Comparison of Efficacy and Safety of Azilsartan and Olmesartan in Patients With Essential Hypertension.

Many patients still have high blood pressure (BP) after treatment with angiotensin II type 1 (AT1) receptor blockers (ARBs). We compared the efficacy and safety of azilsartan to those of olmesartan in a prospective randomized clinical trial. Sixty-four hypertensive patients who were treated with ARBs other than azilsartan and olmesartan were enrolled in this study. We randomly assigned patients to changeover from their prior ARBs to either azilsartan or olmesartan, and followed the patients for 3 months. Systolic BP (SBP) in the azilsartan group was significantly decreased at 3 months, and diastolic BP (DBP) and pulse rate (PR) in the olmesartan group showed significant reductions after 3 months. There were no significant differences in ΔSBP, ΔDBP, or ΔPR (Δ = the value at 3 months minus the value at 0 months) between the groups. Serum levels of creatinine (Cr), uric acid (UA), and potassium (K) in the azilsartan group significantly increased after 3 months. While the changes in Cr, UA, and K were within the respective normal ranges, ΔSBP was positively associated with ΔCr in the azilsartan group. In conclusion, there was no difference in the depressor effects of azilsartan and olmesartan, and there were no serious changes in biochemical parameters with azilsartan and olmesartan.

Isolated pulmonary arterial stenosis caused by Takayasu's arteritis in an elderly male.

Takayasu's arteritis has often been difficult to diagnose because of a lack of typical symptoms and other specific makers. We report here a case of Takayasu's arteritis in a 73-year-old man who was considered to exhibit isolated pulmonary artery involvement. Pulmonary hypertension and right heart failure and severe stenosis in the main trunk and left pulmonary artery were observed. There was nothing remarkable in his routine blood-sample tests other than increased CRP and ESR. There were neither infectious nor collagen diseases. Anti-cardiolipin antibody, Antiphospholipid Syndrome, PR3-ANCA and MPO-ANCA were negative. We diagnosed the patient as having Takayasu's arteritis based on chronic inflammation and the morphologic features of pulmonary artery lesion. However, other large vessels and the aorta were not involved. Treatment was started with glucocorticoids. The symptoms gradually improved, and pulmonary artery pressure estimated by echocardiography decreased along with inflammatiory markers. There were no remarkable changes in the stenotic lesions in the pulmonary artery but the flow limit in the left pulmonary artery was improved.

Antiarrhythmogenic effect of reconstituted high-density lipoprotein against ischemia/reperfusion in rats.

OBJECTIVES: This study analyzed the antiarrhythmogenic effect of reconstituted high-density lipoprotein (rHDL) against ischemia/reperfusion in vivo. BACKGROUND: Recent studies have suggested that a reduction in the plasma HDL level may contribute to cardiac sudden death. Although there are currently only a few therapeutic strategies for increasing HDL, an exciting new therapeutic option, rHDL, has recently been developed to prevent coronary artery disease. METHODS: To analyze the suppression of reperfusion arrhythmia by rHDL (apolipoprotein A-I with 1-palmitoyl-2-oleoyl-phosphatidyl-choline), 92 male Wistar rats were divided into 10 groups: rats that had been pre-treated with or without rHDL, apolipoprotein A-I, or 1-palmitoyl-2-oleoyl-phosphatidyl-choline in the presence or absence of inhibitors of Akt protein kinase, nitric oxide (NO), or extracellular-signal-regulated kinase (ERK) administered intravenously before left coronary artery occlusion. We also used human coronary artery endothelial cells and adenosine triphosphate-binding cassette transporter (ABC) A1-, ABCG1-, or scavenger receptor class B, type I-transfected ldlA7 cells systems. RESULTS: The duration of ventricular tachycardia or ventricular fibrillation after reperfusion in rHDL-pre-treated rats was much shorter than that in untreated rats. Apolipoprotein A-I or 1-palmitoyl-2-oleoyl-phosphatidyl-choline alone had no effect. The effect of rHDL was blocked by inhibitors of Akt, NO, and ERK. Plasma NO concentration in the rHDL group was significantly higher. In addition, rHDL activated phospho(p)-Akt, p-ERK, and p-endothelial NO synthesis in endothelial cells. The rHDL activated p-ERK in ABCA1- or ABCG1-transfected but not scavenger receptor class B, type I-transfected ldlA7 cells. CONCLUSIONS: The rHDL-induced NO production, probably mediated by ABCA1 or ABCG1 through an Akt/ERK/NO pathway in endothelial cells, may suppress reperfusion-induced arrhythmias. The HDL-based therapy may hold the promise of reducing the incidence of such arrhythmias after ischemia/reperfusion.

