Intermittent heat exposure induces thoracic aorta injury in spontaneously hypertensive rats by activating the AMPK/mTOR/ULK1 pathway / 南方医科大学学报

OBJECTIVE@#To investigate the effects of different manners of heat exposure on thoracic aorta injury in spontaneously hypertensive rats (SHRs) and explore the underlying mechanism.@*METHODS@#Normal 6 to 7-week-old male SHRs were randomized into control group (cage at room temperature), intermittent heat exposure group (SHR-8 group, exposed to 32 ℃ for 8 h daily for 7 days) and SHR-24 group (with continuous exposure to 32 ℃ for 7 days). After the treatments, the pathologies of the thoracic aorta of the rats were observed with HE staining, and the expressions of Beclin1, LC3B and p62 were detected with Western blotting and immunofluorescence assay; TUNEL staining was used to observe cell apoptosis in the thoracic aorta, and the expressions of caspase-3, Bax, and Bcl-2 were detected using Western blotting. The effects of intraperitoneal injections of 3-MA (an autophagy agonist), rapamycin (an autophagy inhibitor) or compound C 30 min before intermittent heat exposure on the expressions of proteins associated with autophagy, apoptosis and the AMPK/mTOR/ULK1 pathway in the aorta were examined with immunohistochemistry.@*RESULTS@#In SHR-8 group, the rats showed incomplete aortic intima with disordered cell distribution and significantly increased expressions of Beclin1, LC3II/LC3I and Bax, lowered expressions of p62 and Bcl-2, and increased apoptotic cells in the thoracic aorta (P < 0.05). Pretreatment with 3-MA obviously inhibited the expressions of autophagy- and apoptosis-related proteins, whereas rapamycin promoted their expressions. Compared with the control group, the rats in SHR-8 group had significantly down-regulated p-mTOR and up-regulated p-AMPK and p-ULK1 expression of in the aorta; Treatment with compound C obviously lowered the expressions of p-AMPK and p-ULK1 and those of LC3B and Beclin1 as well.@*CONCLUSION@#In SHRs, intermittent heat exposure causes significant pathologies and promotes autophagy and apoptosis in the thoracic aorta possibly by activating the AMPK/mTOR/ULK1 pathway.

Effect of gemigliptin on cardiac ischemia/reperfusion and spontaneous hypertensive rat models

Diabetes is associated with an increased risk of cardiovascular complications. Dipeptidyl peptidase-4 (DPP-IV) inhibitors are used clinically to reduce high blood glucose levels as an antidiabetic agent. However, the effect of the DPP-IV inhibitor gemigliptin on ischemia/reperfusion (I/R)-induced myocardial injury and hypertension is unknown. In this study, we assessed the effects and mechanisms of gemigliptin in rat models of myocardial I/R injury and spontaneous hypertension. Gemigliptin (20 and 100 mg/kg/d) or vehicle was administered intragastrically to Sprague-Dawley rats for 4 weeks before induction of I/R injury. Gemigliptin exerted a preventive effect on I/R injury by improving hemodynamic function and reducing infarct size compared to the vehicle control group. Moreover, administration of gemigliptin (0.03% and 0.15%) powder in food for 4 weeks reversed hypertrophy and improved diastolic function in spontaneously hypertensive rats. We report here a novel effect of the gemigliptin on I/R injury and hypertension.

Observation on the changes of cerebral venules wall matrix in spontaneous hypertensive rat with high-salt diet / 中国脑血管病杂志

Objective To investigate the changes of wall matrix of the cerebral venules in the high-salt fed spontaneously hypertensive (SHR) rats. Methods Six SI1R and six Wistar Kyoto (WKY) male rats at the age of 10 weeks were experimented. Rats in the SHR group were given high-salt diet ( 1% sodium chloride drinking water and 4% high-salt) for 10 months,and rats in the WKY group were given normal drinking water and fed for 10months,The rats were all raised in the Institute of Neurology,Huashan Hospital, Fudan University. The feeding conditions were kept at a constant temperature of 22-24 and constant humidity of 55 ±5% ,with artificial light and shade for 12 h each. Morphological changes of cerebral small vessels were observed by hcmatoxylin-eosin (HE) staining. Venules were differentiated from arterioles through the presence of ot-smooth muscle actin. Immunofluorescence was performed to observe the expression of collagen I (COL I ) .collagen IV ( COLIV) ,fibronectin (FN) and laminin (LN) in cerebral venules. The brain tissue was divided into cortex,deep gray matter and hippocampus regions. The collagen deposition and expression of related extracellular matrix of venules in these regions were compared. Results ( 1) HE staining showed vascular remodeling of arterioles in high-salt fed SHR, which was consistent with the pathological characteristics of arteriosclerotic cerebral small vessel disease. ( 2) Compared with the WKY group,the high-salt fed SHR group showed obviously increased cerebral venules COL I deposition and LN expression (153 ± 12 ts. 106 ±8,/=3. 253 =0. 004; 135 ±11 vs. 99 ±9,1 = 2. 575,/' =0. 017); COLIV deposition had an increasing trend,but without statistically significant difference (118 ± 12 vs. 99 ± 4,t = 1. 508,/' = 0. 142). There was no significant difference in FN expression ( 104 ±4 vs. 101 ±3,/= 0.664,P =0.512). (3) Compared with the group,the SHR group had significantly increased deposition of COLlin cortex and deep gray matter venules (159 ± 15 vs. 108 ±7,/=3.075,/'=0.007; 139 ± 12 i5.96±9,/= 2. 868, P =0. 009); No statistically significant difference was found bftween the two groups in hippocampus region ( 169 ± 16 133 ±9 ,i = 1. 926,P =0.072) ;No statistical significance was found between the high-salt diet SHR group and the WKY group in COLIV and fibronectin deposi.ion of venules in these regions (P > 0.05);Compared with the group,the L\ expression of deep gray matter venules in the SHR group after high-salt diet was significantly increased (125 ± 12 vs. TJ ±5,1 =3.767,/J = 0.002) ,and there was no statistically significant difference in both cortical and hippocampal regions (138 ±18 vs. 109 ±7,/= l.460,/>=0. 174; 153 ± 16 m. 133 ± 13,/= 0.960, P = 0. 359) . Conclusions Tic expression of COL I and LN of cerebral venules wall was increased in the high-salt fed SHR. The COL 1 deposition was most significant in cortex and deep gray matter,and the LN deposition was mainly in deep gray matter.

