Nobuyuki Ura

Blockade of the Renin-Angiotensin System Increases Adiponectin Concentrations in Patients With Essential Hypertension

Abstract—Adiponectin, an adipocyte-derived protein, has been suggested to play an important role in insulin sensitivity. We examined the association between insulin sensitivity (M value) evaluated by the euglycemic-hyperinsulinemic glucose clamp and adiponectin concentrations in 30 essential hypertensives (EHT) and 20 normotensives (NT) and investigated the effect of blockade of the renin-angiotensin system (RAS) on adiponectin concentrations. EHT were divided into 12 insulin-resistant EHT (EHT-R) and 18 non–insulin-resistant EHT (EHT-N) using mean−1 SD of the M value in NT. There were no intergroup differences in age, gender, and body mass index (BMI). EHT-R had significantly higher levels of insulin and triglyceride and lower levels of adiponectin than did NT and EHT-N. EHT-R had higher levels of free fatty acid and lower levels of high-density lipoprotein (HDL) cholesterol than did EHT-N. Adiponectin concentrations were positively correlated with M value and HDL cholesterol and negatively correlated with BMI, insulin, free fatty acid, and triglyceride but not with blood pressure. M value, BMI, and HDL cholesterol were independent determinants of adiponectin concentrations in multiple and stepwise regression analyses. Sixteen EHT were treated with an angiotensin-converting enzyme inhibitor (temocapril, 4 mg/d; n=9) or an angiotensin II receptor blocker (candesartan, 8 mg/d; n=7) for 2 weeks. Treatment with temocapril or candesartan significantly decreased blood pressure and increased M value and adiponectin concentrations but did not affect BMI and HDL cholesterol. These results suggest that hypoadiponectinemia is related to insulin resistance in essential hypertension and that RAS blockade increases adiponectin concentrations with improvement in insulin sensitivity.

Estimation of glomerular filtration rate by the MDRD study equation modified for Japanese patients with chronic kidney disease

BackgroundAccurate estimation of the glomerular filtration rate (GFR) is crucial for the detection of chronic kidney disease (CKD). In clinical practice, GFR is estimated from serum creatinine using the Modification of Diet in Renal Disease (MDRD) study equation or the Cockcroft-Gault (CG) equation instead of the time-consuming method of measured clearance for exogenous markers such as inulin. In the present study, the equations originally developed for a Caucasian population were tested in Japanese CKD patients, and modified with the Japanese coefficient determined by the data.MethodsThe abbreviated MDRD study and CG equations were tested in 248 Japanese CKD patients and compared with measured inulin clearance (Cin) and estimated GFR (eGFR). The Japanese coefficient was determined by minimizing the sum of squared errors between eGFR and Cin. Serum creatinine values of the enzyme method in the present study were calibrated to values of the noncompensated Jaffé method by adding 0.207 mg/dl, because the original MDRD study equation was determined by the data for serum creatinine values measured by the noncompensated Jaffé method. The abbreviated MDRD study equation modified with the Japanese coefficient was validated in another set of 269 CKD patients.ResultsThere was a significant discrepancy between measured Cin and eGFR by the 1.0 × MDRD or CG equations. The MDRD study equation modified with the Japanese coefficient (0.881 × MDRD) determined for Japanese CKD patients yielded lower mean difference and higher accuracy for GFR estimation. In particular, in Cin 30–59 ml/min per 1.73 m2, the mean difference was significantly smaller with the 0.881 × MDRD equation than that with the 1.0 × MDRD study equation (1.9 vs 7.9 ml/min per 1.73 m2; P <?0.01), and the accuracy was significantly higher, with 60% vs 39% of the points deviating within 15%, and 97% vs 87% of points within 50%, respectively (both P <?0.01). Validation with the different data set showed the correlation between eGFR and Cin was better with the 0.881 × MDRD equation than with the 1.0 × MDRD study equation. In Cin less than 60 ml/min per 1.73 m2, the accuracy was significantly higher, with 85% vs 69% of the points deviating within 50% (P <?0.01), respectively. The mean difference was also significantly smaller (P <?0.01). However, GFR values calculated by the 0.881 × MDRD equation were still underestimated in the range of Cin over 60 ml/min per 1.73 m2.ConclusionsAlthough the Japanese coefficient improves the accuracy of GFR estimation of the original MDRD study equation, a new equation is needed for more accurate estimation of GFR in Japanese patients with CKD stages 3 and 4.

