Three-dimensional pharmacophore models were generated for AT1 and ET(A) receptors based on highly selective AT1 and ET(A) antagonists using the program Catalyst/HipHop. Both the best pharmacophore model for selective AT1 antagonists (Hypo-AT(1)-7) and ETA antagonists (Hypo-ET(A)-1) were obtained through a careful validation process. All five features contained in Hypo-AT(1)-7 and Hypo-ET(A)-1 (hydrogen-bond acceptor (A), hydrophobic aliphatic (Z), negative ionizable (N), ring aromatic (R), and hydrophobic aromatic (Y)) seem to be essential for antagonists in terms of binding activity. Dual AT1 and ET(A) receptor antagonists (DARAs) can map to both Hypo-AT(1)-7 and Hypo-ET(A)-1, separately. Comparison of Hypo-AT(1)-7 and Hypo-ET(A)-1, not only AT1 and ET(A) antagonist pharmacophore models consist of essential features necessary for compounds to be highly active and selective toward their corresponding receptor, but also have something in common. The results in this study will act as a valuable tool for designing and researching structural relationship of novel dual AT1 and ET(A) receptor antagonists.
Angiotensin II Type 1 Receptor Blockers ; chemistry ; Drug Design ; Endothelin Receptor Antagonists ; Models, Molecular ; Molecular Conformation

BACKGROUND/AIMS: This study was performed to observe blood pressure (BP) control rate with changes in patterns of antihypertensive drugs in patients with hypertension. METHODS: The subjects were first prescribed antihypertensive drugs from 2001 to 2009 at [Nowon] health center. The study population consisted of 1588 subjects, and they were observed with 15 additional prescriptions through prospective cohort methods. Patient initial systolic blood pressures (SBP) were >140 mmHg in all cases. RESULTS: BP was controlled in 31.3% of subjects through the first prescribed antihypertensive drugs. Calcium channel blockers (CCB) were the most common first-choice medications (52.3%), which lowered BP by 12.9 mmHg at the first prescription. The most common converted drugs in monotherapy were CCB, and CCB were converted to angiotensin II type 1 receptor blockers (ARB). Dichlozide (DCZ) was the most common medication added to CCB. The combination patterns involved addition of DCZ, CCB, and beta blockers (BB). The most common combination pattern was DCZ+CCB, and CCB (72.9%) showed the strongest BP control rate at the endpoint. Among the combination therapies, BB+DCZ+CCB (69.2%) showed the strongest BP control rate at the endpoint. CONCLUSIONS: The control rate was increased with additional visits but reached a plateau (69.8%) after the 14th visit. The percentages of monotherapy and combinations were 53.3% and 46.7%, respectively. To increase the overall control rate, further studies are needed to evaluate uncontrolled hypertension from the viewpoint of resistant hypertension.
Angiotensin II Type 1 Receptor Blockers ; Antihypertensive Agents ; Blood Pressure ; Calcium Channel Blockers ; Cohort Studies ; Humans ; Hypertension ; Prescriptions ; Prospective Studies

BACKGROUND/AIMS: Fimasartan is an angiotensin type 1 receptor blocker (ARB) which has comparable efficacy and tolerability with other ARBs. The aim of this study was to evaluate 24-hour blood pressure (BP) lowering efficacy and the tolerability of the low dose fimasartan compared with valsartan in patients with mild to moderate hypertension. METHODS: This study was a phase II, prospective, multicenter, randomized, double-blind, parallel-grouped trial. A total of 75 hypertensive patients, whose mean ambulatory BP monitoring values were ≥ 135/85 mmHg, were randomized to either fimasartan 30 mg or valsartan 80 mg daily. The primary efficacy endpoint was the change in the mean 24-hour systolic BP (SBP) values from the baseline and at the week 8. Secondary endpoints included the change in the mean 24-hour diastolic BP values, the daytime and the nighttime mean BP values at week 8, the trough-to-peak (T/P) ratio and the smoothness index. RESULTS: At week 8, the mean 24-hour SBP values significantly decreased in both groups; –10.5 ± 11.9 mmHg (p < 0.0001) in the fimasartan group and –5.5 ± 11.6 mmHg (p = 0.0307) in the valsartan group. The difference between two groups was 4.3 ± 2.9 mmHg but there was no statistical significance (p = 0.1392). The global T/P ratio in the fimasartan 30 mg groups were 0.48 and 0.40 in the valsartan 80 mg group, respectively (p = 0.3411). The most frequent adverse events (AEs) were acute pharyngitis and there were no cases of severe AEs. CONCLUSIONS: In mild-to-moderate hypertensive patients, low dose (30 mg) fimasartan showed comparable 24-hour BP lowering efficacy compared with valsartan (80 mg). There was no difference in tolerability between two groups.
Angiotensin II Type 1 Receptor Blockers ; Blood Pressure Monitoring, Ambulatory ; Blood Pressure* ; Humans ; Hypertension* ; Pharyngitis ; Prospective Studies ; Receptor, Angiotensin, Type 1 ; Valsartan

