尿毒症患者偶测血压与动态血压的对比研究

目的评价尿毒症患者不同偶测血压(CBP)水平的动态血压特点.方法选择75例服用或未用降压药物的尿毒症患者,男性44例,女性31例;平均年龄(52.4±16.5)岁,尿毒症病程平均(27.9±34.8)月.根据CBP结果分为正常血压组;1、2、3级高血压组;进行24小时动态血压测定(ABPM).结果4组资料显示随CBP值升高,ABPM值亦升高;各组ABPM均低于CBP值,随着血压分级的提高,其ABPM24小时均值,日间均值,夜间均值相应升高,各组间存在着非常显著,或显著性差异.随着血压总体水平的提高,血压负荷也增加,尤其是夜间血压负荷增加明显,本文各组的夜间血压负荷均高于日间.在6例未服降压药的正常血压尿毒症患者中发现,5/6例有昼夜节律消失或减弱,4/6例血压负荷异常,2/6例ABPM升高.75例中昼夜节律消失或减弱者为64例,占83%.结论尿毒症ABPM水平与CBP水平呈正比.尿毒症高血压患者ABPM特点与高血压患者相似,血压正常的尿毒症ABPM存在异常改变,值得进一步研究.     

Hemodynamic effects of quinapril, a novel angiotensin-converting enzyme inhibitor

The hemodynamic effects of quinapril, a novel nonsulfhydryl-containing angiotensin-converting enzyme (ACE) inhibitor, were assessed in 10 patients with mild-to-moderate essential hypertension. Compared with placebo, quinapril (20 mg) administered twice daily for 4 weeks significantly lowered blood pressure by decreasing total peripheral resistance without producing tachycardia, an increase in cardiac output, or a rise in plasma catecholamines. Quinapril significantly reduced renal, but not forearm, vascular resistance. Renal blood flow, glomerular filtration rate, and filtration fraction remained unchanged. Left ventricular wall stress was markedly reduced by quinapril, but during the relatively short treatment period, only a nonsignificant trend toward reduction in left ventricular mass was observed. These findings suggest that quinapril is an effective antihypertensive agent that lowers peripheral resistance without increasing cardiac output or disturbing autoregulation of renal hemodynamics.     

Effects of chronic nitrendipine on casual (office) and 24-hour ambulatory blood pressure

To assess the clinical efficacy of chronic nitrendipine therapy in mild to moderate essential hypertension, we studied blood pressure (BP) and heart rate responses in 22 subjects receiving maintenance nitrendipine therapy. Ten subjects (45%) whose hypertension was controlled with chronic monotherapy had an 11/12 mm Hg decrease in supine BP (P less than 0.05) with a mean (+/- SD) dose of 71 +/- 15 mg/day. The 12 (55%) subjects whose hypertension was not controlled with monotherapy had a comparatively higher baseline BP than the other 10 (156/105 +/- 10/6 compared with 150/98 +/- 15/4 mm Hg; P less than 0.05). Eight of the 10 subjects demonstrating office BP control with chronic nitrendipine monotherapy who also had full-time employment underwent continuous ambulatory BP monitoring before and after maintenance monotherapy. Nitrendipine induced a reduction in the mean 24-hour BP and mean BP at home, but did not reduce the BP during work or while asleep. These data suggest that nitrendipine lowers BP when assessed by casual office methods. The ambulatory BP monitor data demonstrate that the hypotensive response to chronic nitrendipine is modified during work periods, which are generally associated with increased adrenergic activity. Ambulatory BP monitoring may be superior to office (casual) monitoring in the assessment of the overall efficacy of antihypertensive drugs.     

