G蛋白偶联受体激酶4对内皮素B型受体的异常调节在原发性高血压发生中的作用

目的探讨G蛋白偶联受体激酶4(G protein-coupled receptor kinase 4,GRK4)对内皮素B型受体(endothelin receptor B,ETB)的异常调节在原发性高血压中的作用及机制。方法选用12~14周龄,体质量300 g左右的雄性自发性高血压大鼠(spontaneously hypertensive rats,SHRs)及其对照鼠(Wistar-Kyoto,WKY)各10只,通过无创鼠尾测压仪测定血压,采用右肾上腺静脉插管灌注ETB受体特异性激动剂BQ3020后观察尿流速及尿钠排泄率,荧光定量PCR检测大鼠肾脏GRK4 mRNA水平,Western blot测定大鼠肾脏GRK4及ETB受体的蛋白表达差异,免疫共沉淀法检测ETB受体磷酸化情况,在动物水平观察高血压状态下ETB受体的功能情况。结果 ETB受体激动剂BQ3020对WKY大鼠有明显利尿排钠作用,且这种利尿排钠作用可以被ETB受体抑制剂BQ788阻断,但在SHR大鼠BQ3020的利尿排钠作用受损[尿流速:(11.23±2.16)vs(3.49±1.32),P<0.05];尿钠排泄率:[(1 551.43±393.47)vs(601.16±128.15),P<0.05];在SHR大鼠肾皮质GRK4的蛋白水平及mRNA水平均较WKY大鼠高[蛋白:(1.38±0.10)vs(0.85±0.07),P<0.05];mRNA:[(2.23±0.15)vs(0.78±0.16),P<0.05],SHR大鼠ETB受体总蛋白水平与WKY大鼠相比差异无统计学意义(P>0.05),但ETB受体磷酸化水平增高。结论 GRK4可能通过对内皮素B型受体的异常调节,参与了原发性高血压发生与发病。     

阿托伐他汀联合坎地沙坦酯治疗原发性高血压的临床研究

目的探究阿托伐他汀联合坎地沙坦酯治疗原发性高血压的临床疗效。方法选取2012年1月—2014年11月义马煤业集团股份有限公司收治的原发性高血压患者300例,随机分为对照组和治疗组,每组150例。对照组口服坎地沙坦酯片,2片/次,1次/d。治疗组口服阿托伐他汀钙片1片/次,1次/d,坎地沙坦酯片的用法用量同对照组。两组患者均连续治疗10周。观察两组的临床疗效,同时比较治疗前后两组患者收缩压、舒张压、超敏C反应蛋白(hs-CPR)、内皮素(ET)、一氧化氮(NO)的变化。结果治疗后,两组总有效率分别为76.67%、90.67%,两组比较差异有统计学意义(P0.05)。治疗后,两组患者收缩压、舒张压、hs-CRP、ET均较治疗前显著降低,NO显著升高,同组治疗前后比较差异有统计学意义(P0.05);且治疗组这些观察指标的改善程度优于对照组,两组比较差异有统计学意义(P0.05)。结论阿托伐他汀联合坎地沙坦酯治疗原发性高血压具有较好的临床疗效,可改善患者的血管内皮功能和炎症反应,值得在临床上进一步推广和应用。     

门静脉高压症患者胃黏膜内皮素受体的基因表达

【目的】探讨内皮素受体（ETR）亚型基因表达在门静脉高压症胃病（PHG）中的变化及作用。【方法】采用逆转录聚合酶链式反应（RT-PCR）分析42例肝硬化门静脉高压症患者PHG病变部位ETA受体和ETB受体mRNA的变化。【结果】轻度PHG胃黏膜ETAR mRNA、ETBR mRNA表达明显升高，与无PHG组及对照组比较差异均有显著意义（P〈0．001），重度PHG的ETAR mRNA、ETBR mRNA表达进一步增强，与轻度PHG者比较差异亦有显著意义（P〈0．001）；【结论】PHG患者ETR基因过度表达可能是加重胃黏膜损害的重要因素之一。     

Acute renal impairment characterization using diffusion magnetic resonance imaging: Validation by histology

