Toshio Kushiro

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.

Usefulness of Pravastatin in Primary Prevention of Cardiovascular Events in Women Analysis of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA Study)

Background— It is well known that statins reduce the risk of cardiovascular disease. However, the effect of statins in women for the primary prevention of cardiovascular disease has not been determined. We conducted an exploratory analysis of the effect of diet plus pravastatin therapy on the primary prevention of cardiovascular events in women with data from a large-scale primary prevention trial with pravastatin. Methods and Results— Patients with hypercholesterolemia (5.7 to 7.0 mmol/L) and no history of coronary heart disease or stroke were randomized to diet or diet plus pravastatin 10 to 20 mg/d and followed up for ≥5 years. We investigated the effect of diet plus pravastatin treatment on cardiovascular events in 5356 women during the 5-year follow-up. The incidence of cardiovascular events in the women was 2 to 3 times lower than that in men. The occurrence of cardiovascular events was 26% to 37% lower in the diet plus pravastatin treatment group than in the diet alone group. Although these differences did not reach statistical significance, the overall risk reductions were similar to those in men. Notably, women ≥60 years of age treated with diet plus pravastatin had markedly higher risk reductions for coronary heart disease (45%), coronary heart disease plus cerebral infarction (50%), and stroke (64%) than did women treated with diet alone. Conclusions— Treatment with pravastatin in women with elevated cholesterol but no history of cardiovascular disease provides a benefit similar to that seen in men, and this benefit is more marked in older women. This treatment should be considered routinely for primary cardiovascular protection in women with elevated cholesterol levels.

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.

Blood pressure response to hyperinsulinemia in salt-sensitive and salt-resistant rats.

We investigated the role of insulin in salt-sensitive hypertension in Dahl salt-sensitive and salt-resistant rats. The rats were kept in metabolic cages, and sodium intake and urinary sodium excretion were measured. In salt-sensitive rats receiving a 0.3% NaCl diet, sodium retention was significantly greater at weeks 1 and 2 in rats that received an insulin infusion than in those receiving a saline infusion. Mean arterial blood pressure and plasma norepinephrine levels were significantly higher at week 3 in insulin-treated rats than in saline-treated rats (mean arterial pressure, 137 +/- 3 mm Hg versus 119 +/- 3 mm Hg, p < 0.05; plasma norepinephrine, 0.40 +/- 0.02 ng/ml versus 0.27 +/- 0.01 ng/ml, p < 0.05). Insulin did not influence sodium retention, mean arterial pressure, or plasma norepinephrine in salt-resistant rats. Coadministration of an alpha-blocker (bunazosin, 10 mg/kg per day for 3 weeks) in salt-sensitive rats abolished the insulin-induced elevations in mean arterial pressure and sodium retention. When salt-sensitive rats were fed a low salt diet (0.03% NaCl), insulin did not raise mean arterial pressure. Thus, insulin elevated blood pressure only in the salt-sensitive model. The sympathetic nervous system and sodium retention in the early phase of insulin overload may contribute to elevation of mean arterial pressure in this model.

Home Blood Pressure and Cardiovascular Outcomes in Patients During Antihypertensive Therapy Primary Results of HONEST, a Large-Scale Prospective, Real-World Observational Study

