Dose- and administration time-dependent effects of nifedipine gits on ambulatory blood pressure in hypertensive subjects

Previous chronotherapy studies have shown that the circadian pattern of blood pressure (BP) remains unchanged after either morning or evening dosing of several calcium channel blockers (CCB), including amlodipine, isradipine, verapamil, nitrendipine, and cilnidipine. This trial investigated the antihypertensive efficacy and safety profile of the slow-release, once-a-day nifedipine gastrointestinal therapeutic system (GITS) formulation administered at different times with reference to the rest-activity cycle of each participant. We studied 80 diurnally active subjects (36 men and 44 women), 52.1±10.7 yrs of age, with grade 1-2 essential hypertension, who were randomly assigned to receive nifedipine GITS (30 mg/day) as a monotherapy for eight weeks, either upon awakening in the morning or at bedtime at night. Patients with uncontrolled BP were up-titrated to a higher dose, 60 mg/day nifedipine GITS, for an additional eight weeks. BP was measured by ambulatory monitoring every 20 min during the day and every 30 min at night for 48 consecutive hours before and after therapy with either dose. The BP reduction after eight weeks of therapy with the lower dose of 30 mg/day was slightly, but not significantly, larger with bedtime dosing. The efficacy of 60 mg/day nifedipine GITS in non-responders to the initial 30 mg/day dose was twice as great with bedtime as compared to morning dosing. Moreover, bedtime administration of nifedipine GITS reduced the incidence of edema as an adverse event by 91%, and the total number of all adverse events by 74% as compared to morning dosing (p=0.026). Independent of the time of day of administration, a single daily dose of 30 mg/day of nifedipine GITS provides full 24 h therapeutic coverage. The dose-dependent increased efficacy and the markedly improved safety profile of bedtime as compared to morning administration of nifedipine GITS should be taken into account when prescribing this CCB in the treatment of essential hypertension.     

Comparison between levels of trace elements in normal and cancer inoculated mice by XRF and PIXE

Determination of Rb, Br, Se, Zn, Cu, Fe, and Br/Rb ratio in tissues of mice inoculated with colon and melanoma cancer cells is described. A group of 19 Balb/c mice inoculated with C26 colon carcinoma, 4 C57B1/6 mice inoculated with B16 melanoma, and 13 control mice of both kinds were under investigation. The study was conducted on samples of blood, liver, kidneys, colon, and skin, and the trace element levels in normal and inoculated mice were compared. The inoculation was by subcutaneous injection either at the back or intrafootpad. The blood samples were taken 1, 2, and 3 wk after inoculation, and after 4 wk all the animals were sacrificed. Two nondestructive, complementary analytical methods were used: a modified X-ray fluorescence (XRF) for solid tissue and particleinduced X-ray emission (PIXE) for blood samples. The detection limit (DL) in the PIXE method was 0.35 (μg/g dry wt in 600 s counting time and in XRF, 1 μg/g dry sample for Rb, Br, Se and Zn and 2 μg/g for Cu and Fe in 200 s counting time. In all the cases studied, cancerous tissue developed at the site of the injection, and a significant difference in the trace element levels was observed between tissue samples obtained from normal and inoculated mice. The most pronounced effect was an increase in Rb level in the tumor by a factor ranging between 4 and 10 relative to normal tissue, with a corresponding decrease in the Br/Rb ratio (p < 0.05). Smaller changes were found in the Br, Se, Zn, and K levels. The changes in trace element levels in the inner organs were much smaller and seem to be influenced by the site of injection.     

Direct analysis of human blood (mothers and newborns) by energy dispersive X-ray fluorescence

This work is an application of energy dispersive X-ray fluorescence (EDXRF) as analytical technique for trace element determination in human tissues. Potassium (K), calcium (Ca), iron (Fe), copper (Cu), zinc (Zn), bromine (Br), rubidium (Rb) and lead (Pb) were determined directly in blood samples from 66 mothers at delivery after full-term pregnancies. The corresponding 66 cord-blood samples of the newborns were also analysed, in order to find element correlations between maternal and newborn blood at birth. The studied samples were obtained from mothers aged between 15 and 39 years old, the gestational age being between 35 and 41 weeks and the newborns' weight between 2.310 and 4.310 kg. Samples were lyophilised and analysed without any chemical treatment. Very low levels of Pb were found both in maternal and fetal cord blood samples. Cu values ranged from 3 to 13 microg g-1, both for mothers and children. A correlation between Cu and Fe concentrations in maternal and fetal cord blood was found. Zn is considered as one of the key elements in newborn health. Concentrations between 10 and 40 microg g-1 were measured. A positive correlation between Br levels in mothers and children was observed. Positive correlations for mothers were observed between Zn and Rb as well as K and Fe. The corresponding correlations in fetal cord blood samples were not observed, however positive correlations were found between Ca and K; Cu and Fe. The mean concentrations for each element were similar in maternal and in fetal cord blood, except for Cu and Zn, being higher in maternal samples. No correlations between element concentrations and pathologies of the mothers were observed.     

