No abstract available.
Angiotensin II ; Angiotensin Receptor Antagonists ; Angiotensins ; Hyperkalemia ; Receptors, Angiotensin

BACKGROUND: Renin-ngiotensin system (RAS) blockers have been used to delay the progression of various renal diseases, but these medications cause hyperkalemia and the elevation of serum creatinine which impede the continuation of the medications. So far, there have been no data on the changes of serum creatinine or serum potassium after withdrawal of the RAS blockers. METHODS: We reviewed medical records of 60 patients who stopped the RAS blockers due to the elevation of serum creatinine or hyperkalemia between March 1995 and May 2005. They were assigned to either the elevated creatinine group or the hyperkalemia group according to the cause of the withdrawal. RESULTS: In the elevated creatinine group (n=37), the serum creatinine and GFR values at the point of withdrawal were 4.0+/-1.8 mg/dL and 18.2+/-10.4 mL/min/1.73m2, respectively. After discontinuation of the medications, a decrease in serum creatinine and an increase in GFR were noted at one month. After one month, however, serum creatinine increased continuously up to 6 months. Serum potassium levels decreased significantly after the drug withdrawal until the end of the study period. In the hyperkalemia group (n=23), the serum creatinine and serum potassium values at the point of withdrawal were 3.0+/-1.0 mg/dL and 6.4+/-0.4 mEq/L, respectively. A significant decrease in serum potassium was also noted after the withdrawal and this decrease lasted up to 6 months. But the transient decrease of serum creatinine, observed in the creatinine group, was not seen in this group. CONCLUSION: It was found that there was a beneficial effect on serum creatinine and GFR immediately after the withdrawal of RAS blockers only when they were stopped due to elevation of the serum creatinine concentration. The serum potassium levels were consistently decreased after the withdrawal of RAS blockers in both elevated creatinine and hyperkalemia groups.
Angiotensin II* ; Angiotensin Receptor Antagonists ; Angiotensins* ; Creatinine* ; Humans ; Hyperkalemia ; Medical Records ; Potassium* ; Renal Insufficiency, Chronic*

Whether immunosuppressive therapy may have beneficial effects in the treatment of IgA nephropathy remains controversial. ACE inhibitor or angiotensin II receptor antagonist(AIIA) are suggested to reduce urinary protein excretion(Up) in patients with renal diseases. We therefore investigated the effects of the angiotensin II receptor antagonist losartan on the proteinuria and renal function in patients with IgA nephropathy. AIIA reduced blood pressure in patients with hypertension, but there were no significant differences statistically before and after therapy. AIIA reduced Up after 1-4 months(2.8+/-1.1 to 1.1+/-1.0g/24h, p=0.001) and 7-13 months(2.8+/-1.1 to 1.7+/-0.6g/24h, p=0.017). There were no significant changes of serum creatinine levels after AIIA treatment. Cough or angioedema were not observed during AIIA treatment. In conclusion, AIIA may be useful in the treatment of patients with IgA nephropathy and proteinuria.
Angioedema ; Angiotensin II* ; Angiotensin Receptor Antagonists* ; Angiotensins* ; Blood Pressure ; Cough ; Creatinine ; Glomerulonephritis, IGA ; Humans ; Hypertension ; Losartan ; Proteinuria ; Receptors, Angiotensin*

Pharmacotherapy for the treatment of heart failure has advanced considerably in recent years, and clinical trials have demonstrated the favorable long-term effects of angiotensin-converting enzyme inhibitors (ACEI) and beta-blockers on the morbidity and mortality. Although the current guidelines recommend ACEI and beta-blockers as standard therapy for heart failure, as they have demonstrated benefits in terms of mortality, only one third of patients with heart failure are receiving both classes of drug due to concern over their adverse effects. The benefit of ACEI has been attributed largely to blockade of angiotensin II production, but also to the accumulation of bradykinin. The accumulation of bradykinin however, has been implicated as contributing to adverse effects, such as a dry cough, associated with ACEI treatment, and has also been suggested to result in prejunctional norepinephine release. Recently, many clinical trials have shown that angiotensin receptor blockers (ARBs) had similar effect on the mortality and morbidity of patients with heart failure. The side effects, notably the cough, are significantly less than with ACE inhibitors. ARBs could also be recommended for patients who can not tolerate ACE inhibitors for symptomatic treatment. In combination with ACEI, ARBs may improve the symptoms of heart failure, and reduce hospitalizations due to heart failure deterioration. Whether concomitant beta-blockade negatively affects the effect of ARB will require further evaluation. In this paper, recent large clinical trials of ARBs therapy in heart failure, and the ongoing clinical trials, were reviewed for the recommendation of the optimal conditions for ARBs treatment in heart failures.
Angiotensin II* ; Angiotensin Receptor Antagonists* ; Angiotensin-Converting Enzyme Inhibitors ; Angiotensins* ; Bradykinin ; Cough ; Drug Therapy ; Estrogens, Conjugated (USP)* ; Heart ; Heart Failure* ; Hospitalization ; Humans ; Mortality ; Receptors, Angiotensin*