Positive correlation between chymase-like angiotensin II-forming activity in mononuclear cells and serum cholesterol level.

OBJECTIVES: The local renin-angiotensin system is important in cardiovascular diseases. The present study examined the association between angiotensin (Ang) II-forming activity in fractionated peripheral leukocytes and atherosclerotic risks such as blood pressure, smoking, age and serum cholesterol level, and used a new analytical approach for the measurement of chymase-like activity in peripheral blood to assess the relationship between the chymase-like activities in leukocytes and atherosclerotic risks. METHODS: Peripheral blood samples were obtained from normal and high blood pressure patients in the presence or absence of ischemic heart disease. Mononuclear cell or polymorphonuclear cell fraction of leukocyte was isolated by centrifugation with either Lymphoprep or Polymorphprep, respectively. Chymase-like, angiotensin converting enzyme, and cathepsin G-dependent Ang II-forming activities in the homogenates of mononuclear cell or polymorphonuclear cell fraction were measured using Ang I as a substrate. RESULTS: The chymase-like Ang II-forming activity in the mononuclear cell fraction slightly or significantly increased in non-smoker patients with high blood pressure (systolic and diastolic blood pressure, p = 0.11; mean blood pressure, p < 0.05). Chymase-like Ang II-forming activity in the mononuclear cell fraction positively correlated with serum total cholesterol (p < 0.05) level. CONCLUSIONS: Our data indicates that chymase in mononuclear cells from peripheral blood is activated by high blood pressure or hypercholesterolemia.

Higher small arterial elasticity in hypertensive patients treated with angiotensin II receptor blockers.

Although evidence from basic research suggests the involvement of angiotensin II (Ang II) in the progression of arteriosclerosis, the clinical data are limited. In the present study, hypertensive outpatients who were well controlled with antihypertensive medication and had similar blood pressure levels were studied, and arterial elasticity was compared between those receiving Ang II receptor blockers (ARBs) and those treated with other antihypertensive agents. The effects of HMG-CoA reductase inhibitors (STs) on arterial elasticity were also evaluated. The study enrolled 298 outpatients who had been diagnosed with essential hypertension whose blood pressure was controlled to 150/95 or less by antihypertensive treatment (excluding angiotensin converting enzyme [ACE] inhibitors) for at least 2 months. The small artery elasticity index (SAEI) was determined for each patient from the radial artery pulse waves using a non-invasive pulse wave analysis system CR-2000. The mean of two blood pressure measurements taken from subjects lying in a recumbent position during SAEI analysis was used for the data analysis. The patients were grouped according to the use of ARBs and STs, and two-way analysis of variance (ANOVA) was used for statistical comparisons. A backward stepwise multiple regression analysis was carried out to identify factors contributing to the SAEI. Hypertensive patients receiving ARB treatment had a significantly higher SAEI compared to those not receiving ARBs, despite the similar blood pressure levels of both groups. No significant effects of ST treatment on the SAEI were observed (two-way ANOVA). A backward stepwise multiple regression analysis for the SAEI suggested that ARB treatment was an independent determinant of the SAEI after the adjusting of age, gender, total cholesterol, high density lipoprotein cholesterol, smoking and systolic blood pressure. Our results suggested that while providing blood pressure control similar to that of other antihypertensive agents, ARBs may also increase vascular elasticity and thereby delay the progression of arteriosclerosis.

