Total Ischaemic Burden European Trial (TIBET): Effects of ischaemia and treatment with atenolol, nifedipine SR and their combination on outcome in patients with chronic stable angina

OBJECTIVES: To study the relationship between presence or absence of ischaemicevents on Holter monitoring and occurrence of a hard or hard+softendpoint. DESIGN: A randomized double-blind parallel group study of atenolol,nifedipine and their combination, with ambulatory monitoringoff-treatment and after 6 weeks of randomized treatment andprospective follow-up of 2 years on average. SETTING: Europe. SUBJECTS: 682 men and women with a diagnosis of chronic stable anginaand who were not being considered for surgery. MAIN OUTCOME: Hard endpoints were cardiac death, nonfatal myocardial infarctionand unstable angina; soft endpoints were coronary artery bypasssurgery, coronary angioplasty and treatment failure. RESULTS: The study showed no evidence of an association between the presence,frequency or total duration of ischaemic events on Holter monitoring,either on or off treatment, and the main outcome measures. Therewas a non-significant trend to a lower rate of hard endpointsin the group receiving combination therapy. Compliance, as measuredby withdrawal from trial medication, was clearly poorest inthe nifedipine group with similar with drawal rates in the atenololand combination therapy groups. CONCLUSION: The recording of ischaemic events in 48 h Holter monitoringfailed to predict hard or hard+soft endpoints in patients withchronic stable angina.     

Verapamil protection of ischemic isolated rabbit heart: dependence on pretreatment

Verapamil may protect ischemic myocardium by several mechanisms: prevention of Ca overload as a direct effect of blocking Ca influx through slow channels, coronary vasodilatation, decreased contractility, or cardioplegia produced by high doses. We manipulated the experimental situation to ask whether the first mechanism alone could be protective. We studied isovolumically contracting rabbit hearts perfused at 37 degrees C, paced at 150/min, and maximally vasodilated by dipyridamole. Hearts were subjected to 60 min of low flow ischemia followed by 60 min reperfusion. Two groups were exposed to verapamil 0.5 microM beginning either 2 to 4 min before ischemia or 10 min after the onset of ischemia (when pressure development had ceased) and continuing until reperfusion. Developed pressure recovered during reperfusion to 70 +/- 4% of its initial value in hearts treated with verapamil before ischemia compared to 40 +/- 5% for control hearts and 35 +/- 11% for hearts treated with verapamil 10 min after the onset of ischemia. There was significant preservation of phosphocreatine at 10 min of ischemia and of ATP at 60 min in the early verapamil group compared to the other two. When verapamil was present before ischemia, pressure development during early ischemia was reduced to about 50% of control. Consequently there was substantial sparing of high energy phosphates and enhanced recovery of mechanical function. If verapamil was added 10 min after the onset of ischemia, when it no longer could affect cardiac work, there was no protection. Therefore, in the isolated rabbit heart, verapamil had an important protective effect only by reducing contractility of ischemic myocardium.     

Effects of nicorandil on cell proliferation and cholesteryl ester accumulation in arterial smooth muscle cells in culture

Summary Ca²⁺ regulates a variety of cellular mechanisms in vascular cells as well as in platelets. Nicorandil interacts with the intracellular Ca²⁺-activated processes in vascular smooth muscle cells, while Ca²⁺ channel blockers such as verapamil and diltiazem block voltage-dependent Ca²⁺ channels. The effects of nicorandil are due to the hyperpolarization of the membrane, interference with mobilization of Ca²⁺ from the intracellular storage sites, and blockade of receptor-operated Ca²⁺ channels. In the present study, the effects of nicorandil on cell proliferation and cholesteryl ester accumulation in rat arterial smooth muscle cells in culture were compared to Ca²⁺ channel blockers. Smooth muscle cells were prepared from rat thoracic aorta, and the rate of proliferation was determined by measuring the cell number and by [³H]-thymidine incorporation into cellular DNA. The effect of nicorandil on cholesteryl ester content in smooth muscle cells was determined by thin-layer chromatography of the cell extracts. Nicorandil at concentrations of 10^–6 to 10^–4 M, as well as Ca²⁺ channel blockers (verapamil and diltiazem) inhibited the proliferation and DNA synthesis of cultured smooth muscle cells. The acute inhibitory effects on cell proliferation were observed significantly 16 hours after the addition of the three agents in serum-stimulated cells. These effects were dose dependent, both in acute and in chronic treatment with the three agents. Addition of 10^–5 M nicorandil to medium supplemented with 10% serum resulted in a decrease of the net cholesteryl ester content by 18±1%, while cellular free cholesterol content was the same as control. Similar results were also obtained in the presence of verapamil and diltiazem. These data suggest that nicorandil may suppress atheroma formation, not only by inhibiting cell proliferation but also by decreasing cholesteryl ester accumulation in arterial smooth muscle cells.     

