Angiotensin II Type 1 Receptor Blockers ; pharmacology ; Animals ; Cell Proliferation ; drug effects ; Cells, Cultured ; Collagen Type I ; biosynthesis ; Hepatocytes ; cytology ; metabolism ; Tetrazoles ; pharmacology ; Valine ; analogs & derivatives ; pharmacology ; Valsartan

OBJECTIVETo explore the pathogenic changes of myocardial apoptosis in heart hypertrophy during hypertension and evaluate the anti-apoptosis effect of Valsartan.

METHODSThirty spontaneously hypertensive rats (SHRs) were divided into two groups: 15 treated with Valsartan (20 mg x kg(-1) x d(-1)) (SHR + Valsartan group), the others with placebo (SHR + placebo group), with 15 normal Wistar rats as control. Systolic blood pressure was measured by the tail-cuff method. The observation period was from 8 to 16 weeks of age. Cardiac apoptosis was evaluated by a Terminal Deoxynucleotidyl Transferase-Mediated dUTP-biotin Nick End Labeling (TUNEL) assay.

RESULTSMean blood pressure values were 127 +/- 2 mm Hg in controls, 163 +/- 6 mm Hg in the SHR + Valsartan group and 193 +/- 7 mm Hg in the SHR + placebo group at 16 weeks of age, whereas the blood pressure in 8-week-old SHR and Wistar rats were 175 +/- 3 mm Hg and 125 +/- 5 mm Hg, respectively. The ratio of the heart weight over body weight declined in Wistar (3.07 +/- 0.03 mg/g) and SHR + Valsartan groups (3.22 +/- 0.19 mg/g) compared with the SHR + placebo group (4.02 +/- 0.31 mg/g) (P < 0.05). The density of TUNEL-positive cells in Wistar and SHR +/- Valsartan groups was 23.3 +/- 3.3 nuclei/HPF and 35.0 +/- 1.3 nuclei/HPF, both of which were significantly less than that of the SHR + placebo group (116.7 +/- 11.3 nuclei/HPF).

CONCLUSIONSIn response to chronic pressure overload, cardiomyocyte-specific apoptosis contributes to the transition from compensatory hypertrophy to decompensation. Apoptosis may be effectively inhibited by Valsartan in the early stage of hypertension.

Animals ; Antihypertensive Agents ; pharmacology ; Apoptosis ; drug effects ; Cardiomegaly ; pathology ; Hypertension ; pathology ; Myocardium ; cytology ; Rats ; Rats, Inbred SHR ; Rats, Wistar ; Tetrazoles ; pharmacology ; Valine ; analogs & derivatives ; pharmacology ; Valsartan

High performance liquid chromatography-time-off-flight mass spectrometer (HPLC-TOFMS) technology coupled with partial least squares discriminant analysis (PLS-DA) processed by SIMCA-P software was applied to investigate serum endogenous metabolites alternations of valsartan in spontaneous hypertension rats (SHR). And MetPA platform was used to connect identified potential biomarkers in corresponding metabolic pathways to find possible therapeutic mechanism of valsartan. Valsartan significantly declined the blood pressure of SHRs (P < 0.05) at fourth week. The metabolic profiling significantly changed and four metabolites involved in G protein-coupled pathway were identified. Metabolomics is able to detect holistic and microcosmic alternations in organism, so as to elucidate therapeutic mechanism of drugs.
Animals ; Biomarkers ; blood ; Blood Pressure ; Chromatography, High Pressure Liquid ; Discriminant Analysis ; Least-Squares Analysis ; Mass Spectrometry ; Metabolome ; Metabolomics ; Rats ; Rats, Inbred SHR ; Valsartan ; pharmacology

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 observe the effects of angiotensin II type 1 receptor blocker valsartan in preventing hepatic fibrosis induced by dimethylnitrosamine in rats.