Influence of age and hypertension on the association between small artery compliance and coronary artery disease.

Small artery elasticity index (SAEI) as determined by a new non-invasive pulse-wave contour analysis has been used to identify abnormalities of the arterial wall associated with aging, hypertension (HT), endothelial dysfunction, and coronary artery disease (CAD). The present study examined the influence and interaction of CAD risk factors on the association between SAEI in risk-associated patients with CAD (case subjects, n = 178) and without CAD (control subjects, n = 202). Case subjects had a lower SAEI than control subjects, and age was consistently and negatively correlated with SAEI. The HT was related to reduced SAEI in female subjects overall and in male case subjects. In male patients with hypertension, the association between SAEI and CAD was significant (P < .05) after considering conventional risk factors of CAD. In conclusion, age and HT should be considered when using SAEI in the early diagnosis of CAD, and lower SAEI could be of greatest diagnostic value in male patients with HT.

Role of prehypertension in the development of coronary atherosclerosis in Japan.

BACKGROUND: Hypertension is an important risk factor of coronary heart disease. A new guidelines for hypertension prevention and management in The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure in the United States recommended lifestyle modification or medical treatment for subjects with prehypertension. However, whether prehypertension increases the risk of coronary atherosclerosis in the Japanese population is still unknown. METHODS: A cross-sectional study in a clinical setting was conducted. The subjects were 705 patients (417 males and 288 females) aged 30 years and older who underwent a first-time coronary angiography for suspected or known coronary heart disease at 5 major cardiology departments in the Fukuoka metropolitan area between September 1996 and August 1997. RESULTS: Compared to subjects with normal blood pressure, those with prehypertension had an increased risk of coronary atherosclerosis even after adjusting for other factors. CONCLUSION: Prehypertension may be an important clinical entity which requires treatment in the Japanese population.

Human chymase expression in a mice induces mild hypertension with left ventricular hypertrophy.

A number of in vitro studies have suggested potential pathophysiological roles of human (h-) chymase. However, the lack of an appropriate animal model has left the in vivo roles of chymase unclear. To approach this problem, a transgenic mouse (TGM) model carrying the h-chymase gene was established. The h-chymase cDNA transgene was constructed with the chicken beta actin promoter and cytomegalovirus immediate early gene enhancer, and injected into mouse oocytes. Homozygous mice with a high copy number of the h-chymase gene suffered from intrauterine death. In three heterozygous TGM lines, h-chymase transgene expression was detected in entire organs, including the heart, vessels, skin, liver, lung, and brain. The h-chymase immunoreactivity was localized in the extracellular matrices of each organ, especially on the basement membranes of vessels. Aortic and hepatic chymase-dependent angiotensin II formations were significantly higher than those in the wild-type littermates. Three independent TGM lines showed the same phenotypic changes: elevation of blood pressure, left ventricular hypertrophy, emaciation with reduction in the lipid tissue, leukocytosis, and oligotrichia. The angiotensin II subtype 1 (AT1) receptor antagonist valsartan suppressed the elevated blood pressure completely and left ventricular hypertrophy incompletely, but did not affect the other phenotypes. These data suggested that in vivo expression of h-chymase caused mild hypertension (AT1 receptor-dependent) with left ventricular hypertrophy (partially AT1 receptor-dependent), and also chronic inflammatory changes (AT1 receptor-independent).

Chymase inhibitor improves survival in hamsters with myocardial infarction.