PURPOSE: Angiotensin II plays a potent role in renal injury not only by vasoconstrictive effects but also by biochemical effects. We investigated the effect of angiotensin II on ZO-1 (zonular occludens-1), a component of the slit diaphragm domain connecting slit diaphragm structure and actin cytoskeleton, in the glomerular epithelial cells (podocytes) for the glomerular damage. We tried to find that this effect could be prevented by losartan, an angiotensin II type 1 receptor blocker. METHODS: Glomerular epithelial cells were treated with various concentrations of angiotensin II and losartan. The distribution of ZO-1 was observed by confocal microscope and the change of ZO-1 expression was measured by Western blotting and RT-PCR. RESULTS: The intensities of fluorescences and bands of ZO-1 protein were decreased by angiotensin II in a dose-dependent manner by confocal microscopy and Western blot analysis, respectively. ZO-1 also moved from peripheral to inner cytoplasm and lost its linear pattern. These distributional changes of ZO-1 protein by angiotensin II were reversed by losartan in a dose-dependent manner. Angiotensin II reduced the amount and mRNA expresssion of ZO-1 which were also reversed by losartan. CONCLUSION: Angiotensin II decreases the amount of ZO-1 protein and changes its localization through angiotensin II type 1 receptor. These findings suggest that angiotensin II-added condition induces the cytoplasmic translocation and suppresses the production of ZO-1 in podocytes at transcriptional level, and could be prevented by angiotensin receptor antagonists.
Actin Cytoskeleton ; Adherens Junctions ; Angiotensin II Type 1 Receptor Blockers ; Angiotensin II* ; Angiotensin Receptor Antagonists ; Angiotensins* ; Blotting, Western ; Cytoplasm ; Diaphragm ; Epithelial Cells* ; Losartan ; Microscopy, Confocal ; Podocytes ; Receptor, Angiotensin, Type 1 ; RNA, Messenger

There are several widely used combinations of angiotensin II receptor blocker (ARB)/thiazide. The complimentary mechanism of action for such anti-hypertensive therapies is that, while ARB inhibits the vasoconstricting and aldosterone-secreting effects of angiotensin II, hydrochlorothiazide affects the renal tubular mechanisms of electrolyte reabsorption and increases excretion of sodium and chloride in the distal tubule, consequently promoting water excretion. In addition, hypokalemia, which may be triggered by a hydrochlorothiazide-induced increase in urinary potassium loss, is resisted by the use of ARB. Hence, the ARB/thiazide combination is safe in terms of potassium imbalance. For these reasons, fixed-dose ARB/thiazide combination anti-hypertensive drugs have been widely used for the treatment of hypertension. However, there have not been many studies done regarding cases where patients under such regimens showed severe hyponatremia, even when the amount of thiazide included was low. Here we report two cases in which severe hyponatremia occurred following treatment with the ARB/thiazide combinations. Upon discontinuation of the regimen, both patients showed recovery from hyponatremia.
Angiotensin II Type 1 Receptor Blockers ; Angiotensin II* ; Angiotensins* ; Antihypertensive Agents ; Humans ; Hydrochlorothiazide ; Hypertension ; Hypokalemia ; Hyponatremia* ; Potassium ; Receptors, Angiotensin* ; Sodium ; Water