Ambulatory 24-h blood pressure monitoring in essential hypertensives treated with the angiotensin-converting enzyme inhibitor ramipril

A double-blind, crossover study was carried out on the antihypertensive effect of 5 mg ramipril. Continuous 24-h blood pressure monitoring was performed on 15 essential hypertensives [mean (+/- SD) blood pressure 155.2 +/- 6.5/101.3 +/- 4.8 mmHg], 24 h prior to treatment and 48 h after having received either antihypertensive therapy or placebo; the patients taking part in the study had not taken any antihypertensive treatment 4 weeks prior to the beginning of the trial. After receiving 5 mg ramipril the mean 24-h blood pressure was significantly (P less than 0.05) reduced to 148.3 +/- 5.8/91.5 +/- 5.5 mmHg. After 48 h the blood pressure increased to 153.1 +/- 4.8/96.0 +/- 6.4 mmHg. In the placebo group there was only a slight, non-significant reduction in blood pressure on day 1 (154.3 +/- 6.9/97.3 +/- 5.7 mmHg) and during day 2 the blood pressure increased to 155.4 +/- 5.3/99.5 +/- 5.9 mmHg. The results showed that a once-daily administration of 5 mg ramipril produced a reduction in blood pressure, which lasted 24 h. This simple therapeutic regime offers the advantage of being easy for patients to follow and, therefore, promotes compliance with therapy.     

Acute effects of captopril on serum angiotensin-converting enzyme activity, the renin-aldosterone system and blood pressure in patients with sarcoidosis

Captopril, an orally active angiotensin-converting enzyme (ACE) inhibitor, was administered to three patients in an active stage of sarcoidosis. The serum ACE level, aldosterone concentration in plasma and blood pressure decreased rapidly after administration, while plasma renin activity was not significantly changed. It is suggested that inhibition of ACE by captopril offers a possible therapeutic approach to the treatment of sarcoidosis.     

Effects of the angiotensin-converting enzyme inhibitor enalapril on blood haematopoietic progenitors and Acetyl-N-Ser-Asp-Lys-Pro concentrations

Acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) is a physiological inhibitor of the proliferation of haematopoietic stem cells. In 12 healthy volunteers treated with the angiotensin-converting enzyme (ACE) inhibitor enalapril (20 mg day⁻¹ for 15 days), we studied plasma and urinary AcSDKP levels, the in vitro degradation of AcSDKP by plasma ACE and the numbers of circulating haematopoietic progenitors (granulocyte-monocytic colony forming unit: CFU-GM; burst forming unit-erythroid: BFU-E; and mixed colony forming unit: CFU-mixed). During treatment, plasma and urinary AcSDKP concentrations increased 2- to 5-fold, degradation of AcSDKP was reduced, and CFU-mixed significantly increased by 100% while BFU-E and CFU-GM significantly decreased by 16% and 26%, respectively. These results indicate that ACE inhibitors may be of value during chemotherapy or radiotherapy, warranting further study.     

脓毒症时大鼠心脏的变化及血管紧张素转化酶抑制剂的保护作用

目的研究脓毒症大鼠心脏功能、心肌力学的改变及血浆血管紧张素Ⅱ浓度变化,并探讨血管紧张素转化酶抑制剂(ACEI)对心脏的保护作用。方法Wistar大鼠随机分为对照组(32只)、脂多糖(LPS)组(32只,予LPS 4 mg/kg静脉注射)及LPS ACEI组(32只,予雅施达2 mg/ kg连续灌胃3 d,第4天静脉注射LPS)。各组动物均经右颈总动脉左心室内插管,监测左室功能变化,并于实验前(O点)及给药后2、4、6 h采血(每时间点8只)行血管紧张素Ⅱ、肌钙蛋白T (TNT)检测。结果①脓毒症状态下TNT显著升高,应用ACEI后明显降低[(1．30±0．53)μg/L vs (0．40±0．34)μg/L,P＜0．01)]。②脓毒症状态下,血管紧张素Ⅱ浓度升高,且可被ACEI制剂雅施达抑制[(1223．27±483．72)ng/L vs(383．0±182．22)ng/L,P＜0．01)]。③脓毒症状态下左心室收缩峰压(LVPP)、左心室压力上升(下降)最大速率(±dp/dt)均有不同程度变化,左心室舒张末期压(LVEDP)升高,应用ACEI可明显降低。结论①脓毒症可致大鼠心肌发生明显损伤,该损伤的发生可能和AngⅡ有关;②ACEI可明显改善脓毒症时的心肌损伤。     

