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ABSTRACT: INTRODUCTION: The recently approved angiotensin II (Ang II) type 1 (AT1) receptor blocker (ARB) azilsartan strongly reduces blood pressure (BP) in patients with hypertension. We previously reported that azilsartan showed unique binding behavior to the AT1 receptor because of its 5-oxo-1,2,4-oxadiazole moiety. However, the ability of azilsartan to block Ang II-dependent AT1 receptor activation is not yet clear. MATERIALS AND METHODS: Azilsartan and a derivative of azilsartan (azilsartan-7H) that lacks a carboxyl group at the benzimidazole ring were used. Ang II-induced inositol phosphate (IP) production and extracellular signal-regulated kinase (ERK) activation were analyzed in a cell-based wash-out assay. RESULTS: Azilsartan, but not azilsartan-7H, completely blocked Ang II-induced IP production and ERK activation. Our previous report demonstrated that azilsartan mainly interacts with Tyr(113), Lys(199), and Gln(257) in the AT1 receptor. The interactions between azilsartan and Tyr(113) and Gln(257), but not Lys(199), were critical for blocking Ang II-induced IP production and ERK activation after wash-out. CONCLUSIONS: Although our findings regarding the molecule-specific effects of azilsartan are based on basic research, they may lead to an exciting insight into the mechanism of azilsartan.
Journal of Renin-Angiotensin-Aldosterone System 04/2013; · 2.44 Impact Factor
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Emi Kawachi,
Yoshinari Uehara,
Koki Hasegawa,
Eiji Yahiro,
Setsuko Ando,
Yasuhiro Wada,
Tsuneo Yano,
Hiroaki Nishikawa,
Masashi Shiomi, Shin-Ichiro Miura,
Yasuyoshi Watanabe,
Keijiro Saku
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ABSTRACT: Background: High-density lipoprotein (HDL) plays a major role in reverse cholesterol transport. Many researchers have been working to enhance the biochemical function of HDL for use in therapy. Although HDL therapy using injections of apolipoprotein (apo)-A-I mimetics, apo A-I Milano or full-length apo A-I is dramatically effective, it is still unclear whether apo A-I or apo A-I mimetics actually enter atherosclerotic plaque and remove cholesterol from the lipid burden. We synthesized a novel 24-amino acid apo A-I mimetic peptide (known as FAMP) that potently removes cholesterol via specific ATP-binding cassette transporter A1. We then investigated the potential of FAMP to image developing plaque lesions in vivo. Methods and Results: FAMP was modified with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and radiolabeled with gallium-68 (68Ga) for noninvasive positron emission tomography (PET) in an animal model (familial hypercholesterolemic myocardial infarction-prone rabbits: WHHL-MI) with atherosclerotic lesions. The 68Ga-DOTA-FAMP was dramatically taken up by atherosclerotic tissues in the blood vessels and aorta of WHHL-MI rabbits, but not the control rabbits. Conclusions: An apo A-I mimetic peptide with 68Ga-DOTA is a promising candidate diagnostic tracer for PET imaging of the atherosclerotic lipid burden and may contribute to the development of a tool for the diagnosis of plaque with PET.
Circulation Journal 03/2013; · 3.77 Impact Factor
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Internal Medicine 01/2013; 52(5):637-8. · 0.94 Impact Factor
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Internal Medicine 01/2013; 52(5):639. · 0.94 Impact Factor
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Internal Medicine 01/2013; 52(7):833-4. · 0.94 Impact Factor
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ABSTRACT: Objective We compared the efficacies of irbesartan and olmesartan after successful stent implantation in patients with stable angina. Methods Twenty-six patients were randomly divided into irbesartan and olmesartan groups and treated for approximately eight months (at follow-up coronary angiography). Results There were no differences in blood pressure (BP) reduction or late loss between the groups. The BP levels in both groups at follow-up were significantly reduced. The equality of variance of systolic (S)BP (i.e., the intragroup standard deviation of SBP) in the irbesartan group was significantly smaller than that observed in the olmesartan group at follow-up. In addition, log[pentraxin-3] was significantly decreased in all of the patients at follow-up, with no differences between the groups. Interestingly, the levels of log[high-sensitive C-reactive protein(hs-CRP)] measured at 0 weeks were positively associated with in-stent late loss, and among independent biochemical variables in addition to age, gender, body mass index and the kind of angiotensin receptor blockers at 0 weeks, only these levels were related to in-stent late loss, as assessed by a multivariate analysis. Conclusion The ability of irbesartan to reduce BP is comparable to that of olmesartan, and irbesartan exhibits a lower variance of systolic BP after treatment. The level of log[hs-CRP] before stent implantation is a predictor of in-stent late loss.
