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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: 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: 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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Shin-ichiro Miura,
Yoshihiro Kiya,
Hiroyuki Hanzawa,
Naoki Nakao,
Masahiro Fujino, Satoshi Imaizumi,
Yoshino Matsuo,
Hiroaki Yanagisawa,
Hiroyuki Koike,
Issei Komuro,
Sadashiva S Karnik,
Keijiro Saku
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ABSTRACT: Small differences in the chemical structures of ligands can be responsible for agonism, neutral antagonism or inverse agonism toward a G-protein-coupled receptor (GPCR). Although each ligand may stabilize the receptor conformation in a different way, little is known about the precise conformational differences. We synthesized the angiotensin II type 1 receptor blocker (ARB) olmesartan, R239470 and R794847, which induced inverse agonism, antagonism and agonism, respectively, and then investigated the ligand-specific changes in the receptor conformation with respect to stabilization around transmembrane (TM)3. The results of substituted cysteine accessibility mapping studies support the novel concept that ligand-induced changes in the conformation of TM3 play a role in stabilizing GPCR. Although the agonist-, neutral antagonist and inverse agonist-binding sites in the AT(1) receptor are similar, each ligand induced specific conformational changes in TM3. In addition, all of the experimental data were obtained with functional receptors in a native membrane environment (in situ).
PLoS ONE 01/2012; 7(6):e37974. · 4.09 Impact Factor
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ABSTRACT: This study analyzed the antiatherogenic effects of newly developed apolipoprotein A-I (ApoA-I) mimetic peptide/phospholipid complexes (ETC-642) against the aortic plaque burden in vivo. We used human macrophage cells to analyze cholesterol efflux by ETC-642. Watanabe-heritable hyperlipidemic (WHHL) rabbits were divided into 3 groups: low- (15mg/kg) and high-dose ETC-642 (50mg/kg), and placebo. The test material was injected twice/week for 12 weeks. The aortic plaque burden was assessed by intravascular ultrasound (IVUS) at 0 and 12 weeks. Plasma lipid profiles were analyzed by capillary isotachophoresis every 4 weeks. ETC-642 had an effect on cholesterol efflux comparable to that of conventional rHDL. In WHHL rabbits, high-dose ETC-642 inhibited the progression of aortic atherosclerosis compared to placebo. There was no change in the percentage of plaque volume (%PV) in the high-dose group between before (30.9%) and after infusion (28.6%), whereas there was a significant increase in the control group from 27.8% to 37.9%. ETC-642 significantly reduced charge-modified low-density lipoprotein (LDL) by converting more negative-charged modified LDL to less negative-charged LDL, and reduced small dense (sd) LDL by converting it into large, buoyant (lb) LDL. Changes in the %PV were positively correlated with changes in negative-charged modified LDL (r=0.61, p<0.01) and sdLDL (r=0.59, p<0.01), and negatively correlated with changes in less negative-charged LDL (r=-0.43, p<0.01) and lbLDL (r=-0.57, p<0.01). In conclusion, the ETC-642-induced remodeling of sdLDL to large and lbLDL and the enhancement of cholesterol efflux may prevent progression of the aortic plaque burden. HDL-based therapy may be useful for preventing the progression of plaque volume.