PURPOSE: This prospective study aimed to evaluate the safety and efficacy of potassium-exchange resin (PER, Kalimate(R) or Argamate(R)) for managing hyperkalemia induced by Renin-Angiotensin System (RAS) blockers in chronic kidney disease (CKD) patients without their discontinuation. METHODS: Besides conservative remedies including low-potassium diet, all hyperkalemic CKD patients (n=21, [K] > or =5.6 mEq/L) received PER added on angiotensin-converting enzyme inhibitor (Moexipril, n=2) or angiotensin-receptor blocker (Irbesartan, n=19) with, at least, weekly monitoring of serum [K] if its level remains more than 5.5 mEq/L for more than 2 months (mean+/-SD, 6.8+/-5.9 mon; range, 2-26 mon). RESULTS: Baseline serum [K] on RAS blocker alone (5.1+/-0.4 mEq/L; 4.2-6.3 mEq/L) increased to 6.0 +/-0.4 mEq/L (p<0.05) before adding PER, and then it was significantly decreased to 5.3+/-0.6 mEq/L at the first clinic visit (p<0.05) and to 5.0+/-0.7 mEq/L at the last clinic visit (p<0.05) following the administration of PER added on RAS blocker. During the study period, GFR, serum creatinine and urinary protein excretion didn't change significantly. CONCLUSION: The development of hyperkalemia on RAS blockers in CKD patients doesn't necessarily lead to withdrawal of RAS blockers when the cautious add-on therapy of potassium-exchange resin with other conservative remedies launches, unless severe refractory hyperkalemia persists.
Ambulatory Care ; Angiotensin II Type 1 Receptor Blockers ; Angiotensin-Converting Enzyme Inhibitors ; Creatinine ; Diet ; Humans ; Hyperkalemia ; Prospective Studies ; Renal Insufficiency ; Renal Insufficiency, Chronic* ; Renin-Angiotensin System*

Angiotensin II Type 1 Receptor Blockers ; therapeutic use ; Angiotensin-Converting Enzyme Inhibitors ; therapeutic use ; Heart Failure ; drug therapy ; Humans ; Renin-Angiotensin System ; drug effects

BACKGROUND AND OBJECTIVES: Angiotensin II (Ang II) has been suggested to accelerate vascular senescence, however the molecular mechanism(s) remain unknown. METHODS: We cultured human coronary artery smooth muscle cells (hCSMCs) and treated Ang II and/or fimasartan. Or we transfected adenoviral vectors expressing CYR61 (Ad-CYR61) or antisense CYR61 (Ad-As-CYR61). Cellular senescence was evaluated senescence-associated β-galactosidase (SA-β-gal) assay. The molecular mechanisms were investigated real-time PCR and western blots. RESULTS: SA-β-gal-positive cells significantly increased in Ang II-treated hCSMCs (5.77±1.43-fold compared with the control). The effect of Ang II was significantly attenuated by pretreatment with the Ang II type 1 receptor blocker, fimasartan (2.00±0.92-fold). The expression of both p53 and p16 senescence regulators was significantly increased by Ang II (p53: 1.39±0.17, p16: 1.19±0.10-fold vs. the control), and inhibited by fimasartan. Cysteine-rich angiogenic protein 61 (CYR61) was rapidly induced by Ang II. Compared with the control, Ad-CYR61-transfected hCSMCs showed significantly increased SA-β-gal-positive cells (3.47±0.65-fold). Upon transfecting Ad-AS-CYR61, Ang II-induced senescence (3.74±0.23-fold) was significantly decreased (1.77±0.60-fold). p53 expression by Ang II was significantly attenuated by Ad-AS-CYR61, whereas p16 expression was not regulated. Ang II activated ERK1/2 and p38 MAPK, which was significantly blocked by fimasartan. ERK and p38 inhibition both regulated Ang II-induced CYR61 expression. However, p53 expression was only regulated by ERK1/2, whereas p16 expression was only attenuated by p38 MAPK. CONCLUSIONS: Ang II induced vascular senescence by the ERK/p38 MAPK–CYR61 pathway and ARB, fimasartan, protected against Ang II-induced vascular senescence.
Aging ; Angiotensin II Type 1 Receptor Blockers ; Angiotensin II ; Angiotensins ; Blotting, Western ; Cell Aging ; Coronary Vessels ; Humans ; Muscle, Smooth, Vascular ; Myocytes, Smooth Muscle ; p38 Mitogen-Activated Protein Kinases ; Real-Time Polymerase Chain Reaction ; Receptor, Angiotensin, Type 1

OBJECTIVETo study the effect of angiotensin II on phosphoinositide-3 kinase/Akt cascade in cultured fibroblasts derived from patients with hypertrophic scars.