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: Weight reduction is a lifestyle intervention that has been introduced for prevention and management of chronic kidney disease (CKD). We investigate the additive anti-proteinuric effect of weight reduction on the usage of angiotensin II receptor blockers (ARBs) and its potential mechanisms in hypertensive CKD patients. METHODS: This study is a subanalysis of data from an open-label, randomized, controlled clinical trial. Among the 235 participants, 227 were assigned to subgroups according to changes in body weight. RESULTS: Fifty-eight participants (25.6%) were assigned to group 1 (≥1.5% decrease in body weight after 16 weeks), 32 participants (14.1%) were assigned to group 2 (1.5–0.1% decrease in body weight), and 136 participants (59.9%) were assigned to group 3 (≥ 0.0% increase in body weight). Characteristics at enrollment were not different among the three groups, but mean differences in weight and percent changes in urinary sodium excretion over the period were statistically different (P < 0.001 and P = 0.017). Over the study period, unintentional weight loss independently increased the probability of reduced albuminuria (group 1, relative risk 6.234, 95% confidence interval 1.913–20.315, P = 0.002). Among urinary cytokines, only podocalyxin level decreased significantly in participants who lost weight (P = 0.013). CONCLUSION: We observed that weight loss had an additive effect on the anti-proteinuric effects of ARBs in nondiabetic hypertensive CKD patients, although it was minimal. An additive effect was shown in both obese and non-obese participants, and its possible mechanism is related to reduction of podocyte damage.
Albuminuria ; Angiotensin II* ; Angiotensin Receptor Antagonists* ; Angiotensins* ; Body Weight ; Cytokines ; Humans ; Hypertension ; Life Style ; Podocytes ; Proteinuria* ; Receptors, Angiotensin* ; Renal Insufficiency, Chronic* ; Sodium ; Weight Loss*

The physiological roles of brain angiotensin II in mediating water deprivation-induced drinking and in regulating renal renin release were assessed in male Sprague-Dawley rats. Specific AT1 receptor antagonists, losartan and SK 1080, and antisense oligonucleotide (AS-ODN) directed to AT1 receptor mRNA were intracerebroventricularly (i.c.v.) administered in conscious unrestrained rats. When water was given 20 min after i.c.v. injection of AT1 receptor antagonists in 48-h water-deprived rats, losartan and SK 1080 produced approximatly 20% and 50% decrease in 1-h water intake, respectively. In contrast, i.c.v. treatment of the AS-ODN to AT1 receptor mRNA for 24-h did not alter 1-h water intake in 24-h water-deprived rats, but prevented the increase in overnight water intake after 24-h water-deprivation. Six-day i.c.v. treatment of AS-ODN did not alter either the basal plasma renin concentration or renal cortical levels of renin and renin mRNA. The present results suggest that endogenous brain Ang II plays an important role in thirst and water intake through AT1 receptors, but further studies are required to elucidate its regulatory role in renal renin synthesis.
Angiotensin II* ; Angiotensin Receptor Antagonists* ; Angiotensins* ; Animals ; Brain* ; Drinking* ; Humans ; Losartan ; Male ; Negotiating ; Plasma ; Rats* ; Rats, Sprague-Dawley ; Receptors, Angiotensin* ; Renin* ; RNA, Messenger ; Thirst ; Water

