• 한국임상약학회지
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• 제22권4호
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• pp.330-339
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• 2012

Background : Hypertension is treated with both lifestyle modification and pharmacotherapy. The Seventh Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7), published in 2003, provides a streamlined management approach to hypertension for the primary care physician. The JNC-7 is the gold standard also in Korea. According to the JNC-7, special therapeutic considerations are recommended for high-risk individuals with compelling indications. The presence of compelling indications in any given patient should be considered when selecting specific pharmacotherapy to treat hypertension. However, in patients with compelling indications, it is unknown that hepatotoxicity is caused by Calcium Channel Blocker (CCB), one of 1st anti-hypertensive drugs. Now, the CCB is the most used 1st anti-hypertensive drug in Korea Therefore, we evaluated the changes in blood liver function parameters (ALT, AST, Total bilirubin, serum albumin) for the study group. Methods : We randomly collected and retrospectively analyzed Electronic Medical Record data (n=28,788) of patients, and who took calcium channel blockers(non-dihydropyridines; diltiazem, verapamil, dihydropyridines; amlodipine, barnidipine, benidipine, clinidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, nicardipine, nifedipine, nimodipine), with having liver function tests (LFTs) from July 1st 2009 to June 30th 2010 at the Seoul National University Hospital in Korea. Control groups are two antihypertensive agents: RAS blockade (ARB; candesartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, ACE-I; cilazapril, enalapril, fosinopril, imidapril, perindopril, ramipril) and, Diuretics (loop; furosemide, torsemide, thiazide; hydrochlorothiazide[HCTZ], indapamide). Patients not having LFT results at these three standard points of time(baseline, during, medication, and after finishing medication) were excluded. The collected data were analyzed by using the SPSS (Version12.0) and Microsoft Excel (Version2007). Results : 711 patients who were treated CCB (297), RAS blockade (232) or Diuretics (182) monotherapy were selected for the study. In selected patients, liver damage degree(changes of each LFTs value) was higher in diuretics group than other groups, followed by RAS blockade and CCB. In diuretics group's was loop-diuretics group was higher than thiazide-diuretics group. In CCB group, Nondihydropyridine-CCB's damage degree was higher than Dihydropyrine-CCB's that. Conclusions : Despite the limitations due to the retrospective study, among patients with abnormal LFTs, the use of CCBs led to a less liver damage than other 1st anti-hypertensive agents. It can be recommended CCBs as one of the initial treatments of hypertension in patients with liver disease.

• The Korean Journal of Physiology and Pharmacology
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• 제1권4호
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• pp.413-423
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• 1997