Elemental concentrations in Nigerians with affective disorders using proton-induced X-ray emission

The concentrations of a number of elements are determined in the plasma and erythrocytes of 21 Nigerians (11 females, 10 males) with symptomatic affective disorders (11 depressives, 10 manics) and in 40 normal controls using proton-induced X-ray emission (PIXE) analysis. The study shows that there is significant elevation of plasma K and Zn, as well as the erythrocyte S in the patients relative to the controls. The plasma and erythrocyte Cu, and the erythrocyte P, Ca, Fe, and Zn are significantly lower in the patients compared to the controls. However, the plasma levels of Ca, S, Fe, and Br are similar in both the patients and the controls. Similarly, the concentrations of K, Br, and Rb show no significant difference in the erythrocytes of patients and controls.     

Effects of elements in human blood pressure control

This review enumerates and discusses the elements involved in the control of human blood pressure via a historical evolutionary form. The older and most recent element literature presentations were researched using MEDLINE and a manual review of documents cited. Independent data extraction and cross-referencing was performed. Of the 28 known elements that can influence blood pressure, 15 were found to be involved in human blood pressure regulation. The elements were divided into four groups: electrolyte, composed of sodium, potassium, calcium, and magnesium; metal, which included zinc, copper, and iron; toxic, made up of lead, mercury, cadmium, barium, thallium, arsenic; miscellaneous (lithium and selenium). Evolutionary historical data, possible mechanisms of actions, and interactions between elements that have been shown to influence blood pressure are discussed. Controversy exists over the therapeutic use of elements to alter blood pressure but is absent in the case of the toxic group where preventive control is a proven public health matter. The significance of these 15 elements in the regulation of human blood pressure has been established and ongoing studies will continue to reinforce their influence and importance.     

葛根素对冷激诱导的高血压小鼠的影响

目的：检测葛根素灌胃对冷激诱导的高血压小鼠的血压血脂及肾脏结构的影响。方法：小鼠分为正常对照组、冷激对照组、冷激葛根素饲喂组（2,5,10ms／kg bw3组）（n=12）。以寒冷刺激（4±2℃）建立小鼠高血压模型,每天定时灌胃葛根素治疗,对照组给予聚乙烯吡咯烷酮溶液。连续饲喂18d．检测各组小鼠血压、血脂含量,石蜡切片观察肾脏结构。结果：冷激对照组小鼠血压显著高于正常对照组（P〈0．01）,葛根素饲喂组血压显著低于冷激对照组（P〈0．05）。冷激对照组TG含量显著高于正常对照组（P〈0．01）,而冷激饲喂组TG含量明显降低（P〈0．05）;冷激饲喂组TC含量与冷激对照组相比有所降低但无统计学意义;2mg／kg BW葛根素组LDL-C显著低于冷激对照组（P〈0．01）,各组间HDL-C含量比较无统计学意义,但葛根素饲喂组HDL-C／LDL-C值显著高于冷激对照组。冷激对照组肾小管上皮细胞水肿,内腔极度缩小,肾小球明显胀大,肾小囊腔显著变窄,葛根素饲喂组肾小管水肿基本消失,内腔明显增大,肾小球、肾小囊结构趋于正常。结论：葛根素灌服具有降血压、降血脂、改善病变肾脏结构的作用。     

Rhythmic clock gene expression in heart, kidney and some brain nuclei involved in blood pressure control in hypertensive TGR(mREN-2)27 rats

