MicroRNA-155 mediates endogenous angiotensin II type 1 receptor regulation:implications for innovative type 2 diabetes mellitus management

Type 2 diabetes mellitus(T2DM)is a lifelong condition and a threat to human health.Thorough understanding of its pathogenesis is acutely needed in order to devise innovative,preventative,and potentially curative pharmacological interventions.MicroRNAs(miRNA),are small,non-coding,one-stranded RNA molecules,that can target and silence around 60%of all human genes through translational repression.MiR-155 is an ancient,evolutionarily well-conserved miRNA,with distinct expression profiles and multifunctionality,and a target repertoire of over 241 genes involved in numerous physiological and pathological processes including hematopoietic lineage differentiation,immunity,inflammation,viral infections,cancer,cardiovascular conditions,and particularly diabetes mellitus.MiR-155 Levels are progressively reduced in aging,obesity,sarcopenia,and T2DM.Thus,the loss of coordinated repression of multiple miR-155 targets acting as negative regulators,such as C/EBPβ,HDAC4,and SOCS1 impacts insulin signaling,deteriorating glucose homeostasis,and causing insulin resistance(IR).Moreover,deranged regulation of the renin angiotensin aldosterone system(RAAS)through loss of Angiotensin II Type 1 receptor downregulation,and negated repression of ETS-1,results in unopposed detrimental Angiotensin II effects,further promoting IR.Finally,loss of BACH1 and SOCS1 repression abolishes cytoprotective,anti-oxidant,anti-apoptotic,and anti-inflam matory cellular pathways,and promotesβ-cell loss.In contrast to RAAS inhibitor treatments that further decrease already reduced miR-155 Levels,strategies to increase an ailing miR-155 production in T2DM,e.g.,the use of metformin,mineralocorticoid receptor blockers(spironolactone,eplerenone,finerenone),and verapamil,alone or in various combinations,represent current treatment options.In the future,direct tissue delivery of miRNA analogs is likely.

The Role for AVE0991 (MAS-Receptor Angiotensin II (1-7) Agonist) in Reducing Cisplatin-Induced Acute Kidney Injury on C57BL/6 Mice

Acute Kidney Injury (AKI) is a condition that causes nephrotoxicity in kidney tissues due to cisplatin-induced cancer treatments. Hence, it is proposed in this review that AVE0991 (a MAS-receptor Angiotensin II (1-7) agonist) may reduce cisplatin-induced acute kidney injury by promoting nitric oxide production.

Effects of chronic peripheral pretreatment with an angiotensin II type-1 receptor blocker on apoptosis-related molecules in rats with cerebral ischemia/reperfusion injury

Chronic systemic treatment with blockers of angiotensin II type-1 （AT1） receptors inhibits ischemia-induced apoptosis and reduces ischemic neuronal damage. However, the molecular mechanisms of AT1 receptor blockers in modulating neuronal apoptosis remain poorly understood. Pretreatment with irbesartan significantly suppressed cell apoptosis at 1-7 days following cerebral ischemia/reperfusion, increased levels of brain-derived neurotrophic factor, and elevated the ratios of Bcl-2/Bax and phosphorylated cyclic adenosine monophosphate response element-binding protein （pCREB）/CREB in the ischemic cortex at 1 day after reperfusion, as well as suppressing caspase-3 activation. Cerebral ischemia increased the mRNA expression of AT1 and AT2 receptors in the ischemic cortex, whereas irbesartan blocked this increase in AT1 expression but potentiated the expression of AT2. Therefore, this AT1 receptor blocker was neuroprotective by increasing the ratios of Bcl-2/Bax and pCREB/CREB, increasing brain-derived neurotrophic factor levels, inhibiting caspase-3 activation, and modulating AT receptor expression.

Spectrofluorimetric method for determination of some angiotensin II receptor antagonists

A simple, rapid, accurate and highly sensitive spectrofluorimetric method has been developed for determination of some angiotensin II receptor antagonists (AIIRA’s), namely Losartan potassium (Los-K), Irbesartan (Irb), Valsartan (Val) and Candesartan cilexetil (Cand) in pure forms as well as in their pharmaceutical dosage forms. All the variables affecting the relative fluorescence intensity (RFI) were studied and optimized. Under the optimum conditions, linear relationships with good correlation coefflcients (0.9982–0.9991) were obtained over the concentration range from 0.006 mg/mL to 1.7 mg/mL. Good accuracy and precision were successfully obtained for the analysis of tablets containing each drug alone or combined with hydrochlorothiazide (HCTZ) without interferences from the co-formulated HCTZ or the additives commonly present in tablets.

