• The Korean Journal of Physiology and Pharmacology
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• 제1권2호
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• pp.151-159
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• 1997

In an attempt to investigate whether hemorrhage affects the gene expression of the renin-angioteusin system (RAS) components in the brain and peripheral angiotensin-generating tissues, changes in mRNA levels of the RAS components in response to hemorrhage were measured in conscious unrestrained rats. Wistar rats were bled at a rate of 3 ml/kg/min for 5 min, and then decapitated 7 h after hemorrhage. Levels of mRNA for renin, angiotensinogen and angiotensin $II-AT_1$ receptor subtypes ($AT_{1A}$ and $AT_{1B}$) were determined with the methods of northern blot and reverse transcriptase-polymerase chain reaction (RT-PCR). Hemorrhage produced a profound hypotension with tachycardia, but blood pressure and heart rate recovered close to the basal level at 7 h. Plasma and renal renin levels were significantly increased at 7 h. Hemorrhage induced rapid upregulation of gene expression of both $AT_{1A}$ and $AT_{1B}$ receptor subtypes in the brainstem and hypothalamus, downregulation of them in the adrenal gland and liver. However, renin mRNA level increased in the brainstem, decreased in the liver, but was not changed in the hypothalamus, kidney and adrenals after hemorrhage. Angiotensinogen mRNA level was not significantly changed in any of the tissue except a slight increase in the liver. The kidney and liver did not show any significant change in gene expression of the RAS components. These results suggest that gene expression of the RAS in central and peripheral tissues are, at least in part, under independent control and the local RAS in each organ plays specific physiologic role.

• Archives of Pharmacal Research
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• 제19권5호
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• pp.390-395
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• 1996

To investigate whether $AT_{1}$ receptor antagonists are acting by increasing endothelium-de-pendent and -independent relaxation of aortas in normotensive rats, $AT_{1}$ receptor antagonists, losartan and KR-30988, and angiotensin converting enzyme inhibitor, captopril, were orally administered for two weeks (50 mg/kg, b.i.d.). THe blood pressure, heart rate and body weight were not significantly changed by losartan, KR-30988 and captopril compared to the control group. In aortic preparations, the $pD_{2}$ of KR-30988 for ACh-induced relaxation was 8.33 $\pm$ 0.16, significantly (p <0.05) lower than that of control group $(7.71 \pm 0.15)$. ACh-induced relaxation was significantly increased on losartan-treated group (p<0.01) at $10^{-6}$ M of ACh, and in captopril-treated group (p<0.05) at the range of $10^{-7}$ -$10^{-5}$ M of ACh. The $pD_{2}$ values for histamine-induced relaxatio of losartan, KR-30988 and captopril were 5.57 $\pm$ 0.10, 5.85 $\pm$ 0.21 and 5.60 $\pm$ 0.01, respectively, with significant differences in all groups (p<0.01) compared to that of control group (5.13 $\pm$ 0.09). ACh-induced relaxations of aortic preparations were not changed by pretreatment of indomethacin ($10_{-5}$ M), and completely bolcked by pretreatment of L-NAME $(10_{-5}M)$ in all groups. Sodium nitroprusside-induced relaxations were not significantly changed by all drugs tested in this experiments. These results suggest that $AT_{1}$ receptor antagonists, losartan and KR-30988, enhance the endothelium-dependent relaxatio on aortic preparations through the release of, or increase sensitivity, to nitric oxide in nor-motensive rats.

• The Korean Journal of Physiology
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• 제27권2호
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• pp.217-225
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• 1993

