The treatment of hypertension

1 A 'retrospective' of the development of the drug treatment of hypertension is presented from the early days of ganglion blockers to the present time together with a review of the evidence of benefit from treatment.
2 Current issues and debates are summarised including shortfalls in the control of hypertension in populations, difficulties surrounding the measurement of blood pressure, disagreement on the levels of blood pressure to treat, the goal blood pressures to aim at, issues surrounding lifestyle measures such as the low salt diet and low intensity exercise, and treatment with diuretics and with calcium antagonists.
3 A 'perspective' is presented on some avenues for progress in the years ahead. These will include the identification of genetic markers to determine the hypertensive individuals with the greatest risk of death and of cardiovascular complications.     

Cardioprotection by nisoldipine: role of timing of administration

Nisoldipine was administered at 10^–9M, a dose lackingnegative inotropism, to isolated and perfused rabbit heartssubmitted to 60 min ischaemia (1 ml.min^–1) followed by30 min reperfusion. The drug was delivered either 30 min beforeischaemia, at the onset and after 30 min of ischaemia and duringreperfusion only. Cardiac protection was evaluated in termsof recovery of left ventricular pressure during reperfusion,release of creatine phosphokinase (CPK), mitochondrial function,tissue content of adenosine triphosphate (ATP) and creatinephosphate (CP), calcium homeostasis and the occurrence of oxidativestress, established measuring content and release of reducedand oxidized glutathione. The cytoprotective action of nisoldipine occurs in the absenceof negative inotropism and is closely related to the time ofadministration. Optimal myocardial preservation is achievedwhen nisoldipine is given before or at the onset of ischaemia.Prophylactic administration of nisoldipine improved the recoveryof the developed pressure from 159±10 (SE) mmHg to 478±19mmHg, P<0.01 and reduced the release of CPK from 830±29to 229±27 mU. min^–1 g^–1 wet wt, P<0.01.The accumulation of tissue and mitochondrial calcium was reducedfrom58±11 and49±9 to 14±6 and 10±4 mmol.kg^–1 dry wt respectively, P<0.01. This resulted ina signficant (P<0.01) preservation of all indices of mitochondrialfunction, allowing a higher recovery of ATP and CP after reperfusion(from 4.1±0.7 and 10.0±0.6 to 16.1±1.0and 29.9±0.2 µmol.g^–1 dry wt respectively,P<0.001). Reperfusion-induced myocardial accumulation and release of oxidizedglutathione were reduced from 0.493±0.07 nmol.mg^–1protein and 0.768±0.063 nmol.min^–1g^–1 wetwt to 0.225±0.07 and 0.157±0.038 respectively,P<0.01. Similar data were obtained when nisoldipine was givenat the time of ischaemia, while administration 30 min afterthe onset of ischaemia showed only a trend towards protection.Nisoldipine lost its protective effect when given on reperfusion. A multifactorial analysis of the data suggest that the cardioprotectiveeffect of nisoldipine is related to the maintenance of membraneintegrity, possibly since nisoldipine is highly lipophilic.     

母体钙代谢与补钙对妊娠的影响

妊娠期缺钙严重影响母婴的安全健康 ,其原因是由于妊娠期母体钙代谢发生变化 ,使母体血清游离钙离子浓度降低 ,血清铅浓度增高。有关研究表明 ,母体缺钙导致血铅竞争性过高 ,使胎儿身长、体重均小于胎龄儿 ,胎儿宫内发育迟缓的发生率增高 ,甚至发生早产、死胎等。同时发现血清钙离子可能对内源性一氧化氮合成释放起调节作用 ,而内皮素是最强的缩血管物质之一 ,母体补钙可调节一氧化氮与内皮素的平衡 ,从而降低妊高征的发生率。因此孕期补充钙剂是非常重要的。     

RELATIONSHIP BETWEEN PLATELET CYTOSOLIC FREE CALCIUM CONCENTRATION AND PLASMA RENIN ACTIVITY

1. Plasma renin activity (PRA) and platelet cytosolic free calcium concentration ([Ca2+]i) were simultaneously determined in 18 untreated essential hypertensive subjects and 17 normotensive controls. A significant positive correlation was found between [Ca2+]i and PRA (slope = 42 nmol/l/ng/ml/h) in these 35 subjects. 2. Two determinations more than one week apart in nine subjects confirmed the parallel fluctuations of [Ca2+]i and PRA. A strict sodium restriction produced a progressive PRA elevation associated with a parallel rise in [Ca2+]i in one subject. 3. These results are consistent with the hypothesis that angiotensin II causes a concentration-dependent calcium mobilization.     