Evaluation of a novel angiotensin II receptor 1 antagonist intesartan as anti-hypertension drug

Aim The preclinical studies of a novel angiotensin II receptor 1 antagonist 2-（4-（ （1,7＇-dimethyl-2＇- propyl-1H ,3 ＇H-2,5＇-bibenzo [ d ] imidazol-3＇-yl ） methyl） -1H-indol-l-yl ） benzoic acid （ intesartan ）. Methods The affinity to AT1 receptor of intesartan was tested through radioactive receptor binding assay by -y-counter. The anti-hypertensive activity in spontaneously hypertensive rats （SHRs） at different doses in vivo was tested by tail noninvasive arterial blood pressure measurement system. Pharmacokinetic parameters were analyzed by high per- formance liquid chromatography （HPLC） method. Besides, acute toxicity tests in ICR and Ames reverse mutation assay in tester strain （TA97, TA98, TA100 and TA102） was also detected. Results The binding assays sugges- ted that intesartan displayed high affinity to angiotensin II AT1 receptor with an ICs0 value of （0.36 ± 0. 18） nmol · L^-1. In vivo anti-hypertensive experiments showed that intesartan had an efficient and long-acting effect in reduc- ing blood pressure which could last more than 24 h at the doses of 2 mg· kg^-1, 5 mg · kg^-1 , and 10 mg · kg^-1 in spontaneously hypertensive rats. The minimum effective dose of it was 2 mg · kg^-1 and the T/P value was 54. 18%. Acute toxicity tests suggested that intesartan was safe with the LDs0 value of 526.20 mg · kg^-1. Ames assay proved that it would not cause the mutations of salmonella typhimurium. And the pharmacokinetic experiments showed that it could be absorbed efficiently and metabolized smoothly both in blood and in tissues in wistar rats. Conclusions Intesartan could be considered as a novel anti-hypertension candidate with efficient, long-acting and low toxicity chracteristics.

EFFECT OF ANGIOTENSIN Ⅱ RECEPTOR SUBTYPE ⅠON THE FIRING RATE IN CATECHOLAMINERGIC TUMOR CELLS

Objective To study the action of brain angiotensin Ⅱ(Ang Ⅱ) receptors and underlying intracellular mechanism in the catecholaminergic system Methods Action potentials (APs) of the primary co cultured catecholaminergic tumor (CATH.a) cells were recorded with the whole cell patch clamp configuration in current clamp mode. Expression of Ang Ⅱ receptors subtypes (AT 1 and AT 2 ) was detected by RT PCR technique. Results The differentiated CATH.a cells represented a neuron like characterization. All CATH.a cells expressed mRNA encoding both Ang Ⅱ AT 1 and AT 2 receptor subtypes. Ang Ⅱ increased the firing rate in the CATH.a cells, which was inhibited completely by addition administration of the AT 1 but not AT 2 receptor antagonist, and partially by using the inhibitors of signal molecules, U73122 (10 μmol·L -1 ), or KN 93 (10 μmol·L -1 ), or calphostin C (10 μmol·L -1 ). Conclusion Ang Ⅱ increases firing rate in CATH.a cells via AT 1 receptor. The CATH.a cells expressing functional AT 1 and AT 2 receptor subtypes may be of general utility for the study of the Ang Ⅱ receptor induced modulation of brain catecholaminergic system.