The role of endogenous brain angiotensin ll (Ang ll) in mediating the cardiovascular and vasopressin responses to hemorrhage was assessed in conscious spontaneously hypertensive rats (SHR), and normotensive Wistar-Kyoto (WKY) rats. Artificial cerebrospinal fluid (aCSF) with or without losartan (DuP 753), a specific Ang ll receptor subtype I $(AT_1)$ antagonist and saralasin, a combined $AT_1/AT_2$ antagonist was administered into the cerebral lateral ventricle. Hemorrhage was performed at a rate of 3 ml/kg/min far 5 min. Intracerebroventricular administration of losartan and saralasin had no effect on the basal blood pressure. However, in response to acute hemorrhage, central Ang ll antagonists produced a remarkably greater fall in blood pressure, a reduced tachycardia, and an enhanced renin release compared with the aCSF control experiment in SHR, but effected no significant change in WKY rats. Central Ang ll-blocked SHR showed significantly lower blood pressure and heart rate during the recovery period than the aCSF control rats. Vasopressin release tallowing the hemorrhage was attenuated by icv Ang ll antagonists: the effect was more pronounced in SHR than in WKY rats. Centrally administered losartan and saralasin produced remarkably similar effects on the cardiovascular function and vasopressin responses to hemorrhage. These data suggest that brain Ang ll acting primarily through AT, receptors plays an important physiological role in mediating rapid cardiovascular regulation and vasopressin release in response to hemorrhage especially in Hypertensive rats.

• 생명과학회지
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• 제20권7호
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• pp.969-976
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• 2010

피리딜 이미다졸 시리즈의 비펩타이드 안지오텐신 수용체 리간드로 새롭게 개발된 KR-31125에 대한 생체 내활성을 동물모델에서 검증하였다. 척수장애 동물모델에서 KR-31125는 비대칭 농도의존적으로 로자탄보다 18배 이상의 경쟁적인 혈압강하 효과를 나타내었으며, 기타 수용체 촉진제들의 영향을 받지 않았다. 안지오텐신으로 유도된 정상혈압 쥐모델에서는 대조화합물인 로자탄과 비교하여 경구효과는 동등하였으나 더 빠른 초기효과가 관찰되었다. 또한 신성고혈압 쥐모델에서 KR-31125는 로자탄보다 3배 이상의 지속형 혈압강하 효과를 나타내었고, 이뇨제를 투여하여 레닌을 활성화시킨 개실험 모델에서 KR-31125는 로자탄보다 20배 이상의 지속적인 경구혈압강하 효과를 나타내었다. 이러한 KR-31125의 생체 내 활성특징은 대사물질을 통하여 효과를 발휘하는 로자탄과 달리 동일물질의 효과에 의한 것으로 고혈압 및 혈관질환과 깊은 관련이 있는 안지오텐신 조절시스템에 대한 세포영상, 비침투성 진단등의 도구물질로서 가능성이 높을 것으로 판단된다.

• The Korean Journal of Physiology and Pharmacology
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• 제19권4호
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• pp.299-307
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• 2015

Severe acute pancreatitis (SAP) is normally related to multiorgan dysfunction and local complications. Studies have found that local pancreatic renin-angiotensin system (RAS) was significantly upregulated in drug-induced SAP. The present study aimed to investigate the effects of angiotensin II receptors inhibitor valsartan on dual role of RAS in SAP in a rat model and to elucidate the underlying mechanisms. 3.8% sodium taurocholate (1 ml/kg) was injected to the pancreatic capsule in order for pancreatitis induction. Rats in the sham group were injected with normal saline in identical locations. We also investigated the regulation of experimentally induced SAP on local RAS expression in the pancreas through determination of the activities of serum amylase, lipase and myeloperoxidase, histological and biochemical analysis, radioimmunoassay, fluorescence quantitative PCR and Western blot analysis. The results indicated that valsartan could effectively suppress the local RAS to protect against experimental acute pancreatitis through inhibition of microcirculation disturbances and inflammation. The results suggest that pancreatic RAS plays a critical role in the regulation of pancreatic functions and demonstrates application potential as AT1 receptor antagonists. Moreover, other RAS inhibitors could be a new therapeutic target in acute pancreatitis.