芪蛭降糖胶囊治疗糖尿病肾脏疾病3b期大量蛋白尿的多中心、随机对照研究

目的观察芪蛭降糖胶囊治疗糖尿病肾脏疾病（diabetic kidney disease,DKD）3b期大量蛋白尿的疗效和安全性。方法将符合DKD 3b期诊断标准的患者采用随机数字表法分为试验组和对照组,每组84例。两组患者先进行2周的洗脱期治疗,后给予西医基础治疗,对照组予缬沙坦胶囊160 mg,每日1次,试验组给予芪蛭降糖胶囊,每次5粒,每日3次。以随访点为基线,随访1、3、6个月,观察指标为血压、24 h尿蛋白定量（24 h uPQ）、血浆白蛋白（ALB）、血清肌酐（SCr）,并计算肾小球滤过率（eGFR）。同时记录两组患者低血糖反应、凝血功能异常、胃肠道反应、过敏反应、高钾血症、肌酐倍增及总体不良事件的发生率。结果最终纳入有效病例试验组81例,对照组80例。与治疗前比较,对照组收缩压、舒张压均在治疗后1个月明显下降（P〈0.05）,6个月时下降更显著（P〈0.01）,对照组收缩压在随访1、3、6个月,舒张压在第6个月时均低于同期试验组水平（P〈0.05）。随访第1、3、6个月,试验组24 h UPQ均显著低于治疗前（P〈0.01）,同时也低于同期对照组（P〈0.05）,对照组随访1、3、6个月24 h UPQ与治疗前比较,差异无统计学意义（P〉0.05）。试验组ALB呈上升趋势,在随访的第6个月明显高于本组治疗前（P〈0.05）,也高于对照组同期水平（P〈0.05）,对照组ALB水平无明显变化。两组患者SCr均呈升高趋势,在随访的第3、6个月,试验组SCr均高于治疗前（P〈0.05）,而对照组SCr升高的幅度高于试验组,3次随访均明显高于治疗前（P〈0.05）。两组eGFR呈下降趋势,对照组下降幅度高于试验组（P〈0.05）。试验组随访1、3、6个月肾功能进展例数分别为0例、8例（9.55%）、18例（21.4%）;对照组分别为7例（8.3%）、18例（21.4%）、34例（40.5%）,随访第3、6个月时,两组肾功能进展例数比较,差异有统计学意义（P〈0.05）。两组不?     

天麻钩藤汤加减治疗肝阳上亢型原发性高血压疗效观察及对神经递质节律的影响

目的:观察天麻钩藤汤加减治疗原发性高血压肝阳上亢型患者的临床治疗效果及对神经递质节律影响。方法:选取2017年1月至2018年1月郑州市第六人民医院收治的原发性高血压肝阳上亢型患者100例作为研究对象,将达到病例选择范围的93例患者按照治疗药物不同分为对照组(n=44)和观察组(n=49)。对照组采取西药基础治疗,观察组采用西药基础治疗+天麻钩藤汤加减治疗。疗程结束后,观察2组血压水平、神经递质节律、中医症状积分。结果:1)观察组晨起平均收缩压、24 h平均收缩压、夜间平均收缩压、晨起平均舒张压、夜间平均舒张压、24 h平均舒张压明显低于对照组(P<0.05);2)观察组神经肽Y、神经元特异性烯醇化酶、血管加压素、强啡肽-A显著低于对照组(P<0.05),P物质、脑源性神经营养因子显著高于对照组(P<0.05);3)观察组甘氨酸、γ-氨基丁酸显著低于对照组(P<0.05),天冬氨酸、谷氨酸显著高于对照组(P<0.05);4)观察组治疗后中医症状总积分显著低于对照组(P<0.05)。结论:针对原发性高血压肝阳上亢型患者,在西药治疗基础上,增加天麻钩藤汤加减治疗,能够有效促进患者神经递质节律的恢复,调节血压,同时对降低中医症状积分,值得临床推广应用。     