EFFECT OF ANGIOTENSIN II RECEPTOR ANTAGONIST AND ENDOTHELIN RECEPTOR ANTAGONIST ON NITROGLYCERIN TOLERANCE IN RATS

Objective. To investigate whether angiotensin II receptor antagonist and endothelin receptor antagonist can improve the nitroglycerin (Nit) tolerance in vivo. Methods. Twenty- four rats were divided into 4 groups (n=6,each): Control group, Nitroglycerin (Nit) group, Nit＋ bosentan group and Nit＋ losartan group. Nitroglycerin tolerance was induced by 2- day treatment of nitroglycerin patch (0.05 mg/h). AngiotensinⅡ receptor antagonist losartan ( 10 mg· kg－ 1· d－ 1 ) and endothelin receptor antagonist bosentan ( 100 mg· kg－ 1· d－ 1 ) were given by gavage for 2 days respectively. Results. The least hypotensive response to sodium nitroprusside (SNP) was observed in Nit group . The effective percentages of hypotensive response to SNP were increased in both Nit＋ losartan group and Nit＋ bosentan group compared with Nit group [(31.95± 4.45 )％ vs (21.00± 3.69 )％ , P< 0.01 and (33.18± 6.16 )％ vs (21.00± 3.69 )％ , P< 0.01 ,respectively]. The maximal vessel relaxation induced by SNP was the same in 4 different groups but the highest EC50 (concentration which produces 50％ of the maximal response to SNP) was found in tolerant group[(34± 10) nmol/ L,P < 0.01 .The ET- 1 amounts in plasma and vascular tissue were markedly increased by 54％ and 60％ in Nit group compared with those in control group(P< 0.01).The ET- 1 amounts in plasma and vascular tissue were decreased by 30％ and 37％ in Nit＋ losartan group compared with those in Nit group (P< 0.01). Conclusion. Endothelin receptor antagonist and angiotensinⅡ receptor antagonist could prevent against the Nit tolerance .

The Significance of Angiotensin Converting Enzyme Inhibitor or Angiotensin II Receptor Blocker Use in Sudden Cardiac Death

Objectives: To investigate the relationship between the use of angiotensin converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) and hyperkalemia in patients diagnosed with sudden cardiac death. Methods: We examined oral ACE inhibitor or ARB use among cardiopulmonary arrest patients brought by ambulance to our emergency room during a 5-year period from January 2012 to December 2016. The cause of death was determined to be sudden cardiac death, despite temporary return of spontaneous circulation after starting cardiopulmonary resuscitation. Subjects were dichotomized into 2 groups, those taking and those not taking an ACE inhibitor or ARB. Variables determined retrospectively included serum potassium, estimated glomerular filtration rate as an index of kidney function and time from cardiopulmonary arrest to return of spontaneous circulation. The Mann-Whitney U-test was used to compare continuous data, and the chi-square test to compare categorical data between groups. The results are expressed as the median plus range. Statistical significance was assumed at p Results: Thirty-five patients met the inclusion criteria. The mean age was 77.1 years (range, 35 - 93 years), and there were 26 males and 9 females. Eleven subjects were ACE inhibitor or ARB users, and 24 were non-users. The serum potassium level was significantly higher in users than non-users (median, 6.2 mEq/L (range, 4.5 - 10.0) vs. 5.2 mEq/L (range, 3.6 - 8.3);p = 0.001). The estimated glomerular filtration rate was significantly lower in users than non-users (median, 25.1 mL/min/1.73 m2 (range, 4.6 - 60.3) vs. 46.9 mL/min/1.73 m2 (range, 19.8 - 97.1);p = 0.009). There was no significant difference in time from cardiopulmonary arrest to return of spontaneous circulation between the 2 groups (median, 24 minutes (range, 3 - 111) vs. 29 minutes (range, 10 - 54);p = 0.355). Conclusion: It is possible that hyperkalemia induced by ACE inhibitor or ARB use is a cause of sudden cardiac death, especially in patients with chronic kidney disease.

Involvement of Angiotensin II Type 1 Receptor and Calcium Channel in Vascular Remodeling and Endothelial Dysfunction in Rats with Pressure Overload

Vascular remodeling is an adaptive response to various stimuli,including mechanical forces,inflammatory cy tokines and hormones.In the present study,we investigated the role of angiotensinII type 1 receptor(ATIR)and calcium channel in carotid artery remodeling in response to increased biomechanical forces by using the transverse aortic constriction(TAC)rat model.TAC was induced on ten week-old male Sprague Dawley rats and these models were treated with ATIR blocker olmesartan(1 mg/kg/day)or/and calcium channel blocker(CCB)amlodipine(0.5 mgkgday)for 14 days.After the treatment,the right common carotid artery proximal to the band(RCCA-B)was collected for further assay.Results showed that olmesartan,but not amlodipine,significantly prevented TAC-induced adventitial hyperplasia.Similarly,olmesartan,but not amlodipine,significantly prevented vascular inflammation,as indicated by increased tumor necrosis factor a(TNF-a)and increased p65 phosphorylation,an indicator of nuclear factor K-light-chain-enhancer of activated B cells(NFkB)activation in RCCA-B.In contrast,both olmesartan and amlodipine reversed the decreased expression of endothelial nitric oxidase synthase(eNOS)and improved endothelium-dependent vasodilation,whereas combination of olmesartan and amlodipine showed no further synergistic protective effects.These results suggest that AT1R was involved in vascular remodeling and inflammation in response to pressure overload,whereas ATIR and subsequent calcium channel were involved in endothelial dysfunction.