Effect of Lumbricus Peptides on TLR4/NF-<i>κ</i>B Signaling Pathway in Spontaneous Hypertensive Rat Kidney / 中国实验方剂学杂志

@# <b>Objective:</b>to observe the effect and mechanism of lumbricus peptides on early renal injury in spontaneous hypertensive rats (SHR) based on Toll-like receptors 4 (TLR4)/nuclear factor-<i>κ</i>B(NF-<i>κ</i>B) signaling pathway. <b>Method:</b>The 40 SHRs were randomly divided into model group (equal volume of distilled water by intragastric administration), lumbricus peptides low, middle and high dose groups (126, 252, 504 mg·kg^-1), and Benazepril group (0.9 mg·kg^-1), <i>n</i>=8 in each group. 8 male rats with normal blood pressure at the same age were set as the normal control group,with equal volume of distilled water. After treatment for 60 consecutive days, enzyme-linked immunosorbent assay (ELISA) was used to determine microalbumin (mAlb)and <i>N</i>-acetyl-<i>β</i>-<i>D</i>-glucosaminidase (NAG) content in 24 h urine as well as the level of serum angiotensinⅡ (AngⅡ). Ultrastructural changes of rat kidneys were observed by transmission electron microscope. Western blot was used to detect renal TLR4, NF-<i>κ</i>B p65 protein levels. Immunohistochemical method was used to detect renal tumor necrosis factor-<i>α</i> (TNF-<i>α</i>) and interleukin 10 (IL-10) expression. <b>Result:</b>As compared with the normal control group, the levels of urine mAlb, NAG and serum Ang Ⅱ were increased in the model group (<i>P</i><0.05); the expression of TLR4 and NF-<i>κ</i>B p65 protein was increased (<i>P</i><0.05); expression of TNF-<i>α</i> was increased (<i>P</i><0.05), while IL-10 expression was decreased (<i>P</i><0.05). Transmission electron microscopy of kidney tissues showed that most of the glomeruli of the model group had podocyte foot process fusion, mesangial cells and mesangial matrix hyperplasia. As compared with the model group, the levels of urine mAlb, NAG, and serum Ang Ⅱ were decreased in the rats in lumbricus peptides groups and benazepril group (<i>P</i><0.05); the expression of TLR4 and NF-<i>κ</i>B p65 protein was decreased (<i>P</i><0.05); the positive expression of TNF-<i>α</i> in kidney was decreased to different extent (<i>P</i><0.05), but the expression of IL-10 was increased (<i>P</i><0.05). Transmission electron microscopy of kidney tissues showed that the damage of kidneys in rats after administration of high-dose lumbricus peptides and benazepril was improved in varying degrees. <b>Conclusion:</b>lumbricus peptides can reduce early renal damage in SHRs, and its mechanism may be achieved by regulating the AngⅡ-TLR4/NF-<i>κ</i>B pathway.

The relationship between left ventricular myocardial strain and different stages of cardiac dysfunction in spontaneously hypertensive rats evaluated by two-dimensional strain echocardiography / 中华超声影像学杂志

