Humans ; Stroke Volume ; Valsartan/therapeutic use* ; Heart Failure/drug therapy* ; Hypotension/drug therapy* ; Aminobutyrates/therapeutic use* ; Drug Combinations ; Angiotensin Receptor Antagonists/therapeutic use* ; Tetrazoles/therapeutic use* ; Treatment Outcome ; Ventricular Function, Left

Humans ; Stroke Volume ; Valsartan/therapeutic use* ; Heart Failure/drug therapy* ; Hypotension/drug therapy* ; Aminobutyrates/therapeutic use* ; Drug Combinations ; Angiotensin Receptor Antagonists/therapeutic use* ; Tetrazoles/therapeutic use* ; Treatment Outcome ; Ventricular Function, Left

Aminobutyrates ; Angiotensin Receptor Antagonists ; China ; Consensus ; Drug Combinations ; Heart Failure/drug therapy* ; Humans ; Neprilysin ; Stroke Volume ; Tetrazoles ; Valsartan

Olmesartan,an angiotensin Ⅱ receptor blocker,is a commonly used antihypertensive drug.Several case reports and cohort studies in recent years have described a severe gastrointestinal adverse event with chronic diarrhea,intestinal malabsorption,and weight loss after the administration of olmesartan.In such cases,the patients recovered after discontinuing olmesartan.This adverse effect is called olmesartan-associated enteropathy(OAE).This article reviews the potential pathogenesis and clinical characteristics of OAE,which broadens the disease spectrum for the differential diagnosis of chronic diarrhea and intestinal malabsorption.
Angiotensin Receptor Antagonists ; Humans ; Imidazoles ; Intestinal Diseases/diagnosis* ; Tetrazoles/adverse effects*

OBJECTIVE: To explore the effects of olmesartan on age-associated migration and invasion capacities and microRNA (miRAN) axis in human aortic vascular smooth muscle cells (HA-VSMCs). METHODS: Cultured HA-VSMCs were divided into control group, bleomycin-mediated senescence (BLM) group and bleomycin + olmesartan treatment group. Wound-healing assay and Boyden chambers invasion assay were used to assess the changes in migration and invasion of the cells, gelatin zymography was used to analyze matrix metalloproteinase-2 (MMP-2) activation in the cells. The differentially expressed miRNAs were identified by miRNA microarray assay and validated by quantitative real-time PCR. MiR-3133 inhibitor was used to examine the effects of molecular manipulation of olmesartan on age-associated migration and invasion and MMP-2 activation in the cells. RESULTS: Compared with those of the control group, the percentage of the repopulated cells and the number of cells crossing the basement membrane increased significantly in BLM group [(78.43±12.76)% (42.47±7.22)%, < 0.05; 33.33±5.51 13.00±4.36, < 0.05]. A significant increase of MMP-2 activation was found in BLM group as compared with the control group (1.66 ± 0.27 0.87 ± 0.13, < 0.05). Olmesartan significantly inhibited BLM-induced enhancement of cell migration and invasion and MMP-2 secretion in the cells. MiR-3133 was significantly downregulated in BLM group and upregulated in olmesartan group. Transfection with miR-3133 inhibitor significantly reversed the effects of olmesartan on age-associated migration and invasion of the cells [(85.87±7.39)% (49.77±3.05)%; 34.67±2.31 20.00±4.58, < 0.05] and MMP-2 activation in the cells (1.76±0.19 0.94±0.10, < 0.05). CONCLUSIONS Olmesartan inhibits the migration and invasion of ageassociated HA-VSMCs probably by upregulating of the miR-3133 axis.
Cell Movement ; Cell Proliferation ; Cells, Cultured ; Humans ; Imidazoles ; Matrix Metalloproteinase 2 ; MicroRNAs ; genetics ; Muscle, Smooth, Vascular ; Myocytes, Smooth Muscle ; Tetrazoles