Antagonism of Angiotensin II AT1 Receptor and Silencing of CD44 Gene Expression Inhibit Cardiac Fibroblast Activation via Modulating TGF-<i>β</i>1/Smad Signaling Pathway

Angiotensin II (Ang II) is known to elicit cardiac fibrosis by activating the AT1 receptor and CD44 expression in the in vivo model. However, the cellular/molecular mechanisms underlying cardiac fibrosis are still not well understood. This study examines the roles of the AT1 receptor and CD44 gene expression in collagen synthesis through Ang II stimulated cardiac fibroblasts. Fibroblasts were isolated from the neonatal rat hearts;the activation of fibroblasts was evaluated using the assays of cell viability and migration, and silencing of CD44 gene expression was conducted with small interfering RNA (siRNA). Results showed that Ang II significantly increases the cell proliferation and migration in a dose-dependent manner. Upon activation, the protein levels of TGF-β1, Smad2, Smad4 and collagen I were significantly increased (all p < 0.05 vs. unstimulated cells), but these changes were significantly downregulated by the AT1 receptor blocker, telmisartan (all p < 0.05 vs. Ang II activated cells). Furthermore, mRNA and protein level of CD44 were upregulated, and there was a linear correlation between CD44 and TGF-β1 as demonstrated by Pearson correlation analysis (r = 0.955, p < 0.01). Gene transfection of fibroblasts with Ad-CD44 siRNA, as evidenced by low levels of CD44 mRNA and protein, significantly reduced the production of collagen I. In summary, these results indicate that the proliferation, migration and collagen production from Ang II activated cardiac fibroblasts are potentially mediated by the AT1 receptor and CD44. Such a signaling mechanism could be crucial for the production of collagen and the development of tissue fibrosis in the heart.

Association of Polymorphisms in Angiotensin-converting Enzyme and Type 1 Angiotensin Ⅱ Receptor Genes with Coronary Heart Disease and the Severity of Coronary Artery Stenosis

To explore the relation of angiotensin-converting enzyme （ACE） and angiotensin Ⅱ type 1 receptor （AT1R） gene polymorphism with coronary heart disease （CHD） and the severity of coronary artery stenosis, 130 CHD patients who underwent coronary angiography were examined for the number of affected coronary vessels （≥75% stenosis） and coronary Jeopardy score. The insertion/deletion of ACE gene polymorphism and AT1R gene polymorphism （an A→C transversion at nucleotide position 1166） were detected by using polymerase chain reaction （PCR） and restriction fragment length polymorphism （RFLP） in CHD patients and 90 healthy serving as controls. The resuits showed that DD genotype and of ACE were more frequent in CHD patients than that in control group （38.5% vs 14.4%, P〈0.001）. The frequency of the ATIR A/C genotypes did not differ between the patients and the controls （10% vs 13.1%, P〉0.05）. The relative risk associated with the ACE-DD was increased by AT1R-AC genotype. Neither the number of affected coronary vessels nor the coronary score differed among the ACE I/D genotypes （P〉0.05）. But the number of affected coronary vessels and the coronary score were significantly greater in the patients with the AT1R-AC genotype than in those with the AA genotype （P〈0.05）. In conclusion, DD genotype may be risk factor for CHD and MI in Chinese people, and is not responsible for the development of the coronary artery stenosis. The AT1R-C allele may increase the relative risk associated with the ACE-DD genotype, and may be involved in the development of the stenosis of coronary artery.