METHODSExcept rats in the control group, all were given intraperitoneal injections of 1% dimethylnitrosamine (DMN 1 ml/kg, two or three consecutive days/a week for 6 weeks). From the first day of the intraperitoneal injection, rats in treatment groups were given valsartan for 8 weeks by gastric gavage. Liver tissue and blood samples of all rats were examined at 56 days (8 weeks). AngII levels were determined by radioimmunoassay. Hepatic mRNA levels of Collagen type I (Col I) and tissue inhibitor of metalloproteinase1 (TIMP1) were evaluated by reverse-transcription polymerase chain reaction (RT-PCR).

RESULTSValsartan significantly attenuated the degree of liver fibrosis and decreased the hepatic AngII content compared with DMN treated rats (P<0.01). mRNA levels of Col I and TIMP1 were upregulated in DMN treated rats compared with normal rats. Valsartan downregulated the elevation of Col I and TIMP1 mRNA levels (P<0.01).

CONCLUSIONHepatic AngII content of the model group was increased, the local tissue RAS was activated in DMN induced liver fibrosis. Valsartan can retard the progression of hepatic fibrosis and may provide an effective new strategy for anti-liver fibrosis therapy.

Angiotensin II Type 1 Receptor Blockers ; pharmacology ; therapeutic use ; Animals ; Dimethylnitrosamine ; Female ; Liver Cirrhosis, Experimental ; chemically induced ; prevention & control ; Male ; Random Allocation ; Rats ; Rats, Wistar ; Tetrazoles ; pharmacology ; therapeutic use ; Valine ; analogs & derivatives ; pharmacology ; therapeutic use ; Valsartan

OBJECTIVETo investigate the effects of ox-LDL, ACEI and ARB on expressions and activities of TF and TFPI in VSMC.

METHODS(1) Rabbit VSMC was cultured by explant-attached method in vitro. (2) The effects of ox-LDL and valsartan on TF and TFPI expressions were analyzed by immunohistochemistry and immunofluorescence. Laser scanning confocal microscopy were applied to analyze the effects of ox-LDL and valsartan on TF expression. The effects of ox-LDL, valsartan and captopril on TF and TFPI antigen expressions were analyzed by ELISA. Chromogenic substrate method was used to determine the effects of ox-LDL, valsartan and captopril on TF activity. The effects of ox-LDL and valsartan on TF mRNA expression were analyzed by RT-PCR.

RESULTS(1) ox-LDL could upregulate TF antigen, activity and TF expression at mRNA level and downregulate TFPI antigen. (2) Valsartan and captopril could reduce TF antigen and activity in VSMC treated by ox-LDL, and valsartan reduce it in a dose-dependent manner. Valsartan could also attenuate TF expression at mRNA level in VSMC treated by ox-LDL. (3) Using ELISA, valsartan and captopril could also enhance TFPI antigen in VSMC treated by ox-LDL.

CONCLUSIONOur study showed upregulated TF and downregulated TFPI expression and activity by ox-LDL and these effects could be reversed by ACEI and ARB indicating a new insight on the antiatherosclerotic effects of ACEI and ARB.

Animals ; Captopril ; pharmacology ; Cells, Cultured ; Endothelium, Vascular ; cytology ; metabolism ; Male ; Proton-Translocating ATPases ; biosynthesis ; genetics ; RNA, Messenger ; biosynthesis ; Rabbits ; Tetrazoles ; pharmacology ; Thromboplastin ; biosynthesis ; genetics ; Valine ; analogs & derivatives ; pharmacology ; Valsartan

