Tsutomu Koike

Increased levels of small dense low-density lipoprotein cholesterol associated with hemorheological abnormalities in untreated, early-stage essential hypertensives

Among subfractions of low-density lipoprotein cholesterol (LDL-C), small dense LDL-C (SdLDL-C) has been highlighted as the most atherogenic lipoprotein cholesterol. The present study aimed to compare the relationship of SdLDL-C with blood viscosity, a surrogate marker for cardiovascular disease, with that of other lipid fractions with blood viscosity in essential hypertensives (EHTs). In 128 untreated, early-stage EHTs, blood viscosity was measured with a falling-ball microviscometer, and serum levels of lipid fractions were determined. Blood and plasma viscosity was significantly higher in 49 patients with dyslipidemia (fasting serum level of LDL-C >140 mg dl−1, triglyceride >150 mg dl−1 or high-density lipoprotein cholesterol (HDL-C)<40 mg dl−1) compared with 79 patients without dyslipidemia, although hematocrit and RBC rigidity index ‘k’ did not differ between the two groups. Together, SdLDL-C, LDL-C, triglyceride and large LDL-C were positively correlated with blood viscosity, but for HDL-C, the correlation was negative. After adjusting for non-lipid variables that correlated with blood viscosity (that is, the age, body mass index, resting diastolic blood pressure, sex, hematocrit, plasma viscosity and homeostasis model of assessment of insulin resistance), SdLDL-C was most strongly associated with blood viscosity among the lipid fractions. These data suggest that SdLDL-C could strongly increase blood viscosity in EHTs.

Blood rheology and platelet function in untreated early-stage essential hypertensives complicated with metabolic syndrome.

We examined whether hemorheology and platelet function are affected in essential hypertensives (EHTs) of the World Health Organization stage I when complicated with metabolic syndrome (Mets). In 156 untreated EHTs, blood viscosity and platelet surface markers were determined. Blood viscosity was significantly elevated in 54 subjects with Mets compared with 102 subjects without Mets. Hematocrit and plasma viscosity increased in the group with Mets, although red blood cell rigidity index “k” did not differ between groups. As a whole group, blood viscosity correlated positively with hematocrit and plasma viscosity. Additionally, plasma viscosity correlated positively with plasma leptin, triglyceride, homeostasis model assessment index, C-reactive protein, and plasma fibrinogen, but negatively with high-density lipoprotein cholesterol. In contrast, no differences were seen in platelet surface markers between groups. In conclusion, EHTs of the early stage complicated with Mets are characterized by increased blood viscosity due to hemoconcentration and increased plasma viscosity.

Effects of uninephrectomy on renal structural properties in spontaneously hypertensive rats

1. To investigate effects of a reduction in nephron numbers on renal structural properties in hypertension, either unilateral nephrectomy (UNX) or sham operation (SO) was performed at 5 weeks of age in spontaneously hypertensive rats (SHR) and Wistar‐Kyoto (WKY) rats (n = 9 for each operation for each strain).

Increased blood viscosity is associated with reduced renal function and elevated urinary albumin excretion in essential hypertensives without chronic kidney disease

Increased blood viscosity reduces blood flow and elevates vascular resistance in the cardiovascular system. The aim of this study was to elucidate how blood viscosity could affect renal function and eventually contribute to renal damage in essential hypertensives (EHT). In 164 untreated EHT without apparent renal damage (96 men, 56±12 years old, creatinine clearance 123±33 ml min−1 per 1.73 m2 and urinary albumin excretion 19±19 mg per day), blood and plasma viscosity was determined using a falling ball microviscometer. Blood viscosity correlated negatively with creatinine clearance (r=−0.185, P=0.018) and positively with urinary albumin excretion (r=0.253, P=0.001). This indicated that increased blood viscosity is associated with reduced renal function and worsening of albuminuria in EHT. Stepwise multiple regression analysis identified blood viscosity as an independent determinant of creatinine clearance (R2=0.058) and urinary albumin excretion (R2=0.216). In conclusion, increased blood viscosity may be a risk for development of renal disease in EHT.

Imbalance of Renal Production Between 5-Hydroxytryptamine and Dopamine in Patients With Essential Hypertension Complicated by Microalbuminuria

