Hideyuki Oniki

Sex differences in the association between serum uric acid levels and cardiac hypertrophy in patients with chronic kidney disease.

Several studies have documented an association between serum uric acid (SUA) concentration and cardiac hypertrophy in hypertensive patients; however, the association remains unclear in chronic kidney disease (CKD) patients. If there is an association between SUA and hypertrophy in these patients, it is unknown whether the association is different between men and women. Our aim in this study is to determine whether SUA is associated with cardiac hypertrophy in CKD patients, focusing on any sex differences. Two hundred sixteen CKD patients (117 men and 99 women) were enrolled in this cross-sectional study. Patients prescribed uric acid-lowering agents and those with congestive heart failure, valvular heart disease, or ischemic heart disease were excluded from this study. Left ventricular mass index (LVMI) and left ventricular hypertrophy (LVH) were assessed using echocardiography. The prevalence of LVH was 58% in men and 47% in women. In multivariate linear regression analysis, SUA levels did not correlate with LVMI in men, whereas SUA was independently associated with LVMI in women (β=0.27, P=0.02). Multivariate logistic regression analysis also revealed that diabetes mellitus (odds ratio (OR), 4.41; P=0.01) was associated with LVH in men, whereas age (OR, 1.13; P<0.01), hypertension (OR, 7.38; P=0.03) and SUA (OR, 1.91; P=0.03) were associated with LVH in women. In female CKD patients, SUA levels were associated with LVMI and LVH, whereas there was no association in male patients. These observations suggest that an association between SUA levels and the development of cardiac hypertrophy is more likely in women than in men.

High salt intake promotes a decline in renal function in hypertensive patients: a 10-year observational study

We investigated the influence of long-term salt load on renal function in hypertensive patients. The subjects were 133 hypertensive patients (80 women and 53 men, mean age 60±9 years) who underwent at least five successful 24 h home urine collections during the 10-year observation period. Blood pressure (BP) and 24-h urinary salt and creatinine excretion levels were measured. BP decreased from 143±12/85±8 to 129±14/68±11 mm Hg during the 10.5-year observation period, and this decrease was associated with patients taking an increased number of antihypertensive drugs (1.3±1.0 to 2.2±1.1). The estimated glomerular filtration rate (eGFR) also significantly decreased from 71.7±14.6 to 64.7±16.5 ml min−1 (P<0.01), and the change in eGFR was −0.68 ml min−1 per year on average. The average salt excretion was 8.6±2.2 g per day and showed a significant negative correlation with the change in eGFR (r=−0.21, P=0.02). Subjects with an average salt excretion<8 g per day showed a significantly slower decline in renal function than those with an average salt excretion ⩾8 g per day (the change in eGFR: −0.41±1.10 vs. −0.83±1.19 ml min−1 per year, P<0.05). In the multivariate analysis, the average salt excretion (partial r=−0.19, P=0.03) and baseline eGFR (partial r=−0.23, P=0.01) were significantly associated with the change in eGFR. This association was independent of BP change or an increased number of antihypertensive drugs. The results suggest that long-term salt load promotes a decline in renal function in hypertensive patients; thus, salt restriction is encouraged, to prevent renal damage.

Upregulation of endothelium-derived hyperpolarizing factor compensates for the loss of nitric oxide in mesenteric arteries of Dahl salt-sensitive hypertensive rats.