Internal Medicine 01/2013; 52(7):713-9. · 0.94 Impact Factor
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Internal Medicine 01/2013; 52(3):405-406. · 0.94 Impact Factor
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ABSTRACT: The renin-angiotensin system hormone angiotensin II (Ang II) plays a central role in the pathophysiology of vasoconstriction, cardiovascular hypertrophy and hyperplasia. Two distinct subtypes of Ang II receptor, type 1 (AT1) and type 2 (AT2), have been identified, and both have been shown to belong to the G protein-coupled receptors (GPCRs) superfamily. AT1 and AT2 receptors may have antagonistic action. While the crystal structures of GPCRs obtained from the rhodopsin, opsin, and ß1 and ß2- adrenergic receptors have recently been described in different conformational states, the crystal structures of Ang II receptors have not been elucidated. The conformation range and dynamics of the effects of ligands on GPCRs may differ from one receptor to another. This review focuses on the structure and function of Ang II receptors, such as the movement of transmembrane helices, functional selectivity for AT1 receptor activation, the possibility of constitutive activity of wild-type Ang II receptors and the homo- and hetero-dimerization of Ang II receptors.
Current pharmaceutical design 11/2012; · 4.41 Impact Factor
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ABSTRACT: Angiotensin II (Ang II) type 1 (AT1) receptor is a member of the G protein-coupled receptor (GPCR) superfamily and contains 359 amino acids. AT1 receptor blockers (ARBs, e.g., eprosartan, losartan, candesartan, valsartan, telmisartan, olmesartan, irbesartan, and azilsartan) have been developed and are available for clinical use, and basic and clinical studies have shown that ARBs are useful for preventing the development of cardiovascular disease. While most ARBs have common molecular structures (biphenyl-tetrazol and imidazole groups), they also show slightly different structures. Some of the benefits conferred by ARBs may not be class-specific effects, and instead may be molecule-specific effects. Their common molecular structures are thought to be responsible for their class effects, whereas their slightly different structures may be important for promoting molecule-specific effects. This review focuses on current evidence regarding the class- and molecule-specific differential effects of ARBs from basic experiments to clinical settings.
Current pharmaceutical design 11/2012; · 4.41 Impact Factor
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ABSTRACT: For the past century, the renin-angiotensin system (RAS) has been recognized as one of the major blood pressure-regulating systems. Angiotensin II (Ang II) is the final physiologically active product of RAS, and it works not only as a strong vasopressor but also as a promotor of tissue remodeling in various organs such as heart, arteries, and kidneys. RAS is the predominant pathway of Ang II formation in human plasma, but not in the tissues. There are several alternative pathways producing angiotensin II in human tissues, and they are involved in structural remodeling of the cardiovascular system. Proteinases such as chymase, kallikrein, cathepsin G, and elastase-2 are probably responsible for angiotensin-converting enzyme (ACE)-independent Ang II formation in human tissues. In particular, chymase is an important Ang II-generating enzyme in the human heart. It is important to elucidate the mechanisms of the ACE-independent Ang II formation in human tissues; long-term inhibition of the local Ang II formation may become one of the strategies to prevent cardiovascular remodeling.