Prevalence of chronic kidney disease (CKD) in the Japanese general population predicted by the MDRD equation modified by a Japanese coefficient

BackgroundThe number of patients with end-stage renal disease (ESRD) in Japan has continuously increased in the past three decades. In 2005, 36 063 patients whose average age was 66 years entered a new dialysis program. This large number of ESRD patients could be just the tip of the iceberg of an increasing number of patients with chronic kidney disease (CKD). However, to date, a nationwide epidemiological study has not been conducted yet to survey the CKD population.MethodsData for 527 594 (male, 211 034; female, 316 560) participants were obtained from the general adult population aged over 20 years who received annual health check programs in 2000–2004, from seven different prefectures in Japan: Hokkaido, Fukushima, Ibaraki, Tokyo, Osaka, Fukuoka, and Okinawa prefectures. The glomerular filtration rate (GFR) for each participant was estimated from the serum creatinine values, using the abbreviated Modification of Diet in Renal Disease (MDRD) study equation modified by the Japanese coefficient.ResultsThe prevalences of CKD stage 3 in the study population, stratified by age groups of 20–29, 30–39, 40–49, 50–59, 60–69, 70–79, and 80–89 years, were 1.4%, 3.6%, 10.8%, 15.9%, 31.8%, 44.0%, and 59.1%, respectively, predicting 19.1 million patients with stage 3 CKD in the Japanese general adult population of 103.2 million in 2004. CKD stage 4 + 5 was predicted in 200 000 patients in the Japanese general adult population. Comorbidity of hypertension, diabetes, and proteinuria increased as the estimated GFR (eGFR) decreased. The prevalence of concurrent CKD was significantly higher in hypertensive and diabetic populations than in the study population overall when CKD was defined as being present with an eGFR of less than 40 ml/min per 1.73 m2 instead of less than 60 ml/min per 1.73 m2.ConclusionsAbout 20% of the Japanese adult population (i.e., approximately 19 million people) are predicted to have stage 3 to 5 CKD, as defined by a GFR of less than 60 ml/min per 1.73 m2.

Blockade of the renin-angiotensin system decreases adipocyte size with improvement in insulin sensitivity.

Objective Based on results of in vitro studies, it has been hypothesized that blockade of the renin–angiotensin system (RAS) promotes the recruitment and differentiation of pre-adipocytes and that increased formation of small insulin-sensitive adipocytes counteracts ectopic deposition of lipids, thereby improving insulin sensitivity. We investigated the effect of RAS blockade on insulin sensitivity, adipocyte size, and intramuscular lipid content in fructose-fed rats (FFR) as a model of insulin-resistant hypertension. Design and methods Six-week-old male Sprague–Dawley rats were divided into two groups: those fed a standard chow (control) and those fed a fructose-rich chow for 6 weeks. FFR were treated with a vehicle or with 1 mg/kg per day of temocapril, an angiotensin-converting enzyme inhibitor, or 0.1 mg/kg per day of olmesartan, an angiotensin II type 1 receptor blocker, for the last 2 weeks. Insulin sensitivity (M value: mg/kg per min) was estimated by the euglycemic hyperinsulinemic glucose clamp method. Sizes of adipocytes derived from epididymal fat and triglyceride content in the soleus muscle were determined. Results FFR had lower M value, higher blood pressure, larger adipocyte size, higher ratio of epididymal fat pads over body weight (%fat pads), and higher intramuscular triglyceride than did the control rats. Both temocapril and olmesartan significantly improved the M value and decreased blood pressure and adipocyte size without change in %fat pads in FFR. Adipocyte size was negatively correlated with the M value. Treatment for 2 weeks decreased, but not significantly, intramuscular triglyceride. Conclusions RAS blockade decreases adipocyte size without change in epididymal %fat pads accompanied by improvement in insulin sensitivity.

Slower Decline of Glomerular Filtration Rate in the Japanese General Population: A Longitudinal 10-Year Follow-Up Study

The prevalence of stage 3 to 5 chronic kidney disease (CKD) in Japan (18.7%) is considerably higher than that in the United States (4.5%). This study investigated in the Japanese general population whether this higher prevalence of CKD might reflect to a progressive decline of renal function, and in turn to the increased risk of end-stage renal disease. A decline in renal function over 10 years was examined in 120,727 individuals aged 40 years or older who participated in the annual health examination program of the two periods over 10 years, 1988–1993 and 1998–2003. Renal function was assessed with estimated glomerular filtration rate (GFR) using the abbreviated Modification of Diet in Renal Disease (MDRD) Study equation modified by a Japanese coefficient. The rate of GFR decline in the participants was 0.36 mL/min/1.73 m2/year on average. In the male population aged 50–79, the mean rate of GFR decline was significantly higher in the presence of hypertension than in its absence. The rate of GFR decline was more than two times higher in participants with proteinuria than in those without proteinuria in both sexes. The rate was significantly higher in participants with an initial GFR <50 mL/min/1.73 m2 among the groups younger than age 70 and in participants with an initial GFR <40 mL/min/1.73 m2 in the group with age 70–79. Based on the slow rate of GFR decline, we concluded that the decline in renal function progresses slowly in the Japanese general population. Hypertension, proteinuria and lower GFR were found to be significant risk factors for a faster decline of GFR.