Hypertensive TGR(mREN-2)27 rats exerting inverted blood pressure (BP) profile were used to study clock gene expression in structures responsible for BP control. TGR and control Sprague Dawley male rats were synchronized to the light:dark cycle 12:12 with food and water ad libitum. Daily rhythm in per2, bmal1, clock and dbp expression in the suprachiasmatic nucleus (SCN), rostral ventrolateral medulla (RVLM), nucleus of the solitary tract (NTS), heart and kidney was determined in both groups. Sampling occurred in regular 4 h intervals when rats of both strains were 11-weeks-old. Blood pressure and relative heart weight were significantly elevated in TGR rats in comparison with control. Expression of bmal1 and clock was up regulated in SCN of TGR rats but daily rhythm in per2 and dbp expression was similar in both groups. Mesor of per2 expression in RVLM was significantly higher in TGR than in control rats. In NTS of TGR rats expression of per2 was phase delayed by 3.5 h in comparison with control and bmal1 did not exert rhythmic pattern. Our study provided the first evidence about modified function of central and peripheral circadian oscillators in TGR rats at the level of clock gene expression. Expression of clock genes exerted up regulation in SCN and RVLM and down regulation in NTS. Circadian oscillators in selected brain structures were influenced more than oscillators in the heart and kidney by additional renin gene. Interactions of RAS and circadian system probably contribute to the development of inverted BP profile in TGR rats.     

游泳训练对高血压大鼠血压及血栓前状态分子的影响

目的:观察10周游泳训练对自发性高血压大鼠(SHR)血压及血栓前状态分子血管性血友病因子(vWF)、组织型纤溶酶原激活物(t-PA)、纤溶酶原激活物抑制物(PAI-1)的影响。方法:选取10周龄雄性SHR(18只),随机分为对照组(8只)和训练组(10只),SHR训练组进行5次/周,每次60 min,共持续10周的无负重游泳训练,期间每2周测定大鼠血压。10周训练后,分别测定两组SHR血小板聚集率、血浆vWF、t-PA和PAI-1。结果:与对照组相比,训练组SHR经4周游泳训练后,血压显著下降(P<0.05),经10周游泳训练后,血压、血小板聚集率、血浆vWF水平、PAI-1活性显著降低(P<0.01),血浆t-PA活性显著提高(P<0.01)。结论:适宜游泳训练能有效平抑(或改善) SHR的血压,坚持4周训练即可产生显著的作用,还可明显改善SHR血栓前状态,预防高血压血栓性并发症。     

Study of trace elements in blood of cancer patients by proton-induced X-ray emission (PIXE) analysis

Proton-induced X-ray emission (PIXE) analysis was employed to determine the concentrations of six elements in the plasma and erythrocytes of 18 cancer subjects (15 males and 3 females) with neoplastic disorders and in 70 controls (35 males and 35 females). It was found that the concentrations of Br, K, and Zn were significantly elevated in the erythrocytes of the cancer subjects compared to the controls, whereas the concentration of Fe was significantly depressed, but with no difference observed in the concentration of Ca. In the plasma, the concentrations of Br, Cu, Ca, and K were significantly elevated, whereas the concentrations of Fe and Zn were found to be significantly depressed compared to the controls.     

Elemental analysis of proteins by microPIXE

The identification and quantification of metals bound to proteins is a crucial problem to be solved in structural biology. This paper describes the technique of particle induced X-ray emission with a microfocused beam (microPIXE) as a tool for analysing the elemental composition of liquid and crystalline protein samples. The proton beam induces characteristic X-ray emission from all elements in the protein, which can be interpreted in terms of the metal content of the protein molecule with a relative accuracy of between 10% and 20%. The compelling advantage of this method is that the sulphur atoms in the methionines and cysteines of the protein provide an internal calibration of the number of protein molecules present so that systematic errors are minimised and the technique is entirely internally self-consistent. This is achieved by the simultaneous measurement of the energy of backscattered protons (Rutherford backscattering), to enable us to determine the matrix composition and thickness, and so correct the PIXE data for the self-absorption of X-rays in the sample. The theoretical background to the technique is described, and the technical and experimental procedures are outlined. Examples of recent measurements are given which have informed a range of investigations in structural biology. The use of the technique is increasing and we envisage that future developments will enable it to become a routine high-throughput method.     