The transmural heterogeneous changes of transient outward potassium currents (Ito) in rabbit hypertrophic cardiaomyocytes and the effects of long-term prophylactic treatment with volsartan were investigated. Rabbits were divided into hypertrophy group (left ventricular hypertrophy induced by partial ligation of abdominal aorta), vol-treated group (volsartan was administrated after the ligation), and control group (sham operated). Myocytes were isolated by a two-step enzymatical method. The sub-endocardial (Endo) and sub-epicardium (Epi) tissues were separated from midmyocardium (Mid) with a razor. Whole-cell patch-clamp technique was used to record potassium currents. The results showed that membrane capacitance was larger in hypertrophic cells than those in control and vol-treated cells (P<0.01 vs control cells, n=30). The densities of Ito in hypertrophic cells were reduced by sub-epicardium (Epi) (27.8 +/- 2.9) %, midmyocardium (Mid) (41.0+/-4.7) %, and sub-endocardium (Endo) (20.3 +/- 3.4) % compared with those in control cells. The decrease of Ito density was more pronounced in Mid than in Epi and Endo (P<0.01 vs Epi or Endo). There were no significant differences in Ito densities between vol-treated group and control group in three layers separately. In conclusion, volsartan can inhibit the transmural heterogeneous changes of Ito in left ventricular hypertrophic cardiomyocytes in rabbit.
Animals ; Antihypertensive Agents ; pharmacology ; Biological Transport, Active ; drug effects ; Female ; Hypertrophy, Left Ventricular ; drug therapy ; pathology ; Male ; Myocytes, Cardiac ; pathology ; Patch-Clamp Techniques ; Potassium Channels ; drug effects ; Rabbits ; Tetrazoles ; pharmacology ; Valine ; analogs & derivatives ; pharmacology ; Valsartan

Objective: To investigate the effect and mechanism of sacubitril/valsartan on left ventricular remodeling and cardiac function in rats with heart failure. Methods: A total of 46 SPF-grade male Wistar rats weighed 300-350 g were acclimatized to the laboratory for 7 days. Rats were then divided into 4 groups: the heart failure group (n=12, intraperitoneal injection of adriamycin hydrochloride 2.5 mg/kg once a week for 6 consecutive weeks, establishing a model of heart failure); heart failure+sacubitril/valsartan group (treatment group, n=12, intragastric administration with sacubitril/valsartan 1 week before the first injection of adriamycin, at a dose of 60 mg·kg^-1·d^-1 for 7 weeks); heart failure+sacubitril/valsartan+APJ antagonist F13A group (F13A group, n=12, adriamycin and sacubitril/valsartan, intraperitoneal injection of 100 μg·kg^-1·d^-1 APJ antagonist F13A for 7 weeks) and control group (n=10, intraperitoneal injection of equal volume of normal saline). One week after the last injection of adriamycin or saline, transthoracic echocardiography was performed to detect the cardiac structure and function, and then the rats were executed, blood and left ventricular specimens were obtained for further analysis. Hematoxylin-eosin staining and Masson trichrome staining were performed to analyze the left ventricular pathological change and myocardial fibrosis. TUNEL staining was performed to detect cardiomyocyte apoptosis. mRNA expression of left ventricular myocardial apelin and APJ was detected by RT-qRCR. ELISA was performed to detect plasma apelin-12 concentration. The protein expression of left ventricular myocardial apelin and APJ was detected by Western blot. Results: Seven rats survived in the heart failure group, 10 in the treatment group, and 8 in the F13A group. Echocardiography showed that the left ventricular end-diastolic diameter (LVEDD) and the left ventricular end-systolic diameter (LVESD) were higher (both P<0.05), while the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were lower in the heart failure group than in the control group (both P<0.05). Compared with the heart failure group, rats in the treatment group were featured with lower LVEDD and LVESD (both P<0.05), higher LVEF and LVFS (both P<0.05), these beneficial effects were reversed in rats assigned to F13A group (all P<0.05 vs. treatment group). The results of HE staining showed that the cardiomyocytes of rats in the control group were arranged neatly and densely structured, the cardiomyocytes in the heart failure group were arranged in disorder, distorted and the gap between cells was increased, the cardiomyocytes in the treatment group were slightly neat and dense, and cardiomyocytes in the F13A group were featured similarly as the heart failure group. Masson staining showed that there were small amount of collagen fibers in the left ventricular myocardial interstitium of the control group, while left ventricular myocardial fibrosis was significantly increased, and collagen volume fraction (CVF) was significantly higher in the heart failure group than that of the control group (P<0.05). Compared with the heart failure group, the left ventricular myocardial fibrosis and the CVF were reduced in the treatment group (both P<0.05), these effects were reversed in the F13A group (all P<0.05 vs. treatment group). TUNEL staining showed that the apoptosis index (AI) of cardiomyocytes in rats was higher in the heart failure group compared with the control group (P<0.05), which was reduced in the treatment group (P<0.05 vs. heart failure group), this effect again was reversed in the F13A group (P<0.05 vs. treatment group). The results of RT-qPCR and Western blot showed that the mRNA and protein levels of apelin and APJ in left ventricular myocardial tissue of rats were downregulated in heart failure group (all P<0.05) compared with the control group. Compared with the heart failure group, the mRNA and protein levels of apelin and APJ were upregulated in the treatment group (all P<0.05), these effects were reversed in the F13A group (all P<0.05 vs. treatment group). ELISA test showed that the plasma apelin concentration of rats was lower in the heart failure group compared with the control group (P<0.05); compared with the heart failure group, the plasma apelin concentration of rats was higher in the treatment group (P<0.05), this effect was reversed in the F13A group (P<0.05 vs. treatment group). Conclusion: Sacubitril/valsartan can partially reverse left ventricular remodeling and improve cardiac function in rats with heart failure through modulating Apelin/APJ pathways.
Aminobutyrates/pharmacology* ; Animals ; Apelin/metabolism* ; Biphenyl Compounds ; Collagen/metabolism* ; Doxorubicin/pharmacology* ; Fibrosis ; Heart Failure/pathology* ; Male ; Myocytes, Cardiac/pathology* ; RNA, Messenger/metabolism* ; Rats ; Rats, Wistar ; Valsartan/pharmacology* ; Ventricular Function, Left/drug effects* ; Ventricular Remodeling