Serological markers in diagnosis of pediatric inflammatory bowel disease and as predictors for early tumor necrosis factor blocker therapy

Objective: To describe the prevalence of serological markers in newly diagnosed treatment-naïve pediatric inflammatory bowel disease (IBD), their utility in differentiating Crohn’s disease (CD), ulcerative colitis (UC) and symptomatic non-IBD patients and whether serological markers are associated with early TNF blocker treatment.

Material and methods: Ninety-six children and adolescents <18 years, 58 with IBD and 38 symptomatic non-IBD controls were included. At diagnosis and after 1–2 years, serological antibodies (anti-Saccharomyces cerevisiae antibodies (ASCA), perinuclear anti-neutrophil cytoplasmic antibody (pANCA), flagellin expressed by Clostridial phylum (anti-CBir1), outer membrane porin of Escherichia coli (anti-OmpC), Pseudomonas fluorescens-associated sequence (anti-I2), CRP, ESR and fecal calprotectin were analyzed. The choice of treatment was made at the discretion of the treating pediatrician.

Results: Of the IBD patients, 20 (36%) and 26 (47%) were positive for ASCA and pANCA compared to 3(8%), p?<?.01 and 10 (27%), p?=?.04 of the controls. Thirteen (72%) of UC patients were pANCA positive, versus 13 (35%) of CD patients (p?<?.01). None of the UC patients was ASCA positive versus 20 (54%) of CD patients (p?<?.0001). Compared to conventionally treated patients, the 18 (49%) TNF blocker treated CD patients had higher presence of ASCA (p?<?.01), lower presence of pANCA (p?=?.02) and higher levels of fecal calprotectin, CRP and ESR at diagnosis. In multivariate analyses ASCA and pANCA status, but not CRP, ESR or calprotectin, were independently associated with early TNF blocker treatment.

Conclusions: ASCA and pANCA status were associated with having IBD and with early TNF blocker treatment in CD.     

Efficacy and Duration of Action of the Four Selective Angiotensin II Subtype 1 Receptor Blockers,Losartan, Candesartan,Valsartan and Telmisartan,in Patients with Essential Hypertension Determined by Home Blood Pressure Measurements

Our objective was to compare the efficacy and duration of action of 4 angiotensin II receptor blockers (ARBs)—losartan (25–100 mg), candesartan (2–12 mg), valsartan (40–80 mg), and telmisartan (10–40 mg)—in patients with essential hypertension using self-measurement of blood pressure at home (home BP) and to examine the differential effect of the four ARBs on home pulse pressure (home PP). After a 2-week run-in period, each of the 4 ARBs was assigned to subjects who were diagnosed as having hypertension on the basis of home BP and who were over 30 years old. The subjects were asked to take the ARB once daily in the morning and to measure home BP once in the evening and in the morning. We compared the efficacy of each ARB on home BP and home PP and assessed the duration of the BP-lowering effect using the morning effect versus evening effect ratio (M/E ratio). The antihypertensive effects of telmisartan on home systolic BP (SBP) both in the evening and in the morning and on home diastolic BP (DBP) in the morning were significantly greater than those of losartan. The effect of each ARB on home BP in the morning and in the evening was expressed as a ratio (M/E ratio). The M/E ratios of SBP/DBP in patients treated with losartan, candesartan, valsartan, and telmisartan were 0.49/0.16, 0.69/1.01, 0.82/0.88, and 0.88/0.88, respectively. The home PP-lowering effect was greater for valsartan and telmisartan than for losartan and candesartan in the morning. Among the 4 ARBs, the duration of the BP-lowering effect of losartan did not persist throughout 24 hr. The effects of the other 3 ARBs, in particular telmisartan, persisted over 24 hr when they were administered once daily in the morning. In addition, the duration of the PP-lowering effect was similar to that of the BP-lowering effect. Such long-acting property of several ARBs is essential for the modern antihypertensive treatment, and home BP measurements are useful for determining the duration of action of antihypertensive drugs. Losartan, 25 mg a day, which is usually used as an initial dose in Japan, is apparently insufficient to obtain adequate antihypertensive effect and sufficient duration of action.     