Current pharmaceutical design 11/2012; · 4.41 Impact Factor
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ABSTRACT: Chymase, a chymotrypsin-like serine protease that is abundant in secretory granules from mast cells, has been identified to be a key enzyme in the local renin-angiotensin system (RAS) that generates angiotensin II (Ang II) independent of angiotensin converting enzyme (ACE). The pathophysiological significance of alternative Ang II-forming pathways in human cardiovascular disease remains controversial. Although chymase inhibitors, unlike ACE inhibitors and Ang II type 1 receptor blockers (ARBs), may only play a small role in the regulation of the systemic RAS, the possible applications of chymase inhibitors as new drugs that inhibit the local RAS to prevent cardiovascular diseases are described in animal models. In this review, we discuss the possible application of chymase inhibitors as new drugs to inhibit the RAS in mainly cardiovascular diseases.
Current pharmaceutical design 11/2012; · 4.41 Impact Factor
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ABSTRACT: Although the use of drug-eluting stents (DES) has reduced the rate of restenosis, some problems remain regarding the usefulness of DES in small coronary arteries in addition to late thrombosis and a longer duration of dual-antiplatelet therapy. We considered 335 patients with 698 lesions who underwent DES or bare-metal stent (BMS) implantation, and randomly selected 172 DES and 124 BMS lesions that had undergone a complete data analysis and evaluation. Patients had a history of stable angina with at least 1 lesion with 50% diameter stenosis in a vessel and with a successfully minimum stent implantation (stent diameter=2.5mm). The baseline characteristics including the clinical presentation and cardiovascular risk factors were similar between the DES and BMS groups, except for the percentage of dyslipidemia (DL). Pre-procedure reference vessel diameter (RVD pre) in the DES group was significantly smaller than that in the BMS group (p<0.01), and stent length in the DES group was significantly longer (p<0.01). There was no significant difference in the cumulative incidence of major adverse cardiac events including the target lesion revascularization rate, whereas in-stent restenosis (ISR) in the DES group was significantly lower than that in the BMS group. In a multivariate analysis of ISR, diabetes mellitus, prior percutaneous coronary intervention, and DES use in clinical background were identified as independent predictors of ISR. In addition, RVD pre, stent length, and DES use in angiographical background were also identified. In conclusion, DES use is an independent predictor of ISR, although the DES group included more severely diseased small coronary arteries.
Journal of Cardiology 11/2012; · 1.28 Impact Factor
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ABSTRACT: The angiotensin II type 1 (AT(1)) receptor blocker (ARB) candesartan strongly reduces blood pressure (BP) in patients with hypertension and has been shown to have cardioprotective effects. A new ARB, azilsartan, was recently approved and has been shown to provide a more potent 24-h sustained antihypertensive effect than candesartan. However, the molecular interactions of azilsartan with the AT(1) receptor that could explain its strong BP-lowering activity are not yet clear. To address this issue, we examined the binding affinities of ARBs for the AT(1) receptor and their inverse agonist activity toward the production of inositol phosphate (IP), and we constructed docking models for the interactions between ARBs and the receptor. Azilsartan, unlike candesartan, has a unique moiety, a 5-oxo-1,2,4-oxadiazole, in place of a tetrazole ring. Although the results regarding the binding affinities of azilsartan and candesartan demonstrated that these ARBs interact with the same sites in the AT(1) receptor (Tyr(113), Lys(199) and Gln(257)), the hydrogen bonding between the oxadiazole of azilsartan-Gln(257) is stronger than that between the tetrazole of candesartan-Gln(257), according to molecular docking models. An examination of the inhibition of IP production by ARBs using constitutively active mutant receptors indicated that inverse agonist activity required azilsartan-Gln(257) interaction and that azilsartan had a stronger interaction with Gln(257) than candesartan. Thus, we speculate that azilsartan has a unique binding behavior to the AT(1) receptor due to its 5-oxo-1,2,4-oxadiazole moiety and induces stronger inverse agonism. This property of azilsartan may underlie its previously demonstrated superior BP-lowering efficacy compared with candesartan and other ARBs.Hypertension Research advance online publication, 4 October 2012; doi:10.1038/hr.2012.147.