Atherosclerosis 06/2011; 218(2):300-7. · 3.79 Impact Factor
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ABSTRACT: Reconstituted (r) high-density lipoprotein (HDL) protects against coronary artery disease by promoting reverse cholesterol transport (RCT), thereby preventing atherosclerosis. In addition, rHDL has many pleiotropic effects, such as anti-oxidant, anti-inflammatory, and anti-thrombotic properties. In this study, the effects of chronic rHDL administration on blood pressure (BP), plasma lipoprotein, and charge-based HDL subfractions were examined. Thirteen male spontaneously hypertensive rats (SHRs) were randomly divided into two groups [control group (n = 6) and rHDL group (n = 7)] which received infusions of placebo [phosphate-buffered saline (PBS)] or rHDL (containing apolipoprotein A-I 6 mg/kg) administered intravenously every other day for 3 weeks. Systolic blood pressure (SBP) was measured regularly every 4 days from the beginning of the study. Three weeks after the beginning of the study, cardiac functions were recorded by echocardiography and plasma samples were collected. Although there were no significant differences in SBP, cardiac functions, or biochemical parameters between the two groups, intermediate-migrating HDL (iHDL) in the rHDL group (0.68 +/- 0.04) was significantly lower than that in the control group (0.81 +/- 0.03) based on an analysis by capillary isotachophoresis. In conclusion, chronic administration of rHDL decreased iHDL. Further investigations are needed to understand the mechanisms by which rHDL affects lipid profiles and its relation to clinical outcomes.
Clinical and Experimental Hypertension 05/2010; 32(3):202-8. · 1.07 Impact Factor
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ABSTRACT: We previously reported that the angiotensin II type 1 (AT(1)) receptor blocker (ARB) olmesartan has two important interactions to evoke inverse agonism (IA). We refer to these interactions as the "double-chain domain (DCD)." Since the clinical pharmacotherapeutic relevance of olmesartan is still unclear, we examined these effects in rats and humans. We analyzed the effects at an advanced stage of renal insufficiency in Dahl salt-sensitive hypertensive rats (Study 1). Rats were fed a high-salt diet from age 9 weeks and arbitrarily assigned to three treatment regimens at age 16 to 21 weeks: olmesartan (2 mg/kg/day) with DCD, a compound related to olmesartan without DCD (6 mg/kg/day, R-239470) or placebo. We also compared the depressor effects of olmesartan to those of other ARBs in patients with essential hypertension (Study 2). Thirty essential hypertensive outpatients who had been receiving ARBs other than olmesartan were recruited for this study. Our protocol was approved by the hospital ethics committee and informed consent was obtained from all patients 12 weeks prior to switching from ARBs other than olmesartan to olmesartan. In Study 1, olmesartan induced a more prominent suppression of the ratio of urinary protein excretion to creatinine at age 21 weeks without lowering blood pressure among the three groups. In Study 2, the depressor effect of olmesartan was significantly stronger than those of other ARBs, which do not contain the DCD. These additive effects by olmesartan may be due to DCD.
Clinical and Experimental Hypertension 01/2010; 32(2):129-36. · 1.07 Impact Factor
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ABSTRACT: Since little is known about the effects of reconstituted high-density lipoprotein (rHDL) in left ventricular (LV) remodeling, these effects were examined in rats after acute myocardial infraction (MI). Sixteen male Wistar rats were randomly divided into three groups: Sham-operated (n=6), and MI rats that received a permanent ligation around the proximal left coronary artery and infusions of placebo (MI group, n=5) or rHDL (containing as apolipoproteinA-I 6mg/kg) administered intravenously (MI+rHDL group, n=5). rHDL was infused once a week for 4 weeks. In addition, in vitro assays were performed to examine the effect of rHDL. The MI+rHDL group showed a significant increase in LV ejection fraction (EF) between weeks 1 and 4, a decrease in LV end-systolic diameter, compared with the progressive deterioration of LV size and function in the MI group. In addition, the MI+rHDL group showed a significant decrease in fibrotic area of MI in LV compared to that in the MI group, while there were no significant increases in capillary density or cell size in LV in the MI+rHDL group. Interestingly, the MI+rHDL group showed a significant activation of retinoblastoma and ERK (extracellular-signal-regulated kinase) but not cleaved caspase-3, p38 MAPK or Jun N-terminal kinase. rHDL suppressed H(2)O(2)-induced arrest of cell growth in myocytes. This effect was blocked by PD98059, an ERK inhibitor. In conclusions, rHDL-promoted cell survival has beneficial morphological effects that help to prevent LV remodeling and improve function after MI, and may prevent arrest of cell growth through ERK pathway in myocytes.