Objective@#To investigate the relationship between multi-dimensional myocardial strain and global cardiac function in different stages of cardiac dysfunction in spontaneously hypertensive rats (SHR) by two-dimensional strain echocardiography.@*Methods@#According to cardiac function measurements, SHR of 28 to 102 weeks were divided into 3 groups: Normal group[Group A, normal left ventricular ejection fraction(LVEF) and left ventricular end-diastolic pressure(LVEDP), n=13], diastolic dysfunction group (Group B, normal LVEF but increased LVEDP, n=24), and systolic dysfunction group (Group C, decreased LVEF and increased LVEDP, n=17), with WKY rats at similar weeks of age as controls (group a, n=7; group b, n=12; and group c, n=16). Morphological parameters of left ventricular were measured by echocardiography. Using EchoPac workstation, systolic peak longitudinal strain, circumferential and radial strain were calculated at the left ventricular middle levels. Extracellular collagen content was observed histologically.@*Results@#Left atrial dimension increased in group B and larger in group C, and dilated left ventricular and thickened wall were only found in group C. Systolic peak longitudinal strain of group B was significantly lower than group A and group a(all P<0.05), and deteriorated in group C(P<0.05), while systolic peak circumferential and radial strain and LVEF were only significantly decreased in group C (all P<0.05), while there was no significant difference between Group A and Group B(all P>0.05). Collagen content in endocardial and mid-layer myocardium increased in group B and C, and increased epicardial collagen occurred in group C. Systolic peak longitudinal strain, circumferential and radial strain were correlated positively with LVEF(r=0.65, 0.80, 0.80, all P<0.01).@*Conclusions@#In SHR, systolic peak longitudinal strain obtained by echocardiography is decreased in the period of diastolic dysfunction, while the damage of systolic peak circumferential and radial strain leads to the systolic dysfunction.

The relationship between left ventricular myocardial strain and different stages of cardiac dysfunction in spontaneously hypertensive rats evaluated by two‐dimensional strain echocardiography / 中华超声影像学杂志

Objective To investigate the relationship between multi‐dimensional myocardial strain and global cardiac function in different stages of cardiac dysfunction in spontaneously hypertensive rats ( SHR ) by two‐dimensional strain echocardiography . MethodsAccording to cardiac function measurements ,SHR of 28 to 102 weeks were divided into 3 groups :Normal group[ Group A , normal left ventricular ejection fraction( LVEF) and left ventricular end‐diastolic pressure( LVEDP) , n ＝13] ,diastolic dysfunction group ( Group B , normal LVEF but increased LVEDP , n ＝24) ,and systolic dysfunction group ( Group C ,decreased LVEF and increased LVEDP , n ＝ 17 ) ,with WKY rats at similar weeks of age as controls ( group a , n ＝ 7 ;group b , n ＝ 12 ; and group c , n ＝ 16 ) . Morphological parameters of left ventricular were measured by echocardiography . Using EchoPac workstation ,systolic peak longitudinal strain ,circumferential and radial strain were calculated at the left ventricular middle levels . Extracellular collagen content was observed histologically . Results Left atrial dimension increased in group B and larger in group C ,and dilated left ventricular and thickened wall were only found in group C .Systolic peak longitudinal strain of group B was significantly lower than group A and group a ( all P ＜ 0 .05 ) ,and deteriorated in group C( P ＜ 0 .05 ) ,while systolic peak circumferential and radial strain and LVEF were only significantly decreased in group C ( all P＜ 0 .05 ) ,w hile there was no significant difference between Group A and Group B( all P ＞0 .05) . Collagen content in endocardial and mid‐layer myocardium increased in group B and C , and increased epicardial collagen occurred in group C . Systolic peak longitudinal strain , circumferential and radial strain were correlated positively with LVEF( r ＝0 .65 ,0 .80 ,0 .80 ,all P ＜0 .01) . Conclusions In SHR ,systolic peak longitudinal strain obtained by echocardiography is decreased in the period of diastolic dysfunction ,w hile the damage of systolic peak circumferential and radial strain leads to the systolic dysfunction .

Effect of alpha-lipoic acid supplementation on blood pressure, renal oxidant-antioxidant status and renal damage in spontaneously hypertensive rats

Objective: To investigate the effect of alpha-lipoic acid (ALA) supplementation on systolic blood pressure (SBP), renal oxidant-antioxidant status and renal damage in spontaneously hypertensive rats (SHR) and SHR administered with Nω-nitro-L-arginine methyl ester (L-NAME). Methods: Male rats were divided into four groups (SHR, SHR+ALA, SHR+L-NAME, SHR+ALA+L-NAME). The respective group of rats was administered with ALA (100 mg/kg/day) from age 4 weeks to 28 weeks and L-NAME (25 mg/kg/day) from age 16 weeks to 28 weeks. SBP was measured every two weeks and twenty four hour urine was collected at 4 weeks, 16 weeks and 28 weeks for estimation of protein, creatinine and N-acetyl-β-D-glucosaminidase. At the end of 28 weeks, rats were sacrificed and blood and kidneys collected for assessment of blood creatinine, kidney thiobarbituric acid reactive substances, protein carbonyls, superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione S-transferase, glutathione disulfide, glutathione, total antioxidant status and nitric oxide as well as histopathological examination. Results: ALA supplementation significantly reduced SBP of SHR and SHR+L-NAME rats when compared to their respective non-supplemented groups. Renal oxidant status markers including thiobarbituric acid reactive substances and protein carbonyls were significantly reduced on SHR and SHR+L-NAME rats supplemented with ALA at 28 weeks as well as ALA supplementation significantly increased renal antioxidants including superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferase, glutathione and glutathione/glutathione disulfide ratio at 28 weeks. No significant change in nitric oxide levels was observed between the ALA supplemented and non-supplemented groups. Renal dysfunction was ameliorated on ALA supplementation as evidenced by significant reduction in urine protein levels, N-acetyl-β-D-glucosaminidase activity and significant increase of creatinine clearance in SHR and SHR+L-NAME at 28 weeks. Renal histopathological examination showed that ALA supplementation prevented vascular damage in SHR and ameliorated glomerular damage in SHR+L-NAME at 28 weeks. Conclusions: ALA has hypotensive and renoprotective effects on both SHR and SHR+L-NAME, which could be due to its ability to ameliorate oxidative stress in the kidneys.