The importance of the kidney in the development of hypertension was first demonstrated by Goldblatt and his colleagues more than fifty years ago. Many hormones and other regulatory factors have been proposed to play a major role in the development of hypertension. Among these factors angiotensia II (ANG II) is closely involved in renal hypertension development since it directly regulates $Na^+$ reabsorption in the renal proximal tubule. Thus the aim of the present study was to examine signaling pathways of low dose of ANC II on the $Na^+$ uptake of primary cultured rabbit renal proximal tubule cells (PTCs) in hormonally defined seum-free medium. The results were as follows: 1) $10^{-11}$ M ANG II has a significant stimulatory effect on growth as compared with control. Alkaline phosphatase exhibited significantly increased activity. However, leucine aminopeptidase and ${\gamma}-glutamyl$ transpeptidase activity were not significant as compared with control. In contrast to $10^{-11}$ M ANG II stimulated $Na^+$ uptake $(108.03{\pm}2.16% of that of control)$, $10^{-9}$ M ANG II inhibited ($92.42{\mu}2.23%$ of that of control). The stimulatory effect of ANG II on $Na^+$ uptake was amiloride-sensitive and inhibited by losartan (ANG II receptor subtype 1 antagonist) and not by PD123319 (ANG II receptor subtype 2 antagonist). 2) Pertussis toxin (PTX) alone inhibited $Na^+$ uptake by $85.52{\pm}3.52%$ of that of control. In addition, PTX pretreatment prevented the AMG II-induced stimulation of $Na^+$ uptake. 8-Bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP), forskolin, and isobutylmethylxanthine (IBMX) alone inhibited $Na^+$ uptake by $88.79{\pm}2.56,\;80.63{\pm}4.38,\;and\;84.47{\pm}4.74%$ of that of control, respectively, and prevented the ANG II-induced stimulation of $Na^+$ uptake. However, $10^{-11}$ M ANG II did not stimulate cAMP production. 3) The addition of 12-O-te-tradecanoylphorbol-13-acetate (TPA, 0.01 ng/ml) to the PTCs produced significant increase in $Na^+$ uptake ($114.43{\pm}4.05%$ of that of control). When ANG II and TPA were added together to the PTCs, there was no additive effect on $Na^+$ uptake. Staurosporine alone had no effect on $Na^+$ uptake, but led to a complete inhibition of ANG II- or TPA-induced stimulation of Na'uptake. ANG II treatment resulted in a $111.83{\mu}4.51%$ increase in total protein kinase C (PKC) activity. In conclusion, the PTX-sensitive PKC pathway is the main signaling cascade involved in the stimulatory effects of ANG II on $Na^+$ uptake in the PTCs.

• Journal of Yeungnam Medical Science
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• 제36권1호
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• pp.26-35
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• 2019

Background: Dysregulation of hepatic glucose production (HGP) contributes to the development of type 2 diabetes mellitus. Telmisartan, an angiotensin II type 1 receptor blocker (ARB), has various ancillary effects in addition to common blood pressure-lowering effects. The effects and mechanism of telmisartan on HGP have not been fully elucidated and, therefore, we investigated these phenomena in hyperglycemic HepG2 cells and high-fat diet (HFD)-fed mice. Methods: Glucose production and glucose uptake were measured in HepG2 cells. Expression levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase ${\alpha}$ ($G6Pase-{\alpha}$), and phosphorylation levels of insulin receptor substrate-1 (IRS-1) and protein kinase C ${\zeta}$ ($PKC{\zeta}$) were assessed by western blot analysis. Animal studies were performed using HFD-fed mice. Results: Telmisartan dose-dependently increased HGP, and PEPCK expression was minimally increased at a $40{\mu}M$ concentration without a change in $G6Pase-{\alpha}$ expression. In contrast, telmisartan increased phosphorylation of IRS-1 at Ser302 ($p-IRS-1-Ser^{302}$) and decreased $p-IRS-1-Tyr^{632}$ dose-dependently. Telmisartan dose-dependently increased $p-PKC{\zeta}-Thr^{410}$ which is known to reduce insulin action by inducing IRS-1 serine phosphorylation. Ectopic expression of dominant-negative $PKC{\zeta}$ significantly attenuated telmisartan-induced HGP and $p-IRS-1-Ser^{302}$ and -inhibited $p-IRS-1-Tyr^{632}$. Among ARBs, including losartan and fimasartan, only telmisartan changed IRS-1 phosphorylation and pretreatment with GW9662, a specific and irreversible peroxisome proliferator-activated receptor ${\gamma}$ ($PPAR{\gamma}$) antagonist, did not alter this effect. Finally, in the livers from HFD-fed mice, telmisartan increased $p-IRS-1-Ser^{302}$ and decreased $p-IRS-1-Tyr^{632}$, which was accompanied by an increase in $p-PKC{\zeta}-Thr^{410}$. Conclusion: These results suggest that telmisartan increases HGP by inducing $p-PKC{\zeta}-Thr^{410}$ that increases $p-IRS-1-Ser^{302}$ and decreases $p-IRS-1-Tyr^{632}$ in a $PPAR{\gamma}$-independent manner

