• Biomolecules & Therapeutics
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• 제28권5호
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• pp.423-430
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• 2020

Telmisartan is an angiotensin-II receptor blocker and acts as a selective modulator of peroxisome proliferator-activated receptor gamma (PPARγ). Several studies have demonstrated that telmisartan ameliorates depression and memory dysfunction and reduces brain inflammation. We hypothesized that the beneficial effects of telmisartan on brain could be due to modulation of the blood-brain barrier (BBB) function. Here, we examined the effect of telmisartan on tumor necrosis factor alpha (TNF-α)-induced expression of intercellular adhesion molecule 1 (ICAM-1) which plays an important role in leukocyte transcytosis through the BBB. Telmisartan blocked TNF-α-induced ICAM-1 expression and leukocyte adhesion in U87MG human glioma cells but showed no effect on human brain microvascular endothelial cells. In U87MG cells, a PPAR antagonist, GW9662 did not block the effect of telmisartan on ICAM1 expression but rather potentiated. Moreover, GW9662 caused no change in TNF-α-induced ICAM-1 expression, suggesting no implication of PPARγ in the telmisartan effect. Further studies showed that telmisartan blocked TNF-α-induced activation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and nuclear factorkappa B (NF-κB). In contrast, inhibitors of JNK, ERK1/2 and NF-κB but not p38, blocked ICAM-1 expression induced by TNF-α. Thus, our findings suggest that the beneficial effect of telmisartan is likely due to the reduction of astrocytic ICAM1 expression and leukocytes adhesion to astrocytes, and that this response was mediated by the inhibition of JNK/ERK1/2/NF-κB activation and in the PPAR-independent manner. In conclusion, this study enhances our understanding of the mechanism by which telmisartan exerts the beneficial brain function.

• The Korean Journal of Physiology and Pharmacology
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• 제14권4호
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• pp.241-248
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• 2010

The present sutdy aimed to determine whether olmesartan, an angiotensin II (Ang II) type 1 ($AT_1$) receptor blocker, can influence the CA release from the isolated perfused model of the rat adrenal medulla. Olmesartan ($5{\sim}50{\mu}M$) 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 ${\mu}M$). Olmesartan did not affect basal CA secretion. Also, in adrenal glands loaded with olmesartan (15 ${\mu}M$), the CA secretory responses evoked by Bay-K-8644 (10 ${\mu}M$, an activator of voltage-dependent L-type $Ca^{2+}$ channels), cyclopiazonic acid (10 ${\mu}M$, an inhibitor of cytoplasmic $Ca^{2+}$-ATPase), veratridine (100 ${\mu}M$, an activator of voltage-dependent $Na^+$ channels), and Ang II (100 nM) were markedly inhibited. However, at high concentrations ($150{\sim}300{\mu}M$), olmesartan rather enhanced the ACh-evoked CA secretion. Taken together, these results show that olmesartan at low concentrations inhibits the CA secretion evoked by cholinergic stimulation (both nicotininc and muscarinic receptors) as well as by direct membrane depolarization from the rat adrenal medulla, but at high concentrations it rather potentiates the ACh-evoked CA secretion. It seems that olmesartan has a dual action, acting as both agonist and antagonist at nicotinic receptors of the isolated perfused rat adrenal medulla, which might be dependent on the concentration. It is also thought that this inhibitory effect of olmesartan 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 on the CA secreton.

• 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

• The Korean Journal of Physiology and Pharmacology
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• 제22권6호
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• pp.661-670
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• 2018

Fimasartan, a new angiotensin II receptor antagonist, reduces myocyte damage and stabilizes atherosclerotic plaque through its anti-inflammatory effect in animal studies. We investigated the protective effects of pretreatment with fimasartan on ischemia-reperfusion injury (IRI) in a mouse model of ischemic renal damage. C57BL/6 mice were pretreated with or without 5 (IR-F5) or 10 (IR-F10) mg/kg/day fimasartan for 3 days. Renal ischemia was induced by clamping bilateral renal vascular pedicles for 30 min. Histology, pro-inflammatory cytokines, and apoptosis assays were evaluated 24 h after IRI. Compared to the untreated group, blood urea nitrogen and serum creatinine levels were significantly lower in the IR-F10 group. IR-F10 kidneys showed less tubular necrosis and interstitial fibrosis than untreated kidneys. The expression of F4/80, a macrophage infiltration marker, and tumor necrosis factor $(TNF)-{\alpha}$, decreased in the IR-F10 group. High-dose fimasartan treatment attenuated the upregulation of $TNF-{\alpha}$, interleukin $(IL)-1{\beta}$, and IL-6 in ischemic kidneys. Fewer TUNEL positive cells were observed in IR-F10 compared to control mice. Fimasartan caused a significant decrease in caspase-3 activity and the level of Bax, and increased the Bcl-2 level. Fimasartan preserved renal function and tubular architecture from IRI in a mouse ischemic renal injury model. Fimasartan also attenuated upregulation of inflammatory cytokines and decreased apoptosis of renal tubular cells. Our results suggest that fimasartan inhibited the process of tubular injury by preventing apoptosis induced by the inflammatory pathway.

• Journal of Pharmaceutical Investigation
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• 제40권1호
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• pp.51-57
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• 2010

Losartan potassium, 2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol mono-potassium salt, is a new class of antihypertensive agents, and is an antagonist in angiotensin receptor. The purpose of the present study was to evaluate the bioequivalence of two Losartan potassium tablets, Cozaar tablet (MSD Pharmaceutical Co., Ltd.) and Losata tablet (Kyung Dong Pharmaceutical Co., Ltd.), according to the guidelines of the Korea Food and Drug Administration (KFDA). The release of losartan from the two losartan potassium formulations in vitro was tested using KP VIII Apparatus II method with various dissolution media. Twenty eight healthy male subjects, $23.86{\pm}1.80$ years in age and $67.27{\pm}6.60\;kg$ in body weight, were divided into two groups and a randomized $2{\times}2$ cross-over study was employed. After a single tablet containing 50 mg as losartan potassium was orally administered, blood samples were taken at predetermined time intervals, and the concentrations of losartan in serum were determined using HPLC with fluorescence detector. The dissolution profiles of two formulations were similar in all tested dissolution media. The pharmacokinetic parameters such as $AUC_t$, $C_{max}$ and $T_{max}$ were calculated, and Equiv Test/K-BE Test 2002 was utilized for the statistical analysis of the parameters using logarithmically transformed $AUC_t$, $C_{max}$ and untransformed $T_{max}$. The results showed that the differences between two formulations based on the reference drug, Cozaar, were -2.70%, 1.45% and 2.31% for $AUC_t$, $C_{max}$ and $T_{max}$, respectively. There were no sequence effects between two formulations in these parameters. The 90% confidence intervals using logarithmically transformed data were within the acceptance range of log 0.8 to log 1.25 (e.g., log 0.8852~log 1.0655 and log 0.8319~log 1.2342 for $AUC_t$ and $C_{max}$, respectively). Thus, the criteria of the KFDA bioequivalence guideline were satisfied, indicating Losata tablet was bioequivalent to Cozaar tablet.