BACKGROUNDMany studies have suggested that angiotensin II (Ang II) and its receptors may be involved in the development of asthma. However, the expression of angiotensin II receptors (AGTR) is not clear in the lung tissue of chronic asthmatics. This study was designed to determine the relationship between airway remodeling, dysfunction and the expression of AGTRs in a rat model of asthma.

METHODSRats were sensitized with ovalbumin (OVA) for 2 weeks. Sixty minutes before an inhalation challenge, the rats were pretreated either with valsartan (15, 30, 50 mg x kg(-1) x d(-1)) or saline intragastrically. Then the rats received an OVA challenge for 30 alternative days. Acetylcholine (Ach)-induced bronchoconstriction was measured after the final antigen challenge. White cell counts in bronchoalveolar lavage fluid (BALF) and morphological changes in the airways were then assessed. The levels of transforming growth factor-beta 1 (TGF-beta(1)) and platelet-derived growth factor (PDGF) in BALF were detected by ELISA. The levels of AGTR1 and AGTR2 mRNA and protein in lung tissues were measured by RT-PCR and Western blotting.

RESULTSAGTR1 mRNA and protein levels in repeatedly OVA-challenged rats were significantly increased as compared with negative controls. The AGTR1 mRNA expression versus white cell counts of BALF and airway wall thickness (mainly in small airways) in lungs of chronic antigen-exposed rats were positively correlated. Valsartan decreased the level of AGTR1 in repeatedly OVA-challenged rats. However, AGTR2 mRNA and protein levels in the OVA-challenged rats and high-dose valsartan-treated rats (50 mg x kg(-1) x d(-1)) were also increased. Valsartan significantly decreased inflammatory cell accumulation and attenuated Ach-evoked bronchoconstriction in repeatedly antigen-challenged rats. Valsartan also decreased allergen-induced structural changes in rat airway (including total airway wall thickness and smooth muscle area) and the levels of TGF-beta(1) and PDGF in BALF.

CONCLUSIONSAGTR1 expression is potentially associated with airway remodeling and dysfunction in asthma. Ang II and AGTR1 may participate in airway inflammation and airway remodeling of chronic antigen-exposed rats. Valsartan, a AGTR1 antagonist, could inhibit AGTR1 expression and partially inhibits structural airway changes as well as airway inflammation in chronic OVA-exposed rats.

Angiotensin II Type 1 Receptor Blockers ; pharmacology ; Angiotensin Receptor Antagonists ; Animals ; Asthma ; chemically induced ; genetics ; metabolism ; Blotting, Western ; Bronchoalveolar Lavage Fluid ; chemistry ; Enzyme-Linked Immunosorbent Assay ; Gene Expression ; drug effects ; Lung ; drug effects ; metabolism ; pathology ; Male ; Ovalbumin ; Platelet-Derived Growth Factor ; metabolism ; Rats ; Rats, Wistar ; Receptor, Angiotensin, Type 1 ; genetics ; metabolism ; Receptor, Angiotensin, Type 2 ; genetics ; metabolism ; Receptors, Angiotensin ; genetics ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Tetrazoles ; pharmacology ; Transforming Growth Factor beta1 ; metabolism ; Valine ; analogs & derivatives ; pharmacology ; Valsartan

Adolescent ; Adult ; Female ; Humans ; Immunohistochemistry ; Liver ; chemistry ; Liver Cirrhosis ; metabolism ; Male ; Middle Aged ; RNA, Messenger ; analysis ; Receptor, Angiotensin, Type 1 ; analysis ; genetics

OBJECTIVEAngiotensin II is an important pro inflammation factor in the cardiovascular system. This experiment is aimed to study the effects of angiotensin II on inducible nitric oxide synthase expression in human umbilical endothelial cells.

METHODSHuman umbilical endothelial cells were cultured in vitro and treated with angiotensin II alone or in combination with AT1, AT2 and NF-kappaB inhibitors respectively. The inducible nitric oxide synthase expressions at protein and mRNA levels were measured with Western blot and reverse transcription-polymerase chain reaction (RT-PCR), and the activity of NF-kappaB was analyzed with EMSA.