Inter-relations between the calcium set-points of Parfitt and Brown in primary hyperparathyroidism: a sequential citrate and calcium clamp study

Abstract. The objective of the present study was to compare the calcium set-points of E. M. Brown and A. M. Parfitt obtained by sequential citrate and calcium clamp in patients with primary hyperparathyroidism and healthy controls. Twenty-six patients with primary hyperparathyroidism were investigated and compared to 22 healthy volunteers. All participants were investigated by sequential calcium lowering and raising comprising the following four phases: Phase (1) blood ionized calcium lowering of about 0·20 mmol l^-1; phase (2) steady-state (relative) hypocalcaemia of blood ionized calcium 0·20 mmol l^-1 below baseline; phase (3) blood ionized calcium is raised to about 0·20 mmol l^-1 above baseline; and phase (4) (relative) hypercalcaemia of blood ionized calcium 0·20 mmol l^-1 above baseline. Serum parathyroid hormone (1–84) was measured by an immunoradiometric assay. Blood ionized calcium was measured by a calcium selective electrode. We found the calcium set-points of Parfitt to be 1·42 mmol l^-1 (SD 0·12, n= 52) vs. 1·25 mmol l^-1 (SD 0·04, n= 44) in patients and controls, respectively (P < 0·001). The calcium set-points of Brown were 1·32 mmol l^-1 (SD 0·10, n= 26) vs. 1·13 mmol l^-1 (SD 0·04, n= 22), respectively (P < 0·001). By comparing the calcium set-points of Parfitt and Brown, a strikingly good correlation was observed, in patients (r= 0·91, P < 0·001) and in controls (r= 0·85, P < 0·001). We demonstrate in this paper in vivo that Brown's and Parfitt's calcium set-points are raised in primary hyperparathyroidism and return to normal following parathyroidectomy. The values for Brown's and Parfitt's calcium set-points are significantly different, but strikingly well correlated, supporting the view that Brown and Parfitt describe two different points on the same sigmoidal curve, corresponding to 50% and about 85% inhibition of PTH maximum, respectively. The mathematical form of the sigmoidal curve between blood ionized calcium and parathyroid hormone is very similar in primary hyperparathyroidism and normal humans.     

西洋参茎叶皂甙单体Rb_3对大鼠血流动力学及单钙通道活动的影响

单体皂甙Ｒｂ３自西洋参茎叶皂甙中提取。Ｒｂ３３０ｍｇ·ｋｇ－１可使麻醉大鼠在体心脏的ＭＡＰ，±ｄＰ／ｄｔｍａｘ和ＬＶＳＰ减少。用斑片钳的连细胞电压钳法证明．Ｒｂ３３００ｍｇ·Ｌ－１使Ｌ、Ｂ、Ｔ型钙通道的开放时间缩短、开放概率减少，其作用与异搏定３７．５ｍｇ·Ｌ－１相似，与ＢａｙＫ８６１１５μｍｏｌ·Ｌ－１作用相反。确切地证明Ｒｂ３对钙通道有阻滞作用。     

硝苯地平对抗吗啡戒断所致焦虑作用研究

目的··：评价钙拮抗剂硝苯地平对戒断后期焦虑症状及复吸的治疗作用。方法··：大鼠自然戒断后，采用Ｖｏｇｅｌ＇ｓ饮水冲突模型（简称Ｖｏｇｅｌ冲突模型）观察吗啡依赖大鼠的焦虑情绪与硝苯地平的作用。结果··：２０，３０，５０ｍｇ·ｋｇ－１的硝苯地平能明显增加大鼠的舔水次数和被电击次数，并呈剂量相关性，以３０ｍｇ·ｋｇ－１作用最为明显。结论··：钙离子拮抗剂可治疗吗啡戒断所致的焦虑症状，可能与５－ＨＴ等神经递质的释放或与ＧＡＢＡ能神经有关     

