Role of Endothelin ETA Receptor Antagonism in the Post-Transplant Renal Response to Angiotensin II in the Rat

The role of endothelins in the renal damage associated with ischaemic-reperfusion (I-R) injury during organ transplantation was determined by selective blockade of the ET(A) receptors with the receptor antagonist ABT-627. The integrity of kidney function was determined 2 and 8 weeks after transplantation by investigation of the renal response to angiotensin II. Under pentobarbitone anaesthesia (70 mg x kg(-1), I.P.), rats underwent a right nephrectomy. Transplantation of the left kidney was performed after 2 h cold ischaemia without or with ABT-627 treatment. Control animals underwent left renal denervation. The renal response to angiotensin II was measured 2 weeks later following blockade of endogenous production of angiotensin II with captopril. A further transplant group was allowed to recover for 8 weeks before the terminal study. In the control group, angiotensin II reduced renal blood flow (RBF), glomerular filtration rate (GFR), urine flow rate (UV), and fractional sodium excretion (FE(Na)) by 29 +/- 5 %, 19 +/- 4 %, 25 +/- 4 % and 32 +/- 7 %, respectively. Conversely, in the transplant group, angiotensin II left RBF unchanged and increased GFR (59 +/- 12 %) and UV (93 +/- 8 %). FE(Na) decreased by 24 +/- 9 %. In both the transplant group treated with ABT-627 and the long-term recovery group, the renal response to angiotensin II was normalised. In conclusion, renal transplantation following 2 h cold I-R injury resulted in a temporary abnormal renal response to angiotensin II, which was reversed by ET(A) receptor antagonism at the time of transplantation.     

Effect of Muscarinic Cholinergic Receptor Blockade on Heart Activity in Rat Fetuses

Bulletin of Experimental Biology and Medicine - The development of arterial hypertension in male Wistar rats with fructose-induced metabolic syndrome (12.5% of fructose solution as the only...     

Association between Angiotensin II Type 1 Receptor Polymorphism and Sudden Cardiac Death in Myocardial Infarction

Objective. The renin-angiotensin system is involved in the pathogenesis of coronary artery disease and myocardial infarction (MI). Angiotensin II (Ang II) has many adverse effects such as vasoconstriction and vascular remodeling, and these actions are mediated by the angiotensin II type 1 receptor (AT1R). Patients and Methods. A total of 1376 patients were recruited from January 2010 to April 2012. The study group consisted of 749 patients with ACS (317 females and 432 males) and of 627 healthy controls. Results. The ACS patients demonstrated a lower proportion of AA genotypes and AC genotypes but higher proportions of CC genotypes than the control population. The AT1R CC genotype conferred a 2.76-fold higher risk of MI compared with the genotype AC and AA. In addition, the CC genotype was also associated with a 4.08 times higher risk of left anterior descending artery infarction and a 3.07 times higher risk of anterior wall infarction. We also found that the CC genotype was independently associated with sudden cardiac death. In Summary. This study demonstrated that the AT1R CC genotype is an independent risk factor for ACS incidence, and this genotype is associated with a greater ACS severity and greater risk of sudden cardiac death.     

Effects of Gestation on Ovine Fetal and Maternal Angiotensin Receptor Subtypes in the Heart and Major Blood Vessels

Previous studies in fetal sheep have concluded that (a) the vascular AT(1) angiotensin II (Ang II) receptor subtype is present in the external umbilical artery, but not in other systemic blood vessels, and (b) carotid arterial rings contract in vitro in response to Ang II. These contractions are blocked by the AT(1) specific receptor antagonist losartan. The aim of the present study was to resolve the apparent contradiction of these earlier conclusions, by examining the distribution of Ang II receptor subtypes in different regions of the ovine fetal cardiovascular system, and to find out at what stage in development AT(1) receptors first appear. We measured AT(1) and AT(2) receptors in hearts, carotid arteries, aortae and umbilical vessels from fetal sheep aged 65-144 days (term approximately 150 days), and in hearts and aortae from lambs, and adult pregnant and non-pregnant ewes. Both AT(1) and AT(2) receptors were present in aortae of fetuses > 118 days gestation, and carotid arteries of fetuses > 121 days gestation, while in younger fetuses only AT(2) receptors were found. The proportion of carotid artery and aortic AT(1) receptors increased with age, while the proportion of AT(2) receptors decreased. The internal umbilical artery contained both subtypes, but there was no relationship between receptor density and gestational age. The external umbilical artery had only AT(1) receptors. The highest density of Ang II receptors was found in the fetal heart where the AT(2) subtype predominated. The density of fetal cardiac Ang II receptors declined with age (r = -0.44, P < 0.02) due to the decrease in the AT(2) subtype. The density in late gestation fetal hearts was greater than in lamb or adult hearts (P < 0.001). Our study shows that fetal systemic blood vessels contain AT(1) receptors, and we have documented for the first time that the appearance of AT(1) receptors is both different in different regions of the fetal cardiovascular system and is developmentally regulated. Together with the in vitro contractile studies, this suggests that Ang II can play an important role in fetal blood pressure regulation via AT(1) receptors in the fetal systemic vasculature, as well in the umbilicoplacental vessels. Experimental Physiology (2001) 86.1, 71-82.     

