Atsuhiko Takahashi

Kinins contribute to the improvement of insulin sensitivity during treatment with angiotensin converting enzyme inhibitor.

Although angiotensin converting enzyme inhibitors and alpha 1-blockers have been reported to improve insulin sensitivity, their mechanisms of action have not been elucidated. To investigate the role of kinins in insulin sensitivity, we treated 4-week-old spontaneously hypertensive rats with either an angiotensin converting enzyme inhibitor (enalapril), an alpha 1-blocker (doxazosin), or an angiotensin II antagonist (losartan) for 3 weeks. A control group received no drugs. In addition, 18 rats treated with enalapril or doxazosin received a simultaneous administration of a kinin antagonist (Hoe 140). Glucose clamp testing was performed in each group. Enalapril (128 +/- 1 mmHg) and doxazosin (132 +/- 2 mmHg) decreased mean blood pressure compared with control levels (148 +/- 1 mmHg) (P < .01). The glucose requirement for the clamp test during the administration of enalapril (25.8 +/- 0.5 mg/kg per minute) or doxazosin (28.6 +/- 0.7 mg/kg per minute) was higher than that of the control group (19.8 +/- 0.5 mg/kg per minute) (P < .05). Although Hoe 140 did not alter the glucose requirement of doxazosin (27.8 +/- 0.5 mg/kg per minute), it decreased that of enalapril (22.6 +/- 0.9 mg/kg per minute) (P < .05) without affecting the changes in mean blood pressure induced by enalapril. In addition, losartan decreased mean blood pressure but did not affect the glucose requirement. Thus, the improvement in insulin sensitivity produced by an angiotensin converting enzyme inhibitor is mostly dependent on kinins but not on angiotensin II antagonism, and an alpha 1-blocker improves insulin sensitivity irrespective of kinins.

Four Blood Pressure Indexes and the Risk of Stroke and Myocardial Infarction in Japanese Men and Women A Meta-Analysis of 16 Cohort Studies

Background— Information has been sparse on the comparison of 4 blood pressure (BP) indexes (systolic BP [SBP], diastolic BP, pulse pressure, and mean BP [MBP]) in relation to long-term incidence of stroke and myocardial infarction, particularly in middle-aged and older Asians. Methods and Results— The Japan Arteriosclerosis Longitudinal Study Group conducted a meta-analysis of 16 cohort studies in Japan. A total of 48 224 men and women 40 to 89 years of age participated at baseline, and 1231 stroke events and 220 myocardial infarction events occurred during an average 8.4-year follow-up. Multivariate-adjusted hazard ratios with a 1-SD higher value for each BP index were determined by Poisson regression. Analyses were also done in 4 age-sex groups. All 4 BP indexes were significantly related to all stroke risk. Stroke risk was most strongly related to MBP and SBP in both sexes and most weakly related to pulse pressure. Both stroke subtypes, ischemic and hemorrhagic, were most strongly related to MBP and SBP in both sexes. In addition, in men and women 70 to 89 years of age, MBP or SBP showed the strongest relation to all stroke risk. Myocardial infarction risk was most strongly related to SBP or MBP in both sexes. For any end points in any age-sex groups, pulse pressure was not the strongest predictor. Conclusions— The long-term incident risk of stroke and myocardial infarction associated with high BP in East Asian populations should be assessed mainly on the basis of SBP. MBP also may be an important predictor, but pulse pressure is a less important predictor for cardiovascular disease risk.

Effect of morning and bedtime dosing with cilnidipine on blood pressure, heart rate, and sympathetic nervous activity in essential hypertensive patients

Cilnidipine has a blocking action against N-type calcium channels as well as L-type calcium channels. We studied the effect of morning and bedtime dosing on circadian variation of blood pressure (BP), heart rate (HR), and activity of the autonomic nervous system, using an open randomized crossover study in 13 essential hypertensive patients. An automated device allowed 24-hour monitoring of ambulatory BP and HR and the power spectrum of the R-R interval, at the observation period, the morning dosing regimen, and the bedtime dosing regimen. Morning dosing and bedtime dosing with cilnidipine reduced the average systolic BP over 24 hours, during daytime, and during nighttime. The average HR and the average LF/HF ratio over 24 hours, during daytime, and during nighttime, were similar for the three periods. Both morning and bedtime dosing reduced the maximum systolic BP in the early morning and suppressed the morning rise of BP, which were accompanied by partial inhibition of the increase in LF/HF ratio. Our results show that cilnidipine administered once daily is an efficient antihypertensive drug regardless of the time of dosing, without reflex tachycardia and increase in sympathetic nervous activity, and with partial inhibition of the morning activation of the sympathetic nervous system.