Effect of alpha-lipoic acid supplementation on blood pressure, renal oxidant-antioxidant status and renal damage in spontaneously hypertensive rats

Objective: To investigate the effect of alpha-lipoic acid (ALA) supplementation on systolic blood pressure (SBP), renal oxidant-antioxidant status and renal damage in spontaneously hypertensive rats (SHR) and SHR administered with N

Effects of NO on T lymphocyte subsets in peripheral blood of spontaneously hypertensive rats / 西安交通大学学报(医学版)

Objective To investigate whether NO can relieve hypertensive cerebrovascular and renal injury by regulating the ratio of peripheral blood T lymphocyte subsets and reducing proinflammatory cytokine release . Methods Twelve-week SHR and WKY rats were randomly divided into three groups :WKY group ,SHR group and SHR+NO intervention group ,with 6 rats in each group .Rats in SHR+ NO intervention group were injected intraperitoneally with sodium nitroprusside according to 10 μg/(kg · d) for 4 weeks ,while WKY group and SHR group were injected intraperitoneally with an equal amount of saline for 4 weeks .After measuring the tail artery blood pressure ,basilar artery and renal pathological changes were observed by HE staining ;the rates of CD4+ /CD8+ and CD4+ CD25+ T cells were detected by flow cytometry ;and the expression of TNF-α was detected by ELISA .Results The expressions of CD4+ /CD8+ and TNF-αin SHR group were significantly higher than those in WKY group (P<0 .01) while the rate of CD4+ CD25+ in SHR group was significantly lower than that in WKY group (P<0 .01) .The expressions of CD4+ /CD8+ and TNF-α in SHR+ NO intervention group were significantly lower than those in SHR group whereas the rate of CD4+ CD25+ was significantly higher than that in SHR group (P<0 .05) .Conclusion NO can improve the target organ damage caused by hypertension by regulating the peripheral blood T lymphocyte subsets ratio and reducing the release of proinflammatory factors .

Icariside Ⅱ improves left ventricular cardiomyocyte apoptosis in spontaneously hypertensive rats / 中国药理学通报

Aim To observe the effect of icariside Ⅱ(ICS Ⅱ)on cardiomyocyte apoptosis in spontaneously hypertensive rats (SHR)and to explore its possible mechanism. Methods Thirty male 13-week-old SHRs were randomly divided into model group,ICS Ⅱ low, medium,high and positive drug group (n = 6),ho-mologous male Wistar-Kyoto rats as control group (n =6). After a week of adaptive feeding,ICS Ⅱ low,me-dium and high dose groups were given ICS Ⅱ 4,8,16 mg · kg - 1 (ig,qd),and the positive drug group was given losartan 20 mg·kg - 1 . At the same time,the WKY and SHR group were given equal volume double distilled water. After 12 weeks of administration,the blood pressure was measured in rats. Then,the rats were sacrificed and the left ventricles were separated in order to calculate the left ventricular mass index. HE staining was used to observe the pathological changes of the left ventricle,and the apoptosis of the left ventricu-lar myocardium was detected by TUNEL staining. The expressions of Bcl-2 and Bax mRNA in left ventricle were detected by real time RT-PCR,and Bcl-2,Bax and cleaved-caspase-3 protein expressions were detec-ted by Western blot. Results Compared with WKY group,the blood pressure and left ventricular mass in-dex increased in SHR group (P < 0. 05),and the my-ocardial cell arrangement was disordered and the cell hypertrophy and apoptosis were obvious,accompanied by rupture of filament ;the level of Bax mRNA was up-regulated (P < 0. 05),and Bcl-2 mRNA was down-regulated (P < 0. 05 );the expressions of Bax and cleaved-caspase-3 protein were up-regulated (P <0. 05),and the level of Bcl-2 protein was down-regu-lated (P < 0. 05 ),and the ratio of Bax / Bcl-2 in-creased (P < 0. 05). Compared with SHR group,the blood pressure and left ventricular mass index de-creased in ICS Ⅱ middle,high group and the positive drug group (P < 0. 05);moreover,the arrangement of myocardial cells became more orderly,the cell hyper-trophy and the apoptosis of myocardial cells were im-proved;the level of Bax mRNA was down-regulated and Bcl-2 mRNA was up-regulated (P < 0. 05);the expression of Bax and cleaved-caspase3 protein were down-regulated and the level of Bcl-2 protein was up-regulated (P < 0. 05 );the ratio of Bax / Bcl-2 de-creased (P < 0. 05). Conclusions ICS Ⅱ can im-prove the left ventricular cardiomyocytes apoptosis in SHR,and its mechanism is related to the decrease of blood pressure and the inhibition of mitochondrial ap-optosis pathway.