METHODSThe expression of AT1 and AT2 receptor was detected by immunofluorescence staining. Cultured human skin fibroblasts were treated with Ang II (10(-9) - 10(-7) mol/L), with or without an AT1 receptor blocker, valsartan or an AT2 receptor antagonist, PD123319. The phosphorylation of Akt was detected by western blotting, and PI3K activity was measured by Assay of PI3-K activity.

RESULTSImmunofluorescence staining showed that cultured fibroblasts derived from hypertrophic scars expressed both AT1 and AT2 receptors. Ang II increased Akt phosphorylation and PI3K activity in cultured hypertrophic scar fibroblasts in a dose- and time-dependent manner. Additionally, Ang II-induced Akt phosphorylation was blocked by wortmannin, a PI3-K inhibitor. This Ang II-activated PI3-K/Akt cascade was significantly inhibited by valsartan, an AT1 receptor specific blocker (P<0.05), whereas enhanced by PD123319, an AT2 receptor antagonist (P<0.05).

CONCLUSIONThese results indicate that Ang II receptors regulates PI3-K/Akt cascade of hypertrophic scars fibroblasts via AT1 and AT2.

Angiotensin II ; pharmacology ; Angiotensin II Type 1 Receptor Blockers ; pharmacology ; Angiotensin II Type 2 Receptor Blockers ; Cells, Cultured ; Cicatrix, Hypertrophic ; metabolism ; pathology ; Fibroblasts ; cytology ; drug effects ; metabolism ; Humans ; Imidazoles ; pharmacology ; Phosphatidylinositol 3-Kinases ; metabolism ; Proto-Oncogene Proteins c-akt ; metabolism ; Pyridines ; pharmacology ; Receptor, Angiotensin, Type 1 ; Signal Transduction ; Tetrazoles ; pharmacology ; Valine ; analogs & derivatives ; pharmacology ; Valsartan

BACKGROUND: Angiotensin converting enzyme inhibitors (ACEIs) or Angiotensin II type 1 receptor blockers (ARBs) are compelling indication drugs for hypertensive patients with diabetes mellitus. But prescription rate in 2005 year study of Pohang . Gyeongju area was only 30.8%. Therefore, a study on the change of prescription rate in the same area after 3 years was done. METHODS: During three months from January 2008, 152 hypertensive patients with diabetes mellitus on their prescribed antihypertensive medications by 9 family physicians in visiting order were analyzed. After the analysis, the infl uencing factors for such prescriptions were ascertained by directly visiting each physicians who prescribed them. RESULTS: A regimen of 16 antihypertensive agents were prescribed by these family physicians. Prescription count of ACEIs or ARBs was 101 cases (66.4%). ACEIs single therapy was 19 cases (12.5%), ACEIs combination therapy was 7 cases (4.6%), ARBs single therapy was 31 cases (20.4%) and ARBs combination therapy was 44 cases (28.9%). The ACEIs or ARBs which were selected by physicians that followed "compelling indication" was 5 (55.6%), "excellent reduce pressure effect" was 3 (33.3%) and "public relations of new medicine" was 1 (11.1%). CONCLUSION: In prescribing antihypertensive agents for patients with diabetes mellitus, selection of ACEIs or ARBs was increased from 30.8% to 66.4%. Education of recommended standard by participating in such study and developing of excellent new medicines may increase such change.
Angiotensin II Type 1 Receptor Blockers ; Angiotensin-Converting Enzyme Inhibitors ; Antihypertensive Agents ; Diabetes Mellitus ; Humans ; Hypertension ; Physicians, Family ; Prescriptions ; Primary Health Care