RESULTSAngiotensin II up-regulated inducible nitric oxide synthase expressions at the protein and mRNA levels at 5 h (P < 0.05), the activity of NF-kappaB was enhanced at 2 h (P < 0.05). These effects could be blocked by AT1 and NF-kappaB inhibitors but not by AT2 inhibitor.

CONCLUSIONAngiotensin II can upregulate the expression of inducible nitric oxide synthase through NF-kappaB pathway in human umbilical endothelial cells. AT1, other than AT2, play a key role in this process.

Angiotensin II ; pharmacology ; Angiotensin II Type 1 Receptor Blockers ; pharmacology ; Angiotensin II Type 2 Receptor Blockers ; Cell Line ; Endothelial Cells ; chemistry ; drug effects ; Heart Failure ; metabolism ; Humans ; NF-kappa B ; metabolism ; Nitric Oxide Synthase Type II ; biosynthesis ; Reverse Transcriptase Polymerase Chain Reaction ; Umbilical Veins ; cytology ; Up-Regulation

Angiotensin II ; biosynthesis ; genetics ; Animals ; Carbon Tetrachloride ; Carbon Tetrachloride Poisoning ; Curcuma ; chemistry ; Drugs, Chinese Herbal ; therapeutic use ; Liver Cirrhosis, Experimental ; chemically induced ; drug therapy ; metabolism ; Male ; Phytotherapy ; Rats ; Rats, Sprague-Dawley ; Receptor, Angiotensin, Type 1 ; biosynthesis ; genetics

OBJECTIVESTo investigate the protective effects of Sapindus saponins in spontaneously hypertensive rats, and the possible cellular and molecular mechanisms.

METHODSThirty-two 16-week-old spontaneously hypertensive rats were randomly divided into four groups (8 in each group): model group (placebo), positive control group (27 mg/kg of Captopril Tablets), Sapindus saponins groups (27 mg/kg and 108 mg/kg, respectively). Another 8 healthy Wistar-Kyoto strain (WKY) rats were used as the normal group. The animals were treated for 8 weeks. Blood pressure of rats was determined by non-invasive blood pressure meter (BP-6). Furthermore, the contents of angiotensin II (Ang II) in plasma and myocardial tissue were determined by enzyme-linked immunosorbent assay (ELISA), the gene expression of receptor angiotensin type 1 (AT1R) in aorta was determined by quantitative realtime polymerase chain reaction (qRT-PCR). The protein expression of transforming growth factor-β1 (TGF-β1) and AT1R in heart was determined by immunohistochemical staining. The protein expression of p-phosphorylation of p38 mitogen-activated protein kinase (p-p38MAPK) was determined by Western blotting. The contents of interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF) in serum were determined by radioimmunoassay. And the histopathological and morphological changes of aorta and heart tissue samples were assessed semi-quantitatively by hematoxylin-eosin (HE) or Masson staining.

RESULTSThirty minutes after single or continuous treatment, systolic blood pressure (SBP) was reduced significantly in Sapindus saponins groups. And the contents of AngII, IL-1, IL-6 and TNF-α in serum, the expression of AT1R mRNA, p-p38MAPK and TGF-β1 were significantly suppressed dose-dependently (P<0.05 or P<0.01). With the Sapindus saponins treatment, compared with those of the model group, the cardiac and aortic pathological changes were ameliorated significantly.

CONCLUSIONSOur findings suggest that Sapindus saponins might have protective effects in spontaneously hypertensive rats, the cellular and molecular mechanisms of which might be relevant to the regulation of inflammatory responses mediated by p-p38MAPK signal pathway based on activated Ang II and AT1R.

Angiotensin II ; metabolism ; Animals ; Aorta ; drug effects ; pathology ; physiopathology ; Blood Pressure ; drug effects ; Collagen ; metabolism ; Female ; Hypertension ; blood ; drug therapy ; enzymology ; physiopathology ; Interleukin-1 ; blood ; Interleukin-6 ; blood ; Male ; Phosphorylation ; drug effects ; Protective Agents ; pharmacology ; therapeutic use ; Rats, Inbred SHR ; Receptor, Angiotensin, Type 1 ; metabolism ; Renin-Angiotensin System ; drug effects ; Sapindus ; chemistry ; Saponins ; pharmacology ; therapeutic use ; Transforming Growth Factor beta1 ; metabolism ; Tumor Necrosis Factor-alpha ; blood ; p38 Mitogen-Activated Protein Kinases ; metabolism

