The target compounds were prepared from 5-aminobenzimidazolone by two steps reaction, and their AChE inhibitory activities were measured by Ellman method in vitro. The AChE inhibitory activity of compound 4d is the best of them, and its IC50 value is equal to 7.2 μmol·L(-1), which is better than that of rivastigmine; moreover the 4d had no inhibitory activities to BuChE. Therefore, the inhibitory activities of 5-aminobenzimidazolone derivatives to acetylcholinesterase are worth further researching.
Acetylcholinesterase ; metabolism ; Benzimidazoles ; chemical synthesis ; chemistry ; Cholinesterase Inhibitors ; chemical synthesis ; chemistry ; Drug Design ; Phenylcarbamates ; chemistry ; Rivastigmine ; Structure-Activity Relationship

OBJECTIVETo study the effects of telmisartan on voltage dependant potassium channel (Kv) expression in lymphocytes from spontaneously hypertensive rat (SHR).

METHODSPeripheral blood was collected from male SHR aged 16 and 4 weeks. Peripheral lymphocytes were separated from heparinized whole blood by standard Ficoll-Hypaque density gradient centrifugation. The whole-cell Kv currents were recorded with patch-clamp technique in the absence and presence of telmisartan(10, 30, 100 µmol/L). Real-time PCR was used to determine Kv1.3 mRNA expression in lymphocytes.

RESULTS(1) The currents density of Kv was higher in lymphocytes from 16 weeks-old SHR [ (119.0 ± 9.6) pA/pF] than from 4 weeks-old SHR [(59.0 ± 7.2) pA/pF, P < 0.05]. (2) Currents density was positively correlated with systolic blood pressure in 16 weeks-old SHR (r = 0.837, P < 0.05). (3) The lymphocytes Kv 1.3 mRNA expression was significantly higher in 16-weeks-old SHR than in 4-weeks-old SHR (P < 0.05). (4) Telmisartan reduced the whole-cell Kv currents in a concentration-dependent manner (10.5 ± 3.4)% at 10 µmol/L, (45.8 ± 3.7)% at 30 µmol/L and (81.6 ± 4.2)% at 100 µmol/L, P < 0.01.

CONCLUSIONSThe lymphocyte Kv channel is upregulated in 16 weeks-old SHR suggesting a role of Kv in the pathophysiology of hypertension. Kv current in lymphocyte could be significantly blocked by telmisartan in a concentration dependent manner.

4-Aminopyridine ; pharmacology ; Animals ; Benzimidazoles ; pharmacology ; Benzoates ; pharmacology ; Lymphocytes ; drug effects ; metabolism ; Male ; Patch-Clamp Techniques ; Potassium Channels, Voltage-Gated ; drug effects ; Rats ; Rats, Inbred SHR ; metabolism

OBJECTIVETo observe the effects of telmisartan on Kv1.3 and Kv1.5 potassium channels expressed in Xenopus oocytes.

METHODSKv1.3 and Kv1.5 potassium channel currents expressed in Xenopus oocytes were recorded and observed in the absence and presence of telmisartan using standard two-microelectrode voltage clamp techniques.

RESULTSTelmisartan resulted in a concentration- and voltage-dependent inhibition effect on Kv1.3 channel current (IC(50) 2.05 micromol/L)and on Kv1.5 channel current (IC(50) 2.37 micromol/L).

CONCLUSIONSTelmisartan blocks open-state Kv1.3 channel which could be one of the mechanisms related to its immunomodulatory and anti-atherosclerosis effect. Telmisartan also blocks open-state Kv1.5 channel which might partly account for its effect on reducing the incidence of atrial fibrillation.

Animals ; Benzimidazoles ; pharmacology ; Benzoates ; pharmacology ; In Vitro Techniques ; Kv1.3 Potassium Channel ; drug effects ; Kv1.5 Potassium Channel ; drug effects ; Oocytes ; drug effects ; metabolism ; Patch-Clamp Techniques ; Xenopus

OBJECTIVETo explore the effects of carbendazim on the testicular development and spermatogenic function of male rats and its action mechanism.