• 대한약리학회지
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• 제30권3호
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• pp.321-330
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• 1994

허혈전처치(ischemic preconditioning)의 재관류심근손상 보호작용과 그 기전을 규명하기 위한 연구의 일환으로 허혈전처치가 심근세포의 산소라디칼 생성능력에 미치는 영향을 검토하였다. 흰쥐 적출심장의 Langendorff 관류표본에서 실험적인 허혈(30분)-재관류(20분)손상을 유도하였고, 허혈전처치는 재관류손상 유도전에 5분 허혈-5분 재관류를 3회 반복하여 시행하였다. 허혈심근 재관류손상의 지표로 심수축기능, 세포질효소 유출, 칼슘 유입 및 미세형태학적 변화를, 그리고 심근세포의 산소라디칼 생성기전으로 xanthine oxidase system의 변동을 허혈전처치와 비전처치 재관류 심장들에서 비교검토하였다. 연구 성적은 다음과 같다. 1. 허혈전처치는 허혈-재관류 심장의 관상혈류량, 심박수, 좌심실압 등 심기능의 저하를 현저히 회복시켰다(회복률; 91%) 2. 허혈-재관류 심장에서 lactate dehydrogenase 유출증가는 허혈전처치에 의해 현저히 저하되었다. 3. 허혈-재관류 심근세포의 전자현미경상 미세구조는 허혈전처치시 비교적 잘 보존되었으며, 특히 myofibril 구조의 보존이 매우 뚜렷하였다. 4. 허혈-재관류시 산화성 조직손상 척도의 하나인 malondialdehyde 생성이 허혈전처치에 의하여 현저히 감소되었다. 5. 허혈전처치 심장에서 xanthine oxidase(D,O 및 D/O형)활성은 변화되지 않았으나 그 기질인 hypoxanthine의 조직함량은 현저히 감소되었다. 이상의 결과들로 부터 허혈전처치는 세포수준에서 허혈심근의 재관류손상을 방지하며, 허혈전처치에 따른 산소라디칼 생성 감소가 재관류손상 방지에 일부 기여할 수 있으리라 사료된다.an을 2주간 처치한 경우에도 영향을 받지 않았다. 이상의 결과로 미루어 아마도 losartan의 내피세포에 대한 작용은 constitutive NO 생성을 증가시키나 inducible NO 생성에는 영향을 미치지 않을 것으로 여겨진다.cium ion이 상당히 중요한 역할을 하는데, 특히 소뇌에서의 NO생성의 감소는 이들 약물들의 치명적 부작용인 tardive dyskinesia와 매우 깊은 관련을 추측할 수 있다. 그러나, 더 많은 약물들의 검색으로 일관적인 기본 결과가 필요 되고 또 각개 약물의 특정적 기전이 연구되기 위하여 현재 실험중이다.(신칭(新稱), Cystostereum subabruptum), 털융단버섯(신칭(新稱), Tomentella pilosa), 노란소나무무늬버섯(신칭(新稱), Asterostroma laxum), 붉은소나무비늘버섯(신칭(新稱), Hymenochaete cruenta), 가루소나무비늘버섯(신칭(新稱), Hymenochaete fuliginosa), 소나무비늘버섯(신칭(新稱), Hymenochaete tabacina), 갈색시루삔버섯(신칭(新稱), Inonotus radiatus), 벚나무진흙버섯(신칭(新稱), Phellinus pomaceus), 회주름구멍버섯(신칭(新稱), Antrodia crassa), 층주름구멍버섯(신칭(新稱), Antrodia serialis), 흰그물구멍버섯(신칭(新稱), Ceriporia reticulata), 겹친손등버섯(신칭(新稱), Oligoporus balsameus), 점박이손등버섯(신칭(新稱), Oligoporus guttulatus), 무른흰살버섯(신칭(新稱), Oxyporus cuneatus), 각목버섯(신칭(新稱),