妊娠期低水平铅暴露对新生儿钙磷代谢及造血系统的影响

目的 :研究妊娠期低水平铅暴露对新生儿钙磷代谢及造血系统的影响。 方法 :分别测定 79例汉族及5 9例维吾尔族 (维族 )母亲及新生儿脐血铅、钙、磷、碱性磷酸酶、血红蛋白、红细胞游离原卟啉的含量 ,分析脐血铅对新生儿钙、磷、碱性磷酸酶及血红蛋白、红细胞游离原卟啉的影响。 结果 :(1)汉族产妇血铅 6 3 87μg/L ,新生儿脐血铅 4 7.71μg/L ,维族产妇血铅 87 92 μg/L ,新生儿脐血铅 6 1.5 7μg/L ,维族产妇及新生儿脐血铅均高于汉族产妇及新生儿脐血铅含量 (P <0 .0 5 ～ 0 .0 1) 。 (2 )以脐血铅 10 0 μg/L为界将新生儿分为高铅组和低铅组 ,两组血钙相比差异有统计学意义 (P <0 .0 1) ,而两组血红蛋白及红细胞游离原卟啉相比差异均无统计学意义 (P >0 .0 5 )。 结论 :妊娠期低水平铅暴露可致新生儿血钙下降 ,但对新生儿血红蛋白及红细胞游离原卟啉则无影响     

Sevelamer hydrochloride with or without alphacalcidol or higher dialysate calcium vs calcium carbonate in dialysis patients: an open-label, randomized study.

BACKGROUND: Sevelamer hydrochloride was recently proposed as a phosphate binder to prevent hypercalcaemia in place of calcium alkaline salts in dialysis patients. So far, it has been evaluated only in patients receiving calcitriol, without comparison with CaCO(3) alone, although the latter was found to be as effective as the combination of calcitriol and Al(OH)(3) in suppressing parathyroid hormone (PTH) without inducing hypercalcaemia and to have a better lowering effect on serum phosphate. Moreover, this bile salt binder may decrease serum 25-OH vitamin D. Therefore, we compared for 5 months two strategies for controlling moderate hyperparathyroidism: CaCO(3) alone vs sevelamer in conjunction with measures to increase calcium balance. METHODS: Forty-two patients were randomized: 21 continued their treatment with 4.8 g/day CaCO(3) and 21 were switched to sevelamer (initial dose: 2.4 g/day, increased to 4.4 g/day). Each month, when serum-corrected calcium decreased below 2.30 mmol/l, dialysate calcium was increased or alphacalcidol was given at each dialysis session, according to serum PO(4) levels. The following parameters were monitored: serum Ca, PO(4), bicarbonate and protein, weekly; and serum PTH, 25-OH vitamin D and total, LDL and HDL cholesterol monthly. RESULTS: Except for higher serum phosphate at month 1, lower serum bicarbonate at month 2 and lower LDL cholesterol at month 5 in the sevelamer group, no difference was found between the two groups. Compared with baseline levels, PTH increased and 25-OH vitamin D decreased significantly in both groups, these two parameters being inversely correlated. CONCLUSIONS: Given comparable control of plasma calcium, phosphate and 25-OH vitamin D, PTH control is comparable in both strategies. Sevelamer does not induce greater vitamin D depletion than CaCO(3). The transient decrease of serum bicarbonate after discontinuation of CaCO(3) in the sevelamer group suggests a less optimal prevention of acidosis. The sevelamer-induced decrease in LDL cholesterol gives this drug a potential advantage in cardiovascular prevention.     

Preselection Thymocytes Are More Sensitive to T Cell Receptor Stimulation Than Mature T Cells

During T cell development, thymocytes which are tolerant to self-peptides but reactive to foreign peptides are selected. The current model for thymocyte selection proposes that self-peptide–major histocompatibility complex (MHC) complexes that bind the T cell receptor with low affinity will promote positive selection while those with high affinity will result in negative selection. Upon thymocyte maturation, such low affinity self-peptide–MHC ligands no longer provoke a response, but foreign peptides can incidentally be high affinity ligands and can therefore stimulate T cells. For this model to work, thymocytes must be more sensitive to ligand than mature T cells. Contrary to this expectation, several groups have shown that thymocytes are less responsive than mature T cells to anti-T cell receptor for antigen (TCR)/CD3 mAb stimulation. Additionally, the lower TCR levels on thymocytes, compared with T cells, would potentially correlate with decreased thymocyte sensitivity. Here we compared preselection thymocytes and mature T cells for early activation events in response to peptide–MHC ligands. Remarkably, the preselection thymocytes were more responsive than mature T cells when stimulated with low affinity peptide variants, while both populations responded equally well to the antigenic peptide. This directly demonstrates the increased sensitivity of thymocytes compared with T cells for TCR engagement by peptide–MHC complexes.