BACKGROUND In the kidney, 5-hydroxytryptamine (5-HT) and dopamine (DA) are formed by the same enzyme, l-aromatic amino acid decarboxylase, but act on renal function and glomerular structure in an opposite direction. The present study was designed to explore whether rates of renal production of 5-HT relative to that of DA are altered in patients with essential hypertension and microalbuminuria. METHODS We measured urinary levels of 5-HT and DA, reflecting renal production of 5-HT and DA as well as 24-hour ambulatory blood pressure and urinary albumin excretion in 82 consecutive untreated, essential hypertensives without overt proteinuria. RESULTS Urinary 5-HT excretion and the ratio of urinary 5-HT to DA were significantly higher in 22 patients with microalbuminuria than in the remaining patients with normoalbuminuria, although urinary DA levels did not differ between the groups. The 24-hour systolic and diastolic blood pressures were also higher in the microalbuminuric group than in the normoalbuminuric group. Multiple regression analysis revealed that urinary 5-HT excretion and 24-hour systolic blood pressure were independently associated with urinary albumin excretion. Furthermore, urinary 5-HT excretion was positively correlated with creatinine clearance as well as blood pressure but tended to be negatively correlated with fractional excretion of sodium. CONCLUSIONS Renal production of 5-HT is enhanced compared with that of DA in essential hypertensives with microalbuminuria. This imbalance may contribute to the genesis of hypertensive glomerular damage.

Pubertal administration of antiserum against nerve growth factor regresses renal vascular remodeling in spontaneously hypertensive rats

To investigate the role of nerve growth factor (NGF) in the development of hypertensive renal vascular remodeling, antiserum against NGF (anti‐NGF) or vehicle was injected at 3 weeks of age in spontaneously hypertensive rats (SHR) and Wistar–Kyoto (WKY) rats (n = 9 for each treatment in each strain). Flow‐pressure (F‐P) and pressure‐glomerular filtration rate (P‐GFR) relationships at vasodilated perfused kidneys were determined at 10 weeks of age. In the vehicle rats, blood pressure, renal noradrenaline content, the gradient of F‐P (minimal vascular resistance at pre‐ and post‐glomerular vasculature) and the X‐intercept of P‐GFR (preglomerular : postglomerular vascular resistance ratio) were greater in SHR than in WKY rats, although the gradient of P‐GFR (glomerular filtration capacity) did not differ significantly between the strains. Blood pressure and renal noradrenaline content were lower in SHR receiving anti‐NGF than in SHR receiving vehicle, although such difference was not observed in WKY rats. The gradient of F‐P was less but the gradient of P‐GFR was greater in SHR receiving anti‐NGF compared with SHR receiving vehicle, although the similar differences did not occur in WKY rats. Blood pressure and renal noradrenaline content remained greater in SHR treated with anti‐NGF compared with WKY rats treated with vehicle; however, the gradient of F‐P did not differ significantly between them. Contrary, anti‐NGF did not affect the X‐intercept of P‐GFR in either strain. In conclusion, NGF could contribute to the genesis of renal vascular remodeling, at least in part, through modification of renal sympathetic activity and blood pressure in SHR.

Renal vascular structural properties and their alterations by removal of uraemic toxins in a rat model of chronic kidney disease

Renal vascular structural properties and their alterations by removal of uraemic toxins with AST‐120, an oral adsorbent, were examined in subtotal nephrectomized rats. Eight‐ or 9‐week‐old Sprague‐Dawley rats received 3/4 nephrectomy (n = 18) and thereafter were fed 24.5% protein diet with (AST; n = 9) or without (AST–; n = 9) AST‐120 (0.4 g/100 g bodyweight). Sham‐operated rats (Sham; n = 9) received the diet without AST‐120. At 21–22 weeks of age, flow–pressure (F‐P) and pressure–glomerular filtration rate (P‐GFR) relationships were determined for maximally vasodilated, perfused kidneys. The gradient of F‐P (minimal renal vascular resistance reflecting the overall luminal dimensions of pre‐ and post‐glomerular vasculature) was lower in AST– than Sham rats. In contrast, the x‐intercept (preglomerular : post‐glomerular vascular resistance ratio) and gradient (glomerular filtration capacity) of P‐GFR did not differ between the two groups. The vascular wall and lumen at the interlobular arteries were greater in AST– than Sham rats. Although the vascular wall and lumen at the interlobular arteries were less in AST than in AST– rats, the gradient of F‐P and the x‐intercept of P‐GFR did not differ between the two groups. In contrast, the glomerular filtration capacity was greater in AST than AST– rats. In conclusion, the lumen of both pre‐ and post‐glomerular resistance vessels increased and glomerular filtration capacity failed to increase in subtotal nephrectomized rats. Uraemic toxins could play an important role in the development of structural alterations in glomeruli rather than renal resistance vessels in chronic kidney disease.