The contribution of skeletal muscle tumor necrosis factor-α to insulin resistance and hypertension in fructose-fed rats

Objective The aim of this study was to determine the role of tumor necrosis factor-α (TNF-α) in skeletal muscle tissue in insulin resistance and hypertension and the effect of anti-hypertensive medicine on skeletal muscle TNF-α in fructose-induced insulin-resistant and hypertensive rats(fructose-fed rats: FFR). Design and methods Six-week-old male Sprague-Dawley rats were fed either normal rat chow or fructose-rich chow. For the last 2 weeks of a 6-week period of either diet, the rats were treated with a vehicle (control or FFR); temocapril, an angiotensin converting enzyme inhibitor (ACEI); or CS-866, an angiotensin II type 1 receptor blocker (ARB). The euglycemic hyperinsulinemic glucose clamp technique was performed to evaluate insulin sensitivity (M value). TNF-α levels in soleus and extensor digitorum longus (EDL) muscles and epididymal fat pads were measured. We also measured the TNF-α concentration in an incubated medium secreted from soleus muscle strips with or without angiotensin II. Results TNF-α levels were significantly higher in the soleus and EDL muscles, but not in the epididymal fat, in the FFRs compared with the control rats. Temocapril and CS-866 lowered systolic blood pressure, improved insulin resistance, and reduced TNF-α in both skeletal muscles. There were significant negative correlations between M values and TNF-α levels in both soleus and EDL muscles. Also, the soleus muscle strip incubation with 10−7 mol/l angiotensin II increased TNF-α secreted into the incubation medium compared to the incubation without angiotensin II. These results suggest that skeletal muscle TNF-α is linked to insulin resistance and hypertension and that angiotensin II may be one of the factors that regulate skeletal muscle TNF-α.

The effects of an angiotensin-converting enzyme inhibitor and an angiotensin II receptor antagonist on insulin resistance in fructose-fed rats

The aim of this study was to compare the effects of an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II receptor (AT) antagonist on insulin resistance, especially on muscle fiber composition in fructose-induced insulin-resistant and hypertensive rats. Six-week-old male Sprague-Dawley rats were fed either normal rat chow (control) or a fructose-rich diet (FFR). For the last two weeks of a six-week period of either diet, the rats were treated with gum arabic solution as a vehicle (control or FFR), angiotensin-converting enzyme inhibitor (FFR+ACE), temocapril (1 mg/kg/ day) or an angiotensin II receptor antagonist (FFR+AT), CS-866 (0.3 mg/kg/day), by gavage, and then the euglycemic hyperinsulinemic glucose clamp technique was performed to evaluate insulin sensitivity. At the end of the glucose clamp, the soleus muscle was dissected for determination of the muscle fiber composition by ATPase methods. Blood pressure at the glucose clamp in the FFR group was significantly higher than that of the control group, and both temocapril and CS-866 significantly lowered the blood pressure of the FFR group. The average rate of glucose infusion during the glucose clamp, as a measure of insulin sensitivity (M value), was significantly lower in the FFR rats compared to the controls (15.4 +/- 0.4, 10.9 +/- 0.6 mg/kg/min, for control and FFR, respectively, P < .01). Both temocapril and CS-866 partially improved the M values compared to FFR (13.2 +/- 0.7, 12.8 +/- 0.5 mg/kg/min, for FFR+ACE, FFR+AT, respectively, P < .01 compared with FFR, P < .05 compared with control). The composite ratio of type I fibers of the soleus muscle was decreased significantly in the FFR rats compared with the controls (82% +/- 2%, 75% +/- 2%, for control and FFR, respectively, P < .01), and both temocapril and CS-866 restored a composite ratio of type I fibers to the same level as that of the controls (81% +/- 1%, 80% +/- 1% for FFR+ACE and FFR+AT, respectively). The M value was significantly correlated with the composition of type I and type II fibers. These results suggest that the fiber composition of skeletal muscle is correlated to insulin resistance, and that both ACE inhibitors and AT antagonists may modulate the muscle fiber composition in a hypertensive and insulin-resistant animal model, fructose-fed rats, to the same extent.

