Uran Onaka

Angiotensin-Converting Enzyme Inhibitor Prevents Age-Related Endothelial Dysfunction

Vascular relaxation via endothelium-derived hyperpolarizing factor (EDHF) declines in association with aging and also with hypertension, and antihypertensive treatment improves the endothelial dysfunction connected with hypertension. We tested whether the angiotensin-converting enzyme inhibitor improves EDHF-mediated responses in normotensive rats, with special reference to the age-related process. Wistar-Kyoto rats (WKY) were treated with either 20 mg · kg−1 · d−1 enalapril (WKY-E group) or a combination of 50 mg · kg−1 · d−1 hydralazine and 7.5 mg · kg−1 · d−1 hydrochlorothiazide (WKY-H group) from 9 to 12 months of age. Twelve-month-old WKY (WKY-O) and 3-month-old WKY (WKY-Y) served as controls (n=6 to 10 in each group). The 2 treatments lowered systolic blood pressure comparably. EDHF-mediated hyperpolarization to acetylcholine (ACh) in mesenteric arteries was significantly improved in WKY-E, but not in WKY-H, compared with WKY-O, and the hyperpolarization in WKY-E was comparable to that in WKY-Y (hyperpolarization to 10−5 mol/L ACh in the presence of norepinephrine: WKY-O, −14±2 mV; WKY-E, −22±3 mV; WKY-H, −15±2 mV; and WKY-Y, −28±0 mV). EDHF-mediated relaxation, as assessed by relaxation to ACh in norepinephrine-precontracted rings in the presence of indomethacin and NO synthase inhibitor, was also significantly improved in WKY-E, but not in WKY-H, to a level comparable to that in WKY-Y (maximum relaxation: WKY-O, 45±6%; WKY-E, 63±8%; WKY-H, 43±4%; and WKY-Y, 72±4%). Hyperpolarization and relaxation to levcromakalim, an ATP-sensitive K+ channel opener, were similar in all groups. These findings suggest that the angiotensin-converting enzyme inhibitor prevents the age-related decline in EDHF-mediated hyperpolarization and relaxation in normotensive rats, presumably through an inhibition of the renin-angiotensin system.

Inhibitory action of insulin-sensitizing agents on calcium channels in smooth muscle cells from resistance arteries of guinea-pig

The actions of troglitazone, pioglitazone, metformin and bezafibrate, agents that improve insulin‐resistance, on voltage‐dependent Ca2+ channels in arterial smooth muscle cells were examined by use of the conventional and nystatin‐perforated whole‐cell clamp methods. Single cells were freshly isolated from resistance mesenteric arteries of guinea‐pigs. The actions of these agents on 77 mM K+‐induced contraction of the isolated arteries were also examined with the use of isometric tension recording. The thiazolidinedione derivatives, troglitazone and pioglitazone, inhibited whole‐cell Ca2+ currents in a dose‐dependent manner with dissociation constants of 3.0 μM and 44.9 μM and Hill coefficients of 0.61 and 0.68, respectively. These two agents inhibited the 77 mM K+‐induced contraction with similar potencies as those inhibiting the Ca2+ currents. Metformin and bezafibrate had no apparent effects on the Ca2+ current or high K+‐induced contraction. The inhibitory action of troglitazone on Ca2+ currents was not affected by the command potential, the holding potential, or the stimulation frequency, suggesting that its mode of the action differs from that of known organic Ca2+ channel antagonists. The inhibitory action of troglitazone on Ca2+ currents was not affected by the addition of insulin to, or the removal of glucose from, the solutions. In conclusion, the thiazolidinedione derivatives directly inhibited the voltage‐dependent Ca2+ channels in a different manner from that of organic Ca2+ channel antagonists. This inhibitory action on Ca2+ channels was not a common feature of insulin‐sensitizing agents.