Angiotensin receptor blockers (ARBs) have organ-protective effects in heart failure and may be also effective in doxorubicin-induced cardiomyopathy (DOX-CMP); however, the efficacy of ARBs on the prevention of DOX-CMP have not been investigated. We performed a preclinical experiment to evaluate the preventive effect of a novel ARB, fimasartan, in DOX-CMP. All animals underwent echocardiography and were randomly assigned into three groups: treated daily with vehicle (DOX-only group, n=22), 5 mg/kg of fimasartan (Low-fima group, n=22), and 10 mg/kg of fimasartan (High-fima group, n=19). DOX was injected once a week for six weeks. Echocardiography and hemodynamic assessment was performed at the 8th week using a miniaturized conductance catheter. Survival rate of the High-fima group was greater (100%) than that of the Low-fima (75%) and DOX-only groups (50%). Echocardiography showed preserved left ventricular (LV) ejection fraction in the High-fima group, but not in the DOX-only group (P=0.002). LV dimensions increased in the DOX-only group; however, remodeling was attenuated in the Low-fima and High-fima groups. Hemodynamic assessment showed higher dP/dt in the High-fima group compared with the DOX-only group. A novel ARB, fimasartan, may prevent DOX-CMP and improve survival rate in a dose-dependent manner in a rat model of DOX-CMP and could be a treatment option for the prevention of DOX-CMP.
Angiotensin Receptor Antagonists/*therapeutic use ; Animals ; Biphenyl Compounds/*therapeutic use ; Cardiomyopathies/chemically induced/mortality/*prevention & control ; Doxorubicin/*toxicity ; Echocardiography ; Hemodynamics ; Pyrimidines/*therapeutic use ; Rats ; Rats, Sprague-Dawley ; Receptor, Angiotensin, Type 1/chemistry/*metabolism ; Survival Rate ; Tetrazoles/*therapeutic use ; Ventricular Function, Left/physiology

BACKGROUNDThe development of diabetic cardiomyopathy is multifactorial. Insulin resistance (IR) and excessive activity of the renin-angiotensin system are confirmed reasons for diabetic cardiomyopathy. Renin-angiotensin system (RAS) inhibitors can reduce tissue Ang II levels, with beneficial effects on cardiovascular function. Therefore, in type-2 diabetes mellitus (T2DM), blockade of the RAS may have the function of protecting against diabetic cardiomyopathy through increasing insulin sensitivity and inhibiting excessive activity of RAS. However, this has not been confirmed.

METHODSThe effect of valsartan, an angiotensin receptor blocker (ARB), on diabetic cardiomyopathy in the presence of T2DM was studied. Wistar rats with T2DM and T2DM treated with valsartan were studied. Glucose infusion rates (GIR), index of IR, heart weight, the heart weight-to-body weight ratio (HW/BW), myocardial apoptotic index, cardiac hydroxyprolin content, and cardiac tissue collagen type I and collagen type III content were measured.

RESULTSGIR in T2DM rats and T2DM rats treated with valsartan decreased (P < 0.01). In T2DM rats treated with valsartan, heart weight, myocardial apoptotic index, cardiac hydroxyprolin content, and cardiac tissue collagen type I and collagen type III content were higher than in control rats, but lower than in T2DM rats. In rats with T2DM, GIR was negatively and significantly correlated with all the variables. However, in T2DM rats treated with valsartan or normal control rats, none of the correlations was significant.

CONCLUSIONSIn the presence of T2DM, diabetic cardiomyopathy is related with IR. Valsartan can not alleviate IR, but can protect against diabetic cardiomyopathy and remove the correlation between IR and diabetic cardiomyopathy.