Olmesartan Is an Angiotensin II Receptor Blocker with an Inhibitory Effect on Angiotensin-Converting Enzyme

Angiotensin II receptor blockers (ARBs) are widely used for the treatment of hypertension. It is believed that treatment with an ARB increases the level of plasma angiotensin II (Ang II) because of a lack of negative feedback on renin activity. However, Ichikawa (Hypertens Res 2001; 24: 641–646) reported that long-term treatment of hypertensive patients with olmesartan resulted in a reduction in plasma Ang II level, though the mechanism was not determined. It has been reported that angiotensin 1-7 (Ang-(1-7)) potentiates the effect of bradykinin and acts as an angiotensin-converting enzyme (ACE) inhibitor. It is known that ACE2, which was discovered as a novel ACE-related carboxypeptidase in 2000, hydrolyzes Ang I to Ang-(1-9) and also Ang II to Ang-(1-7). It has recently been reported that olmesartan increases plasma Ang-(1-7) through an increase in ACE2 expression in rats with myocardial infarction. We hypothesized that over-expression of ACE2 may be related to a reduction in Ang II level and the cardioprotective effect of olmesartan. Administration of 0.5 mg/kg/day of olmesartan for 4 weeks to 12-week-old stroke-prone spontaneously hypertensive rats (SHRSP) significantly reduced blood pressure and left ventricular weight compared to those in SHRSP given a vehicle. Co-administration of olmesartan and (D-Ala7)−Ang-(1-7), a selective Ang-(1-7) antagonist, partially inhibited the effect of olmesartan on blood pressure and left ventricular weight. Interestingly, co-administration of (D-Ala7)−Ang-(1-7) with olmesartan significantly increased the plasma Ang II level (453.2±113.8 pg/ml) compared to olmesartan alone (144.9±27.0 pg/ml, p<0.05). Moreover, olmesartan significantly increased the cardiac ACE2 expression level compared to that in Wistar Kyoto rats and SHRSP treated with a vehicle. Olmesartan significantly improved cardiovascular remodeling and cardiac nitrite/nitrate content, but co-administration of olmesartan and (D-Ala7)−Ang-(1-7) partially reversed this anti-remodeling effect and the increase in nitrite/nitrate. These findings suggest that olmesartan may exhibit an ACE inhibitory action in addition to an Ang II receptor blocking action, prevent an increase in Ang II level, and protect cardiovascular remodeling through an increase in cardiac nitric oxide production and endogenous Ang-(1-7) via over-expression of ACE2.

Correlations of adiponectin level with insulin resistance and atherosclerosis in Japanese male populations

objective  Adiponectin, which is secreted specifically by adipose tissue, has been shown to have an anti‐atherosclerotic effect and to improve insulin resistance. The aim of this study was to determine the correlations of plasma adiponectin concentration with insulin resistance and atherosclerosis.

Captopril potentiates the myocardial infarct size-limiting effect of ischemic preconditioning through bradykinin B2 receptor activation

OBJECTIVES To investigate the role of kinin in preconditioning against infarction, the present study assessed the effect of captopril, a kininase II inhibitor, on preconditioning and arterial plasma kinin levels. BACKGROUND Recent studies suggest a possible contribution of kinin to preconditioning against infarction. However, its role and the site of kinin production remain uncharacterized. METHODS Six groups of rabbits (n = 6 to 13) underwent 30-min coronary occlusion and 3-h reperfusion. The infarct size and area at risk were determined by tetrazolium staining and fluorescent particles, respectively. Arterial blood was sampled under baseline conditions, before the 30-min ischemia and after reperfusion for radioimmunoassay of the kinin level. RESULTS Infarct size expressed as a percentage of area at risk (%IS/AR) was 42.9 +/- 2.9% (mean +/- SEM) in the control group, 34.5 +/- 3.3% in the group preconditioned with 2 min of ischemia/5 min of reperfusion and 41.7 +/- 5.1% in the group given captopril (1 mg/kg body weight) alone before the 30-min ischemia. These %IS/AR values were not significantly different between the three groups. However, a combination of captopril and subsequent preconditioning with 2 min of ischemia markedly limited %IS/AR to 21.2 +/- 2.4%. This potentiation of 2 min of preconditioning by captopril was not observed when 2 micrograms/kg body weight of Hoe 140, a specific bradykinin B2 receptor antagonist, was administered before preconditioning (%IS/AR = 41.2 +/- 5.7%), whereas Hoe 140 alone did not modify infarct size (%IS/AR = 38.5 +/- 5.1%). Arterial plasma kinin levels were comparable between the control rabbits, the group given captopril alone and the group that received captopril plus 2 min of preconditioning at baseline (3.8 +/- 1.0, 6.3 +/- 1.9 and 5.2 +/- 1.7 pg/ml, respectively), and there was no significant change in kinin levels after the captopril injection or the combination of captopril plus 2 min of preconditioning. CONCLUSIONS The present results indicate that captopril is capable of potentiating preconditioning without increasing the arterial kinin level and that the beneficial effect of captopril can be inhibited by Hoe 140. These findings support the hypothesis that kinin produced locally in the heart during preconditioning may contribute to the cardioprotective mechanism through bradykinin receptor activation.