A Novel Angiotensin Type I Receptor Antagonist,Fimasartan, Prevents Doxorubicin-induced Cardiotoxicity in Rats

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.

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Influence of the Angiotensin II Type I Receptor Gene 1166A > C Polymorphism on BP and Aortic Pulse Wave Velocity Among Malays

Angiotensin II type 1 receptor ( AGT1R ) gene 1166A > C polymorphism has been shown to be associated with essential hypertension and aortic stiffness as measured by carotid femoral pulse wave velocity (PWV). This study was carried out to investigate the association of the 1166A > C polymorphism with blood pressure (BP) and PWV among Malay hypertensive and normotensive subjects.
Two hundred and one hypertensive subjects without evidence of cardiovascular (CV) complications and 201 age- and sex-matched normotensive subjects were studied in a cross-sectional design. Blood pressures (BP) and PWV were measured, and 1166A > C genotype was determined by polymerase chain reaction followed by restriction enzyme digestion.
The 1166C allele frequency was 7.96% and 7.73% among Malay hypertensive and normotensive subjects, respectively. There was no association of the 1166A > C polymorphism with BP in the hypertensive, normotensive or overall Malay populations. PWV was significantly higher among 1166C allele carriers as compared to non-carriers (10.52 ± 1.82 vs. 10.15 ± 1.80, p = 0.040) in the overall population, but not in the hypertensive and normotensive populations separately. In conclusion, the frequency of 1166C polymorphism is similar among Malay hypertensive and normotensive subjects. This polymorphism has no association with BP but may have an influence on PWV in Malays, which needs further investigation.     

Quantification of the Contribution of Type 1 and Type 2 Angiotensin II Receptors to the Net Tissue Specific Effect of Angiotensin II

Numerous studies have demonstrated changes in receptor number, protein concentration, or mRNA levels and have proposed that these subcellular changes produce physiologic effects. To date, no adequate mathematical analysis has been available to provide a framework for interpretation of such data. In the present study we have combined measurements of angiotensin receptor protein levels with the development of a mathematical model that includes two receptors with opposing actions for a single ligand. This model was used to quantify the net, physiologic response of each receptor population to ANG II stimulation and the effect of altering the expression of receptor populations by a physiologic stimulus. Altered sodium intake was used as the physiologic stimulus and quantification of Western blot analysis and revealed that high sodium diet significantly suppressed AT₁ receptor protein in the adrenal gland and aorta and augmented AT₂ receptor protein in the aorta. A high sodium diet did not significantly alter AT₂ receptor protein in the adrenal gland. Modeling the measured sodium-induced changes in receptor concentration demonstrated that small, subcellular changes in receptor concentration can have a large impact on the net physiologic effect. This model for dual receptor–single ligand interactions should be amenable for other systems. © 2000 Biomedical Engineering Society. PAC00: 8710+e, 8714Ee     

用激光多普勒血流仪检测升主动脉缩窄心衰大鼠的皮肤微循环

目的观察升主动脉缩窄大鼠心衰模型的皮肤微循环。方法用激光多普勒血流仪检测心衰大鼠与对照组大鼠的皮肤血流量、血流速度和血含量。结果实验组的血流量、血流速度较对照组明显降低 ,血流量降低了30 % ,血流速度降低了28 % ,而血含量没有明显改变。结论血流速度变慢可能是升主动脉缩窄大鼠心衰时皮肤微循环改变的一个重要特点。     