Angiotensin II Type 1 Receptor Blockers ; therapeutic use ; Animals ; Apoptosis ; Collagen Type I ; analysis ; Collagen Type III ; analysis ; Diabetes Mellitus, Type 2 ; complications ; drug therapy ; metabolism ; Diabetic Cardiomyopathies ; prevention & control ; Hydroxyproline ; analysis ; Insulin Resistance ; Male ; Myocardium ; chemistry ; pathology ; Rats ; Rats, Wistar ; Tetrazoles ; therapeutic use ; Valine ; analogs & derivatives ; therapeutic use ; Valsartan

Angiotensin II (Ang II) induces the pathological process of vascular structures, including renal glomeruli by hemodynamic and nonhemodynamic direct effects. In kidneys, Ang II plays an important role in the development of proteinuria by the modification of podocyte molecules. We have previously found that Ang II suppressed podocyte AMP-activated protein kinase (AMPK) via Ang II type 1 receptor and MAPK signaling pathway. In the present study, we investigated the roles of AMPK on the changes of p130Cas of podocyte by Ang II. We cultured mouse podocytes and treated them with various concentrations of Ang II and AMPK-modulating agents and analyzed the changes of p130Cas by confocal imaging and western blotting. In immunofluorescence study, Ang II decreased the intensity of p130Cas and changed its localization from peripheral cytoplasm into peri-nuclear areas in a concentrated pattern in podocytes. Ang II also reduced the amount of p130Cas in time and dose-sensitive manners. AMPK activators, metformin and AICAR, restored the suppressed and mal-localized p130Cas significantly, whereas, compound C, an AMPK inhibitor, further aggravated the changes of p130Cas. Losartan, an Ang II type 1 receptor antagonist, recovered the abnormal changes of p130Cas suppressed by Ang II. These results suggest that Ang II induces the relocalization and suppression of podocyte p130Cas by the suppression of AMPK via Ang II type 1 receptor, which would contribute to Ang II-induced podocyte injury.
AMP-Activated Protein Kinases/antagonists & inhibitors/chemistry/*metabolism ; Aminoimidazole Carboxamide/analogs & derivatives/pharmacology ; Angiotensin II/*pharmacology ; Angiotensin II Type 1 Receptor Blockers/pharmacology ; Animals ; Blotting, Western ; Cell Line ; Cell Nucleus/metabolism ; Crk-Associated Substrate Protein/*metabolism ; Cytoplasm/metabolism ; Focal Adhesion Kinase 1/metabolism ; Losartan/pharmacology ; Metformin/pharmacology ; Mice ; Microscopy, Confocal ; Podocytes/cytology/drug effects/metabolism ; Protein Kinase Inhibitors/*pharmacology ; Ribonucleotides/pharmacology ; Signal Transduction/*drug effects

OBJECTIVETo study the effect of valsatan (angiotensin II receptor antagonist, AT1) on hepatocyte growth factor (HGF) in the airways and airway remodeling in asthmatic rats.

METHODSThirty two rats were randomly assigned into A-D four groups. Group A was normal control without treatment. Groups B-D were challenged by ovalbumin (OVA) for 2 weeks, 4 weeks and 4 weeks respectively to induce asthma. Group D received intragastric administration of valsatan (30 microg/kg daily for 4 weeks) after OVA challenge. The expressions of HGF, angiotonin II (AngII) and transforming growth factor (TGF-beta1) in the airways were detected by immunihistochemical staining. The pathological changes of airways were observed by Haematoxylin and Eosin staining.

RESULTSThe HGF expression of Group B was significantly higher than that of Group A (10.69 +/- 0.96% vs 5.49 +/- 1.34%; P < 0.05). Group C also showed an increased HGF level (11.85 +/- 0.87%) compared with Group A (P < 0.05). The HGF level in Group D (15.58 +/- 1.06%) was significantly higer than that of both Group B and Group C (P < 0.05). The expressions of TGF-beta1 and AngII increased with the challenged time, while valsatan treatment decreased significantly the levels of both. Valsatan treatment attenuated airway injuries of asthmatic rats induced by OVA sensitization/challenge.

CONCLUSIONSHGF has protective effects on airways and anti-fibrotic effects. Valsatan can improve airway remodeling possibly by increasing HGF levels in asthmatic rats.

Angiotensin II ; analysis ; Angiotensin II Type 1 Receptor Blockers ; therapeutic use ; Animals ; Asthma ; drug therapy ; metabolism ; pathology ; Bronchi ; chemistry ; drug effects ; pathology ; Hepatocyte Growth Factor ; analysis ; Immunohistochemistry ; Male ; Rats ; Rats, Sprague-Dawley ; Tetrazoles ; pharmacology ; therapeutic use ; Transforming Growth Factor beta1 ; analysis ; Valine ; analogs & derivatives ; pharmacology ; therapeutic use ; Valsartan