Diffusion magnetic resonance imaging has been demonstrated to be a simple, noninvasive and accurate method for the detection of renal microstructure and microcirculation, which are closely linked to renal function. Moreover, serum endothelin‐1 (ET‐1) was also reported as a good indicator of early renal injury. The aim of this study was to evaluate the feasibility and capability of diffusion MRI and ET‐1 to detect acute kidney injury by an operation simulating high‐pressure renal pelvic perfusion, which is commonly used during ureteroscopic lithotripsy. Histological findings were used as a reference. Fourteen New Zealand rabbits in an experimental group and 14 in a control group were used in this study. Diffusion tensor imaging and intravoxel incoherent motion diffusion‐weighted imaging were acquired by a 3.0 T MRI scanner. Significant corticomedullary differences were found in the values of the apparent diffusion coefficient (ADC), pure tissue diffusion, volume fraction of pseudo‐diffusion (fp) and fractional anisotropy (FA) (P < 0.05 for all) in both preoperation and postoperation experimental groups. Compared with the control group, the values of cortical fp_mean, medullary ADC_mean and FA_mean decreased significantly (P < 0.05) after the operation in the experimental group. Also, the change rate of medullary ADC_mean in the experimental group was more pronounced than that in the control group (P = 0.018). No significant change was found in serum ET‐1 concentration after surgery in either the experimental (P = 0.80) or control (P = 0.17) groups. In the experimental group, histological changes were observed in the medulla, while no visible change was found in the cortex. This study demonstrated the feasibility of diffusion MRI to detect the changes of renal microstructure and microcirculation in acute kidney injury, with the potential to evaluate renal function. Moreover, the sensitivity of diffusion MRI to acute kidney injury appears to be superior to that of serum ET‐1.     

Dimensional prefernces in middle and old age

Dimensional preferences in 40 middle-aged (M = 41.62 years) and 40 elderly (M = 72.22 years) females were assessed using a dimensional choice task. Significant age differences in reaction times of choice but not in number of dimensional choices were obtained. There was a perfect rank-order correspondence between the two age groups in dimensional choices with form being the most preferred and color the least preferred perceptual dimension.     

Novel approaches to the treatment of acute renal failure

Acute renal failure (ARF) occurs frequently in hospitalised patients and is associated with significant morbidity and mortality. Many therapeutic strategies have been undertaken both to prevent acute renal injury and, once ARF occurs, to improve renal function and reduce mortality. Among the available pharmacological options, no specific therapy has been shown to alter the course of ARF. This article reviews the efficacy of several strategies in experimental renal disease and raises the possibility that similar interventions might be available to the clinician in the near future for the prevention and management of ARF. The prospect of these novel strategies together with the ever-increasing understanding of the complex pathophysiology of ARF, offers the promise of effective and more physiological therapeutic interventions in this new millennium.     

Atrasentan: targeting the endothelin axis in prostate cancer

Endothelin axis deregulation triggers a series of events that lead to a profound deregulation in cancer cells, including key tumorigenic cellular events such as proliferation, invasion, escape from programmed cell death, new vessel formation, abnormal osteogenesis and the alteration of nociceptive stimuli. Atrasentan is a novel agent that effectively targets this pathway and is able to inhibit and/or reverse several of those events. Biological and clinical activity in patients with prostate cancer has been demonstrated in a Phase III clinical setting by the suppression of markers of biochemical and clinical prostate cancer progression, and by a delay in time to disease progression, especially in patients with bone disease.     

Measurement of brain natriuretic peptide in plasma samples and cardiac tissue extracts by means of an immunoradiometric assay method

Background: The mechanisms of oxygen‐induced effects on blood vessels (vasoconstriction in hyperoxaemia and vasodilatation during hypoxaemia) are uncertain. Many investigators have suggested that the vasoconstriction seen during hyperoxia/hyperoxaemia is mediated through the endothelium as a result of either increased release or activity of vasoconstrictors (oxygen radicals, endothelin, norepinephrine, angiotensin II, or serotonin (5‐HT)), or reduced activity of vasodilators (prostaglandin E₂ and nitric oxide). Serotonin has been assumed to have a central role. Methods: Eight healthy volunteers were exposed to F_iO₂ of 1.0 for 20?min and serum concentrations of serotonin and activated platelets were measured (indicated by concentrations of β‐thromboglobulin (β‐TG)). Results. During hyperoxaemia in humans, serum concentrations of serotonin and β‐TG remained unchanged. Conclusion: If serotonin is involved in oxygen‐induced vasoconstriction, the mechanism is more likely to be either a potentiating effect of serotonin on other vasoconstrictors or increased activity of serotonin on its receptor.     

Pfizer-Pharmacia: the postmerger

Clazosentan (Ro 61-1790, VML-588 or AXV-034) is under study in clinical trials for the treatment of patients with aneurysmal subarachnoid hemorrhage (SAH) by Actelion Pharmaceuticals. It is a synthetic endothelin (ET) A receptor antagonist that decreases and reverses cerebral vasospasm after experimental SAH. Remarkable dose-dependent effects were observed on angiographic vasospasm in the CONSCIOUS-1 human clinical trial, supporting proceeding with a Phase III clinical trial. This study (CONSCIOUS-2) will enroll approximately 765 patients randomized 2:1 to clazosentan 5 mg/h intravenously or placebo. All patients will undergo neurosurgical aneurysm clipping and outcome will be assessed primarily based on mortality and vasospasm-related morbidity.