• Childhood Kidney Diseases
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• 제15권2호
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• pp.125-137
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• 2011

목적: 일반적으로 남자는 여자에 비해 만성 신장병의 발병이 많고 말기 신부전으로의 진행이 더 흔한 것으로 알려져 있다. 본 연구는 일측성 요관 폐쇄를 가진 생쥐에서 신섬유화에 대한 성별과 성호르몬의 효과를 규명하기 위해 시행되었다. 방법: 일측성 완전 요관 폐쇄 7일째 암컷과 수컷 생쥐의 신장에서 ${\alpha}$-smooth muscle actin (${\alpha}$-SMA)의 발현을 측정한 후, 암컷 생쥐에서 난소를 제거하거나 제거 후 다시 $17{\beta}$-estradiol을 보충하여 나타나는 신섬유화 정도를 비교 분석하였다. 결과:일측성 요관 폐쇄를 가진 암컷 신장의 ${\alpha}$-SMA의 발현이 수컷 신장에 비해 현저히 낮았다. 난소 제거와 $17{\beta}$-estradiol의 보충은 일측성 요관 폐쇄를 가진 암컷 신장의 안지오텐신 II 1형 수용체의 발현에는 의미 있는 영향을 주지 않았지만, 안지오텐신 II 2형 수용체의 발현은 정상 암컷과 난소 제거 후 $17{\beta}$-estradiol를 보충한 암컷에서 현저히 증가되었다. 또한, inducible nitric oxide synthase (iNOS) 역시 유사한 변화를 보였다. 결론 : 여성은 폐쇄성 요로병증에서 신섬유화에 대한 저항성과 연관이 있으며 이러한 성별의 차이는 $17{\beta}$-estradiol에 의한 안지오텐신 II 2형 수용체와 iNOS의 발현 증가와 연관이 있을 것으로 사료된다.

• The Korean Journal of Physiology and Pharmacology
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• 제13권4호
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• pp.327-335
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• 2009

The aim of this study was to determine whether losartan, an angiotensin II (Ang II) type 1 ($AT_1$) receptor could influence the CA release from the isolated perfused model of the rat adrenal medulla. Losartan (5${\sim}$50 ${\mu}$M) perfused into an adrenal vein for 90 min produced dose- and time-dependent inhibition of the CA secretory responses evoked by ACh (5.32 mM), high $K^+$ (56 mM, a direct membrane depolarizer), DMPP (100 ${\mu}$M) and McN-A-343 (100 ${\mu}$M). Losartan failed to affect basal CA output. Furthermore, in adrenal glands loaded with losartan (15 ${\mu}$M) for 90 min, the CA secretory responses evoked by Bay-K-8644 (10 ${\mu}$M, an activator of L-type $Ca^{2+}$ channels), cyclopiazonic acid (10 ${\mu}$M, an inhibitor of cytoplasmic $Ca^{2+}$ -ATPase), veratridine (100 ${\mu}$M, an activator of $Na^+$ channels), and Ang II (100 nM) were markedly inhibited. However, at high concentrations (150${\sim}$300 ${\mu}$M), losartan rather enhanced the CA secretion evoked by ACh. Collectively, these experimental results suggest that losartan at low concentrations inhibits the CA secretion evoked by cholinergic stimulation (both nicotininc and muscarinic receptors) as well as by membrane depolarization from the rat adrenal medulla, but at high concentration it rather inhibits ACh-evoked CA secretion. It seems that losartan has a dual action, acting as both agonist and antagonist to nicotinic receptors of the rat adrenal medulla, which might be dependent on the concentration. It is also thought that this inhibitory effect of losartan may be mediated by blocking the influx of both $Na^+$ and $Ca^{2+}$ into the rat adrenomedullary chromaffin cells as well as by inhibiting the $Ca^{2+}$ release from the cytoplasmic calcium store, which is thought to be relevant to the $AT_1$ receptor blockade, in addition to its enhancement of the CA release.

• BMB Reports
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• 제51권12호
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• pp.611-612
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• 2018

$C1q/TNF-{\alpha}-Related$ Protein 1 (CTRP1) has recently been shown to act as a blood pressure regulator, as it induces vasoconstriction. In the aorta, CTRP1 facilitates recruitment of angiotensin II receptor 1 (AT1R) to plasma membrane, through activation of the AKT/AS160 signaling pathway. This leads to activation of the Ras homolog gene family (Rho)/Rho kinase (ROCK) signaling pathway, resulting in vasoconstriction. Accordingly, mice overexpressing Ctrp1 have hypertensive phenotype. Patients with hypertension also display higher circulating CTRP1 levels, compared to healthy individuals, indicating that excessive CTRP1 may affect development of hypertension. Conversely, CTRP1 is regarded as an 'innate blood pressure modulator' because CTRP1 increases blood pressure under dehydration to prevent hypotension. Mice lacking Ctrp1 fail to maintain normotension under dehydration conditions, resulting in hypotension, suggesting that CTRP1 is an essential protein for maintaining blood pressure homeostasis. In conclusion, CTRP1 is a novel, anti-hypotensive vasoconstrictor that increases blood pressure during dehydration-induced hypotension.