Antihypertensive Treatment Improves Endothelium-Dependent Hyperpolarization in the Mesenteric Artery of Spontaneously Hypertensive Rats

BACKGROUND The vascular endothelium releases endothelium-derived hyperpolarizing factor (EDHF). The mesenteric arteries of 6- to 8-month-old spontaneously hypertensive rats (SHRs) exhibit an impairment of the hyperpolarization induced by acetylcholine via EDHF. METHODS AND RESULTS We determined whether antihypertensive treatment can improve EDHF-mediated responses in SHRs. Beginning at age 8 to 9 months, the animals were treated with either enalapril (40 mg x kg(-1) x d(-1)) (SHR-Es) or a combination of hydralazine (25 mg x kg(-1) x d(-1)) and hydrochlorothiazide (7.5 mg x kg(-1) x d(-1)) (SHR-Hs) for 3 months. The control groups were age-matched SHRs (SHR-Cs) and Wistar Kyoto rats (WKYs). The two treatments lowered the blood pressure to comparable extents. The acetylcholine-induced hyperpolarization in the mesenteric artery of treated SHRs improved to a level comparable to that in WKYs (acetylcholine 10(-5) mol/L with norepinephrine 10(-5) mol/L: SHR-E, -14.4 +/- 1.8; SHR-H, -12.0 +/- 1.3; SHR-C, -7.2 +/- 1.2; and WKY, -13.3 +/- 2.3 mV). EDHF-mediated relaxation, as assessed by relaxation to acetylcholine resistant to N(G)-nitro-L-arginine in norepinephrine-contracted rings, was markedly improved in treated SHRs (maximal relaxation: SHR-E, 79.3+/-3.2%; SHR-H, 47.4+/-8.6%; SHR-C, 4.8+/-2.4%; and WKY, 45.1+/-6.0%). When the rings were contracted with 77 mmol/L KCl to eliminate EDHF response, no difference was found in relaxation to acetylcholine among the four groups. Similarly, the hyperpolarization and relaxation to levcromakalim, a K+ channel opener, were comparable among the groups. CONCLUSIONS Antihypertensive treatment improved EDHF-mediated hyperpolarization and relaxation in the mesenteric artery in SHRs, whereas NO-mediated relaxation did not appear to be modulated by drug therapy. Thus, alterations in the EDHF system may play a pivotal role in endothelial dysfunction and its improvement with drug therapy in SHRs.

Troglitazone, an insulin sensitizer, increases forearm blood flow in humans

To test whether troglitazone, a thiazolidinedione insulin sensitizer, increases the peripheral blood flow, the changes in forearm blood flow (FBF) were evaluated by venous occlusion plethysmography in 11 lean healthy male volunteers (age range, 24 to 39 years) after a single oral dose of 200 mg of troglitazone. Forearm vascular resistance (FVR) was calculated from FBF and blood pressure. Two hours after the dose, FBF increased from 3.66+/-0.31 to 4.81+/-0.57 mL/100 mL/min (P < .01), and FVR decreased from 24.7+/-2.2 to 20.2+/-2.2 units (P < .01), whereas both these values did not change during the control recordings obtained without troglitazone. Blood pressure, blood glucose levels, and serum immunoreactive insulin levels did not change significantly during the observation period. Serum concentrations of nitrate ions decreased from 27.0+/-3.5 mmol/L to 23.1+/-2.7 mmol/L (P < .01) after the administration. These results suggest that troglitazone increases muscular blood flow through vasodilation induced by a mechanism other than the correction of hyperinsulinemia or the increase in nitric oxide. The present study provides the first evidence that troglitazone dilates the vasculature in humans.

Hyperinsulinemia and Left Ventricular Geometry in a Work-Site Population in Japan

The present study was designed to test whether hyperglycemia or hyperinsulinemia influences left ventricular mass and geometry. An echocardiogram and 75-g oral glucose tolerance test were performed in 210 normotensive and 180 mildly to moderately hypertensive male workers in a bus company who were free from cardiac diseases and were not taking medication for hypertension and diabetes mellitus. When we divided subjects into four groups according to the left ventricular geometric pattern using left ventricular mass index of 110 g/m2 and relative wall thickness (ratio of 2 x posterior wall thickness to end-diastolic left ventricular diameter) of 0.44, body mass index and systolic blood pressure were higher in those with concentric hypertrophy and eccentric hypertrophy. In addition, hemoglobin A(Ic) level and the sum of fasting and 2-hour postload serum glucose levels were higher in subjects with concentric hypertrophy. In subjects without diabetes mellitus (n=336), 2-hour postload serum insulin level and the sum of fasting and 2-hour postload serum insulin levels tended to be higher in those with concentric hypertrophy and concentric remodeling. In multiple regression analysis, the sum of glucose levels (or hemoglobin A(Ic) level) in all subjects and the sum of insulin (or 2-hour postload insulin) levels in subjects without diabetes mellitus significantly correlated with relative wall thickness, independent of age, systolic blood pressure, and body mass index. Neither glucose nor insulin levels correlated with left ventricular mass index. Our results suggest that hyperglycemia and hyperinsulinemia may promote concentric changes in the left ventricle in normotensive and mildly to moderately hypertensive men.