Atherosclerosis 07/2008; 203(1):137-44. · 3.79 Impact Factor
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Satoshi Imaizumi,
Shin-ichiro Miura,
Kazuto Nakamura,
Yoshihiro Kiya,
Yoshinari Uehara,
Bo Zhang,
Yoshino Matsuo,
Hidenori Urata,
Munehito Ideishi,
Kerry-Anne Rye,
Masataka Sata,
Keijiro Saku
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ABSTRACT: This study analyzed the antiarrhythmogenic effect of reconstituted high-density lipoprotein (rHDL) against ischemia/reperfusion in vivo.
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.
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.
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.
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.
Journal of the American College of Cardiology 05/2008; 51(16):1604-12. · 14.16 Impact Factor
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Noritaka Yasuda,
Shin-ichiro Miura,
Hiroshi Akazawa,
Toshimasa Tanaka,
Yingjie Qin,
Yoshihiro Kiya, Satoshi Imaizumi,
Masahiro Fujino,
Kaoru Ito,
Yunzeng Zou,
Shigetomo Fukuhara,
Satoshi Kunimoto,
Koichi Fukuzaki,
Toshiaki Sato,
Junbo Ge,
Naoki Mochizuki,
Haruaki Nakaya,
Keijiro Saku,
Issei Komuro
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ABSTRACT: The angiotensin II type 1 (AT(1)) receptor is a G protein-coupled receptor that has a crucial role in the development of load-induced cardiac hypertrophy. Here, we show that cell stretch leads to activation of the AT(1) receptor, which undergoes an anticlockwise rotation and a shift of transmembrane (TM) 7 into the ligand-binding pocket. As an inverse agonist, candesartan suppressed the stretch-induced helical movement of TM7 through the bindings of the carboxyl group of candesartan to the specific residues of the receptor. A molecular model proposes that the tight binding of candesartan to the AT(1) receptor stabilizes the receptor in the inactive conformation, preventing its shift to the active conformation. Our results show that the AT(1) receptor undergoes a conformational switch that couples mechanical stress-induced activation and inverse agonist-induced inactivation.
EMBO Reports 03/2008; 9(2):179-86. · 7.36 Impact Factor
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ABSTRACT: Although the sartan family of angiotensin II type 1 (AT(1)) receptor blockers (ARBs), which includes valsartan, olmesartan, and losartan, have a common pharmacophore structure, their effectiveness in therapy differs. Although their efficacy may be related to their binding strength, this notion has changed with a better understanding of the molecular mechanism. Therefore, we hypothesized that each ARB differs with regard to its molecular interactions with AT(1) receptor in inducing inverse agonism. Interactions between valsartan and residues Ser(105), Ser(109), and Lys(199) were important for binding. Valsartan is a strong inverse agonist of constitutive inositol phosphate production by the wild-type and N111G mutant receptors. Substituted cysteine accessibility mapping studies indicated that valsartan, but not losartan, which has only weak inverse agonism, may stabilize the N111G receptor in an inactive state upon binding. In addition, the inverse agonism by valsatan was mostly abolished with S105A/S109A/K199Q substitutions in the N111G background. Molecular modeling suggested that Ser(109) and Lys(199) bind to phenyl and tetrazole groups of valsartan, respectively. Ser(105) is a candidate for binding to the carboxyl group of valsartan. Thus, the most critical interaction for inducing inverse agonism involves transmembrane (TM) V (Lys(199)) of AT(1) receptor although its inverse agonist potency is comparable to olmesartan, which bonds with TM III (Tyr(113)) and TM VI (His(256)). These results provide new insights into improving ARBs and development of new G protein-coupled receptor antagonists.