地高辛对充血性心力衰竭患者血浆去甲肾上腺素和血管紧张素Ⅱ含量及相关性的影响

目的 :观察地高辛对充血性心力衰竭 (Congestiveheartfailure ,CHF)患者神经体液因素的影响及相关性 ,以探讨地高辛在治疗CHF患者中的作用机制并评价疗效。方法 :选用地高辛治疗中、重度 (NY HA心功能分级Ⅲ、Ⅳ级 )CHF患者 2 5例。治疗前、后采用荧光分析及放免分析法分别测定血浆去甲肾上腺素 (Norepinephrine ,NE)及血管紧张素Ⅱ (AngiotensinⅡ ,AngⅡ )的水平。 结果 :( 1)地高辛治疗后血浆NE及AngⅡ分别由治疗前的 2 91pg± 80 pg/ml及 73pg± 60pg/ml下降至 2 13pg± 82pg/ml及 3 6pg± 17pg/ml(P均 <0 .0 1)。( 2 )地高辛治疗后两者的下降幅度有较好的相关性 (r =0 .644,P <0 .0 1)。血浆NE、AngⅡ基础水平与治疗后下降幅度也呈较好的相关性(r分别为 0 .60及 0 .93 ,P分别 <0 .0 1)。结论 :地高辛能明显改善中、重度CHF患者心功能和神经体液明显异常 ,抑制CHF患者NE和AngⅡ活性     

内皮素对大鼠心室肌血管紧张素Ⅱ含量和释放的影响

心血管组织产生的内皮素和血管紧张素Ⅱ,作为内源性生物活性物质在调节心血管功能方面具有重要作用,但它们在体内的相互作用尚不清楚。本工作在离体大鼠心脏灌流模型上证明,内皮素可显著增加心肌细胞血管紧张素Ⅱ的生成和释放,这一作用可被钙通道阻断剂Verapamil所拮抗。结果提示,内皮素可能以钙依赖方式增加心肌细胞血管紧张素Ⅱ的生成和释放。     

Effects of Isoproterenol on T-Wave Amplitude and Heart Rate: A Dose-Response Study

This report examines the hypothesis that electrocardiographic T-wave amplitude is sensitive to graded increases in beta-sympathetic stimulation of the heart. Beta-adrenergic activity was manipulated pharmacologically in 9 healthy men by bolus infusion of isoproterenol in each of six doses: 0.1, 0.25, 0.5, 1.0, 2.0, and 4.0 micrograms. Results indicated that elevations in heart rate above placebo values increased as a linear function of isoproterenol dose. In contrast, the dose-response curve for T-wave amplitude was best described by a quadratic function: an initial reduction in T-wave amplitude at low levels of isoproterenol infusion was followed by a significant reversal of this effect at higher doses. Comparison of the heart rate and T-wave amplitude data points to limitations in the use of the latter as an index of beta-adrenergic activity. One of several possible explanations for the T-wave results would entail a mechanism that preserves ventricular function at high levels of beta-sympathetic stimulation.     

O-甲基酪氨酸对酪氨酸抑制hCG致大鼠离体黄体细胞孕酮生成的拮抗作用

用孕马血清促性腺激素和hCG处理未成年雌性大鼠,在hCG注射后7天取出黄体制成黄体细胞悬浮液,孵育后用放射免疫法测定孕酮含量。实验发现,酪氨酸结合的竞争性抑制剂O—甲基酪氨酸能够翻转酪氨酸抑制hCG的致孕酮生成作用,并与所用剂量有关,如果加大酪氨酸的剂量,则可克服O-甲基酪氨酸的翻转作用。由此提示,O-甲基酪氨酸是一种酪氨酸结合位点的拮抗剂,它通过阻断酪氨酸的结合来抑制酪氨酸的作用。     

双水平无创正压通气对急诊Ⅱ型呼吸衰竭并心衰患者NT-proBNP及CRP的影响

目的 探讨双水平无创正压通气治疗Ⅱ型呼吸衰竭并心衰患者的临床效果。方法 选取我院2016年3月~2018年4月在急诊治疗的92例Ⅱ型呼吸衰竭并心衰患者资料进行分析,根据患者救治过程中是否采用双水平无创正压通气治疗分为观察组56例（基础治疗+双水平无创正压通气）,对照组36例（仅采取基础治疗）,比较两组的动脉血氧分压（PaO2）、动脉血二氧化碳分压（PaCO2）、pH值、氧供（DO2）、氧耗（VO2）、左室射血分数（LVEF%）、每搏输出量（SV）、心肌做功指数（TEI）、血浆氨基末端脑钠肽前体（NT-proBNP）、血清C反应蛋白（CRP）。结果 治疗后,观察组PaO2、pH值、DO2、VO2水平均高于对照组,PaCO2水平均低于对照组（P＜0.05）;观察组患者的LVEF%、SV指数水平均高于对照组,TEI水平均低于对照组（P＜0.05）;治疗后,观察组NT-proBNP、CRP水平均低于对照组（P＜0.05）。结论 双水平无创正压通气治疗Ⅱ型呼吸衰竭并心衰患者有助于改善患者的血气指标、心功能、降低NT-proBNP及CRP水平。     