Trace elemental analysis of cancer-afflicted intestine by PIXE technique

Trace elemental analysis was carried out in the biological samples of cancer-afflicted intestine using the particle-induced X-ray emission technique (PIXE). A 2-MeV proton beam was employed to excite the samples. From the present results, it can be seen that the concentration of the elements Cr, Fe, and Ni are higher in the cancerous tissue of the intestine than those observed in the normal tissue, whereas the concentration levels of the element Zn is slightly lower in the cancer tissue of intestine than that observed in the normal tissue. The concentrations of S, Cl, K, Ca, Ti, Mn, Co, and Cu in the cancer tissue of the intestine are in agreement with those observed in the normal tissues within standard deviations. The present results support the previous observations that Ni and Cr are carcinogenic agents. The observed slightly low levels of zinc in the cancer tissue of the intestine suggest that zinc could possibly inhibit the tumor growth and development of neoplastic transformation. For correctly assessing the role played by the trace elements in initiating, promoting, or inhibiting cancer in various organs, there is a need for the acquisition of more data by trace elemental analysis from several investigations of this type undertaken in different regions.     

Role of zinc in regulation of arterial blood pressure and in the etiopathogenesis of arterial hypertension

Increased gastrointestinal absorption and urinary excretion of zinc has been confirmed in experimental and clinical studies on primary arterial hypertension as a result from changes of intracellular and extracellular zinc content. In arterial hypertension, the levels of zinc in serum, lymphocyte, and bone decrease while increasing in heart, erythrocytes, kidney, liver, suprarenal glands and spleen. These changes result in the loss of zinc homeostasis that leads to various degrees of deficiency, not entirely compensated by nutritional factors or increased absorption in the gastrointestinal tract. Loss of zinc homeostasis can be both cause and effect of high blood pressure. In the present review, the role of zinc metabolism changes and its mechanisms in arterial hypertension are discussed.     

Scanning proton microprobe analysis of strontium in an arctic charr,Salvelinus alpinus,otolith: implications for the interpretation of anadromy

Synopsis Scanning proton microprobe imaging has been used to map the distribution of strontium (Sr) in an arctic charr, Salvelinus alpinus, otolith. X-ray maps show that Sr variation follows an oscillatory zoned pattern which correlates with optically resolved zones (annuli). The internal region of the otolith shows optical zonation but no significant Sr content. Comparison of the optical image with the Sr X-ray map provides evidence of when the fish entered a high Sr environment. This may be interpreted as when the fish migrated from fresh water to a marine environment; this particular fish first migrated to sea in its eighth year. Micro-PIXE point analysis was used to determine the abundance of Sr in annuli along a radius from the nucleus to an outer edge; Sr levels in the internal region were about 10 ppm and variation in the outer zoned region was between 62 and 175 ppm. Detection limits for Sr are in the 1–2 ppm range. Other trace elements, such as transition elements, were found to be present in some growth regions in the 1–20 ppm range. Proton beam analysis is a non-destructive analytical technique capable of preserving the spatial integrity of trace-element data in otoliths such that element distribution may be linked to the growth structure of the otolith.     

Selenium and blood pressure studies in young and adult normotensive,renal, and spontaneously hypertensive animals

With reports of either no change or reduction of blood pressure, the relationship between selenium and blood pressure has not been clear. Normal Se values are not available for the Sprague Dawley (SD) rat or in the young and adult rat with various models of experimental hypertension. This study measured serum Se levels in the young and adult normotensive (NT), Grollman renal hypertensive (RH), and Okamoto-Aoki spontaneous hypertensive rats (SHR). The young animals have statistically significant (P<0.001) lower Se values as measured by the fluorometric method than those found at adulthood. Selenium levels were found to be altered in the adult SHR animals when compared with the RH and NT animals. The serum Se value for the normotensive SD rat was found to be 65.0±3.5 μg/dL, and for the two experimental models, 63.7±4.6 μg/dL for the RH, whereas the SHR level was elevated to 75.04±4.8 μg/dL (P<0.001). Elevated serum Se values in the adult SHR animals suggests an altered metabolism in SHR animals.     

Blunting of circadian rhythms and increased acrophase variability in sleep-time hypertensive subjects