Molecular Endocrinology 02/2008; 22(1):139-46. · 4.54 Impact Factor
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ABSTRACT: Atherosclerotic changes in the rabbit have been evaluated by various methods. Although most previous studies have analyzed atherosclerotic plaque in the femoral, carotid and iliac arteries of rabbits by intravascular ultrasound (IVUS) because of easier access, we established a method for the precise measurement of plaque volume as well as plaque area in the thoracic descending aorta in the Watanabe heritable hyperlipidemic (WHHL) rabbit, which has severe atherosclerosis.
WHHL and Japanese White (JW)rabbits were used. An IVUS catheter was inserted into the right femoral artery and advanced to the left subclavian artery, which was used as an anatomical landmark. After IVUS image acquisition, the catheter was removed. Vessel volume, lumen volume and plaque volume were analyzed.
Atheroma of the aorta was easily detected in WHHL rabbits by IVUS examination, whereas atherosclerosis was not observed in JW rabbits. The atheroma showed a low-echoic lesion compared to the adventitia, with morphological characteristics similar to human lipid-rich, soft atheromatous plaques. In 15-month-old WHHL rabbits, the vessel volume, lumen volume and plaque volume in the thoracic descending aorta were 815 +/- 109, 559 +/- 107 and 256 +/- 10 mm3/ 3 cm, respectively.
We established a method for the precise quantitation of plaque volume by IVUS technology in WHHL rabbits aorta for the first time. This method is useful for evaluating several locally or generally delivered therapeutic agents in a hyperlipidemic animal model.
Journal of Cardiology 11/2007; 50(4):229-34. · 1.28 Impact Factor
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ABSTRACT: Both mildly modified LDL subfraction that carries a more-negative electric charge and remnant-like particles (RLP) are closely related to triglyceride (TG) levels. We examined the relation between the RLP-cholesterol (C) level and charge-based apolipoprotein (apo) B-containing lipoprotein subfractions as determined by capillary isotachophoresis (cITP) in patients with hypercholesterolemia.
cITP apo B lipoprotein subfractions were identified by analyzing plasma depleted of the related lipoproteins. While fast-migrating triglyceride-rich lipoprotein (fTRL) subfraction contained both chylomicrons and VLDL fraction, slow TRL (sTRL) only contained VLDL. cITP fLDL also contained VLDL fraction, i.e., beta-VLDL. Levels of cITP fTRL and sTRL were significantly correlated with serum levels of TG, RLP-C, apo C-II, and C-III. Levels of cITP sTRL were also correlated with apo E. Levels of cITP fLDL were positively correlated with not only LDL-C levels but also levels of TG, RLP-C, apo C-II, C-III, and E.
cITP fast LDL correlated with RLP-C levels and modified the relation between RLP-C and TG levels.
Atherosclerosis 04/2007; 191(1):153-61. · 3.79 Impact Factor
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Atsushi Iwata,
Shin-ichiro Miura, Satoshi Imaizumi,
Yoshihiro Kiya,
Hiroaki Nishikawa,
Bo Zhang,
Hideki Shimomura,
Koichiro Kumagai,
Kunihiro Matsuo,
Kazuyuki Shirai,
Keijiro Saku
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ABSTRACT: Many angiotensin II type 1 receptor blockers (ARBs) are available for clinical use, but because they do not all have the same effects, the present study investigated whether all benefits conferred by ARBs are class effects.
Study 1 was a case-control study of patients with coronary artery disease, which showed that a non-depressor dose of valsartan significantly decreased the rate of target lesion revascularization at 6 months after stenting compared with the control group without ARB treatment. In Study 2, 44 patients with acute myocardial infarction who randomly received an initial lower dose of either valsartan or losartan after stenting were evaluated. The late loss and decrease in %diameter stenosis in the valsartan group were significantly lower than those in the losartan group as assessed by quantitative coronary angiography after 6 months. In addition, the valsartan group showed a significantly lower expression of intracellular adhesion molecule-1 and L-selectin.