Protective effects of mangiferin on inflammatory injury of cerebral tissue in spontaneously hypertensive rats / 中成药

AIM To observe the protective effects of mangiferin on the inflammatory injury and expression of the inflammatory factor in the cerebral tissue of spontaneously hypertensive rats and on MCP-1/CCR2 signal pathway.METHODS Forty spontaneously hypertensive rats were randomly divided into model,benazepril [10 mg/(kg · d)] and mangiferin high,middle and low dose [40,20,10 mg/(kg · d)] groups and other eight rats of same week age served as control group.After consecutive intragastric administration for eight weeks,morphology of the rats' cerebral tissue was observed;their levels of ICAM-1,IL-6 and TNF-α in cerebral tissue were determined by ELISA;their expressions of MCP-1 and CCR2 protein in brain tissue of rats were detected by immunohistochemistry and Western blot and the detection of mRNA expressions of MCP-1 and CCR2 in cerebral tissue of rats were carried out by RT-PCR.RESULTS Compared with the model group,the blood pressure of mangiferin in each dosage group decreased slightly,but there was no significant statistical difference.In the control group and the model group,there was no obvious morphological change in the cerebral tissue.The morphology of rats in the benazepril group,each dose of mangiferin group were all normal.The contents of IL-6,TNF-α,ICAM-1 and MCP1,CCR2 protein and mRNA expression were significantly decreased in the cerebral tissues of spontaneously hypertensive rats.CONCLUSION Mangiferin has obvious anti-inflammatory effects on inflammatory reaction in spontaneously hypertensive rats,its mechanism may be related to inhibiting the expression of MCP/CCR2 signaling pathway.

Effect of Qing-Gan Yi-Shen Qu-Feng Formula on Blood Pressure and Thymus Morphology in Spontaneously Hypertensive Rats / 世界科学技术-中医药现代化

Spontaneously hypertensive rat (SHR) model was employed to investigate the effect of Qing-Gan Yi-Shen Qu-Feng (QGYSQF) formula on blood pressure and thymus morphology.SHR rats along with Wistar-Kyoto (WKY) rats were examined in parallel for changes in blood pressure and thymus morphology.SHR rats were treated with QGYSQF formula or antihypertensive drug.Candesartan was used as control.SHR and WKY rats treated with vehicle were included as controls for hypertension and normal blood pressure,respectively.Blood pressure was measured by tail cuff method in a non-invasive manner.Thymus weight was measured and morphological changes of thymus were observed by hematoxylin and eosin (HE) staining.The areas of thymus medulla and cortex were measured by image analysis software.The results showed that compared to that from the WKY rats,the blood pressure of SHR rats began to increase at 6 weeks of age.The systolic blood pressure of SHR rats was significantly elevated compared to that in WKY rats from 6 to 20 weeks of age (p ＜ 0.01).QGYSQF formula treatment resulted in significantly decreased blood pressure in SHR rats (p ＜ 0.01).Age-dependent atrophy was observed in SHR and WKY rats,which was evidenced by decreased weight of thymus.QGYSQF formula treatment resulted in significantly increased thymus index in 8-week old SHR rats compared to that from age-matched vehicle-treated SHR and WKY rats (p ＜ 0.01).Compared to that from WKY rats,the thymus atrophy of SHR rats progressed faster.Moreover,decreasing in areas of cortex and medulla and the blurring of medulla border were more evident in SHR rats.Compared to that from vehicle-treated SHR rats,QGYSQF formula treatment significantly increased the area of cortex as well as the total area of the thymus in 8-week old SHR rats (p ＜ 0.01).It was concluded that QGYSQF formula significantly attenuated the progression of hypertension in SHR rats.Meanwhile,QGYSQF formula treatment may exert protective effects on thymus when the blood pressure is elevated within a certain range or with shorter duration.

Metformin inhibits myocardial hypertrophy by up-regulating glutathione-S-transferase μ2 / 中国临床药理学与治疗学

AIM:To observe the effect of metformin on the expression of GSTM2 in spontaneously hypertensive rats,and to investigate the mechanism of the reversal of myocardial hypertrophy by metformin.METHODS:Sixteen weeks old WistarKyoto (WKY) and spontaneously hypertensive rats (SHR) were used as the experimental control.Eight weeks old WKY and SHR were administered to metformin (Met) continuously for 8 weeks as the experimental group.Systolic pressure of rats was regularly determined by NIBP instrument of heart rate and blood pressure.The hemodynamic parameters were tested by BL-420 biological experimental system and 4 track physiological recorders.The weights of left ventricle and rats were collected to calculate the left ventricular mass index.The activity of GSTM2 enzyme in left ventricle was detected by Enzyme-linked immunosorbent assay (ELISA).The protein expression of GSTM2 and p47phox and Nox4 in left ventricle were investigated by Western blot.The O2·-levels were measured by staining with dihydroethidium (DHE).RESULTS:Compared with the experimental control,the blood pressure and left ventricular mass index and left ventricular end-diastolic pressure (LVEDP) increased in SHR;the maximal rate of increase and decrease of left-ventricle pressure development (± dp/dt max) decreased significantly in SHR;the protein expression and enzyme activity of left ventricular GSTM2 were significantly decreased;the expression of p47phox,Nox4 and the generation of O2·-were significantly increased in the left ventricles of SHR;the value of P was less than 0.01 and the difference was statistically significant.Compared with the SHR group,the SHR were administered with metformin (Met) continuously for 8 weeks.The left ventricular mass index and left ventricular end-diastolic pressure(LVEDP) decreased observably in SHR administration group;the maximal rate of increase and decrease of left-ventricle pressure development(± dp/dt max) increased in SHR administration group;the protein expression and enzyme activity of left ventricular GSTM2 were significantly increased in SHR administration group.the expression of p47phox,Nox4 and the generation of O2·-was significantly decreased in the left ventricles of SHR administration group;the value of P was less than 0.01 and the difference was statistically significant.CONCLUSION:Metformin can significantly reverse the myocardial hypertrophy in SHR,which might be associated with the up-regulation of GSTM2 expression,decrease the expression of p47phox,Nox4 and O2·-generation,elimination of oxidative stress.