The purpose of the present study was to assess the effects of chronic treatment with an orally active chymase inhibitor, 4-[1-(naphthylmethyl)benzimidazol-2-ylthio]butanoic acid (TEI-E548), in a hamster myocardial infarction model. In the first experiment, after confirming the biochemical inhibitory action of TEI-E548 on human and hamster chymases (Ki = 6.2 and 30.6 nM, respectively), the biological action of TEI-E548 in vivo was assessed by the inhibition of hamster chymase-induced microvascular leakage. In the second experiment, myocardial infarction was produced by coronary artery ligation in male Syrian hamsters. TEI-E548 (0.1% containing chow) was given 24 h after surgery and continued for 3 or 5 weeks, while the control and sham-operated groups were fed a standard chow. The survival rate was assessed in each group. At the end of each study period, blood pressure was measured at the left hind-limb, the heart rate and cardiac function were measured by echocardiography, the end-diastolic pressure by a direct catheterization, and organ weights and biochemical parameters, including plasma renin and angiotensin-converting enzyme activities and plasma angiotensin I and angiotensin II concentrations, were measured. In the first experiment, a standard chow containing 0.1% TEI-E548 completely inhibited the hamster chymase-induced microvascular leakage. In the second experiment, TEI-E548 treatment significantly increased the survival rate (37% versus control), and attenuated cardiac hypertrophy (13% versus control) and end-diastolic left ventricular pressure (34% versus control), but it did not decrease the infarction size nor improve the ejection fraction. The plasma angiotensin II concentration post-myocardial infarction was significantly suppressed by TEI-E548 throughout the study period. We conclude that TEI-E548 is an orally active useful chymase inhibitor and improves survival and cardiac hypertrophy of the post-myocardial infarction hamster.

Reperfusion-induced arrhythmias are suppressed by inhibition of the angiotensin II type 1 receptor.

We examined antiarrhythmic effects of drugs, including renin-angiotensin system (RAS) inhibitors, on reperfusion arrhythmias in rats in vivo. Anesthetized rats were subjected to 5 min of coronary occlusion and 30 min of reperfusion. Arrhythmia scores, calculated as the product of the type of arrhythmia (1 for ventricular tachycardia, 2 for ventricular fibrillation) and its duration (in seconds), were adopted to evaluate the severity of arrhythmias. Reperfusion arrhythmias were suppressed by Na(+)/H(+) exchange inhibitor, Na(+)/Ca(2+) exchange inhibitor and L-type Ca channel antagonist by more than 90%. Angiotensin-converting enzyme inhibitor and angiotensin II (Ang II) type 1 receptor (AT(1)) antagonist also modestly (by 60-70%) but significantly decreased reperfusion arrhythmias. These effects were not reversed by co-administration of bradykinin B(2) receptor antagonist or AT(2) antagonist, respectively. Effects of superoxide dismutase (SOD) were also examined, but SOD proved ineffective. Effects of Na(+)/H(+) exchange inhibitor, Na(+)/Ca(2+) exchange inhibitor and L-type Ca channel antagonist suggest a causative relationship of Ca overload in reperfusion arrhythmias. These transport systems are known to be activated by Ang II. Thus, the antiarrhythmic action of RAS inhibitors might be attributable to the inhibition of the action of Ang II via AT(1).

Efficacy and Tolerability of Nilvadipine in Combination with an Angiotensin II Receptor Antagonist in Patients with Essential Hypertension: A Multicenter, Open-Label, Uncontrolled Study.