This study investigated the effect of multi-glycosides of Tripterygium wilfordii(GTW) on renal injury in diabetic kidney disease(DKD) rats through Nod-like receptor protein 3(NLRP3)/cysteine-aspartic acid protease-1(caspase-1)/gsdermin D(GSDMD) pyroptosis pathway and the mechanism. To be specific, a total of 40 male SD rats were randomized into the normal group(n=8) and modeling group(n=34). In the modeling group, a high-sugar and high-fat diet and one-time intraperitoneal injection of streptozotocin(STZ) were used to induce DKD in rats. After successful modeling, they were randomly classified into model group, valsartan(Diovan) group, and GTW group. Normal group and model group were given normal saline, and the valsartan group and GTW group received(ig) valsartan and GTW, respectively, for 6 weeks. Blood urea nitrogen(BUN), serum creatinine(Scr), alanine ami-notransferase(ALT), albumin(ALB), and 24 hours urinary total protein(24 h-UTP) were determined by biochemical tests. The pathological changes of renal tissue were observed based on hematoxylin and eosin(HE) staining. Serum levels of interleukin-1β(IL-1β) and interleukin-18(IL-18) were detected by enzyme-linked immunosorbent assay(ELISA). Western blot was used to detect the expression of pyroptosis pathway-related proteins in renal tissue, and RT-PCR to determine the expression of pyroptosis pathway-related genes in renal tissue. Compared with the normal group, the model group showed high levels of BUN, Scr, ALT, and 24 h-UTP and serum levels of IL-1β and IL-18(P<0.01), low level of ALB(P<0.01), severe pathological damage to kidney, and high protein and mRNA levels of NLRP3, caspase-1, and GSDMD in renal tissue(P<0.01). Compared with the model group, valsartan group and GTW group had low levels of BUN, Scr, ALT, and 24 h-UTP and serum levels of IL-1β and IL-18(P<0.01), high level of ALB(P<0.01), alleviation of the pathological damage to the kidney, and low protein and mRNA levels of NLRP3, caspase-1, and GSDMD in renal tissue(P<0.01 or P<0.05). GTW may inhibit pyroptosis by decreasing the expression of NLRP3/caspase-1/GSDMD in renal tissue, thereby relieving the inflammatory response of DKD rats and the pathological injury of kidney.
Rats ; Male ; Animals ; Diabetic Nephropathies/genetics* ; Interleukin-18/metabolism* ; Glycosides/pharmacology* ; Tripterygium ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Rats, Sprague-Dawley ; Caspase 1/metabolism* ; Pyroptosis ; Uridine Triphosphate/pharmacology* ; Kidney ; Valsartan/pharmacology* ; RNA, Messenger/metabolism* ; Diabetes Mellitus