This study was designed to determine whether a high-salt diet would alter endothelial function and, if so, the relative contributions of endothelium-derived hyperpolarizing factor (EDHF) and nitric oxide (NO) to any changes in vasomotor responses. Male Dahl salt-sensitive (DS) rats were given either a high-salt diet (8% NaCl, DS-H) or a low-salt diet (0.4% NaCl, DS-L) for 6 weeks. Membrane potentials and contractile responses were recorded from the isolated superior mesenteric arteries. After salt loading, DS-H developed hypertension, while DS-L remained normotensive. No difference was found in acetylcholine (ACh)-induced, endothelium-dependent relaxation between the groups. However, after treatment with indomethacin and NO synthase inhibitor, EDHF-like relaxation was significantly greater in DS-H than in DS-L. In contrast, NO-mediated relaxation was significantly smaller in DS-Hthan in DS-L. Iberiotoxin (IbTx), a specific blocker of large-conductance calcium-dependent potassium (BKCa) channels, attenuated EDHF-like relaxation in DS-H but not in DS-L. IbTx marginally inhibited EDHF-mediated hyperpolarization only in DS-H. Endothelium-independent relaxation in response to sodium nitroprusside or levcromakalim was similar in both groups. In conclusion, EDHF-like relaxation is upregulated through the activation of BKCa channels in the mesenteric arteries of DS-H. As the overall relaxation in response to ACh did not differ between the groups, the upregulation of EDHF appears to compensate for the loss of NO in the mesenteric arteries of DS-H.

Effects of angiotensin II receptor antagonist on impaired endothelium-dependent and endothelium-independent relaxations in type II diabetic rats

Background Diabetes mellitus is an important risk factor for cardiovascular diseases, and vasodilator dysfunction may contribute to vascular complications in diabetes. We previously demonstrated that the angiotensin II receptor blocker (ARB) corrected the impaired endothelium-derived hyperpolarizing factor (EDHF)-mediated arterial hyperpolarization and relaxation associated with hypertension or aging, partially independently of blood pressure. Objective To test whether EDHF-mediated, as well as endothelium-independent, relaxations would be altered in arteries from type II diabetic Goto–Kakizaki rats, and whether ARB would correct these alterations. Methods Goto–Kakizaki rats were treated with either the ARB candesartan or a combination of hydralazine and hydrochlorothiazide for 8 weeks, beginning at 10 weeks of age. Membrane potentials and contractile responses were recorded from the isolated mesenteric arteries. Results The two treatments lowered blood pressure comparably. Acetylcholine-induced, EDHF-mediated hyperpolarization and relaxation in mesenteric arteries were markedly impaired in untreated Goto–Kakizaki rats compared with age-matched Wistar rats, and neither ARB nor the combination therapy improved these responses. On the other hand, relaxations to endothelium-derived nitric oxide, assessed in rings precontracted with high potassium solution, were similar among the four groups. Relaxation to the nitric oxide donor sodium nitroprusside and that to levcromakalim, an ATP-sensitive K+-channel opener, were also impaired in untreated Goto–Kakizaki rats, and the response to sodium nitroprusside was partially improved in treated Goto–Kakizaki rats. Conclusions These findings suggest that EDHF-mediated hyperpolarization and relaxation and endothelium-independent relaxations are both impaired in arteries of type II diabetic rats, and antihypertensive treatment with or without ARB partially corrects endothelium-independent relaxations to the nitric oxide donor but not EDHF-mediated responses.

Chronic fluvastatin treatment alters vascular contraction by inhibiting the Rho/Rho-kinase pathway.

1 In the present study, we investigated the effects of chronic treatment of stroke‐prone spontaneously hypertensive rats (SHRSP) with the statin fluvastatin on vascular Rho/Rho‐kinase pathway mediated contraction, which has been shown to be upregulated in hypertension. 2 Contribution of the Rho/Rho‐kinase pathway to noradrenaline‐induced contraction of arteries from SHRSP was assessed by the inhibitory effect of Y‐27632, a Rho/Rho‐kinase inhibitor. Stroke‐prone spontaneously hypertensive rats were treated with fluvastatin (10 mg/kg per day) for 1 month. 3 Treatment with fluvastatin tended to attenuate the contraction to noradrenaline and significantly decreased the Y‐27632‐sensitive component of the contraction in controls compared with fluvastatin‐treated rats. 4 RhoA, as assessed by western blotting, was also reduced by fluvastatin treatment. 5 These findings suggest that chronic treatment with fluvastatin reduces the contractile response associated with Rho/Rho‐kinase in arteries of hypertensive rats.