Hypertension Research 10/2012; · 2.58 Impact Factor
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ABSTRACT: There is some evidence in prospective randomized clinical trials that the administration of adrenaline (AD) before admission for the treatment of out-of-hospital cardiac arrest did not improve survival to hospital discharge. The aim of this study was to evaluate our real-world experience regarding the efficacy of intravenous AD in out-of-hospital cardiac arrest at our university hospital. In this retrospective study, we enrolled and divided 644 patients into AD (AD administration before arrival at the hospital) and non-AD (no AD administration before arrival at the hospital) groups. The patient characteristics including age, sex, percentage of cardiac cause, location of cardiac arrest, and witnessed arrest were similar between the AD and non-AD groups. There were no significant differences between the AD and non-AD groups with regard to return of spontaneous circulation, survival to hospital admission, survival to hospital discharge, or good neurologic recovery at hospital discharge in all patients. In addition, we excluded the data of patients with extrinsic cause. We analyzed whether intravenous AD before arrival in patients with intrinsic cause was effective. The outcomes in the AD group were similar to those in the non-AD group. In conclusion, our study indicated that AD administration before arrival at the hospital for the treatment of out-of-hospital cardiac arrest did not improve the clinical outcome.
Journal of Cardiology 08/2012; · 1.28 Impact Factor
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Nihon Naika Gakkai Zasshi 07/2012; 101(7):2091-3.
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ABSTRACT: Background: The aim of the present study was to compare 2 direct measurements for low-density lipoprotein cholesterol (LDL-C) with the Friedewald calculation (LDL-C [F]) in serum and their relationship with size-and charge-based LDL subfractions in serum ultracentrifugation fractions in patients with hypercholesterolemia (HC). Methods and Results: Serum samples from 283 HC patients who participated in a statin trial (the PATROL trial) were analyzed. Homogeneous assays for LDL-C were performed using reagents from Sekisui Medical (LDL-C [Se]) and Kyowa Medex (LDL-C [Ky]). Charge-based LDL subfractions were analyzed by capillary isotachophoresis (cITP). In whole serum in HC patients at baseline, LDL-C (Se) and LDL-C (Ky) negatively and positively deviated, respectively, from LDL-C (F). The negative deviation of LDL-C (Se) from LDL-C (F) increased with increasing LDL-C, while the positive deviation of LDL-C (Ky) from LDL-C (F) was positively correlated with charge-modified LDL (cmLDL) as analyzed by cITP. In serum d>1.006g/ml and >1.040g/ml fractions (LDL and small, dense LDL fractions, respectively), the deviation of LDL-C (Ky) from LDL-C (Se) was positively correlated with LDL-apoB (the number of LDL particles) and cmLDL. Conclusions: The 2 homogenous assays for LDL-C differed with regard to reactivity toward LDL particles and cmLDL in patients with HC. Direct measurement of LDL-C that reflects modified LDL, could be a better marker for the risk of coronary heart disease. (Circ J 2012; 76: 2241-2248).
Circulation Journal 06/2012; 76(9):2241-8. · 3.77 Impact Factor
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Keita Noda,
Bo Zhang,
Atsushi Iwata,
Hiroaki Nishikawa,
Masahiro Ogawa,
Takashi Nomiyama, Shin-ichiro Miura,
Hideto Sako,
Kunihiro Matsuo,
Eiji Yahiro,
Toshihiko Yanase,
Keijiro Saku
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ABSTRACT: Dietary habits are associated with obesity, and both are important contributing factors to lifestyle-related diseases. The STYLIST study examined the effects of dietary counseling by registered dietitians and the delivery of proper calorie-controlled meals (UMIN Registration No: 000006582).
Two-hundred adult patients with hypertension and/or diabetes mellitus were randomly divided into 2 groups with/without dietary counseling and consumed an ordinary diet for 4 weeks. Each group was then subdivided into 2 groups with/without dietary counseling and received calorie-controlled lunch and dinner boxes for the next 4 weeks. The calories in the delivered meals were based on the subject's ideal body weight (BW) and physical activity level. BW, waist circumference, blood pressure, and laboratory data, including glycoalbumin, were measured at 0, 4, and 8 weeks. BW and the other parameters were significantly reduced during the study period in patients who received diet counseling in the ordinary diet period and/or delivered meal period but not in patients without dietary counseling, as assessed by linear mixed models for longitudinal data.