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

To reduce cardio-cerebro-vascular and renal morbidity and mortality, the current guidelines on the treatment of hypertension recommend evaluating and managing total cardiovascular risks of the patient with hypertension, not just focused on reducing blood pressure itself. In this point of view, the angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) are considered to be ideal drugs in the treatment of hypertension, because the angiotensin II plays a pivotal role in every stage of cardiovascular disease continuum. Many studies have shown that the ARBs were not only effective in lowering blood pressure, but also had another role in reducing morbidity and mortality of heart failure, myocardial infarction, stroke, diabetic nephropathy, chronic kidney disease, and the recurrence of atrial fibrillation, so called beyond blood pressure lowering effects or pleiotropic effects. However, these favorable effects of ARBs are counter-balanced by some debating issues, myocardial infarction paradox or cancer risk. Furthermore, the issue whether ARBs could replace the role of ACEIs in the treatment of cardiovascular diseases is not resolved yet. Because there have been no randomized studies proving the ARBs are better than ACEIs in terms of cardiovascular morbidity or mortality, the current status of the role of ARBs are an reasonable alternative of ACEIs. In this review, the current issues and status of ARBs will be discussed.
Angiotensin II ; Angiotensin Receptor Antagonists ; Angiotensin-Converting Enzyme Inhibitors ; Angiotensins ; Atrial Fibrillation ; Blood Pressure ; Cardiovascular Diseases ; Diabetic Nephropathies ; Heart Failure ; Humans ; Hypertension ; Myocardial Infarction ; Receptors, Angiotensin ; Recurrence ; Renal Insufficiency, Chronic ; Stroke

To investigate the molecular mechanism of angiotensin II (Ang II) receptor activation in adult rat cardiac fibroblasts, the expressions of cell signal transduction-associated genes were studied by using cDNA microarray. Cardiac fibroblasts of adult Sprague-Dawley rats (230~250 g) were isolated and cultured. The cells were divided into 4 groups: Ang II, Ang II + losartan, Ang II + PD123319, Ang II + losartan + PD123319. The expressions of Ang II receptors were studied by immunohistochemical staining. Total RNA was extracted and purified. After cDNA synthesis and biotin-16-dUTP labeling, the probes were denatured and hybridized with GEArray Q Series mouse G Protein-coupled Receptors Signaling Pathway Finder Gene Array (MM-025) containing 96 genes associated with 11 pathways. The arrays were scanned with a Uniscand1000 scanner and further analyzed with GEArray Analyzer software. RT-PCR was used to further confirm the results of gene microarray. The results of immunohistochemical staining showed that the expression of Ang II type 2 (AT2) receptor was evidently induced by Ang II stimulation when Ang II type 1 (AT1) receptor was blocked. The results of gene array indicated that blocking AT1 receptor changed 34 genes (more than 2 folds), 30 were down-regulated and 4 were up-regulated. The maximum change was not beyond 20 folds. The following 9 pathways were activated: cAMP/PKA, Ca2+, PKC, PLC, MAPK, PI-3 kinase, NO-cGMP, Rho, NF-kappaB pathways. Blockade of AT2 receptor caused 64 genes changing more than 2 folds (48 were down-regulated and 16 were up-regulated). Eleven pathways were basically activated. The change of the following 7 genes was over 30 folds: Cyp19a1 (37 folds), Il1r2 (42 folds), Cflar (53 folds), Bcl21 (31 folds), Pik3cg (278 folds), Cdkn1a (90 folds), Agt (162 folds). According to the activated extent, the signal transduction pathways in turn were PI-3 kinase, NF-kappaB and JAK-STAT pathways. Blocking both AT1 and AT2 receptors changed 46 genes more than 2 folds (36 were down-regulated and 10 were up-regulated). Eleven pathways were basically activated. The results of RT-PCR of IL-1beta and TNF-alpha confirmed the observations in gene microarray. Our results show that Ang II can induce a high expression of AT2 receptor in adult rat cardiac fibroblasts when AT1 receptor is blocked, and the signal mechanism of AT2 receptor is clearly different from that of AT1 receptor.
Angiotensin II ; pharmacology ; Angiotensin Receptor Antagonists ; pharmacology ; Animals ; Fibroblasts ; metabolism ; Gene Expression ; Imidazoles ; pharmacology ; Losartan ; pharmacology ; Myocardium ; cytology ; Pyridines ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptor, Angiotensin, Type 1 ; metabolism ; Receptor, Angiotensin, Type 2 ; metabolism ; Signal Transduction