Relationship between salt intake as estimated by a brief self-administered diet-history questionnaire (BDHQ) and 24-h urinary salt excretion in hypertensive patients.

Assessing an individual’s salt intake is necessary for providing guidance with respect to salt restriction. However, the methods that exist for assessing salt intake have both merits and limitations. Therefore, the evaluation methods should be selected for their appropriateness to the patients and the environment of the medical facilities. The purpose of the present study was to investigate the validity of a brief self-administered diet-history questionnaire (BDHQ) by comparing the responses with 24-h urinary salt excretion. A total of 136 hypertensive outpatients (54 men and 82 women) were included in this study. All subjects were given the BDHQ and performed 24-h home urine collection. The energy-adjusted salt intake as assessed by the BDHQ was 12.3 (95% confidence interval: 11.8–12.9) g per day, and the urinary salt excretion evaluated by 24-h urinary collection was 9.0 (8.4–9.5) g per day. The energy-adjusted salt intake assessed by the BDHQ correlated significantly with the urinary salt excretion evaluated by 24-h urinary collection (r=0.34, P<0.001). In conclusion, the estimated salt intake evaluated by the BDHQ weakly, but significantly, correlated with 24-h urinary salt excretion. In clinical practice, it seems important to utilize both methods to assess an individual’s salt intake in order to provide adequate guidance for salt restriction.

Effects of the Superoxide Dismutase Mimetic Tempol on Impaired Endothelium-Dependent and Endothelium-Independent Relaxations in Type II Diabetic Rats

Endothelium-derived hyperpolarizing factor (EDHF)-mediated hyperpolarization and relaxation, and endothelium-independent relaxations to the nitric oxide donor sodium nitroprusside and the adenosine 5′-triphosphate (ATP)-sensitive K+-channel opener levcromakalim were both impaired in mesenteric arteries of type II diabetic Goto–Kakizaki rats. The treatment with the superoxide dismutase mimetic tempol or its combination with the angiotensin II type 1 receptor blocker candesartan failed to improve EDHF-mediated responses, although both treatments partially improved endothelium-independent relaxations. These findings suggest that increased oxidative stress may in part account for the impaired endothelium-independent relaxations in diabetes, while it does not play a major role in the impaired EDHF-mediated responses.

Differential effects of organic nitrates on arterial diameter among healthy Japanese participants with different mitochondrial aldehyde dehydrogenase 2 genotypes: randomised crossover trial

Objectives To determine whether polymorphisms at codon 487 (*1, GAA=Glu; *2, AAA=Lys) of mitochondrial aldehyde dehydrogenase 2 (ALDH2) influence nitroglycerine (glyceryl trinitrate (GTN))-induced vasodilation, and whether GTN or isosorbide dinitrate (ISDN) is a more effective antianginal agent in each ALDH2 genotype. Design A randomised, open-label, crossover trial with 117 healthy Japanese (20–39 years) whose genotypes were determined (*1/*1, n=47; *1/*2, n=48; *2/*2, n=22) was performed at Kyushu University Hospital, Fukuoka, Japan. Participants were randomly assigned to treatment: sublingual spray of GTN (0.3 mg) or ISDN (1.25 mg). After ≥1 week, measurements were repeated using the other drug. The main outcome measures were the maximal rate of increase in the brachial artery diameter determined by ultrasonography, the time required to attain maximal dilation (Tmax) and the time required to attain 90% maximal dilation (T0.9). Results The maximal artery diameter increase in response to GTN or ISDN did not differ among genotypes. However, GTN Tmax was significantly longer for *2/*2 (299.7 s, 269.0–330.4) than *1/*1 (254.7 s, 238.6–273.4; p=0.0190). GTN T0.9 was significantly longer in the *1/*2 (206.1 s, 191.7–219.3) and *2/*2 (231.4 s, 211.8–251.0) genotypes than *1/*1 (174.9 s, 161.5–188.3; p=0.0068, p<0.0001, respectively). In contrast, the time-course of ISDN-induced vasodilation did not differ among genotypes. GTN Tmax and T0.9 among *1 allele carriers (*1/*1 and *1/*2) were significantly shorter than those of ISDN, whereas the time course of GTN and ISDN vasodilation did not differ among participants carrying *2/*2. Conclusions The amplitude of GTN-induced vasodilation was not influenced by the ALDH2 genotype, but the response was significantly delayed in *2 allele carriers, especially *2/*2. GTN dilated the artery more quickly than ISDN in *1/*1 and *1/*2, but not in *2/*2. Trial registration number UMIN000001492 (UMIN-CTR database).