Effects of chronic cetamolol therapy on resting, ambulatory, and exercise blood pressure and heart rate

We studied blood pressure (BP) and heart rate (HR) responses in 12 patients with hypertension who were receiving cetamolol, a cardioselective beta-blocker with intrinsic sympathomimetic activity. The BP and HR parameters were evaluated at rest (casual, office readings), with ambulatory BP monitoring, and after treadmill exercise testing. At a mean (+/- SD) dose of 46 +/- 21 mg/day, casual supine BP decreased by 10/12 mm Hg (P less than 0.05 for systolic; P less than 0.01 for diastolic) compared with placebo, while HR decreased 4 bpm. Cetamolol resulted in a significant reduction in the mean 24-hour systolic BP. The most striking reduction occurred in the BP at work (23 mm Hg), with almost no decrease in the BP during sleep. Ambulatory HR reductions occurred while the subjects were at work (9 bpm; P less than 0.05) but not while at home (awake) or during sleep. The mean duration of exercise was the same during cetamolol and placebo phases, but both HR and BP fell significantly at peak performance after cetamolol. These data suggest that cetamolol reduces BP without lowering HR at rest. During periods of increased adrenergic activity such as work and dynamic exercise, both HR and BP are reduced.     

The effect of phenylpropanolamine on ambulatory blood pressure

Phenylpropanolamine (PPA) is a sympathomimetic amine and component of many over-the-counter decongestants and anorectic agents. It has been reported to cause elevated blood pressure and even hypertensive crises. The pressor effects with therapeutic doses are not well established. We monitored the effects of acute and chronic PPA dosing using 24-hour ambulatory blood pressure recording as a sensitive method of monitoring blood pressure variability. Eighteen normotensive male subjects were randomly assigned to receive 75 mg PPA (sustained-release preparation) or placebo in a double-blind crossover design with blood pressure monitored on days 1 (D1) and 6 (D6) of each period. There was no significant difference in blood pressure when compared as either 2-hour intervals or 24-hour global means: (placebo) 116/68 (D1), 117/68 (D6); (PPA) 118/69 (D1), 119/69 (D6). Our results document the absence of pressor effect with PPA in therapeutic doses even with repeated measurements and further confirm the reproducibility of 24-hour blood pressure monitoring.     

A multicenter study of the safety and efficacy of benazepril hydrochloride, a long-acting angiotensin-converting enzyme inhibitor, in patients with chronic congestive heart failure

Benazepril hydrochloride is a nonsulfhydryl, long-acting angiotensin-converting enzyme inhibitor that is orally effective. This study was designed to determine the acute hemodynamic effects of this agent in patients with chronic congestive heart failure. Twenty-six patients with New York Heart Association class III or IV congestive heart failure and left ventricular ejection fractions less than 35%, cardiac indexes less than 2.1 L/min/m2, and pulmonary artery wedge pressures greater than 12 mm Hg were given 2 or 5 mg benazepril hydrochloride. All does produced significant (p less than 0.05) increases in cardiac output (26.7% to 31.6% above control) and heart rate (5.4% to 11.2% above control) and decreases in systemic (27.1% to 32.0% below control) and pulmonary (34.8% to 55.5% below control) vascular resistances, mean pulmonary (25.3% to 30.3% below control) and systemic (13.4% to 18.5% below control) arterial pressures, and pulmonary artery wedge pressure (46.9% to 51.1% below control). Twenty-four hours after an initial dose, systemic vascular resistance and pulmonary artery wedge pressures remained below control levels. Angiotensin-converting enzyme activity fell by 67.8% +/- 6.4%, with a 15.8% +/- 7.6% decline in aldosterone levels. Thus benazepril hydrochloride is an effective angiotensin-converting enzyme inhibitor that produces hemodynamic effects that persist for 24 hours after a single oral dose.     