BACKGROUNDRepeated attacks of bronchial asthma lead to different degrees of airway remodeling, the mechanism of which is not yet clear. Some evidences indicate that it is related to the excessive expression of some growth promotion factors. Angiotensin II is a polypeptide that may be involved in airway remodeling. To evaluate its role in airway remodeling in asthma, we observed the effects of an angiotensin II type 1 receptor antagonist (valsartan) on the expression of collagen III, collagen V, and transforming growth factor beta1 (TGF-beta1) mRNA and protein in the airway walls of sensitized rats.

METHODSForty Wistar rats were randomly divided into 5 groups: control group, sensitized group, and valsartan groups 1, 2, and 3. The rats in the sensitized group and in valsartan groups 1, 2, and 3 were sensitized and challenged with ovalbumin. Rats in control group were sensitized and challenged with 0.9% NaCl. Rats from valsartan groups 1, 2, and 3 were drenched with valsartan (10 microg, 20 microg, or 30 microg, respectively) at the time of the ovalbumin challenges. The expression of collagen III, collagen V, and TGF-beta1 protein were detected using immunohistochemical method in combination with image analysis methods. The expression of TGF-beta1 mRNA was detected by in situ hybridization.

RESULTSThe expression in the airways of collagen III and collagen V was significantly higher in rats from the sensitized group (7.73 +/- 0.81, 1.34 +/- 0.28) and from valsartan groups 1, 2, and 3 (5.73 +/- 0.64, 1.13 +/- 0.15; 4.96 +/- 0.51, 0.98 +/- 0.08; 4.43 +/- 0.35, 0.93 +/- 0.06, respectively) than those in the control group (2.65 +/- 0.38, 0.67 +/- 0.08, P < 0.05). In addition, collagen levels were significantly lower in valsartan groups 1, 2, and 3 than those from the sensitized group (P < 0.05). The expression of TGF-beta1 mRNA and protein in the airways was significantly higher in rats from the sensitized group (20.49% +/- 3.46%, 29.73% +/- 3.25%) and from valsartan groups 1, 2, and 3 (16.47% +/- 1.94%, 19.41% +/- 1.87%; 14.38% +/- 1.58%, 18.29% +/- 1.43%; 12.96% +/- 1.73%, 18.63% +/- 1.11%, respectively) than that from the control group (7.84% +/- 1.61%, 5.63% +/- 1.07%, P < 0.05). TGF-beta1 mRNA and protein levels were significantly lower in valsartan groups 1, 2, and 3 than that in the sensitized group (P < 0.05).

CONCLUSIONSAngiotensin II receptor antagonist valsartan can suppress synthesis of collagen III and collagen V by downregulating TGF-beta1 mRNA and protein expression. Valsartan can decrease airway remodeling and could play a role in asthma therapy.

Angiotensin Receptor Antagonists ; Animals ; Asthma ; physiopathology ; Bronchi ; metabolism ; Collagen Type III ; analysis ; Collagen Type V ; analysis ; Immunization ; Male ; Ovalbumin ; RNA, Messenger ; analysis ; Random Allocation ; Rats ; Rats, Wistar ; Tetrazoles ; pharmacology ; Transforming Growth Factor beta ; analysis ; Valine ; analogs & derivatives ; pharmacology ; Valsartan