The combination of dietary counseling by dietitians and delivery of calorie-controlled meals was effective in reducing BW, as well as blood pressure and glycoalbumin, in patients with hypertension and/or diabetes mellitus.
Circulation Journal 05/2012; 76(6):1335-44. · 3.77 Impact Factor
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ABSTRACT: Pentraxin 3 (PTX3) is a novel candidate immunoinflammatory marker that has been reported to be associated with cardiometabolic risk factors and to predict adverse outcomes in patients with coronary artery disease. The purpose of this study was to investigate the association between the plasma levels of PTX3 and plaque vulnerability and the effect of the levels using statin in patients with coronary artery disease.
We determined the associations among the plasma levels of PTX3 and coronary plaque vulnerability in nonculprit coronary lesions with stenosis as assessed by integrated backscatter intravascular ultrasound (study 1). One hundred and eighteen consecutive patients with stable angina who underwent a percutaneous coronary intervention were enrolled. We also enrolled 53 patients with stable angina, and they were treated either with (n=36) or without (n=17) atorvastatin (10 mg/day) (study 2).
In study 1, although there was no association between the plasma levels of PTX3 and plaque vulnerability in all patients, the level of PTX3 was positively correlated with the percentage of lipid volume and negatively correlated with the percentage of fibrous volume in patients without statin treatment. There were no associations between high-sensitivity C-reactive protein levels and percentage of lipid volume and fibrous volume. Moreover, in study 2, statin therapy for 6-8 months significantly decreased the level of PTX3 in addition to high-sensitivity C-reactive protein.
The plasma level of PTX3 may be a useful biomarker for predicting the tissue characteristics of coronary plaque using integrated backscatter intravascular ultrasound. Statin therapy may have a beneficial effect with regard to the reduction of PTX3 levels.
Coronary artery disease 05/2012; 23(5):315-21. · 1.56 Impact Factor
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ABSTRACT: Little is known about the interrelationship between the lipid profile, cholesterol metabolism, and coronary risk factors in patients with hemodialysis (HD) in the presence or absence of coronary artery disease (CAD).
Ninety-five patients with HD were selected (HD group). Fifty-eight age-, gender-, and body mass index (BMI)-matched patients who had at least 1 cardiovascular risk factor were selected as a non-HD group. Total cholesterol (TC), triglyceride, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), non-HDL-C, and the ratio of LDL-C to HDL-C (L/H) in the HD group were significantly lower than those in the non-HD group. All markers of cholesterol absorption (campesterol/TC, sitosterol/TC, and cholestanol/TC) and the ratio of campesterol to lathosterol in the HD group were significantly higher. In addition, in the HD group, L/H was negatively correlated with lathosterol/TC, campesterol/TC, sitosterol/TC, and cholestanol/TC. Finally, CAD was significantly associated with lathosterol/TC (P=0.028), which was positively associated with BMI in the HD group, whereas CAD was significantly associated only with hypertension (P=0.020) in the non-HD group.
HD patients showed lower cholesterol concentrations than non-HD patients, and, as compensation, their cholesterol absorption might be accelerated. However, higher cholesterol synthesis, which was correlated with higher BMI, might be an independent predictor for the presence of CAD in HD patients.
Circulation Journal 05/2012; 76(8):1980-6. · 3.77 Impact Factor
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ABSTRACT: Fifty-four patients were randomly divided into irbesartan and olmesartan groups. Blood pressure (BP) was significantly decreased in all patients at 12 weeks. In particular, BP in patients who initially received irbesartan showed significant reductions. The equality of variance of BP in the irbesartan group was significantly smaller than that in the olmesartan group at 12 weeks. Blood concentrations of adiponectin were significantly increased in the irbesartan group at 12 weeks. Log [pentraxin-3] in the irbesartan group were significantly decreased. In conclusion, the ability of irbesartan to reduce BP is comparable to that of olmesartan with equivalent safety.
Clinical and Experimental Hypertension 05/2012; 34(5):342-9. · 1.07 Impact Factor