METHODSForty clean-grade impubic male Wistar rats were equally randomized into a low-dose, a medium-dose, a high-dose and a control group, treated respectively with carbendazim at 20, 100 and 200 mg/kg (bw) and Tween-80 solution, all by oral gavage once a day for 80 days. After treatment, the rats were weighed, their testes and epididymides immediately excised, their morphological changes observed and the weights of the right testis and epididymis obtained. Sperm motility and counts in the left cauda epididymis were determined. Histopathological changes, cell apoptosis and the expression of Bcl-2/Bax in the testis were detected by HE staining, TUNEL and immunohistochemical SABC method.

RESULTSThe medium- and high-dose groups showed obviously atrophic testes and epididymides, marked histopathological abnormality of the testis, reduced weight of the right testis and epididymis, and decreased sperm motility and counts in the left cauda epididymis (P < 0.01). With the increasing dose of carbendazim, the apoptosis rate and Bax expression were significantly raised, while the expression of Bcl-2 significantly decreased (P < 0.05, P < 0.01).

CONCLUSIONCarbendazim affects the testicular development and spermatogenic function of male rats, and the mechanism may involve cell apoptosis induced by down-regulation of Bcl-2 and up-regulation of Bax.

Animals ; Apoptosis ; drug effects ; Benzimidazoles ; pharmacology ; Carbamates ; pharmacology ; Down-Regulation ; Male ; Rats ; Rats, Wistar ; Spermatogenesis ; drug effects ; Testis ; drug effects ; growth & development ; bcl-2-Associated X Protein ; metabolism

OBJECTIVETo study the effect of peroxisome proliferator activated receptor γ (PPAR-γ) agonist on the angiotensin converting enzyme 2 (ACE2) mRNA expression in monocyte-derived macrophages of essential hypertensive patients.

METHODSTotally 57 essential hypertensive patients were randomly divided into three groups: conventional treatment group (n=18), telmisartan group (n=19), and benazepril group (n=20); 20 patients with normal blood pressure were also selected as the control group. Monocyte-derived macrophages were isolated from blood samples of patients in all four groups. The expression of ACE2 mRNA in monocyte-derived macrophages was detected by RT-PCR before treatment and 4 and 12 weeks after treatment.

RESULTSFour and 12 weeks after treatment, the systolic pressure and diastolic pressure of telmisartan group and benazepril group were significantly lower than that of the conventional treatment group (all P<0.01), and the systolic pressure and diastolic pressure of telmisartan group were significantly lower than that of the benazepril group(both P<0.01) .The expression of ACE2 mRNA in monocyte-derived macrophages were significantly lower in essential hypertensive patients than that in control group (P<0.01). After having been treated for 4 weeks and 12 weeks, the expression of ACE2 mRNA in monocyte-derived macrophages of hypertensive patients in telmisartan and benazepril groups were significantly higher than that in conventional treatment group (all P<0.01), and the expression of ACE2 mRNA in telmisartan group was significantly higher than that in benazepril group (both P<0.01).

CONCLUSIONPPAR-γ agonist could increase the ACE2 mRNA expression in monocyte-derived macrophages of essential hypertensive patients.

Aged ; Benzazepines ; pharmacology ; Benzimidazoles ; pharmacology ; Benzoates ; pharmacology ; Female ; Humans ; Hypertension ; drug therapy ; enzymology ; Macrophages ; enzymology ; Male ; Middle Aged ; PPAR gamma ; agonists ; Peptidyl-Dipeptidase A ; genetics ; metabolism ; RNA, Messenger ; genetics

OBJECTIVETo observe the inhibitory effect of mizolastine on substance P(SP)-induced production of leukotriene B(4) (LTB(4)) and interleukin 5 (IL-5) in mouse skin.

METHODSMice were fed with different doses of mizolastine or other control drugs, 30 min after administration animals were injected intradermally with SP on the back. The treated skin samples were taken and competitive enzyme-link immunoassay (ELISA) method was applied to detect LTB (4) and IL-5 in the skin samples.

RESULTThe LTB(4) and IL-5 levels in 10 mg/kg mizolastine group were (1.23 +/-0.29)pg/ml and (34.28 +/-11.00)pg/ml, respectively, which were lower than those in saline control group [(5.52+/-1.88)pg/ml and (179.62 +/-46.25)pg/ml respectively] or loratadine group [(3.89+/-1.27)pg/ml and (127.74 +/-43.27)pg/ml respectively]. No significant difference was found between 10 mg/kg mizolastine group and dexamethasone group (P=0.161 and P=0.508).