BACKGROUND: Combination therapy with different classes of antihypertensive drugs often is needed to achieve controlled blood pressure (BP). The combination of an angiotensin II receptor antagonist (AIIA) and a calcium antagonist is a preferred option for reducing uncontrolled BP. OBJECTIVE: The aim of this study was to assess the clinical efficacy and tolerability of nilvadipine, a dihydropyridine calcium antagonist, in combination with an AIIA. METHODS: Patients with essential hypertension whose BP was not controlled by an AIIA alone were eligible for this multicenter, open-label, uncontrolled study. One of 3 AIIAs (candesartan cilexetil, losartan potassium, or valsartan) was given for at least 10 weeks before the addition of nilvadipine (daily dose, 4 or 8 mg orally). This combination therapy was given for 8 weeks. BP and heart rate were measured between 2 and 4 weeks before and 0, 4, and 8 weeks after the start of combination therapy. Adverse events were monitored at each visit. RESULTS: Thirty-one patients (18 women [58.1%], 13 men [41.9%]; mean [SD] age, 58.5 [10.5] years) were enrolled. At weeks 4 and 8 of combination therapy, mean systolic BP (SBP) and diastolic BP (DBP) were significantly decreased (P<0.01) (at week 8, by 22.0 mm Hg and 12.5 mm Hg, respectively). The mean BP-lowering effect did not differ significantly between the 3 AIIAs tested. Pulse pressure also decreased significantly at week 8, by 9.6 mm Hg (P<0.01). The responder rate (ie, the percentage of patients with DBP <90 mm Hg or a decrease in DBP ≥10 mm Hg) was 72.0% at week 8. Three patients experienced a total of 4 adverse events: mild or severe flushing, mild headache, and mild palpitation. All of these symptoms resolved after nilvadipine treatment was discontinued. CONCLUSIONS: Nilvadipine in combination with an AIIA showed good antihypertensive efficacy and was well tolerated in the hypertensive patients in this study. This combination also significantly decreased pulse pressure, suggesting that this combination therapy also may have a beneficial effect in elderly patients with isolated systolic hypertension.

Relation between type A behavior pattern and the extent of coronary atherosclerosis in Japanese women.

This study examined the relation of Type A behavior pattern and its components to angiographically documented coronary atherosclerosis in 198 Japanese women. A questionnaire-based interview elicited psychosocial and other factors. Type A behavior pattern was measured by 12 questions. Significant coronary stenosis was defined when a 75% or greater luminal narrowing occurred at one or more major coronary arteries or 50% or greater narrowing occurred at the left main artery. Gensini's score also was calculated. Logistic regression analysis was used to calculate odds ratios and 95% confidence intervals with adjustment for traditional coronary risk factors and the presence of a job. Global Type A behavior pattern showed no material association with the severity of coronary atherosclerosis assessed by both Gensini's score and the presence of significant coronary stenosis. However, its subcomponents, enthusiasm and competitiveness, were positively related to the severity of coronary atherosclerosis, whereas self-confidence and perfectionism were negatively related. These findings suggest overall a null association between global Type A and coronary atherosclerosis as well as the presence of toxic or beneficial components of Type A behaviors in Japanese women.

Chymase inhibition suppresses high-cholesterol diet-induced lipid accumulation in the hamster aorta.

OBJECTIVE: The role of chymase (a mast cell-derived angiotensin II-forming serine proteinase) in aortic lipid deposition was investigated using an orally active, non-peptide chymase inhibitor, SUN-C8257. METHODS: Male golden Syrian hamsters, 8 weeks old, were fed with a standard rodent meal supplemented with or without 0.5% cholesterol and 10% coconut oil for 12 weeks. The hamsters fed high cholesterol diet were further separated into two groups treated with or without SUN-C8257 for 12 weeks. The aortic lipid deposition was visualized by Oil red O staining and planimetrically measured. Immunohistochemical staining for angiotensin II (Ang II) of the aortic root region was performed. Aortic Ang II-forming activity was measured using Ang I as a substrate. Plasma total-, low-density lipoprotein (LDL)-, high-density lipoprotein (HDL)-cholesterol and triglyceride were quantified by enzymatic methods. Plasma Ang I and Ang II were measured by radioimmunoassay. RESULTS: After 12 weeks of high cholesterol diet, aortic chymase activity in the untreated group increased significantly and showed a positive correlation with plasma total- and LDL-cholesterol. This group of hamsters developed marked lipid deposits in the aortic intima. However, treatment with SUN-C8257 significantly suppressed aortic lipid deposition without changing body weight, blood pressure, plasma LDL-cholesterol and Ang II levels. The level of the adventitial Ang II-immunoreactivity was markedly inhibited in the group treated with SUN-C8257. CONCLUSION: Our results suggest that arterial chymase may participate in the acceleration of lipid deposition in arterial walls exposed to high plasma cholesterol and that inhibition of arterial chymase may retard the progression of atherosclerosis.