This study aimed to investigate the relationship between on-treatment morning home blood pressure (HBP) and incidence of cardiovascular events using data from the Home Blood Pressure Measurement With Olmesartan Naive Patients to Establish Standard Target Blood Pressure (HONEST) study, a prospective observational study of 21 591 outpatients with essential hypertension (mean age, 64.9 years; women, 50.6%) enrolled between 2009 and 2010 at clinics and hospitals in Japan. They received olmesartan-based treatment throughout. The primary end point was major cardiovascular events. After a mean follow-up period of 2.02 years, cardiovascular events occurred in 280 patients (incidence, 6.46/1000 patient-years). The risk for the primary end point was significantly higher in patients with on-treatment morning HBP ≥145 to <155 mm Hg (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.12–2.99) and ≥155 mm Hg (HR, 5.03; 95% CI, 3.05–8.31) than <125 mm Hg and with on-treatment clinic blood pressure ≥150 to <160 mm Hg (HR, 1.69; 95% CI, 1.10–2.60) and ≥160 mm Hg (HR, 4.38; 95% CI, 2.84–6.75) than <130 mm Hg. Morning HBP associated with minimum risk was 124 mm Hg by spline regression analysis. Cardiovascular risk was increased in patients with morning HBP ≥145 mm Hg and clinic blood pressure <130 mm Hg (HR, 2.47; 95% CI, 1.20–5.08) compared with morning HBP <125 mm Hg and clinic blood pressure <130 mm Hg. In conclusion, it is essential to control morning HBP to <145 mm Hg, even in patients with controlled clinic blood pressure. Clinical Trial Registration— URL: . UMIN Clinical Trials Registry, trial No. UMIN000002567. # Novelty and Significance {#article-title-18}This study aimed to investigate the relationship between on-treatment morning home blood pressure (HBP) and incidence of cardiovascular events using data from the Home Blood Pressure Measurement With Olmesartan Naive Patients to Establish Standard Target Blood Pressure (HONEST) study, a prospective observational study of 21 591 outpatients with essential hypertension (mean age, 64.9 years; women, 50.6%) enrolled between 2009 and 2010 at clinics and hospitals in Japan. They received olmesartan-based treatment throughout. The primary end point was major cardiovascular events. After a mean follow-up period of 2.02 years, cardiovascular events occurred in 280 patients (incidence, 6.46/1000 patient-years). The risk for the primary end point was significantly higher in patients with on-treatment morning HBP ≥145 to <155 mm Hg (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.12–2.99) and ≥155 mm Hg (HR, 5.03; 95% CI, 3.05–8.31) than <125 mm Hg and with on-treatment clinic blood pressure ≥150 to <160 mm Hg (HR, 1.69; 95% CI, 1.10–2.60) and ≥160 mm Hg (HR, 4.38; 95% CI, 2.84–6.75) than <130 mm Hg. Morning HBP associated with minimum risk was 124 mm Hg by spline regression analysis. Cardiovascular risk was increased in patients with morning HBP ≥145 mm Hg and clinic blood pressure <130 mm Hg (HR, 2.47; 95% CI, 1.20–5.08) compared with morning HBP <125 mm Hg and clinic blood pressure <130 mm Hg. In conclusion, it is essential to control morning HBP to <145 mm Hg, even in patients with controlled clinic blood pressure. Clinical Trial Registration—URL: http://www.umin.ac.jp/ctr/index.htm. UMIN Clinical Trials Registry, trial No. UMIN000002567.

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.

Pravastatin reduces the risk for cardiovascular disease in Japanese hypercholesterolemic patients with impaired fasting glucose or diabetes: Diabetes subanalysis of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study

Diabetes mellitus (DM) is a major risk factor for cardiovascular disease (CVD) in patients with no history of CVD. Evidence for the effect of statins on CVD in the diabetic population in low-risk populations (e.g., Japanese) is limited. We evaluated the effect of pravastatin on risk reduction of CVD related to baseline glucose status in a primary prevention setting. The Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study, in patients with mild-to-moderate hypercholesterolemia (220-270 mg/dL), showed that low-dose pravastatin significantly reduced the risk for CVD by 26%. This exploratory subanalyses examined the efficacy of diet plus pravastatin on CVD in 2210 patients with abnormal fasting glucose (AFG, including 1746 patients with DM and 464 patients with impaired fasting glucose (IFG) at 5 years in the MEGA Study. CVD was threefold higher in AFG patients (threefold higher in DM, and twofold higher in IFG) compared with normal fasting glucose (NFG) patients in the diet group. Diet plus pravastatin treatment significantly reduced the risk of CVD by 32% (hazard ratio 0.68, 95% CI 0.48-0.96, number needed to treat, 42) in the AFG group compared with the diet alone group, and no significant interaction between AFG and NFG (interaction P=0.85) was found. Safety problems were not observed during long-term treatment with pravastatin. In conclusion, pravastatin reduces the risk of CVD in subjects with hypercholesterolemia and abnormal fasting glucose in the primary prevention setting in Japan.

Role of sympathetic activity in blood pressure reduction with low calorie regimen.