Objective: To assess the efficacy and safety of the initiation of sacubitril-valsartan （ARNI） therapy, as compared with ACEI therapy, after hemodynamic stabilization among patients hospitalized for acute decompensated heart failure （ADHF）. Methods: A total of 199 hospitalized patients for ADHF in our department from January 2017 to June 2019 were included in this retrospective analysis. According to the medication early after hemodynamic stabilization, patients were divided into ARNI group (n=92) and ACEI group (n=107). Among the included patients, 61 patients with newly diagnosed heart failure at the time of admission were also divided into ARNI group (n=30) and ACEI group (n=31) according to the applied medication. Clinical baseline data and follow-up results of enrolled patients were collected through the electronic medical records at admission, outpatient and telephone follow-up. The primary effectiveness observation index was left ventricular ejection fraction (LVEF) and left ventricular end diastolic dimension (LVEDD) measured by echocardiography; the secondary observation index was death from any causes and hospitalization for heart failure. Safety outcomes were the incidences of symptomatic hypotension, worsening renal function, hyperkalemia, and angioedema. Results: The clinical baseline characteristics were similar between ARNI group and ACEI group（all P>0.05）. The duration of follow up was (15.2±6.5) months in all patients enrolled, (12.3±5.0) months in ARNI group, and (18.2±6.5) months in ACEI group. At the end of follow-up, prevalence of an absolute LVEF increase of more than 5% was 48.9% (45/92) in ANRI group and 25.2% (27/107) in ACEI group (P=0.001). Percent of LVEF increase to more than 50% was 17.4% (16/92) in ANRI group and 3.7% (4/107) in ACEI group (P=0.001). Percent of patients with more than 10 mm LVEDD reduction was 14.1% (13/92) in ANRI group and 3.7% (4/107) in ACEI group (P=0.009). All-cause mortality rate was 5.7% (5/88) in ARNI group and 15.3% (13/85) in ACEI group (P=0.038). Rate of re-hospitalization due to heart failure was 50% (46/92) in ARNI group and 71% (76/107) in ACEI group（P=0.002）.The rates of symptomatic hypotension, worsening renal function, hyperkalemia, and angioedema were similar between ARNI group and ACEI group (all P>0.05). In patients with first diagnosed heart failure，percent of LVEF increase to more than 50% was 30% (9/30) in ANRI group and 6.5% (2/31) in ACEI group (P=0.017). Percent of more than 10 mm LVEDD reduction was 26.7%(8/30) in ANRI group and 3.2%(1/31) in ACEI group (P=0.012). Percent of an absolute LVEF increase of more than 5% was 53.3% (16/30) in ANRI group and 51.6% (16/31) in ACEI group (P=0.893). Re-hospitalization due to heart failure was 23.3% (7/30） in ARNI group and 73.3% (11/31) in ACEI group（P<0.01）. Rate of all-cause death tended to be lower in patients receiving ARNI (3.4% (1/29)) as compared to patients receiving ACEI (13.0% (3/23), P=0.197）. Conclusions: Among patients with heart failure with reduced ejection fraction hospitalized for ADHF, the initiation of ARNI therapy after hemodynamic stabilization is associated with a more significant improvement of cardiac remodeling and pump function than ACEI therapy and satisfactory safety. In ADHF patients with first diagnosed heart failure, initiation of ARNI therapy after hemodynamic stabilization can more effectively improve cardiac remodeling and pump function than treatment with ACEI.
Aminobutyrates ; Angiotensin Receptor Antagonists/therapeutic use* ; Biphenyl Compounds ; Drug Combinations ; Heart Failure/drug therapy* ; Humans ; Retrospective Studies ; Stroke Volume ; Tetrazoles ; Treatment Outcome ; Valsartan ; Ventricular Function, Left

OBJECTIVETo investigate the protective effects of irbesartan against cardiac inflammation associated with diabetes and obesity in the db/db mouse model of type 2 diabetes and explore the underlying mechanisms.

METHODSTwenty- four 10-week-old diabetic db/db mice were equally randomized into irbesartan treatment (50 mg/kg per day) group and model group, using 12 nondiabetic littermates (db/+) as the controls, The mice were treated with irbesartan or saline vehicle for 16 consecutive weeks, after which the heart pathology was observed and the heart weight, body weight, and serum levels of fasting blood glucose (FBG), total cholesterol(TC), and triglycerides(TG) were measured. The expression of nuclear factor-kappaB (NF-κB) p65 in the myocardium was assessed with immunohistochemistry, the protein levels of P-IκBα ,IκBα and β-actin were analyzed with Western blotting, and the pro-inflammatory cytokines IL-6 and TNF-α mRNA were detected using quantitative real-time PCR (qPCR).

RESULTSCompared with db/+ mice, the saline-treated db/db mice developed obesity, hyperglycemia and hyperlipidemia (P<0.01). Histopathological examination of the heart tissue revealed inflammatory cell infiltration, increased myocardial interstitium and disorders of myocardial fiber arrangement. The diabetic mice showed increased P-IαBα and decreased IκBα protein levels, enhanced activity and expression of NF-κB in the hearts, and increased mRNA expression of IL-6 and TNF-α in the myocardium. These abnormalities were all associated with increased inflammatory response. Treatment with irbesartan improved the heart architecture and attenuated high glucose-induced inflammation in the diabetic mice.