1093 THE RELATION OF DIETARY SALT TO INSULIN SENSITIVITY IN PRIMARY ALDOSTERONISM

Objectives: Whether or not the influence of aldosterone on insulin sensitivity is modified by dietary salt is unknown. In this study, the relationship between dietary salt and insulin sensitivity was investigated in primary aldosteronism (PA). Design and Methods: After the measurements of plasma renin activity (PRA), plasma aldosterone concentration (PAC) and urinary sodium excretion (UNaV) during rest, blood sugar (BS) and insulin (IRI) were evaluated before and after glucose loading of 75 g in 20 PA patients. According to dietary salt estimated by UNaV, subjects were divided into patients with 10.3±2.2 (High salt) and 6.2±2.1 g/day (Low salt) (n=10 of each group). Thereafter, in ten patients, the same study was repeated following low-salt diet instruction (6 g/day) for three months. Results: There was no difference in age, blood pressure, PAC and PAC/PRA between the two groups. Before glucose loading, IRI and HOMA-IR index (i.e., index for insulin sensitivity) was higher in High (12.8±6.8 &mgr;U/ml, 3.13±1.86) than in Low group (5.6±2.7, 1.31±0.72) despite no differences in BS among the two groups (96.8±13.1vs 94.0±7.2 mg/dl). After glucose loading, the increase of IRI estimated by AUC of IRI was greater in High (456.5±267.8 U/ml) than in Low group (254.9±177.1), although BS elevated to the similar extent in both groups. Following low-salt diet instruction, both IRI and HOMA-IR decreased (9.87±7.63 to 7.54±5.03 &mgr;U/ml, 2.54±2.08 to 1.88±1.39) without changes in BS. Thus, in PA, salt restriction enhanced insulin sensitivity and reduced blood level of insulin. Conclusions: These results suggest that insulin sensitivity could be salt-sensitive in PA.

294 RELATION OF SMALL DENSE LOW-DENSITY LIPOPROTEIN CHOLESTEROL TO CAROTID ATHEROSCLEROSIS IN ESSENTIAL HYPERTENSIVES WITH NORMAL RENAL FUNCTION

Objectives: Recently, small dense low-density lipoprotein cholesterol (sdLDL-C) has been highlighted as the most atherogenic lipoprotein in cardiovascular disease. In this study, the relations of sdLDL-C and other lipid parameters to surrogate markers of atherosclerosis were investigated in essential hypertensives (EHT) with normal renal function. Design and Methods: In 137 untreated EHT with GFR≥60 mL/min, plasma levels of sdLDL-C (using assay kit supplied by Denka Seiken Co., Ltd., Niigata, Japan), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), adiponectin and norepinephrine, and blood sugar were measured. Intima-media thickness (IMT) and stiffness index &bgr; (&bgr;) of carotid artery (i.e., index for wall thickness and arterial stiffness of large artery, respectively) was also evaluated by B-mode ultrasonography and ultrasonic phase-locked echo-tracking system, respectively. Results: Although LDL, TG and HDL-C did not associate with IMT, sdLDL-C and ratio of sdLDL-C to LDL significantly correlated with IMT (r = 0.226, 0.181, p < 0.05 of each). Multiple regression analysis demonstrated that sdLDL-C was an independent determinant for IMT together with age, blood sugar and plasma levels of adiponectin and norepinephrine (r2 = 0.323, P < 0.05). In contrast, sdLDL-C and the other lipoproteins did not relate to &bgr;. In addition, either blood pressure or pulse rate did not associate with IMT and &bgr;. Conclusions: These results indicate that in EHT with normal renal function, sdLDL was the best marker for large arterial wall thickness among lipid parameters, and suggest that quantitative measurement of sdLDL could give the useful information for atherosclerosis compared with systemic hemodynamics.

226 PROLONGATION OF QT DISPERSION INDUCED BY MENTAL ARITHMETIC STRESS IN ESSENTIAL HYPERTENSIVES COMPLICATED WITH METABOLIC SYNDROME

Objectives: Psychological stress can increase QT dispersion (QTd), thereby increasing risk for arrhythmia and sudden death especially in coronary heart disease. The present study was designed to examine stress-induced alterations of QTd in essential hypertensives (EHT) complicated with metabolic syndrome (Mets), characterized as high risk for cardiovascular disease. Design and methods: Systemic hemodynamics, plasma noradrenaline and QTd (i.e., difference between maximum and minimum QT interval on electrocardiogram) were evaluated during rest and after a 10-min arithmetic stress in 92 consecutive untreated EHT. The data were compared between 42 EHT with Mets and 50 EHT without Mets (non-Mets). Results: Blood pressure, plasma norepinephrine and QTd did not differ between Mets and non-Mets during rest, although pulse rate was higher in Mets compared with non-Mets. Following arithmetic stress, plasma norepinephrine increased in both Mets and non-Mets (228±12 to 299±13 and 217±12 to 261±12 pg/mL), but its increase was greater in Mets than in non-Mets (p<0.05 for group×stress interaction). Concomitantly, QTd increased in Mets (59±5 to 75±5 msec), but it remained unchanged in non-Mets (59±4 to 62±4 msec) (p<0.05 for group×stress interaction). Thus, stress-induced change in QTd was larger in Mets compared with non-Mets. In contrast, blood pressure and pulse rate increased to the similar extent after arithmetic stress in both groups. Conclusion: Mental arithmetic stress induced prolongation of QT dispersion along with exaggerated activation of sympathetic neural activity in EHT with Mets.