analysis, high urinary L-FABP levels were associated with the increase in albuminuria, progression to end-stage renal disease, or induction of hemodialysis. This was particularly demonstrated in the subgroup of patients without renal dysfunction (n = 59), where high urinary L-FABP levels were associated with the progression of diabetic nephropathy. CONCLUSIONS Urinary L-FABP accurately reflected the severity of diabetic nephropathy in type 2 diabetes, and its level was high in the patients with normoalbuminuria. Moreover, higher urinary L-FABP was a risk factor for progression of diabetic nephropathy.

Regulatory effects of eicosanoids on thymidine uptake by vascular smooth muscle cells of rats

To define the roles of eicosanoids in vascular smooth muscle cells (VSMC) growth, we examined the effects of exogenous eicosanoids on (3H)thymidine uptake by cultured VSMC of Wistar rats. Stable prostacyclin (PGI2) analog, OP-41483, significantly decreased the incorporation of (3H)thymidine into deoxyribonucleic acid (DNA) of VSMC in a dose dependent manner from 10(-8) to 10(-4) M. Prostaglandin E2 (PGE2) and PGD2 ranging from 10(-8) to 10(-4) M also dose-dependently decreased the (3H)thymidine uptake by VSMC. In contrast, stable thromboxane A2 analog, STA2, significantly increased the incorporation of (3H)thymidine into DNA in a dose dependent manner from 10(-8) to 10(-4) M. The dose response curve of STA2 was shifted toward a lowered response when 10(-5) M PGI2 analog, PGE2 or PGD2 was added in the culture medium. Thus, it is indicated that vasodepressor eicosanoids decrease the proliferation of VSMC, whereas vasoconstrictor TXA2 enhances the VSMC growth. Vascular smooth muscle cells possibly autoregulate the cell proliferation through the eicosanoids generation.

Effect of the Hanhin-Awaji earthquake on home blood pressure in patients with essential hypertension☆

At 5:46 am on January 17, 1995, the Hanshin-Awaji district of Japan was struck by a major earthquake. We investigated changes in home blood pressure (BP) of 36 hypertensive patients before and after the earthquake. In the 16 patients who lived within 50 km from the epicenter, the home BP on the day of the earthquake was significantly higher than that just before the earthquake (+11+6 mm Hg; P < .01 for systolic BP and P < .05 for diastolic BP). It remained higher throughout the first week after the earthquake, then gradually returned to the baseline level within 4 weeks. The home BP did not change significantly in the 20 patients who lived farther than 50 km from the epicenter. The earthquake-induced stress increased the BP in these hypertensive patients; however, its pressor effect was not persistent.