Oral peppermint oil is a useful antispasmodic for double-contrast barium meal examination

Background and Aim:  Intraluminally administered peppermint oil (PO) is reportedly a safe and useful antispasmodic for gastroscopy, colonoscopy and double‐contrast barium enema. The aim of this study was to examine the efficacy of oral PO for double‐contrast barium meal examination (DCBM) without other antispasmodics.

Cardiovascular remodeling and metabolic abnormalities in SHRSP.Z-Lepr(fa)/IzmDmcr rats as a new model of metabolic syndrome.

The purpose of this study was to evaluate whether the spontaneously hypertensive rat SHRSP.Z-Leprfa/IzmDmcr (SHRSP fatty) is a useful animal model to clarify molecular mechanisms that underlie metabolic syndrome. We investigated histopathologic changes in the cardiovascular organs and metabolic characteristics of SHRSP fatty rats, which are congenic rats from a cross between SHRSP and Zucker fatty (ZF) rats. The aortic wall and cardiac, carotid, and renal arteries from SHRSP and SHRSP fatty rats were thicker than those of ZF rats. The renal cortex in SHRSP and SHRSP fatty rats showed severe glomerulosclerosis. Pancreatic islands in SHRSP fatty and ZF rats showed marked hyperplasia. Steady-state plasma glucose concentrations were higher in SHRSP fatty than in ZF rats. Non-fasting triglyceride levels in SHRSP fatty rats were higher than in ZF rats. DNA synthesis in cultured vascular smooth muscle cells (VSMCs) from SHRSP fatty and SHRSP rats was significantly higher than that in VSMCs from Wistar-Kyoto (WKY) or ZF rats. Levels of platelet-derived growth factor A-chain and transforming growth factor-β1 mRNAs were higher in VSMCs from SHRSP fatty and SHRSP than from ZF rats. Microarray analysis identified five genes that were significantly upregulated and four genes that were significantly downregulated in visceral adipose tissue of SHRSP fatty rats compared with levels in control strains (SHRSP and ZF rats). These findings suggest that the combination of hypertension and obesity accelerates vascular remodeling, dyslipidemia, and insulin resistance in metabolic syndrome. The phenotype of SHRSP fatty is similar to that of human metabolic syndrome, and therefore, studies of these rats may help clarify the molecular mechanisms that underlie metabolic syndrome in humans.

Association of Fish Consumption-Derived Ratio of Serum n-3 to n-6 Polyunsaturated Fatty Acids and Cardiovascular Risk With the Prevalence of Coronary Artery Disease.

We investigated the relationships between the ratio of serum n-3 polyunsaturated fatty acids (n-3PUFAs: eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) to n-6PUFA (arachidonic acid [AA]) and the prevalence of coronary artery disease (CAD), and assessed the association of the ratio of serum n-3 to n-6 PUFAs with atherosclerosis-related markers.This study was designed as a hospital-based cross-sectional study of 649 consecutive outpatients who had undergone regular examinations between April 2009 and October 2009. We divided the patients into 5 groups based on the quintiles of the EPA/AA ratio or quintiles of the DHA/AA ratio to determine independent factors for the prevalence of CAD.In multivariate logistic regression analyses after adjustment for coronary risk factors and serum n-3PUFAs levels to minimize confounding factors to the extent possible because the serum levels of EPA and DHA showed a strong correlation (r = 0.812, P < 0.0001), the group with the highest EPA/AA ratio had a lower probability of CAD prevalence (odds ratio: 0.328, 95% confidence interval: 0.113 to 0.956, P = 0.041), but this was not true for the DHA/AA ratio. Multivariate analysis showed an increase in the EPA/AA ratio, but not in the DHA/AA ratio, was associated with effects on atherosclerosis-related markers, especially triglyceride-rich lipoproteins, high-density lipoprotein cholesterol (HDL-C) containing apolipoprotein A-1, and leukocyte count in an anti-atherogenic direction.The results suggest a higher EPA/AA ratio, but not a higher DHA/AA ratio, might be associated with a lower prevalence of CAD and improvements of triglyceride metabolism and HDL metabolism, and systemic inflammation.

Variations in insulin sensitivity in spontaneously hypertensive rats from different sources

We investigated the possibility of variations in the genetic transmission of insulin sensitivity in the offspring of spontaneously hypertensive rats (SHRs) and Wistar Kyoto rats (WKYs) obtained from different sources (Charles River, Tokyo, Japan [NCrj]; and Funabashi Farm, Chiba, Japan [Izm]) with the insulin suppression test (IST) using a somatostatin analog, glucose, and insulin. The steady-state blood glucose (SSBG) in the IST and the glucose infusion required (GIR) in the euglycemic-hyperinsulinemic clamp differ significantly between obese and lean Zucker rats, indicating that both methods are useful for identifying insulin resistance. The fasting blood glucose and SSBG of the IST were significantly higher in SHR/Izm than in WKY/Izm. We did not observe a significant difference between SHR/NCrj and WKY/NCrj. These results indicate that the genetic transmission of hypertension and impaired insulin sensitivity may be variable and that insulin resistance does not play an important role in the pathogenesis of hypertension in the SHR.