Variability of urinary salt excretion estimated by spot urine in treated hypertensive patients

Abstract Among the several methods used to assess salt intake, estimating 24 h urinary salt excretion by spot urine seems appropriate for clinical practice. In this study, we investigated variability in urinary salt excretion using spot urine in hypertensive outpatients. Participants included 200 hypertensive patients who underwent spot urinary salt excretion at least three times during the observation period. Mean urinary salt excretion and the coefficient of the variation were 8.62 ± 1.96 g/day and 19.0 ± 10.2%, respectively. In the analysis of participants who underwent assessment of urinary salt excretion at least eight times (n = 54), a significant reduction in mean urinary salt excretion was found at the 5th measurement. On the contrary, the coefficient of the variation of urinary salt excretion continued to increase until the 5th measurement, and became stable thereafter. Mean urinary salt excretion was positively correlated with mean clinic diastolic blood pressure (r = 0.27, p < 0.05). Clinic diastolic blood pressure in the high urinary salt excretion group (≥10 g/day) was significantly higher than that of the low group (76.2 ± 7.5 vs 73.4 ± 8.3 mmHg, p < 0.05). Mean urinary salt excretion in summer was significantly lower than that of the other seasons (7.75 ± 1.94 vs 9.09 ± 2.68 (spring), 8.72 ± 2.12 (autumn), 8.92 ± 2.17 (winter) g/day, p < 0.01). In conclusion, repeated measurements of urinary salt excretion using spot urine are required to assess daily salt intake of hypertensive patients.

Association of body mass index with glomerular filtration rate in Japanese: A cross-sectional study in work-site population

It has been shown that aging and hypertension are important risk factors to promote renal damage. However, little data are available on the effect of obesity on the progression of renal damage, especially in young and middle-aged individuals. The aim of this study was to determine the association between body mass index (BMI) and renal function evaluated by estimated glomerular filtration rate (eGFR) in Japanese men. We studied the cross-sectional association of BMI with eGFR in 3872 Japanese men in a work-site population (18–64 y; mean age 42.1 ± 0.2 y). Estimated glomerular filtration rate was calculated by a novel equation for Japanese men. Estimated glomerular filtration rate was negatively correlated with age, systolic blood pressure (SBP), hemoglobin A1c (HbA1c), and BMI. We performed multiple regression analysis, controlling for factors, such as SBP, low-density lipoprotein-cholesterol, gamma-glutamyl transpeptidase, age, HbA1c, and uric acid. The association between age and eGFR was highly statistically significant. In addition, BMI was still significantly associated with eGFR independently of SBP. Moreover, mean eGFR, which was adjusted for age, SBP, HbA1c, serum uric acid, and gamma-glutamyl transpeptidase, decreased from 88.9 mL/min/1.73 m2 in the first quartile of BMI to 87.5 mL/min/1.73 m2 in the second, 86.9 mL/min/1.73 m2 in the third, and 85.9 mL/min/1.73 m2 in the fourth quartile (test for trend, P < .0001). These results show that a close relationship is present between obesity and decreased eGFR in Japanese men. Keeping appropriate body weight, in addition to appropriate blood pressure, in young and middle age may be important to prevent renal damage in older age.