CONCLUSIONMizolastine might inhibit the production of LTB(4) and IL-5 induced by substance P in mouse skin, suggesting that anti-inflammatory effect and the blockade of histamine H1 receptors might be involved in its anti-pruritic mechanisms.

Animals ; Benzimidazoles ; pharmacology ; Female ; Histamine H1 Antagonists ; pharmacology ; Interleukin-5 ; biosynthesis ; Leukotriene B4 ; biosynthesis ; Male ; Mice ; Mice, Inbred BALB C ; Skin ; metabolism ; Substance P ; antagonists & inhibitors

OBJECTIVETo investigate the effects of telmisartan on endoplasm reticulum (ER) stress signal pathways and cardiomyocyte apoptosis in abdominal aortic banded rats.

METHODSMale SD rats were randomly divided into sham-operated group, abdominal aortic banding group (AAB) and AAB + telmisartan (5 mgxkg(-1)xd(-1) per gavage, beginning at 1 week before AAB for 8 weeks, n = 10 each). Ten weeks post AAB, hemodynamic measurements were performed, whole heart and left ventricular weights were obtained, cardiomyocyte apoptosis was measured by TUNEL method. Myocardial GRP78 and CHOP protein expressions were detected by Western blot and immunohistochemistry.

RESULTSThe ratio of left ventricular weight to body weight, the ratio of heart weight to body weight, left ventricular end diastolic pressure and the apoptosis index were significantly increased while left ventricular end systolic pressure and +/- dp/dt(max) were significantly decreased in AAB group than those in sham-operated group (all P < 0.01), these changes could be significantly attenuated by telmisartan (all P < 0.01). Moreover, myocardial GRP78 and CHOP expressions were significantly upregulated in AAB group than those in sham-operated group and telmisartan could significantly downregulate the increased GRP78, CHOP expressions (all P < 0.01).

CONCLUSIONSIncreased ER stress might be responsible for enhanced cardiomyocyte apoptosis in AAB rats. Telmisartan effectively attenuated the cardiomyocyte apoptosis and cardiac hypertrophy in AAB rats possibly through reducing ER stress.

Animals ; Aorta, Abdominal ; pathology ; Apoptosis ; drug effects ; Benzimidazoles ; pharmacology ; Benzoates ; pharmacology ; Endoplasmic Reticulum ; metabolism ; Heat-Shock Proteins ; metabolism ; Male ; Molecular Chaperones ; metabolism ; Myocytes, Cardiac ; drug effects ; metabolism ; Postoperative Period ; Rats ; Rats, Sprague-Dawley ; Signal Transduction ; Transcription Factor CHOP ; metabolism

AIMTo clarify whether the activation of mitochondrial ATP sensitive potassium channel and calcium activated potassium channel can influence the permeability transition of normal and ischemic brain mitochondria.

METHODSspectrophotometry was used to determine the effect of the two mitochondrial potassium channel agonists on the swelling of normal and ischemic brain mitochondria respectively.

RESULTSIn normal mitochondria, diazoxide and NS1619 could inhibit the decrease of calcium induced mitochondrial absorbance at 520 nm (A520), which were blocked by atractyloside. When compared with the normal mitochondria, mitochondrial A520 decrease in ischemic brain was even more rapid. Diazoxide and NS1619 could still inhibit the calcium induced mitochondrial A520 decrease, which were blocked by atractyloside.

CONCLUSIONActivation of mitochondrial ATP sensitive potassium channel and calcium activated potassium channel can protect brain mitochondria in vitro probably via influencing the mitochondrial permeability transition.

Animals ; Benzimidazoles ; pharmacology ; Brain ; drug effects ; metabolism ; Brain Ischemia ; metabolism ; Cell Membrane Permeability ; Diazoxide ; pharmacology ; KATP Channels ; metabolism ; Male ; Mitochondria ; drug effects ; metabolism ; Mitochondrial Membrane Transport Proteins ; drug effects ; Potassium Channels, Calcium-Activated ; metabolism ; Rats ; Rats, Sprague-Dawley

BACKGROUNDVascular smooth muscle cell proliferation is an important process in the development of atherosclerosis and is associated with other cellular processes in atherogenesis. Telmisartan is reported to have partial peroxisome proliferator-activated receptor (PPAR)-γ activating properties and has been referred to as selective PPAR modulators, but valsartan just blocks angiotensin II (AngII) type 1 (AT1) receptors. This study aimed to compare the different effects of telmisartan and valsartan on human aortic smooth muscle cells (HASMCs) proliferation.