Olmesartan restores the protective effect of remote ischemic perconditioning against myocardial ischemia/reperfusion injury in spontaneously hypertensive rats

OBJECTIVES: Remote ischemic perconditioning is the newest technique used to lessen ischemia/reperfusion injury. However, its effect in hypertensive animals has not been investigated. This study aimed to examine the effect of remote ischemic perconditioning in spontaneously hypertensive rats and determine whether chronic treatment with Olmesartan could influence the effect of remote ischemic perconditioning. METHODS: Sixty rats were randomly divided into six groups: vehicle-sham, vehicle-ischemia/reperfusion injury, vehicle-remote ischemic perconditioning, olmesartan-sham, olmesartan-ischemia/reperfusion and olmesartan-remote ischemic perconditioning. The left ventricular mass index, creatine kinase concentration, infarct size, arrhythmia scores, HIF-1α mRNA expression, miR-21 expression and miR-210 expression were measured. RESULTS: Olmesartan significantly reduced the left ventricular mass index, decreased the creatine kinase concentration, limited the infarct size and reduced the arrhythmia score. The infarct size, creatine kinase concentration and arrhythmia score during reperfusion were similar for the vehicle-ischemia/reperfusion group and vehicle-remote ischemic perconditioning group. However, these values were significantly decreased in the olmesartan-remote ischemic perconditioning group compared to the olmesartan-ischemia/reperfusion injury group. HIF-1α, miR-21 and miR-210 expression were markedly down-regulated in the Olmesartan-sham group compared to the vehicle-sham group and significantly up-regulated in the olmesartan-remote ischemic perconditioning group compared to the olmesartan-ischemia/reperfusion injury group. CONCLUSION: The results indicate that (1) the protective effect of remote ischemic perconditioning is lost in vehicle-treated rats and that chronic treatment with Olmesartan restores the protective effect of remote ischemic perconditioning; (2) chronic treatment with Olmesartan down-regulates HIF-1α, ...

Experimental animal models in attention deficit hyperactivity disorder / 中华行为医学与脑科学杂志

Objective To review the advantages and disadvantages of common attention deficit hyperactivity disorder(ADHD) animal models,published in 2000-2014 at home and abroad,with an attempt to provide new ideas for the future study of the pathogenesis in ADHD.Methods Major online database including CNKI,Wan Fang databases,OVID,Pubmed databases were searched in January 2015,using the key wordsattention deficit hyperactivity disorder, animal modelsand so on,to analysis the advantages and disadvantages of each type of experimental animal models and research value in ADHD.Results Totally 29 studies were enrolled,and the analysis show that the current commonly used experimental animal models of ADHD are spontaneously hypertensive rats,dopamine transporter gene knockout mice,lack of mutant mice model,neonatal 6 hydroxy dopamine damage of juvenile rat model,neonatal hypoxic rats model,X-ray irradiation injury model of rat hippocampus and other brain tissue damage model and isolated feeding model,and each animal model has the advantages,disadvantages and special research value of the pathogenesis of ADHD.Conclusion The specific pathogenesis of ADHD is unclear,but the neuroendocrine changes especially HPA axis attracted much attention in recent years.this paper summarizes the research at home and abroad comparison of several common animal models of ADHD.neuroendocrine changes in SHR and ADHD children have a certain degree of consistency in HPA axis,looking for ADHD children and SHR in neuroendocrine aspects of consistency is likely to open a new path to search the pathogenesis in ADHD.

Study on dynamic changes and gender difference of heart rate variability and blood pressure variability via implantable telemetry technology in spontaneously hypertensive rats / 中国比较医学杂志

Objective To observation dynamic changes and gender difference of heart rate variability and blood pressure variability in unbonded spontaneously hypertensive rats using Telemetry technology .Method Taking sixteen spontaneously hypertensive rats of 3-month-old in SPF grade, there were implanted TL11M2-C50-PXT device intraperitoneally.Seven days later, respectively monitoring chainless blood pressure and electrocardiogram for 24 h continuously time using telemetry system when 3, 5, 7 months of age in spontaneously hypertensive rats .Analysing 24 h systolic pressure , mean blood pressure , diastolic blood pressure , heart rate variability and blood pressure variability . Result Systolic pressure , diastolic pressure and mean pressure , blood pressure variability increased with age of the moon increased in spontaneously hypertensive rats , moreover female SHR rats of blood pressure variability was significantly lower than that of the male rats .Correlated indexes of heart rate variability had no obvious change Between three to seven month -old in male spontaneously hypertensive rats .But RR interval , SDNN, TP, VLF and HF increased significantly with age of the moon increased in female spontaneously hypertensive rats , moreover the female SHR rats of TP , VLF and HF index of heart rate variability were lower than the male rats .Conclusion With the SHR rats age and blood pressure , blood pressure variability increased , and the female SHR rat variability in blood pressure and heart rate was significantly lower than that of the male .