Angiotensin receptor blocker drugs and inhibition of adrenal beta-arrestin-1-dependent aldosterone production: Implications for heart failure therapy

Aldosterone mediates many of the physiological and pathophysiological/cardio-toxic effects of angiotensin II(Ang II). Its synthesis and secretion from the zona glomerulosa cells of the adrenal cortex, elevated in chronic heart failure(HF), is induced by Ang II type 1 receptors(AT1Rs). The AT1R is a G protein-coupled receptor, mainly coupling to Gq/11 proteins. However, it can also signal through β-arrestin-1(βarr1) or-2(βarr2), both of which mediate G protein-independent signaling. Over the past decade, a second, Gq/11 proteinindependent but βarr1-dependent signaling pathway emanating from the adrenocortical AT1R and leading to aldosterone production has become appreciated. Thus, it became apparent that AT1R antagonists that block both pathways equally well are warranted for fully effective aldosterone suppression in HF. This spurred the comparison of all of the currently marketed angiotensin receptor blockers(ARBs, AT1R antagonists or sartans) at blocking activation of the two signaling modes(G protein-, and βarr1-dependent) at the Ang IIactivated AT1R and hence, at suppression of aldosterone in vitro and in vivo. Although all agents are very potent inhibitors of G protein activation at the AT1R, candesartan and valsartan were uncovered to be the most potent ARBs at blocking βarr activation by Ang II and at suppressing aldosterone in vitro and in vivo in post-myocardial infarction HF animals. In contrast, irbesartan and losartan are virtually G protein-"biased" blockers at the human AT1R, with very low efficacy for βarr inhibition and aldosterone suppression. Therefore, candesartan and valsartan(and other, structurally similar compounds) may be the most preferred ARB agents for HF pharmacotherapy, as well as for treatment of other conditions characterized by elevated aldosterone.

Effect of angiotensin Ⅱ type 1 receptor blocker and angiotensin converting enzyme inhibitor on the intraocular growth factors and their receptors in streptozotocin-induced diabetic rats

AIM： To investigate the effect of angiotensin II type 1 receptor blocker （ARB） and angiotensin converting enzyme inhibitor （ACEI） on intraocular growth factors and their receptors in streptozotocin-induced diabetic rats. METHODS： Forty Sprague-Dawley rats were divided into 4 groups： control, diabetes mellitus （DM）, candesartan- treated DM, and enalapril-treated DM （each group, n---10）. After the induction of DM by streptozotocin, candesartan [ARB, 5 mg/（kg · d）] and enalapril [ACEI, 10 mg/（kg · d）] were administered to rats orally for 4Wko Vascular endothelial growth factor （VEGF） and angiotensin II （Ang II） concentrations in the vitreous were measured using enzyme-linked immunosorbent assays, and VEGF receptor 2 and angiotensin II type 1 receptor （ATIR） levels were assessed at week 4 by Western blotting. RESULTS： Vitreous Ang II levels were significantly higher in the DM group and candesartan-treated DM group than in the control （P=0.04 and 0.005, respectively）. Vitreous ATIR increased significantly in DM compared to the other three groups （P〈0.007）. Candesartan-treated DM rats showed higher vitreal ATIR concentration than the enalapril-treated DM group and control （P〈0.001 and P=0.005, respectively）. No difference in vitreous Ang II and ATIR concentration was found between the enalapril- treated DM group and control. VEGF and its receptor were below the minimum detection limit in all 4 groups. CONCLUSION： Increased Ang II and ATIR in the hyperglycemic state indicate activated the intraocular renin-angiotensin system, which is inhibited more effectively by systemic ACEI than systemic ARB.

Effects of angiotensin-converting enzyme inhibitor and angiotensin Ⅱ receptor blocker on one-year outcomes of patients with atrial fibrillation: insights from a multicenter registry study in China

Objective To evaluate the effect of angiotensin-converting enzyme inhibitor(ACEI)/angiotensin Ⅱ receptor blocker(ARB)therapy on the prognosis of patients with atrial fibrillation(AF).Methods A total of 1,991 AF patients from the AF registry were divided into two groups according to whether they were treated with ACEI/ARB at recruitment.Baseline characteristics were carefully collected and analyzed.Logistic regression was utilized to identify the predictors of ACEI/ARB therapy.The primary endpoint was all-cause mortality,while the secondary endpoints included cardiovascular mortality,stroke and major adverse events(MAEs)during the one-year follow-up period.Univariable and multivariable Cox regression were performed to identify the association between ACEI/ARB therapy and the one-year outcomes.Results In total,759 AF patients(38.1%)were treated with ACEI/ARB.Compared with AF patients without ACEI/ARB therapy,patients treated with ACEI/ARB tended to be older and had a higher rate of permanent AF,hypertension,diabetes mellitus,heart failure(HF),left ventricular ejection fraction(LVEF)<40%,coronary artery disease(CAD),prior myocardial infarction(MI),left ventricular hypertrophy,tobacco use and concomitant medications(all P<0.05).Hypertension,HF,LVEF<40%,CAD,prior MI and tobacco use were determined to be predictors of ACEI/ARB treatment.Multivariable analysis showed that ACEI/ARB therapy was associated with a significantly lower risk of one-year all-cause mortality[hazard ratio(HR)(95%CI):0.682(0.527-0.882),P=0.003],cardiovascular mortality[HR(95%CI):0.713(0.514-0.988),P=0.042]and MAEs[HR(95%CI):0.698(0.568-0.859),P=0.001].The association between ACEI/ARB therapy and reduced mortality was consistent in the subgroup analysis.Conclusions In patients with AF,ACEI/ARB was related to significantly reduced one-year all-cause mortality,cardiovascular mortality and MAEs despite the high burden of cardiovascular comorbidities.