METHODSAbility of telmisartan and valsartan to inhibit proliferation of HASMCs was evaluated by the Cell Counting Kit-8 (CCK-8) in continuous cell culture. Whether the antiproliferative effects of telmisartan and valsartan depend on their effects on AngII receptors or activating the peroxisome PPAR-γ was also investigated in this study.

RESULTSTelmisartan inhibited proliferation of HASMCs by 52.4% (P < 0.01) at the concentration of 25 µmol/L and the effect depended on the dose of telmisartan, but valsartan had little effect on HASMCs proliferation (P > 0.05) and no dose response. When tested in cells stimulated with AngII, telmisartan had the same inhibition of HASMCs by 59.2% (P < 0.05) and valsartan also inhibited it by 41.6% (P < 0.05). Telmisartan and valsartan had the same effect on down-regulating AT1 receptor expression and telmisartan was superior to valsartan up-regulating AngII type 2 (AT2) receptor expression. Antiproliferative effects of telmisartan were observed when HASMCs were treated with the PPAR-γ antagonist GW9662 but antiproliferative effects of the PPAR-γ activator pioglitazone were not observed.

CONCLUSIONSTelmisartan, but not valsartan, inhibits HASMCs proliferation and has dose-dependent response without stimulation of AngII. AT2 receptor up-regulation of telmisartan contributes to its greater antiproliferative effects than valsartan. Its PPAR-γ activation does not play a critical role in inhibiting HASMCs proliferation.

Benzimidazoles ; pharmacology ; Benzoates ; pharmacology ; Cell Proliferation ; drug effects ; Humans ; Muscle, Smooth, Vascular ; cytology ; metabolism ; Myocytes, Smooth Muscle ; cytology ; drug effects ; PPAR gamma ; metabolism ; Receptor, Angiotensin, Type 1 ; metabolism ; Receptor, Angiotensin, Type 2 ; metabolism ; Tetrazoles ; pharmacology ; Valine ; analogs & derivatives ; pharmacology ; Valsartan

OBJECTIVETo explore the effect of telmisartan and pyridoxamine on oxidative stress in brain tissue of spontaneously hypertensive rats.

METHODSTwenty-four spontaneously hypertensive rats were randomly divided into four groups (n = 6): hypertensive control group (HC group), telmisartan group (T group ), pyridoxamine group (P group ), telmisartan and pyridoxamine group (TP group). Wistar-Kyoto (WKY) rats of the same age were served as a normal control group (NC group). Drug treatment lasted for 16 weeks the level of hyde (MDA) in rat brain tissue, as well as superoxide dismutase (SOD) activity and nicotinamide adenine dinucleotide phosphate(NADHP) oxidase p47phox mRNA expression were observed in this study.

RESULTSThe MDA level in brain in HC group were higher than that in NC group and the SOD activity were lower (P < 0.05). T group, P group and TP group had lower MDA level and higher SOD activity than HC group (P < 0.05). The NADPH mRNA in brain in HC group were significantly higher than that in NC group (P < 0.01). T group and TP group had decreased levels of NADPH mRNA (P < 0.01), there was no significant difference between HC group and P group (P > 0.05).

CONCLUSIONThe brain tissue of spontaneous hypertensive rats had been under the status of oxidative stress. Single application of either telmisartan or pyridoxamine could inhibit oxidative stress of brain tissue. However, compare with single treatment of telmisartan, no beneficial effects were observed in combined use of telmisartan and pyridoxamine.

Animals ; Benzimidazoles ; pharmacology ; therapeutic use ; Benzoates ; pharmacology ; therapeutic use ; Brain ; drug effects ; metabolism ; Hypertension ; drug therapy ; metabolism ; Male ; NADPH Oxidases ; metabolism ; Oxidative Stress ; drug effects ; Pyridoxamine ; pharmacology ; therapeutic use ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; Superoxide Dismutase ; metabolism