CONCLUSIONTreatment with irbesartan attenuates cardiac inflammation in type 2 diabetic db/db mice, and this effect was probably associated with the suppression of cardiac angiotensin II and NF-κB signaling pathway.

Actins ; metabolism ; Angiotensin II ; metabolism ; Animals ; Biphenyl Compounds ; pharmacology ; Cardiovascular Diseases ; drug therapy ; Diabetes Mellitus, Experimental ; complications ; Diabetes Mellitus, Type 2 ; complications ; Inflammation ; drug therapy ; Interleukin-6 ; metabolism ; Mice ; Obesity ; complications ; Random Allocation ; Real-Time Polymerase Chain Reaction ; Signal Transduction ; Tetrazoles ; pharmacology ; Transcription Factor RelA ; metabolism ; Tumor Necrosis Factor-alpha ; metabolism

BACKGROUNDAtrial fibrillation (AF) is the most frequent tachyarrhythmia in patients with a permanent pacemaker. Angiotensin II receptor antagonists have a protective effect against the occurrence of AF in patients with heart diseases. This study aimed to assess the effectiveness of olmesartan in the prevention of new-onset AF and AF burden in atrioventricular block (AVB) patients with dual-chamber (DDD) pacemaker implantation.

METHODSThis was a single-center, prospective, randomized, single-blind, controlled clinical study. A total of 116 AVB patients, who received DDD pacemakers implantation with the percentage of ventricular pacing (VP%) ≥40% from April 22, 2011 to December 24, 2012, were prospectively randomized to olmesartan group (20 mg per day; n = 57) or control group (n = 59). Patients were followed up using pacemaker programming, 12-lead electrocardiography in the intrinsic sinus rhythm, laboratory examinations, and transthoracic echocardiography at 24 months. Atrial high rate events (AHREs) were defined as 180 beats/min over a minimum of 5 min. AF burden was calculated by the number of hours with AHREs divided by the number of measurement hours.

RESULTSTen (17.5%) patients in the olmesartan group and 24 patients (40.7%) in the control group occurred new-onset AF, and the difference between two groups was statistically significant (P = 0.04). AF burden was lower in olmesartan group than that in control group (8.02 ± 3.10% vs. 13.66 ± 6.14%, P = 0.04). There were no significant differences in mean days to the first occurrence of AHREs and mean cumulative numbers of AHREs between two groups (P = 0.89 and P = 0.42, respectively). Moreover, olmesartan group had smaller values of maximal P-wave durations and P-wave dispersion (PD) after 24 months follow-up compared with the control group (109.5 ± 7.4 ms vs. 113.4 ± 7.1 ms, P = 0.00; and 40.6 ± 4.5 ms vs. 43.3 ± 4.4 ms, P = 0.02, respectively). Left ventricular end-diastolic diameter and left ventricular ejection fraction were not significantly different between two groups (both P > 0.05).

CONCLUSIONThis study suggested that 24-month of olmesartan therapy could reduce new-onset AF and AF burden in patients with DDD pacemakers.

CLINICAL TRIAL REGISTRATIONChiCTR-TRC-12004443; http://www.chictrdb.org.

Aged ; Angiotensin Receptor Antagonists ; therapeutic use ; Atrial Fibrillation ; drug therapy ; Atrioventricular Block ; drug therapy ; Female ; Humans ; Imidazoles ; therapeutic use ; Male ; Middle Aged ; Single-Blind Method ; Tetrazoles ; therapeutic use

OBJECTIVETo observe the effect of Tripterygium glycosides (TG) on the expression of hypoxia-inducible factor-1α and endothelin-1 in the kidney of diabetic rats and explore the possible mechanism underlying the protective effect of TG against diabetic nephropathy.

METHODSSixty 8-week-old male SD rats were randomly divided into normal control group (n=10) and streptozotocin-induced diabetes mellitus (DM) model group (n=50). The diabetic model rats were then randomly divided into DM group, low-dose (8 mg/kg) and high-dose (16 mg/kg) TG treatment groups, and Irbesartan (50 mg/kg) treatment group. After 8 weeks, the levels of blood glucose (BG), 24-h urine protein (24 h Upro), serum creatinine (Scr) and blood urea nitrogen (BUN) were measured. The pathological changes in the renal tissues were examined by optical microscopy, and the mean glomerular area (MGA) and mean glomerular volume (MGV) were measured with pathological image analysis. Immunohistochemical and Western blotting were used to detect the expression of HIF-1α and ET-1 protein in the renal tissue, and their mRNA expressions were detected using real-time fluorescence quantitative PCR.