Study on the Pharmacokinetic-pharmacodynamic Model of Nisoldipine Controlled-release Patches in Spon-taneously Hypertensive Rats / 中国药房

OBJECTIVE:To establish the pharmacokinetic-pharmacodynamic(PK-PD) model of Nisoldipine controlled-release patches(NCRP)in spontaneously hypertensive rats(SHR). METHODS:SHR were randomized into a patch(NCRP)group and a tablet(Nisoldipine tablets)group,with 6 rats in each group. The microdialysis probes were implanted in SHR. Each rat was given 5 mg nisoldipine. Plasma microdialysate was collected within 36 h after administration. HPLC was adopted to determine the plasma concentration of nisoldipine,and WinNonlin 5.3 was employed to calculate Pharmacokinetic parameters. With heart rate and blood pressure as pharmacodynamic indexes,PK-PD model study was conducted. RESULTS:Vs. nisoldipine tablets,NCRP has con-trolled release effect. The relationship between NCRP drug effect and effect-site concentration met the Sigmoid-Emax model. The main parameters of the PK-PD model for heart rate and systolic blood pressure were as follows as Emax of (2.65 ± 0.06) and (10.71 ± 0.87),EC50 of (83.65 ± 35.25) and (1.29 ± 0.26) ng/ml,γ of (0.83 ± 0.91) and (1.2 ± 0.35),Keo of (0.37 ± 0.53) and (0.91±0.24)h-1. CONCLUSIONS:PK-PD model of NCRP in SHR has been established successfully.

Papel do antioxidante (vitamina C) na modulação da pressão sanguínea em ratos espontaneamente hipertensos (SHR) / The role of antioxidant (vitamin C) in the modulation of the blood pressure in spontaneously hypertensive rats (SHR)

A hipertensão essencial humana, bem como a hipertensão desenvolvida em Ratos Espontaneamente Hipertensos (SHR), são caracterizadas pelo desenvolvimento de Pressão Arterial (PA) elevada na medida em que a idade avança, sem identificação da causa primária. Está bem estabelecido que este modelo animal apresenta estresse oxidativo (EOx) concomitante a hipertensão. O mecanismo pelo qual o antioxidante reduz a pressão não está claro, por essa razão, é necessário avaliar o comportamento destas enzimas envolvidas na homeostase da PA. Ratos Wistar-Kyoto (WKY) e SHR machos receberam ácido ascórbico, 200 mg / kg / dia por sonda orogástrica durante cinco semanas. A PA, a Hipertrofia Ventricular Esquerda (HVE), o Sistema Renina-Angiotensina (SRA), o Peptídeo Natriurético Atrial (ANP) e o EOx foram comparados entre os grupos por pletismografia, estereologia, microscopia confocal de varrimento a laser, microscopia eletrônica de transmissão, western blotting e análise do RT-qPCR. Os SHR tratados com ácido ascórbico reduziram a PA e a HVE. Além disso, as enzimas envolvidas na homeostase da PA, a renina e a Enzima Conversora de Angiotensina (ECA) normalizaram-se, bem como os Receptores tipo 1 de Angiotensina II (AT1). A grande quantidade de grânulos de ANP no grupo SHR foi reduzida pelo tratamento com ácido ascórbico. O balanço oxidativo foi restabelecido nos SHR tratados com este antioxidante. O EOx nos SHR eleva os níveis de renina e de PA. Estas espécies reativas de oxigênio podem ser envolvidas no mecanismo de sinalização para aumentar a expressão de ANP nos miócitos atriais. Estes dados também mostram que o tratamento com o antioxidante (vitamin C) reduz o EOx e normaliza a PA ao menos parcialmente pela redução de taxas de renina...

The essential hypertension, as well as the Spontaneously Hypertensive Rat (SHR), is characterized by the development of high BP (BP) with advancing age, with no identified primary cause. It is well established that this animal model presents OxS concomitant hypertension. The mechanism, by which the antioxidant reduces the pressure, is not clear, for this reason, it is necessary to evaluate the behavior of enzymes involved in the homeostasis of BP. Male Wistar-Kyoto (WKY) rats and SHR received ascorbic acid, 200 mg / kg / day by orogastric gavage with lasted five weeks. The BP, Left Ventricular Hypertrophy (LVH), renin-angiotensin system (RAS), Atrial Natriuretic Peptide (ANP) and OxS results have been extensively compared among groups by plethysmography, stereology, confocal laser scanning microscopy, transmission electron microscopy, western blotting and RT-qPCR analysis. The SHR treated with ascorbic acid reduced BP and LVH. Also, the enzymes involved in the homeostasis of BP, renin and Angiotensin Converting Enzyme (ACE) normalized, as well as Angiotensin II type 1 receptor (AT1R). The large amount of ANP granules in SHR group was reduced by treatment with ascorbic acid. Oxidative balance was reestablished in SHR treated with this antioxidant. OxS in SHR elevates renin levels and BP. These reactive oxygen species may be involved in the signaling mechanism for increased expression in ANP atrial myocytes. These data also show that treatment with antioxidant (vitamin C) reduces OxS and normalizes BP at least partly by reducing rates of renin...