Long-Term Compliance with Salt Restriction in Japanese Hypertensive Patients

The purpose of the present study was to investigate the long-term compliance with salt restriction in Japanese hypertensive patients. Subjects included 389 patients, 230 women and 159 men, mean age 58±11 years, who underwent successful 24-h home urine collection more than three times over an interval of a year. Urinary salt, potassium, and creatinine were measured. Additionally, family history, habitual alcohol intake, smoking habit, physical activities, and job status were assessed by use of a questionnaire. During the follow-up period (average 3.5 years), participants underwent urine collection 4.6 times in average. Urinary salt excretion at the last visit was significantly lower than that at the first visit (8.7±3.4 vs. 9.6±4.1 g/day; p<0.01). Urinary potassium excretion also decreased significantly during this period (from 2.0±0.7 to 1.9±0.7 g/day; p<0.05). Among the mean 4.6 urine collections, 45.2% (men 34.6%, women 52.6%) of the patients successfully achieved <6 g (100 mmol of sodium)/day of salt excretion on at least one occasion. The rate of achievement of averaged urinary salt excretion <6 g/day dropped to 10.3% (men 4.4%, women 14.3%). Only 2.3% (men 0.6%, women 3.5%) of the patients achieved <6 g/day on all occasions. There were no significant differences in age, habitual alcohol intake, smoking habit, physical activities, or job status between patients who complied with the salt-restricted diet and those who did not. Results suggest that long-term compliance with salt restriction is poor in Japanese hypertensive patients. Since no specifically defining characteristics were found in the compliant patients, repeated measurements of urinary salt excretion seem to be important to encourage salt restriction.

Prevalence and Lifestyle Characteristics of Hypertensive Patients with Metabolic Syndrome Followed at an Outpatient Clinic in Fukuoka, Japan

A new guideline on metabolic syndrome (MS) in Japanese was introduced in 2005. The purpose of this study was to evaluate the prevalence and lifestyle characteristics of Japanese hypertensive patients with MS. Subjects were 290 patients (mean age: 64±11 years) who had been followed at our hospital. The waist circumference (WC) and body mass index (BMI) were assessed. Subjects who had BMI ≥25 kg/m2 were defined as having BMI obesity, while abdominal obesity was defined as a WC ≥85 cm in men and ≥90 cm in women, respectively. Since all patients had hypertension, the definition of MS was made when the patient had abdominal obesity plus either dyslipidemia or glucose intolerance, or both. Among the subjects, 230 patients underwent 24-h home urine collection to measure urinary salt and potassium excretions. Dietary habits were also assessed by use of a questionnaire. Mean values of BMI and WC were 24.2±3.4 kg/m2 and 87.1±9.6 cm, respectively. Among the total subject group, 39% patients were classified as having BMI obesity, 49% as having abdominal obesity, and 27% as having MS. BMI was significantly correlated with WC both in men (r=0.86; p<0.01) and in women (r=0.79; p<0.01). More men than women belonged to the BMI obesity (46% vs. 33%, p<0.05), abdominal obesity (63% vs. 39%, p<0.01) and MS (39% vs. 18%, p<0.01) groups. There were no significant differences in blood pressure between patients with and without MS, while patients with MS needed a greater number of antihypertensive drugs than those without MS. Mean urinary salt and potassium excretions were 8.9±3.8 g/day and 1.9±0.7 g/day, respectively. Urinary salt excretion of <6 g (100 mmol of sodium)/day was achieved in 20% of the subjects. Urinary salt excretion in the patients with MS was significantly higher than that in the patients without (10.1±4.2 vs. 8.5±3.6 g/day; p<0.01). Only 16% of the patients with MS achieved salt restriction (<6 g/day). The patients with MS had a significantly greater the chance to eat out than the patients without MS. They were also less aware of the need to increase their vegetable consumption. The results suggested that MS is prevalent in Japanese hypertensive patients. Patients with MS showed higher urinary salt excretion and needed more antihypertensive drugs to manage their blood pressure. Dietary counseling focusing not only on sodium restriction but also on the need to increase fruit and vegetable consumption seems to be important.