Effects of chronic administration of an angiotensin-converting enzyme inhibitor on angiotensin-converting enzyme activity in the pars recta of rabbits

1. To determine whether chronic angiotensin-converting enzyme inhibition induces a decrease in proximal tubular angiotensin-converting enzyme activity, urine and blood samples were collected in conscious New Zealand rabbits before and after 16 days administration in drinking water of low doses of captopril (2.6 +/- 0.6 mg 24 h-1 kg-1), high doses of captopril (7.6 +/- 0.9 mg 24 h-1 kg-1) or no captopril (controls). The kidneys were then removed and angiotensin-converting enzyme activity was determined in isolated pars recta of microdissected nephrons as pmol of tritiated hippurylglycylglycine substrate hydrolysed min-1 of incubation and mm-1 of tubule. 2. Both low and high doses of captopril significantly decreased plasma angiotensin-converting enzyme activity and increased plasma renin activity, thus indicating an effective inhibition of circulating angiotensin-converting enzyme. Both low and high doses of captopril also significantly decreased mean arterial pressure and increased water intake and urine flow rate. Neither dose modified creatinine clearance and absolute and fractional sodium excretion. 3. None of the doses altered urinary kallikrein excretion. Urinary excretion of kinins was increased by 98.7% compared with control rabbits by the high dose of captopril (402 +/- 152 vs 251 +/- 104 ng/24 h, P less than 0.01) but was unchanged by the low dose of captopril. 4. Angiotensin-converting enzyme activity in the pars recta was lower in rabbits given the high dose of captopril than in control rabbits (17.6 +/- 7.2 vs 37.3 +/- 9.0 pmol min-1 mm-1, P less than 0.01) but was not decreased in rabbits given the low dose of captopril (40.4 +/- 5.0 pmol min-1 mm-1).(ABSTRACT TRUNCATED AT 250 WORDS)     

Antioxidant and cardioprotective properties of the sulphydryl angiotensin-converting enzyme inhibitor zofenopril

Zofenopril, a new potent sulphydryl angiotensin-converting enzyme (ACE) inhibitor, is characterized by high lipophilicity, selective cardiac ACE inhibition, and antioxidant and tissue protective activities. In vitro and in vivo experiments suggest that zofenopril exerts antioxidant properties at clinically achievable tissue concentrations. In endothelial cells, zofenopril enhances nitric oxide production, attenuates atherosclerotic lesion development and inhibits adhesion molecule expression by reducing reactive oxygen species. These peculiar characteristics are reflected in the drug's cardioprotective activity, which has been shown to be greater than that of non-sulphydryl ACE inhibitors. Cardiac hypertrophy was also reduced by chronic zofenopril administration, independently of its blood pressure-reducing effect. ACE inhibitors with a sulphydryl group could have an advantage in improving vascular function and reducing cardiac impairment compared with non-sulphydryl-containing ACE inhibitors. This could explain zofenopril's remarkable clinical efficacy post-infarction, and potentially beneficial use in prevention and therapy of cardiovascular diseases, such as atherosclerosis, thrombosis and heart failure.     

The effects of benazepril, a new angiotensin-converting enzyme inhibitor, in mild to moderate essential hypertension: a multicenter study

Benazepril hydrochloride is a new angiotensin-converting enzyme inhibitor. In a multicenter study, 206 patients with mild to moderate hypertension were randomized to receive benazepril at a dose of 2, 5, 10, or 20 mg, hydrochlorothiazide, 25 mg, or placebo once daily for 4 weeks. The 20 mg dosage of benazepril lowered blood pressure to a degree equal to that of 25 mg hydrochlorothiazide: -12.2/7.7 mm Hg and -13.4/-7.5 mm Hg, respectively. Hydrochlorothiazide proved to be more effective in black subjects. At lower dosage levels of benazepril (2, 5, and 10 mg), blood pressure reduction was not significantly different from that with placebo. In those patients who failed to achieve goal diastolic blood pressure of less than 90 mm Hg with monotherapy after 4 weeks, the addition of open-label hydrochlorothiazide (25 mg/day) to benazepril, hydrochlorothiazide, or placebo produced a substantial additional decrease in blood pressure over a 2-week period. No definite adverse effects on hematologic measurements, serum biochemistry test results, or urinalyses were noted. Subjective adverse experiences were common in all groups but except in three or possibly four instances were not considered causally related to the study drug.     

