• YAKHAK HOEJI
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• v.58 no.1
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• pp.16-20
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• 2014

KR-31064 was developed for the strong angiotensin II receptor antagonist among the one of pyridyl imidazol series compounds. To investigate the receptor-ligand binding characteristics of this nonpeptide antagonist, binding experiments were deployed in various conditions and ex vivo contractile responses were tested toward the standard compound, losartan. Receptor binding experiments with radiolabeled angiotensin II, the $IC_{50}$ value for KR-31064 resulted 0.67 nM without any activities toward type 2 angiotensin II receptor. The comparative potency against losartan was more than 18 fold and the specific activity in type 1 angiotensin II receptor was more than 10,000 fold comparing to the type 2 receptor. Scatchard analysis of saturation binding data showed KR-31064 acted on the receptor in a competitive mode. KR-31064 inhibited the contractile response derived by angiotensin II ($pK_B$: 9.86) similar to that of losartan with decreased maximum signals. As a potent and specific type 1 angiotensin II receptor antagonist, KR-31064 may have possibilities for the development of diagnostic ligands that can be used as tools for various biochemical research experiments and non-invasive diagnostics.

• The Korean Journal of Physiology and Pharmacology
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• v.3 no.3
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• pp.315-320
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• 1999

Molecular regulation of the renin-angiotensin system (RAS) was investigated in deoxycorticosterone acetate (DOCA)-salt hypertension. The expression of renin, angiotensinogen and angiotensin II receptor genes in the kidney and liver was determined by Northern blot analysis in rats which were made DOCA-salt hypertensive over the period of 2 or 4 weeks. Along with the hypertension, renin mRNA was decreased in the remnant kidney. The expression of angiotensinogen gene was not significantly altered in the kidney, but was significantly decreased in the liver. The expression of angiotensin II receptor gene was increased in the kidney, while it remained unaltered in the liver. The duration of hypertension did not affect the altered gene expression. It is suggested that the components of RAS are transcriptionally regulated in DOCA-salt hypertension in a tissue-specific manner.

• Journal of Genetic Medicine
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• v.2 no.1
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• pp.27-30
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• 1998

Previously, we made a study report on the genotype distribution and the gene frequency of angiotesin I-converting enzyme (ACE) in Korean population, and on the association between hypertension and genetic variance of ACE. This time, we have investigated a rapid mismatch-PCR/RFLP assays for the variant of the angiotesin II type 1 receptor ($AT_1R$) gene (an $A{\rightarrow}C$ transversion at position 1166 of $AT_1R$ gene), a mutation which may interact with the ACE polymorphism in the determining of risk of myocardial infarction. The genotype distributions of Koreans' angiotensin II type 1 receptor gene were AA (66.3%):AC (28.1%):CC (5.6%), thus the AA genotype was most numerous, and the allele frequency was A:C = 0.803:0.197. Genotype distributions were shown as AA (76.8%):AC (20.9%):CC (2.3%), the allele frequency was A:C = 0.872:0.128 in the male group, and AA (47.4%):AC (41.0%):CC (11.6%), A:C = 0.679:0.321 in the female group. Differences were highly significant between the male and female groups (p<0.0001). Genotype distributions between angiotensin II type 1 receptor gene and angiotensin converting enzyme gene showed that there is no significance between $AT_1R$ genotypes and ACE genotypes in total subjects (p>0.05).

• Proceedings of the Korean Biophysical Society Conference
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• 1996.07a
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• pp.23-23
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• 1996

A working molecular model of the angiotensin II type 1 receptor is built based on the seven transmembrane helix structure of the recently refined bacteriorhodopsin atomic coordinates. A multiple copy simultaneous search (MCSS) method is used to search the pharmacophore of angiotensin on the surface of the receptor. Multiple copies of amino acid fragments and organic functional groups are scattered around the possible binding site and the time dependent. (omitted)

• Tuberculosis and Respiratory Diseases
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• v.55 no.5
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• pp.478-487
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• 2003

Background : There have been several studies showing that the angiotensin II and angiotensin converting enzyme(ACE) contributes to the apoptosis of alveolar epithelial cells in idiopathic interstitial pneumonia and the activation of fibroblasts during the process of pulmonary fibrosis. These results suggest that the pulmonary fibrosis can be inhibited by the angiotensin II receptor antagonist(AGIIRA). This study was performed to identify the therapeutic effect of AGIIRA in idiopathic pulmonary fibrosis(IPF). Method : Thirteen patients with IPF, who were diagnosed with an open lung biopsy(6 patients) and furfilling the ATS criteria(7 patients) between March 1999 and October 2001 at the Gachon medical center, were enrolled in this study. Of these patients, eight patients were treated with a regimen including AGIIRA(AT group), and five were treated without AGIIRA(NT group). The pulmonary function tests and dyspnea(ATS scale) were measured at diagnosis and 1 year after treatment. All the data was collected to analyze the therapeutic effect of AGIIRA on the patients with IPF. Results : The AT group contained 8 patients(M:F=4:4) and the NT group contained 5 patients(M:F=3:2). There was no significant difference in the serum angiotensin II level between the two groups($202.5{\pm}58.5$ vs $163.7{\pm}47.3pg/ml$, p>0.05). The AT group showed an upward trend in TLC(+3%), FVC(+4%), FEV1(+3%) and DLco(+2%) compared to the NT group(TLC(-14%), FVC(-3%), FEV1(-4%) except for DLco(+5%)). The dyspnea score in the AT group improved significantly but not in the NT group. Conclusion : These results suggest that the angiotensin II receptor antagonist may have an effect on stabilizing IPF.