The Effects of CCl4 on the Expressions of Aquaporin and Superoxide Dismutase in the Kidney of the Spontaneously Hypertensive Rat / 체질인류학회지

Carbon tetrachloride (CCl4) induces hepatocellular damage, resulting in liver cirrhosis by generating reactive oxygen species (ROS). At the stage of decompensated liver cirrhosis, many patients suffer from the abnormal regulation of sodium and water balance such as ascites. Also, the kidney can be directly damaged by CClCCl4-induced ROS generation. The aquaporin (AQP) is an important transmembrane protein located in the kidney to reabsorb water, and it may be affected by the ROS to alter water balance. ROS is related with the development of hypertension and alteration of antioxidant enzymes. This study was undertaken to investigate the effects of CCl4 on the expression of AQPs (AQP1 and AQP2) and superoxide dismutase (SOD) in the kidney of spontaneously hypertensive rat (SHR) and normotensive Wistar-Kyoto rat (WKY). The SOD is known as a scavenger of ROS, and we hypothesized that oxidative stress in the aged kidneys may be increased by hypertension. Male WKY and SHR were randomly divided into control and CCl4-treated groups at 8, 16 and 24 weeks of age, respectively. The experimental group received olive oil-dissolved CCl4 (1.6 mL/kg) on its back subcutaneous tissue twice a week for 4 weeks, and control animals received olive oil only. After 24 hours following the last injection, blood samples and kidneys were obtained under anesthesia. Renal histopathology was examined by H&E stain, and the expression of AQP1, AQP2, CuZn-SOD and Mn-SOD were evaluated by immunohistochemical methods and Western blot analysis. CCl4 treatment induced the tubular swelling, tubular epithelial atrophy or detachment in both WKY and SHR, and interstitial edema, tubular cast and infiltration of leukocyte in SHR. The BUN levels in both WKY and SHR were increased by CCl4 treatment at 16 weeks of age. The expression of AQP1 were increased by CCl4 treatment at 8 and 24 weeks of age SHR. The expressions of AQP2 in 24 week-old control SHR was decreased compared to 8 week-old control SHR. CCl4 treatment increased the expressions of AQP2 at 8 week-old and 24 week-old SHR, and the increasing of AQP2 was more remakable in advanced age. The expressions of CuZnSOD and MnSOD were increased at 24 week-old control SHR compared to same aged WKY. Whereas the expression of CuZnSOD was increased by CCl4 treatment in 8 week-old SHR, the expression of both CuZnSOD and MnSOD were decreased by CCl4 treatment in 24 week-old SHR. In summary, CCl4-treated SHR showed an increase in AQP expression and a decrease in SODs at the advanced age. These results suggest that CCl4-induced oxidative stress in the aged hypertensive rats may alter water balance via upregulation of AQPs and accelerate renal damage via downregulation of SODs.

Expression of p-PPARγ in the aging thoracic aorta of spontaneously hypertensive rat and inhibitory effect of rosiglitazone

To investigate the expression of phosphorylated peroxisome proliferators-activated receptor γ (p-PPARγ) in the aging thoracic aorta of spontaneously hypertensive rat (SHR) and the inhibitory effect of rosiglitazone on the phosphorylation of PPARγ. Methods: 16, 32 and 64 week-old Wistar-Kyoto rats (WKY) and SHR were randomly and respectively divided into WKY, SHR and SHR+rosiglitazone group (9 in each group). The rats in SHR+rosiglitazone group were treated with rosiglitazone (5 mg/kg, intragastrically) for 56 d, whereas normal saline was applied in WKY and SHR groups. Systolic blood pressure (SBP) of rats was measured by tail cuff method. Histopathological damage of thoracic aorta was analyzed using Hematoxylin-Eosin (HE) staining. Immunohistochemical staining and western blot were performed to test the level of p-PPARγ protein in the thoracic aorta arising from each group. Results: The SBP in 16, 32 and 64 week-old SHR were significantly higher as compared with those in matched WKY rats (P<0.05, respectively). HE staining showed increased content of smooth muscle cell, wrinkled lining endothelium and increased thickness of internal elastic lamina in the thoracic aorta of SHR. Immunohistochemical staining and western blot indicated that the levels of p-PPARγ in the thoracic aorta arising from SHR were obviously higher than those in the thoracic aorta arising from WKY rats (P<0.05, respectively). Importantly, the high SBP, histopathological abnormalities of the thoracic aorta and elevated p-PPARγ expression were prominently abrogated by rosiglitazone treatment in SHR (P<0.05, respectively). Furthermore, the SBP, histopathological abnormalities of the thoracic aorta and p-PPARγexpression were positively correlated with age in SHR (P<0.05, respectively). Conclusions: The PPARγ phosphorylation was observed in the thoracic aorta of SHR and its expression was increased by the increase of age. Furthermore, rosiglitazone inhibited the PPARγ phosphorylation and suppressed vascular aging in SHR.