To investigate the effects of a low calorie regimen on sympathetic function and its relation to blood pressure response, 22 untreated obese essential hypertensive patients (50±2 years, body mass index 29 ±1 kg/m2) were hospitalized and a diet was prescribed of 2,000 kcal/day for 5 days (control period) followed by 800 kcal/day for 21 days without changing salt intake (8-10 g/day). The dose of intravenous phenylephrine infusion needed to elevate systolic blood pressure 20 mm Hg (CD20) and the 24-hour urinary excretion of norepinephrine (UNE) were measured. During the low calorie period, blood pressure normalized in 14 patients (responder group, 124±3/79±4 mm Hg) and eight remained hypertensive (poor responder group, 158±6/103±3 mm Hg). At the control period, blood pressure and body mass index were similar, but the responder group had higher UNE (134±15 μ/day) and CD20 (127±11 μg) than the poor responder group (89±6 μ/day and 79±13 μ, respectively). During the low calorie period, both UNE (87±15 μg/day) and CD20 (74±10 μ) decreased in the responder group; no change was seen in the poor responder group. Changes in UNE and systolic blood pressure were correlated (r=0.6, p<0.05). In conclusion, suppression of sympathetic activity plays a role in blood pressure reduction during moderate caloric restriction.

Pravastatin for Cardiovascular Event Primary Prevention in Patients With Mild-to-Moderate Hypertension in the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study

Lipid-lowering therapy in individuals with high risk of cardiovascular disease reduces the incidence of coronary heart disease. However, few studies have assessed the benefits of cholesterol lowering for primary prevention of coronary heart disease in hypertensive patients with mild dyslipidemia or without conventional dyslipidemia. The large, randomized Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese Study showed a 33% reduction in coronary heart disease incidence with pravastatin as the primary prevention in Japanese patients. We conducted an exploratory analysis of the effect of diet plus pravastatin therapy on the primary prevention of cardiovascular events (coronary heart disease, coronary heart disease plus cerebral infarction, and cardiovascular disease) in the 3277 patients with hypertension during the 5-year follow-up. There were no significant differences in mean baseline total cholesterol, blood pressure levels, or variation in blood pressure during the 5-year period between the diet (n=1664) and diet plus pravastatin (n=1613) groups. In the diet plus pravastatin group, the relative risk of coronary heart disease plus cerebral infarction was reduced by 35% (hazard ratio: 0.65; CI: 0.46 to 0.93; P=0.02), cerebral infarction by 46% (hazard ratio: 0.54; CI: 0.29 to 0.98; P=0.04), and cardiovascular disease by 33% (hazard ratio: 0.67; CI: 0.49 to 0.91; P=0.01). In patients without a history of cardiovascular disease who have hypertension and mildly elevated cholesterol, pravastatin was effective in reducing the incidence of cardiovascular disease, particularly cerebral infarction. Hence, in patients with hypertension with mildly elevated cholesterol levels, treatment with a statin is advisable to reduce the burden of cardiovascular disease.

Close Relationship of Abnormal Glucose Tolerance With Endothelial Dysfunction in Hypertension

Hypertension is frequently accompanied by left ventricular hypertrophy, endothelial dysfunction, and abnormal glucose metabolism. However, no study has examined the relative pathological significance of left ventricular hypertrophy and abnormal glucose metabolism on endothelial dysfunction in hypertension. This study was conducted to evaluate whether abnormal glucose tolerance assessed by 75-g oral glucose tolerance test or left ventricular hypertrophy is more closely associated with endothelial dysfunction in never-treated hypertensive patients without elevated fasting blood glucose. We studied 107 unmedicated hypertensive patients (mean age, 54+/-10 years) whose fasting blood glucose was <7.0 mmol/L. Endothelial function was assessed by change in brachial artery diameter in response to reactive hyperemia, and left ventricular mass index was determined by ultrasonography. Simple linear regression analysis demonstrated that endothelial function significantly correlated with left ventricular mass index and 2-hour blood glucose in 75-g oral glucose tolerance test, but not with fasting blood glucose. Multiple linear regression analysis revealed that endothelial function significantly correlated with 2-hour blood glucose (beta=-2.68, P<0.05) after we controlled for other clinical variables. Patients were divided into 3 groups according to 2-hour blood glucose levels. Endothelial function was more impaired in patients with diabetes (n=12; 4.7+/-1.8%) and in those with impaired glucose tolerance (n=31; 6.3+/-2.9%) than in those with normal glucose tolerance (n=64; 8.4+/-4.5%) (P<0.05), but left ventricular mass index was similar in these 3 groups. Abnormal glucose tolerance assessed by 75-g oral glucose tolerance test, rather than left ventricular hypertrophy, may have direct pathophysiological relevance to endothelial dysfunction in borderline to moderate hypertensive patients.