• 한국축산식품학회지
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• 제44권3호
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• pp.533-550
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• 2024

Peptides with bioactive effects are being researched for various purposes. However, there is a lack of overall research on pork-derived peptides. In this study, we reviewed the process of obtaining bioactive peptides, available analytical methods, and the study of bioactive peptides derived from pork. Pepsin and trypsin, two representative protein digestive enzymes in the body, are hydrolyzed by other cofactors to produce peptides. Bicinchoninic acid assay, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, chromatography, and in vitro digestion simulation systems are utilized to analyze bioactive peptides for protein digestibility and molecular weight distribution. Pork-derived peptides mainly exhibit antioxidant and antihypertensive activities. The antioxidant activity of bioactive peptides increases the accessibility of amino acid residues by disrupting the three-dimensional structure of proteins, affecting free radical scavenging, reactive oxygen species inactivation, and metal ion chelating. In addition, the antihypertensive activity decreases angiotensin II production by inhibiting angiotensin converting enzyme and suppresses blood pressure by blocking the AT1 receptor. Pork-derived bioactive peptides, primarily obtained using papain and pepsin, exhibit significant antioxidant and antihypertensive activities, with most having low molecular weights below 1 kDa. This study may aid in the future development of bioactive peptides and serve as a valuable reference for pork-derived peptides.

• 대한한방내과학회지
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• 제29권4호
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• pp.871-886
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• 2008

Objective : Gypsum fibrosum has been traditionally used in treatment of febrile diseases and recently been shown to have anti-inflammatory effect. Chronic renal failure has a serious clinical symptoms including proteinuria, azotemia, anemia, and hyperlipidemia and has characteristic histopathological changes, glomerular hypertrophy, infiltration of inflammatory cells, and crescentic sclerosis, We investigated the effects of gypsum fibrosum on renal functional and histopathological disorder in chronic renal failure rat model induced 5/6 nephrectomy. Methods : Using Sprague-Dawley rats, CRF was induced by 5/6 nephrectomy. The rats were divided into 3 groups, normal, conrol, and gypsum administered orally with gypsum fibrosum 500mg/kg/day. Body weight, 24 hr proteinuria, hematologic analysis, and histological morphologic changes were followed up after 8 weeks. The glomerular macrophage/monocyte infiltration, $TGF-{\beta}_1$, type IV collagen, and angiotensin II type1 receptor($AT_1$) were evaluated by immunohistochemistry. Resuls : In the CRF control group, functional parameters and histopathologic changes clearly indicated the development of CRF. 24 hr proteinuria significantly increased in the CRF control group over the normal group, and serum creatinine level was lower in the gypsum group than in the control group, LDL-cholesterol was significantly lower in the gypsum group than in the control group. Morphological investigations showed a variety of characteristic features of CRF, glomerular hypertrophy, increasing cellular density of glomerulus, deposition of extra-cellular matrix, fibrotic change, and glomerular sclerosis in the control group, but in the gypsum group, these features diminished significantly. In observation of renal type IV collagen and $AT_1$ expression, positive area significantly increased in the control group over the normal group, and it significantly decreased in the gypsum group compared to the control group. Conclusions : Our findings suggest that gypsum fibrosum inhibits $AT_1$ and type IV collagen expression in renal tissues and attenuates progression of glomerulosclerosis and interstitial fibrosis in chronic renal failure rats, which lead to amelioration of renal function. From these results, we suggest that gypsum fibrosum may have renoprotective effects and could be a useful remedy agent for treating chronic renal failure.