Chaos and spectral analyses of heart rate variability during head-up tilting in essential hypertension

To investigate nonlinear and linear components of heart rate variability (HRV) in essential hypertension (EHT), we analyzed HRV by chaos and spectral analyses in patients with EHT (n = 18) and normotensives (n = 10) during head-up tilting. We used the correlation dimension (CD) and Lyapunov exponents as the parameters of chaos. The CD, an index of complexity, was lower at rest in EHT group than in normotensives, and did not change in EHT group in response to head-up tilting, but decreased in normotensives. Head-up tilting did not change the Lyapunov exponents, an index of sensitive dependence on initial condition, a hallmark of chaos, in both groups. In the spectral analysis, the normalized high-frequency component (%HF) was decreased in EHT group at rest, and head-up tilting increased the low- to high-frequency ratio (L/H) and reduced the %HF in both groups. The CD and Lyapunov exponents at rest were correlated with the %HF and L/H. These results suggest that chaos analysis can assess the different aspect of HRV from spectral analysis and that nonlinear components of HRV may be associated with hypertension through an impaired dynamic regulation of HRV.

Impaired Isoproterenol-Induced Hyperpolarization in Isolated Mesenteric Arteries of Aged Rats

Stimulation of vascular beta-adrenoceptors leads to membrane hyperpolarization, presumably via the beta-adrenoceptor/G(s) protein/adenylate cyclase signaling cascade; the ionic mechanisms of this phenomenon remain unclear. beta-Adrenoceptor-mediated vascular relaxation is impaired with aging; however, little is known concerning whether beta-adrenoceptor-mediated hyperpolarization is altered with aging. We sought to determine the ionic mechanisms of isoproterenol-induced hyperpolarization in the rat mesenteric resistance artery, as well as the age-related changes in isoproterenol-induced hyperpolarization and their underlying mechanisms. Isoproterenol-induced hyperpolarization was inhibited by high-K(+) solution and glibenclamide (10(-6) mol/L), an inhibitor of ATP-sensitive K(+) channels (K(ATP)), but not by apamin, iberiotoxin, or charybdotoxin, inhibitors of Ca(2+)-activated K(+) channels. Isoproterenol-induced hyperpolarization was markedly less in aged rats (>/=24 months) than in adults rats (12 to 20 weeks) (3x10(-6) mol/L; -3.1 versus -9.9 mV; P<0.001; n=8 to 9). Cholera toxin (10(-9) g/mL), an activator of G(s), evoked hyperpolarization only in adult rats. Hyperpolarization to forskolin, a direct activator of adenylate cyclase, was also reduced to some extent in aged rats (10(-5) mol/L; -8.8 versus -13 mV; P<0.05; n=6), whereas hyperpolarization to levcromakalim, a K(ATP) opener, was comparable in both groups. These findings suggest that isoproterenol elicits hyperpolarization via an opening of K(ATP) in the rat resistance artery and that isoproterenol-induced hyperpolarization is attenuated in aged rats mainly because of a defective coupling of beta-adrenoceptors to adenylate cyclase and partly because of a defect at the level of adenylate cyclase, but not because of an alteration of K(ATP) per se.

Long-term compliance of salt restriction and blood pressure control status in hypertensive outpatients.

The purpose of the present study was to investigate the long-term compliance with salt restriction and blood pressure (BP) control status in Japanese hypertensive outpatients. Subjects included 103 patients, 59 women and 44 men, mean age 67 ± 9 years, who underwent successful 24-h home urine collection more than 10 times over an interval of 5 years. Urinary salt, potassium, and creatinine were measured. During the follow-up period (average 8.6 years), participants underwent urine collection 11.4 times in average. Urinary salt excretion at the last visit was significantly lower than that of the first visit (8.2 ± 3.1 vs. 9.6 ± 3.7 g/day; p < 0.01). The achievement of urinary salt excretion <6 g/day increased from 18.5% at the first visit to 26.2% at the last visit. Similarly, BP at the last visit was significantly lower than that of the first visit (130 ± 14/69 ± 11 vs. 145 ± 17/86 ± 12 mmHg; p < 0.01). The achievement rate of BP <140/90 mmHg and <130/85 mmHg also increased significantly during this period (39.2% to 70.8% and 13.7% to 39.6%, respectively, p < 0.01). Results suggest that urinary salt excretion decreased by repeated measurements using 24-h home urine collection. Lifestyle modification including weight loss as well as the intensive antihypertensive treatment contributed to the improved BP control during this period.