• The Korean Journal of Physiology and Pharmacology
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• v.13 no.5
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• pp.385-392
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• 2009

Angiotensin II (Ang II) plays an important role in vascular hypertension. The role of the chemokine CCL5 on Ang II-induced activities in vascular smooth muscle cells (VSMCs) has not been studied. In this study, we elucidated the effect of CCL5 on Ang II-induced 12-lipoxygenase (LO) expression and cell proliferation in spontaneously hypertensive rats (SHR) VSMCs. CCL5 decreased Ang II-induced 12-LO mRNA expression and protein production, and it increased Ang II type 2 ($AT_2$) receptor expression in SHR VSMCs. The inhibitory effect of CCL5 on Ang II-induced 12-LO mRNA expression was mediated through the $AT_2$ receptor. Although treatment of CCL5 alone induced SHR VSMCs proliferation, CCL5 inhibited Ang II-induced VSMCs proliferation and PD123,319, an $AT_2$ receptor antagonist, blocked the inhibitory effect of CCL5 on Ang II-induced VSMCs proliferation. Phosphorylation of p38 was detected in VSMCs treated with Ang II or CCL5 alone. But, decrease of p38 phosphorylation was detected in VSMCs treated with Ang II and CCL5 simultaneously (Ang II/CCL5) and PD123,319 increased p38 phosphorylation in VSMCs treated with Ang II/CCL5. Therefore, these results suggest that the inhibitory effect of CCL5 on Ang II-induced VSMCs proliferation is mediated by the $AT_2$ receptor via p38 inactivation, and CCL5 may play a beneficial role in Ang II-induced vascular hypertension.

• Bulletin of the Korean Chemical Society
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• v.17 no.2
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• pp.182-188
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• 1996

Early attempts to identify plausible conformations of a linear octapeptide hormone, angiotensin-II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe), using various theoretical and experimental methods, have led to various conformational models. So far, no consensus has been made about the solution phase structure and the receptor binding structure of angiotensin-II. The ultimate goal for the conformation study of the peptide hormone is to develop a new potent drug. Therefore, we have devised a strategy for designing the pharmacophore by studying thermodynamically possible conformations of various kinds of angiotensin-II antagonists and angiotensin-II.

• Archives of Pharmacal Research
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• v.18 no.3
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• pp.215-216
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• 1995

• Journal of the Korea Academia-Industrial cooperation Society
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• v.10 no.10
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• pp.2997-3003
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• 2009

The pharmacological profile of KR-31081, a nonpeptide $AT_1$ selective angiotensin receptor antagonist, was investigated by receptor binding studies, functional in vitro assays with rabbit aorta. KR-31081 inhibited the specific binding of $[^{125}I]\;[Sar^1,\;Ile^8]$-angiotensin II to human recombinant $AT_1$ receptor with an 8.6-fold greater potency than losartan ($IC_{50}$: 1.43 and 12.3 nM, respectively), but it did not inhibit the binding of [$^{125}I$] CGP 42112A to human recombinant $AT_2$ receptor ($IC_{50}$: higher than $10{\mu}M$ for both). The Hill coefficient for the competition curve of KR-31081 against $AT_1$ receptor was not significantly different from unity (0.99). Scatchard analysis showed that KR-31081 interacted with human recombinant $AT_1$ receptor in a competitive manner, as with losartan. In functional studies with rabbit aorta, KR-31081 competitively inhibited the contractile response to angiotensin II ($pK_B$ values: 8.66) with 20-70% decrease in the maximum contractile responses, unlike losartan that showed competitive antagonism without any change in the maximum contractile responses to angiotensin II ($pA_2$ values: 7.59). These results suggest that KR-31081 is a highly potent $AT_1$ selective angiotensin II receptor antagonist with a mode of insurmountable antagonism to be developed as the exploratory potential of this compound.

• The Korean Journal of Physiology and Pharmacology
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• v.24 no.4
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• pp.319-328
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• 2020

High fructose intake induces hyperglycemia and hypertension. However, the mechanism by which fructose induces metabolic syndrome is largely unknown. We hypothesized that high fructose intake induces activation of the renin-angiotensin system (RAS), resulting in hypertension and metabolic syndrome. We provided 11-week-old Sprague-Dawley rats with drinking water, with or without 20% fructose, for two weeks. We measured serum renin, angiotensin II (Ang II), and aldosterone (Aldo) using ELISA kits. The expression of RAS genes was determined by quantitative reverse transcription polymerase chain reaction. High fructose intake increased body weight and water retention, regardless of food intake or urine volume. After two weeks, fructose intake induced glucose intolerance and hypertension. High fructose intake increased serum renin, Ang II, triglyceride, and cholesterol levels, but not Aldo levels. High fructose intake increased the expression of angiotensinogen in the liver; angiotensin-converting enzyme in the lungs; and renin, angiotensin II type 1a receptor (AT1aR), and angiotensin II type 1b receptor (AT1bR) in the kidneys. However, expression of AT1aR and AT1bR in the adrenal glands did not increase in rats given fructose. Taken together, these results indicate that high fructose intake induces activation of RAS, resulting in hypertension and metabolic syndrome.