醛固酮受体拮抗剂联合ACEI抗腹膜纤维化机制的研究

目的①药物干预腹膜纤维化的机制研究;②观察单核细胞趋化蛋白-1(MCP-1)、C-JUN/AP-1在大鼠腹膜间皮细胞的表达及其在药物干预后的变化,探讨腹膜透析后腹膜纤维化的机制及解决办法。方法50只Wistar大鼠随机分5组。除A组余腹腔内每日注入20ml4.25%百特透析液,试验第1、3、5、7d腹腔注射脂多糖(LPS)0.6ml/(kg·h),B组腹膜纤维化模型组;C组西拉普利10mg/(kg·d)灌胃;D组安体舒通100mg/(kg·d)灌胃。E组联合给药组。30d后收集大鼠腹膜做病理(HE染色,Masson染色),免疫组化查腹膜间皮细胞MCP-1、C-JUN/AP-1的表达,并腹膜透析液计数腹水中细胞总数和巨噬细胞数及测定转化生长因子-β(TGF-β)的浓度。结果给药组(C、D、E组)的腹膜病理改变比模型组(B组)轻,转化生长因子-β的浓度下降具有统计学意义。各组腹膜间皮细胞均有MCP-1的表达,毛细血管和小静脉内皮细胞都可见其表达,联合给药组腹膜纤维化程度最轻,腹水巨噬细胞计数少,MCP-1、C-JUN/AP-1的表达少。结论联合应用醛固酮(ALDO)受体拮抗剂及ACEI能有效的防治腹膜纤维化。机制可能为抑制腹膜间皮细胞C-JUN/AP-1表达,在转录的水平上降低TGF-β活性,并抑制MCP-1表达,抑制腹膜炎性反应,减轻纤维化。     

Renovascular disease and renal complications of angiotensin-converting enzyme inhibitor therapy

Renal complications of angiotensin-converting enzyme (ACE) inhibitor therapy are widely recognized, but few authors have documented the incidence or spectrum of these conditions. In a retrospective study of 530 consecutive patients presenting to our unit as acute uraemic emergencies over a six-year period, 85 (16 per cent) had renovascular disease that was considered to be responsible for their loss of renal function. Twenty-one (4 per cent) patients had uraemia which could be clearly attributable to ACE inhibitor treatment; 18 of these cases were shown to have significant renovascular pathology. Following withdrawal of the ACE inhibitor the renal failure reversed in the majority of patients. We also examined 400 consecutive hypertensive patients referred over a similar period and, although vascular imaging was performed only when it was considered to be clinically indicated, 58 (14.5 per cent) of these patients were shown to have renovascular pathology. A further five patients with stable chronic renal disease were seen to have a deterioration in their glomerular filtration rate coincident with commencement of ACE inhibitor therapy; this reversed when the agents were withdrawn. These observations indicate that significant renovascular disease may be more common than has been hitherto recognized and that injudicious use of ACE inhibitors may result in serious complications. Methods which may minimize such iatrogenic disease are suggested.     

Lipoproteins of blood serum and the activity of angiotensin-converting enzyme

We studied the influence of native lipoproteins on the activity of the angiotensin-converting enzyme (ACE). Lipoproteins of blood serum were inhibiting the activity of soluble ACE. The ACE activity in blood serum was found to depend on a concentration of total cholesterol and of triglycerides. The maximal ACE activity was observed at a concentration of total cholesterol of 9.41 mM/l and at a concentration of triglycerides of 3.05 mM/l. The albumin-linked non-etherified fatty acids affected the ACE activity neither in water solutions nor in presence of lipoprotein complexes. According to the study, the progression of most frequent atherogenic hyperlipidemia results in a 2-fold increase of the ACE activity. It is suggested that an intensified ACE activity in blood plasma can be regarded as an integral component of biochemical disorders in metabolic syndrome.     