Multiple templates-based homology modeling and docking analysis of angiotensin Ⅱ type 1 receptor

Using the latest reported homologous Chemokine receptors （PDB ID： 3ODU, 3OE0 and 3OE6） as templates, twenty models of angiotensin II （Ang II） type 1 （AT1） receptor （known as p30556） were generated by multiple templates homology modeling. According to the results of the initial validation of these twenty models, the model 0020 was finally chosen as the best one for further studies. Then, a 2 ns molecular dynamic （MD） simulation for model 0020 was conducted in normal saline （0.9%, w/F） under periodical boundary conditions, which was followed by docking studies of model 0020 with several existing AT1 receptor blockers （ARBs）. The docking results reveal that model 0020 possesses good affinities with these docked ARBs which are in accordance with both the IC50 inhibitor values and their curative effects. The results also show more potent interactions between the model 0020 and its ARBs than those of ever reported results, such as hydrogen bonds, hydrophobic interactions, and especially cation-n interactions and π-π interactions which have never been reported before. This may reveal that the structure of the model 0020 is quite close to its real crystal structure and the model 0020 may have the potential to be used for structure based drug design：

Differential Effects of Angiotensin II on Intra-Renal Hemodynamics in Rats;Contribution of Prostanoids, NO and K⁺Channels

Many agents are known to cause qualitative and quantitative differences in intrarenal blood flow. This study tested the hypothesis that angiotensin II (AII) evokes a differential effect on cortical (CBF) and medullary blood flow (MBF) and that AT2 receptor mediates AII-induced increase in renal MBF by mechanisms related to nitric oxide (NO) and prostanoids. AII (100, 300 and 1000 ng/kg/min) increased mean arterial blood pressure (MABP) by 24% ± 7% (p G nitro-L-arginine (L-NNA), an inhibitor of NO synthase (100 mg/L in drinking water) enhanced AII effects on MABP (169 ± 75, p ATP channel blocker, did not affect intra-renal hemodynamics elicited by AII. Blockade of AT2 receptors with PD123319 (50 μg/kg/min) did not change basal or AII-induced changes MABP or CBF but blunted AII-induced increase in MBF by 60% ± 11 % (p 2 receptor agonist, elicited a reduction in MABP and increases in CBF and MBF that were abolished or attenuated by PD123319. These findings demonstrate that AII elicited differential changes in intrarenal blood flow;an AT1-mediated reduction in CBF but an AT2-mediated increase in MBF. The AT2 receptor-mediated increase in MBF involves guanylase cyclase, NO and dilator prostanoids but not KATP channels.

Cardioprotective Effect of Angiotensin n Receptor Antagonist on Perfused Ischemic Reperfusion Injury of Whole Isolated Rat Hearts