A non-depressor dose of ARB may have beneficial effects on coronary restenosis that are associated with the regulation of adhesion molecules, and these effects might not be a class effect of ARBs.
Circulation Journal 02/2007; 71(1):32-8. · 3.77 Impact Factor
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Shin-ichiro Miura,
Masahiro Fujino,
Hiroyuki Hanzawa,
Yoshihiro Kiya, Satoshi Imaizumi,
Yoshino Matsuo,
Sayo Tomita,
Yoshinari Uehara,
Sadashiva S Karnik,
Hiroaki Yanagisawa,
Hiroyuki Koike,
Issei Komuro,
Keijiro Saku
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ABSTRACT: To delineate the molecular mechanism underlying the inverse agonist activity of olmesartan, a potent angiotensin II type 1 (AT1) receptor antagonist, we performed binding affinity studies and an inositol phosphate production assay. Binding affinity of olmesartan and its related compounds to wild-type and mutant AT1 receptors demonstrated that interactions between olmesartan and Tyr113, Lys199, His256, and Gln257 in the AT1 receptor were important. The inositol phosphate production assay of olmesartan and related compounds using mutant receptors indicated that the inverse agonist activity required two interactions, that between the hydroxyl group of olmesartan and Tyr113 in the receptor and that between the carboxyl group of olmesartan and Lys199 and His256 in the receptor. Gln257 was found to be important for the interaction with olmesartan but not for the inverse agonist activity. Based on these results, we constructed a model for the interaction between olmesartan and the AT1 receptor. Although the activation of G protein-coupled receptors is initiated by anti-clockwise rotation of transmembrane (TM) III and TM VI followed by changes in the conformation of the receptor, in this model, cooperative interactions between the hydroxyl group and Tyr113 in TM III and between the carboxyl group and His256 in TM VI were essential for the potent inverse agonist activity of olmesartan. We speculate that the specific interaction of olmesartan with these two TMs is essential for stabilizing the AT1 receptor in an inactive conformation. A better understanding of the molecular mechanisms of the inverse agonism could be useful for the development of new G protein-coupled receptor antagonists with inverse agonist activity.
Journal of Biological Chemistry 08/2006; 281(28):19288-95. · 4.77 Impact Factor
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ABSTRACT: We previously reported that angiotensin-converting enzyme inhibitors (ACE-Is) promote collateral circulation in patients with coronary artery disease (CAD). There have been many reports on the beneficial effects of angiotensin II type 1 receptor blockers (ARBs) on the cardiac microvasculature. Therefore, the following studies were performed to evaluate the association between treatment with an ARB and the enhancement of coronary collateral circulation as assessed by the Rentrop Score (RS) (Study 1) and to compare these results to those obtained with an ACE-I (Study 2). The subjects were 456 patients with angina who underwent coronary angiography. Study 1: Those who had one (1-V), two (2-V) or three significantly stenosed vessels (3-V) and who received only an ARB without any other anti-hypertensive medication were defined as the ARB group (n=81), and age-, sex- and body mass index-matched subjects (n=146) were selected as a comparative group. There were no significant differences in the percentage of patients with RS>or=1 between the two groups. Study 2: Those who received an ACE-I as the only anti-hypertensive treatment were defined as the ACE-I group (n=67), which was matched to the ARB group in Study 1. The percentage of patients with RS>or=1 in the ACE-I group was significantly higher than that in the ARB group as assessed by a Cochran-Mantel-Haenszel analysis. In addition, patients with 3-V disease who were treated with an ACE-I, but not an ARB, were most likely (odds ratio [confidence Interval]): 27.7 [4.8-161.0]) to show enhanced collateral circulation, as assessed by a multiple logistic regression analysis. These results suggest that treatment with an ACE-I, but not treatment with an ARB, was associated with the enhancement of collateral circulation in patients with CAD.
Hypertension Research 03/2006; 29(3):135-41. · 2.58 Impact Factor