Inflammation Alters Angiotensin Converting Enzymes (ACE and ACE-2) Balance in Rat Heart

Angiotensin converting enzymes (ACE) and more recently discovered ACE-2 are important proteins involved in the renin–angiotensin system. The balance between ACE and ACE-2 is important for the regulation of blood pressure and electrolyte homeostasis. Inflammatory diseases like rheumatoid arthritis are associated with increased risk for cardiovascular complications. We studied the effect of inflammation on the expression levels of ACE and ACE-2 in two groups (n = 4/group) of adjuvant arthritis (AA) and healthy (control) rats. The AA group received 0.2 ml of 50 mg ml⁻¹ of Mycobacterium butyricum suspended in squalene into the tail base. On day 12, rats were euthanized and their organs (hearts, liver, kidney, and intestine) were excised. The mRNA of ACE and ACE-2 were determined by real-time polymerase chain reaction. ACE and ACE-2 protein expression in rat heart was determined by Western blot. Inflammation resulted in 80% reduction of ACE-2 gene expression in rat heart. ACE-2/ACE expression ratio was significantly reduced from 0.7 ± 0.4 in control rats to 0.07 ± 0.09 in AA. Similarly, ACE-2/ACE protein expression ratio was also disrupted with a significant reduction in AA animals (6.7 ± 4.8 vs. 0.9 ± 05 in control and AA, respectively). ACE-2 has been found to provide negative feedback of renin–angiotensin system and protection of the heart and kidneys. Disruption of the balance between ACE and ACE-2 observed in inflammation may be, at least in part, involved in the cardiovascular complications seen in patients with inflammatory diseases.     

Effects of Repeated Administration of Pilocarpine and Isoproterenol on Aquaporin-5 Expression in Rat Salivary Glands

Aquaporins are water channel proteins which enable rapid water movement across the plasma membrane. Aquaporin-5 (AQP5) is the major aquaporin and is expressed on the apical membrane of salivary gland acinar cells. We examined the effects of repeated administration of pilocarpine, a clinically useful stimulant for salivary fluid secretion, and isoproterenol (IPR), a stimulant for salivary protein secretion, on the abundance of AQP5 protein in rat salivary glands by immunofluorescence microscopy and semi-quantitative immunoblotting. Unexpectedly AQP5 was decreased in pilocarpine-administered salivary glands, in which fluid secretion must be highly stimulated, implying that AQP5 might not be required for fluid secretion at least in pilocarpine-administered state. The abundance of AQP5, on the other hand, was found to be significantly increased in IPR-administered submandibular and parotid glands. To address the possible mechanism of the elevation of AQP5 abundance in IPR-administered animals, changes of AQP5 level in fasting animals, in which the exocytotic events are reduced, were examined. AQP5 was found to be decreased in fasting animals as expected. These results suggested that the elevation of cAMP and/or frequent exocytotic events could increase AQP5 protein. AQP5 expression seems to be easily changed by salivary stimulants, although these changes do not always reflect the ability in salivary fluid secretion.     

血管紧张素原、血管紧张素Ⅱ一型受体基因多态性与原发性高血压的相关性研究

目的 :探讨血管紧张素原AGT(M2 3 5T)、血管紧张素Ⅱ一型受体AT1 R(A1166C)基因多态性与中国四川籍人群原发性高血压(EH)的关系。方法 :采用聚合酶链反应 (PCR)及限制性片段长度多态性分析 (RFLP)方法分析人类白细胞染色体DNA中AGT、AT1 R基因多态性。结果 :12 2例EH病例组与 87例正常对照组AGT等位基因频率T、M分别为 :T :0 .82 8vs 0 .661,M :0 .172vs 0 .3 3 9。AT1 R等位基因频率A、C分别为 :A :0 .968vs 0 .989,C :0 .0 3 2vs 0 .0 11。各基因型频率及等位基因频率符合Hardy Weinberg平衡定律。EH病例组AGT基因T等位基因频率和TT型明显高于对照组(χ2 =11.7,P <0 .0 1和 χ2 =15 .6,P <0 .0 1)。结论 :AGT基因多态性与EH密切相关 ;而AT1 R基因多态性与EH无关。