24 h and ultradian rhythms of blood pressure (BP) have been previously shown to be disorganized in nocturnal hypertensive subjects. The present study was undertaken to further analyze the ultradian and circadian BP rhythm structure in sleep-time hypertensive subjects with normal or elevated awake-time BP levels. Fourier analysis was used to fit 24, 12, 8, and 6 h curves to mean BP as well as heart rate (HR) time series data derived from 24 h ambulatory blood pressure monitoring. Awake and sleep periods were defined according to individual sleep diaries. Awake-time hypertension was defined as diurnal systolic (SBP) and/or diastolic BP (DBP) means ≥135/85 mmHg. Sleep-time hypertension was defined as nocturnal SBP and/or DBP means ≥120/70 mmHg. The sample included 240 awake-time normotensive subjects (180 sleep-time normotensives and 60 sleep-time hypertensives) and 138 untreated awake-time hypertensive subjects (31 sleep-time normotensives and 107 sleep-time hypertensives). The amplitude and integrity (i.e., percent rhythm) of the 24 and 12 h BP rhythms were lower in the sleep-time hypertensive subjects and higher in the awake-time hypertensive subjects. However, no differences were detected when the integrity and amplitude of the 6 and 8 h mean BP rhythms were analyzed. The sleep-time hypertensive group showed significantly higher 24 h BP rhythm acrophase variability. No differences could be found in any of the HR rhythm parameters. Altogether, the findings suggest a disorganization of the BP circadian rhythm in sleep-time hypertensives that results in reduced 24 h rhythm amplitude and integrity that could be related to cardiovascular risk.     

Elemental microanalysis of individual blood cells

A scanning proton microprobe was used to study single red blood cells in freeze-dried, whole-blood specimens. Simultaneous collection of PIXE and of forward and backward scattered proton data provided information on the heavier elements (Z>27) and on the organic mass under investigation. The trace elemental spectrum of a red cell was found to be reproducible, and no elemental losses were observed during proton bombardment. The spatial resolution of the probe (1.5 μm for these studies) enabled the red cell’s biconcave disk shape to be visualized in quantitative two- and three-dimensional maps of H, C, P, S, Cl, K, and Fe.     

Trace-element analysis by charged-particle-induced reactions as a tool for physicians and chemists

The object of this article is to apprise physicians and chemists of nuclear analytical techniques and, in particular, of ion beam analysis (PIXE and PIGE) for the purpose of application to the clinical diagnostic method. The feasibility of the technique, sampling, and sample preparation for trace element analysis in biological and biomedical samples has been described previously (1–3). Analysis data from normal human blood samples and biomedical samples by ion beam reactions have been compared at the end. Emphasis will be placed on the use of the analytical technique on determination of the range of trace and toxic elements in human blood samples.     

Some observations on the trace element concentrations in human dental enamel

The concentration of trace elements has been measured for dental enamel from 86 healthy human teeth using particle-induced X-ray emission (PIXE). The majority of the teeth (n = 70) were collected from dentists in the county of Oxfordshire in the United Kingdom, although a smaller group (n = 16) were collected from Cornwall. The elements K, Ca, Mn, Fe, Co, Ni, Cu, Zn, Sr, Pb, and Hg have been detected and statistically analyzed by grouping according to sex, age, and geographical location. The concentrations of Fe and Cu were found to be lower in the teeth from female donors (P < 5%) and are believed to result from the continued burden of blood loss during menstruation. Strong positive correlations (P < 0.1%) were found between Ca, Co, Ni, and Zn for all groups; these elements were also found to exhibit a negative correlation (P < 1%) with age for teeth from female donors. This is believed to be related to decalcification during the menopause. Pb was found to exhibit a positive correlation (P < 5%) with age for both sexes, and is believed to substitute for Ca in the Ca hydroxy apatite (HAP) within the dental enamel.     

Biofeedback of R-wave-to-pulse interval normalizes blood pressure

We investigated whether biofeedback of the R-wave-to-pulse interval, a measure related to the pulse wave velocity, enables participants with either high or low arterial blood pressure to modify their blood pressure. Twelve participants with high blood pressure (mean systolic blood pressure = 142.6 ± 13.5 mmHg; mean diastolic blood pressure = 99.9 ± 12.3 mmHg) and 10 participants with low blood pressure (mean systolic blood pressure = 104.8 ± 6.6 mmHg; mean diastolic blood pressure = 73.2 ± 4.2 mmHg) received 3 individual sessions of RPI biofeedback within a 2-week period. Participants with high blood pressure were rewarded for decreasing and participants with low blood pressure for increasing their blood pressure. Standard arm-cuff blood pressure measurements across the sessions served as dependent variables. Participants with high blood pressure achieved significant reductions of systolic (15.3 mmHg) and diastolic (17.8 mmHg) blood pressure levels from the beginning of the first to the end of the last training session. In contrast, participants with low blood pressure achieved significant increases in systolic (12.3 mmHg) and diastolic (8.4 mmHg) blood pressure levels. The degree of blood pressure changes in this study might be of clinical relevance. With prolonged and refined training regimens, even larger effects seem to be likely.