Sociodemographic Correlates of Four Indices of Blood Pressure and Hypertension Among Older Persons in Japan

Background: High blood pressure is a significant risk factor for cardiovascular disease and mortality. Japan has traditionally had higher levels of measured blood pressure than many Western countries, and reducing levels of hypertension has been a major focus of Japanese health policy over recent decades. In the West, hypertension is strongly associated with sociodemographic and behavioral (smoking and body mass index, BMI) factors; studies of the association between sociodemographic factors and biological indicators have not been fully explored in the elderly population of Japan using nationally representative survey data. Objective: To describe hypertension prevalence rates with increasing age and to examine the link between sociodemographic and behavioral factors (including age, gender, education, residence, smoking, and BMI) and measures of blood pressure and overall hypertension in the Japanese population aged ≥68 years. Methods: Data were collected in 2006 during the fourth wave of the Nihon University Japanese Longitudinal Study of Aging, a nationally representative sample of those ≥68. The analytic sample includes 2,634 participants. Pulse pressure, systolic, diastolic, and mean blood pressure, as well as hypertension, were regressed on sociodemographic and behavioral factors. Results: There is no significant difference in the prevalence of overall hypertension by age for men and women from ages 68-69 to 90+. Higher BMI and older age were linked to higher blood pressure and higher chance of having hypertension. More years of education and being female were associated with a lower likelihood of measured hypertension. Smoking, rural residence, and living alone were not significantly associated with the outcome measures. Conclusion: The increase in hypertension with higher BMI raises concerns about future health in Japan as BMI increases. The lack of a relationship between smoking and any measure of blood pressure or hypertension is an indicator that smoking may have different effects in Japan than in other countries. Because there is no effect of living alone on blood pressure, compliance with drug regimes may not be enhanced by living with others in Japan.

Different effects of L-type and L+N-type calcium channel blockers on hamster cheek pouch venules.

Dihydropyridine calcium channel blockers are not uniform in terms of their action on calcium channel. L-type calcium channel blockers dilate the resistance arterioles. Cilnidipine is a dihydropyridine calcium channel blocker that also acts on N-type calcium channels, and may dilate venules through its effect on the sympathetic receptor. The influence of an L-type calcium channel blocker (nifedipine) or this L+N type blocker at 10−7 mol to 10−4 mol on venular diameter was examined by superfusion of male Syrian hamster cheek pouches. Nifedipine dose dependently dilated the arterioles alone, whereas cilnidipine dilated both arterioles and venules. Application of 10−7 mol ω conotoxin, an inhibitor of N-type channels, after nifedipine led to significant dilation of venules, while it had no influence when administered after cilnidipine. These findings indicate that the effects of calcium channel blockers on the venules differ according to the action on N-type calcium channels, and that cilnidipine (an L+N type calcium channel blocker) dilates venules through its additional action on N-type channels.

Renoprotective effect and cost-effectiveness of using benidipine, a calcium channel blocker, to lower the dose of angiotensin receptor blocker in hypertensive patients with albumiuria

In hypertensive patients with chronic renal disease, angiotensin receptor blockers (ARBs) are among the first-line drugs, and calcium channel blockers (CCBs) are recommended as a second line. We examined the effects of two therapeutic strategies using ARBs and benidipine, a CCB, on blood pressure (BP), urinary albumin excretion (UAE), and cost-effectiveness in hypertensive patients with albuminuria. Patients whose BP was 140/90 mmHg or higher despite treatment with low- or medium-dose ARBs were assigned randomly to two groups. In Group A (n=14), the ARB dose was maximized and then benidipine was added until BP targets were reached (<130/85 mmHg). In Group B (n=18), benidipine was administered first and then the ARB dose was increased until BP targets were reached. The BP targets were achieved by ARB alone in 36% of Group A patients and by the addition of benidipine in 83% of Group B patients. Finally, BP decreased in each group, reaching the targets in 93% of Group A patients and 94% of Group B patients after a 4-month therapeutic period. UAE was decreased in both groups after a 4-month therapeutic period compared to the allocation period (−33±6% in Group A, −31±6% in Group B; p<0.001, respectively). The monthly drug cost was higher (11,426±880 vs. 8,955±410 yen, p=0.012) and the cost-effectiveness of antihypertensive treatment was lower (p=0.003) in Group A than in Group B. We conclude that the addition of benidipine to low- or medium-dose ARB is, in light of the renal protection and the cost-effectiveness of this approach, a useful therapeutic strategy for controlling BP in hypertensive patients with albuminuria.