RESULTSHIF-1α and ET-1 expression increased in the kidney of diabetic rats. Compared with the diabetic model rats, the rats receiving TG and Irbesartan treatment showed decreased levels of Scr, BUN, 24h Upro, MGA and MGV, improved renal histopathology, and reduced expression of HIF-1α and ET-1 mRNA and protein in the renal tissue. These changes were more obvious in high-dose TG treatment group. Correlation analysis showed that the expression of HIF-1α was positively correlated with that of ET-1, and they were both positively correlated with kidney weight index (KW/BW), 24 h Upro, MGA, and MGV.

CONCLUSIONHIF-1α and ET-1 are overexpressed in the kidney of diabetic rats. TG can improve kidney damage in diabetic rats and delay the development of diabetic nephropathy by inhibiting the HIF-1α and ET-1 expression.

Animals ; Biphenyl Compounds ; pharmacology ; Blood Glucose ; Blood Urea Nitrogen ; Creatinine ; blood ; Diabetes Mellitus, Experimental ; metabolism ; Endothelin-1 ; metabolism ; Glycosides ; pharmacology ; Hypoxia-Inducible Factor 1, alpha Subunit ; metabolism ; Kidney ; drug effects ; metabolism ; Male ; Rats ; Rats, Sprague-Dawley ; Tetrazoles ; pharmacology ; Tripterygium ; chemistry

BACKGROUNDAngiotensin type 1 receptor (AT 1 R) antagonists are extensively used for blood pressure control in elderly patients with hypertension. This study aimed to investigate the inhibitory effects of AT 1 R antagonist valsartan on platelet aggregation and the occurrence of cardio-cerebral thrombotic events in elderly patients with hypertension.

METHODSTwo-hundred and ten patients with hypertension and aged > 60 years were randomized to valsartan (n = 140) or amlodipine (n = 70) on admission. The primary endpoint was platelet aggregation rate (PAR) induced by arachidonic acid at discharge, and the secondary endpoint was the rate of thrombotic events including brain infarction and myocardial infarction during follow-up. Human aortic endothelial cells (HAECs) were stimulated by angiotensin II (Ang II, 100 nmol/L) with or without pretreatment of valsartan (100 nmol/L), and relative expression of cyclooxygenase-2 (COX-2) and thromboxane B 2 (TXB 2 ) and both p38 mitogen-activated protein kinase (p38MAPK) and nuclear factor-kB (NF-kB) activities were assessed. Statistical analyses were performed by GraphPad Prism 5.0 software (GraphPad Software, Inc., California, USA).

RESULTSPAR was lower after treatment with valsartan (11.49 ± 0.69% vs. 18.71 ± 2.47%, P < 0.001), associated with more reduced plasma levels of COX-2 (76.94 ± 7.07 U/L vs. 116.4 ± 15.89 U/L, P < 0.001) and TXB 2 (1667 ± 56.50 pg/ml vs. 2207 ± 180.20 pg/ml) (all P < 0.001). Plasma COX-2 and TXB 2 levels correlated significantly with PAR in overall patients (r = 0.109, P < 0.001). During follow-up (median, 18 months), there was a significantly lower thrombotic event rate in patients treated with valsartan (14.3% vs. 32.8%, P = 0.002). Relative expression of COX-2 and secretion of TXB 2 with concordant phosphorylation of p38MAPK and NF-kB were increased in HAECs when stimulated by Ang II (100 nmol/L) but were significantly decreased by valsartan pretreatment (100 nmol/L).

CONCLUSIONSAT 1 R antagonist valsartan decreases platelet activity by attenuating COX-2/TXA 2 expression through p38MAPK and NF-kB pathways and reduces the occurrence of cardio-cerebral thrombotic events in elderly patients with hypertension.

Aged ; Aged, 80 and over ; Angiotensin Receptor Antagonists ; therapeutic use ; Blood Platelets ; drug effects ; Blotting, Western ; Cell Line ; Cyclooxygenase 2 ; blood ; Female ; Humans ; Hypertension ; drug therapy ; Male ; Platelet Aggregation ; drug effects ; Real-Time Polymerase Chain Reaction ; Tetrazoles ; therapeutic use ; Thrombosis ; blood ; drug therapy ; Thromboxane B2 ; blood ; Valine ; analogs & derivatives ; therapeutic use ; Valsartan