Objectives Investigated the cardioprotective and mechanisms of losartan on whole isolated ischemic reperfused rat heart. Methods Langendorff perfused systems was used to investigate losartan effect on whole isolated rat hearts in CPK, LDH, MDA, SOD, ang II and arrhythmia. Results Losartan decreased incidence of arrhythmia, improved atrial ventricular block recovery in reperfu-sion period, during ischemic period, CPK and LDH in I/R group increased significantly compared with control group, 51. 33±27. 02 vs 22. 42 ± 13. 33, 31. 80 ±4.56 vs 22. 28 ± 15. 96, respectively, but greatly decreased in losartan group compared with I/R group, 23. 90±21.74 vs 51. 33 ±27. 02 and 11. 50 ±13. 20 vs 31. 80 ±4. 56, respectively. During reperfusion period CPK, LDH increased significantly in I/R group compared with control group, 49. 11 ± 20. 63 vs 12. 14 ±5.92 and 28. 70±4. 69 vs 23. 10±21. 38, respectively, but decreased greatly in losartan group compared with I/R group, 39. 40 ± 9. 60 vs 49. 11 ± 20.63 and 14. 50 ±13. 75 vs 28. 70±4. 69. The content of MDA, ang II in I/R group myocytes is higher than control group's , 26. ± 9. 25 vs 17. 2 ± 3. 37 and 8. 43 ± 3. 81 vs 4. 80 ± 0. 20. However the content of SOD in two groups has no significantly change, 148. 20 ± 8. 72 vs 145. 08±6. 82. the content of MDA in losartan group myocardial tissue is much lower than control group, 15.92±4.05 vs 26. 80 ± 9. 25 and the content of ang II in losartan group myocardial tissue is much higher than I/R group, 12. 44 ± 6. 09 vs 8. 43 ± 3. 21. The department of cardiology of second hospital of Tianjin medical u-niversity Tianjin 300211 However, SOD has no significant change in two groups, 143. 47±7. 91 vs 145. 08 ± 6. 82. Conclusions Losartan against is-chemic - reperfusion injury of whole isolated rat hearts, those beneficial effects are mediate primarily by the inhibited of angiotensin II binding with its receptor and inhibited oxygen free radical scavenging potential.

POLYMORPHISM OF ANGIOTENSIN I TYPE 1 RECEPTOR GENE IN ELDERLY PATIENTS WITH ESSENTIAL HYPERTENSION

Objective To detect the A/C1165 polymorphism of angiotensin Ⅱ type Ⅰ receptor (AT1-R)gene in essential hypertensive elderly. Methods The A/C1166 polymorphism of AT1-R gene was assessed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in a case-control study of 87 essential hypertensive elders (EH) and 55 normolensive elders (NT). Results The genotype frequencies of AA, AC, CC were 0 .805 , 0.161, 0 .034 in EH group and 0 .927 ,0 .073 ,0 .000 in NT group respectively. The frequency of C61166 allele was higher in EH group (0.115) than in NT group (0 .036 )(P<0 .05 ). Conclusion The resultsindicate that A/C1166 polymorphism of AT1-R gene may be associated with essential hypertension in elderly.

AT1 receptor downregulation:A mechanism for improving glucose homeostasis

There is a pathophysiological correlation between arterial hypertension and diabetes mellitus, established since the pre-diabetic state in the entity known as insulin resistance. It is known that high concentrations of angiotensin-Ⅱ enable chronic activation of the AT1 receptor, promoting sustained vasoconstriction and the consequent development of high blood pressure. Furthermore, the chronic activation of the AT1 receptor has been associated with the development of insulin resistance. From a molecular outlook, the AT1 receptor signaling pathway can activate the JNK kinase. Once activated, this kinase can block the insulin signaling pathway, favoring the resistance to this hormone. In accordance with the previously mentioned mechanisms, the negative regulation of the AT1receptor could have beneficial effects in treating metabolic syndrome and type 2diabetes mellitus. This review explains the clinical correlation of the metabolic response that diabetic patients present when receiving negatively regulatory drugs of the AT1 receptor.

血管紧张素II及其受体在血管平滑肌细胞迁移中的作用

目的 :探讨血管紧张素II (AngII)及其受体 (ATRs)在局部血管损伤后血管平滑肌细胞 (VSMC)迁移中的作用及其机制。方法 :以体外培养VSMC为基础 ,采用细胞化学和改良Boyden’schamber的方法 ,观察AngⅡ干预VSMC后AngII受体的表达、VSMC迁移能力的变化、肌动蛋白纤维丝的动态组装变化 ,并探讨AT1R拮抗剂、AT2 R拮抗剂对上述观测指标的影响。结果 :AngII 10 -7mol/L可以刺激VSMC发生迁移 ,该作用是通过影响VSMC内应力纤维动态组装而实现的 ;AngII干预VSMC后可使AT1R表达上调 ,随着作用时间延长AT1R表达水平下降。AT1R拮抗剂可下调AT1R表达。AngII通过AT1R的介导发挥其影响VSMC迁移能力的生物学效应。AT2 R对此无明显影响。结论 :AngII通过AT1R介导来调节VSMC内肌动蛋白微丝的动态组装 ,进而改变VSMC的迁移能力 。