Dual repressive effect of angiotensin II-type 1 receptor blocker telmisartan on angiotensin II-induced and estradiol-induced uterine leiomyoma cell proliferation

BACKGROUND: Although uterine leiomyomas or fibroids are the most common gynecological benign tumor and greatly affect reproductive health and well-being, the pathophysiology and epidemiology of uterine leiomyomas are poorly understood. Elevated blood pressure has an independent, positive association with risk for clinically detected uterine leiomyoma. Angiotensin II (Ang II) is a key biological peptide in the renin-angiotensin system that regulates blood pressure. METHODS: In this study, we investigated the potential role of Ang II (1-1000 nM) in the proliferation of rat ELT-3 leiomyoma cells in vitro. RT-PCR and western blot analysis with cell proliferation and DNA transfection assays were performed to determine the mechanism of action of Ang II. RESULTS: Ang II induced ELT-3 leiomyoma cell proliferation (P < 0.01) and the expression of Ang II type 1 receptor (AT(1)R) and AT(2)R mRNA and protein was confirmed. Regarding the intracellular signaling pathway, the Ang II-induced cell proliferation was AT(1)R-, epidermal growth factor receptor-, extracellular-regulated kinase- and protein kinase C-dependent but was not dependent on the AT(2)R or phosphatidylinositol-3 kinase or JAK kinase. The AT(1)R blocker telmisartan, effectively repressed Ang II-induced and estradiol-induced cell proliferation (P < 0.01). AT(1)R, but not AT(2)R, plays a role in Ang II-induced ELT-3 cell proliferation. CONCLUSIONS: These experimental findings in vitro highlight the potential role of Ang II in the proliferation of leiomyoma cells.     

An increase in [Ca2+]i activates basolateral chloride channels and inhibits apical sodium channels in frog skin epithelium

 The aim of this study was to investigate the mechanisms by which increases in free cytosolic calcium ([Ca²⁺]_i) cause a decrease in macroscopic sodium absorption across principal cells of the frog skin epithelium. [Ca²⁺]_i was measured with fura-2 in an epifluorescence microscope set-up, sodium absorption was measured by the voltage-clamp technique and cellular potential was measured using microelectrodes. The endoplasmic reticulum calcium-ATPase inhibitor thapsigargin (0.4 μM) increased [Ca²⁺]_i from 66 ± 9 to 137 ± 19 nM (n = 13, P = 0.002). Thapsigargin caused the amiloride-sensitive short circuit current (I _sc) to drop from 26.4 to 10.6 μA cm^–2 (n = 19, P<0.001) concomitant with a depolarization of the cells from –79 ± 1 to –31 ± 2 mV (n = 18, P<0.001). Apical sodium permeability (P ^a _Na) was estimated from the current/voltage (I/V) relationship between amiloride-sensitive current and the potential across the apical membrane. P ^a _Na decreased from 8.01·10^–7 to 3.74·10^–7 cm s^–1 (n = 7, P = 0.04) following an increase in [Ca²⁺]_i. A decrease in apical sodium permeability per se would tend to decrease I _sc and result in a hyperpolarization of the cell potential and not, as observed, a depolarization. Serosal addition of the chloride channel inhibitors 4,4′-diisothiocyanatostilbene-2,2′-disulphonic acid (DIDS), diphenylamine-2-carboxylate (DPC), indanyloxyacetic acid 94 (IAA-94) and furosemide reversed the depolarization induced by thapsigargin, indicating that chloride channels were activated by the increase in [Ca²⁺]_i. This was confirmed in wash-out experiments with ³⁶Cl where it was shown that thapsigargin increased the efflux of chloride from 32.49 ± 5.01 to 62.63 ± 13.3 nmol·min^–1 cm^–2 (n = 5, P = 0.04). We conclude that a small increase in [Ca²⁺]_i activates a chloride permeability and inhibits the apical sodium permeability. The activation of chloride channels and the closure of apical sodium channels will tend to lower the macroscopic sodium absorption. Received: 25 June 1996 / Received after revision: 28 August 1996 / Accepted: 2 September 1996