Postural effects on diastolic blood pressure are differently recorded by a non-invasive ambulatory blood pressure monitor and a standard auscultatory device,

Summary. The aim of this study was to determine the influence of change of posture on blood pressure as recorded with an automatic ambulatory blood pressure monitor and a standard auscultatory device. The blood pressure difference between sitting and supine and between standing and supine posture was 1.1/3.9 and 6.5/6.3 mmHg, respectively, for the monitor recordings, and 0.7/6.7 and 7.9/14.8 mmHg, respectively, for the standard recordings. All differences were significant, except the systolic blood pressure difference between sitting and supine posture. There were no significant differences in systolic blood pressure between monitor and standard recordings in any posture. The corresponding differences in diastolic blood pressure were significant in sitting (-4.6 mmHg) and standing postures (-10.3 mmHg), but not in supine posture (-1.8 mmHg). It is concluded that a change of posture contributes to blood pressure variability, and agreement between diastolic blood pressure in supine subjects, as recorded by an ambulatory monitor and a standard device, does not necessarily mean agreement in standing (or sitting) subjects.     

Temporal enhancement of renin-aldosterone blockade by enalapril, an angiotensin-converting enzyme inhibitor

Interruption of the renin-aldosterone system with angiotensin-converting enzyme inhibitors (CEI) should result in a low aldosterone secretion, but most investigators have measured aldosterone production only indirectly by plasma aldosterone (PA) levels or urinary metabolites. We evaluated the effects of CEI of the aldosterone secretion rate (ASR) and compared them with PA, urinary tetrahydroaldosterone (THA), plasma renin activity (PRA), and electrolyte balance in six normotensive subjects in a metabolic unit during a control period (5 days) and during administration of 10 mg/day enalapril for 28 days. Our results demonstrated that (1) the ASR did not decline until after 1 wk of CEI therapy and this was reflected by a corresponding decline in the urine potassium:sodium ratio, (2) upright PA levels at day 1 declined, but supine PA levels were unchanged, (3) THA excretion remained essentially unchanged and the THA:ASR ratio rose progressively during therapy, (4) PRA rose and was maximal on day 3, but subsequently declined. In conclusion, enalapril-induced hypoaldosteronism required several days to become demonstrable and this was not accurately assessed by PA or THA--possibly due, in part, to altered aldosterone metabolism. The simultaneous decline in both PRA and ASR could be due to a decrease in renin substrate. Caution is therefore warranted when assessing aldosterone secretion indirectly by either PA levels or urinary metabolites during CEI therapy.     

Targeting of captopril to the kidney reduces renal angiotensin-converting enzyme activity without affecting systemic blood pressure

We have synthesized a prodrug of the angiotensin-converting enzyme (ACE) inhibitor captopril by coupling this drug covalently to the low molecular weight protein (LMWP) lysozyme. Such drug-LMWP conjugates can be used for renal drug delivery, since LMWPs accumulate specifically in the proximal tubular cells of the kidney. In the present study, we compared the effects of captopril-lysozyme and free captopril in male Wistar rats. ACE activity in plasma and the kidney was measured after intravenous bolus injection of either the captopril-lysozyme conjugate (33 mg. kg(-1), corresponding to 0.2 mg. kg(-1) captopril) or equivalent dosages of free captopril and lysozyme. The administration of the captopril-lysozyme conjugate resulted in less plasma ACE inhibition and a longer-lasting renal ACE inhibition compared with the free drug. Effects on blood pressure and natriuresis were studied during intravenous infusion of captopril-lysozyme (275 mg. kg(-1). 6 h(-1) conjugate, corresponding to 5 mg. kg(-1). 6 h(-1) captopril) or an equimolar dosage of free captopril. Captopril-lysozyme did not affect systemic blood pressure, whereas free captopril lowered blood pressure significantly (-23 +/- 32% versus control after 6 h). Captopril-lysozyme increased natriuresis about 3-fold compared with control levels (260 +/- 32% after 6 h), whereas free captopril treatment resulted in a reduced sodium excretion (26 +/- 12%). Furthermore, captopril at a lower dose, which only moderately lowered blood pressure, showed an increased sodium excretion. We conclude that renal delivery of captopril using captopril-lysozyme results in reduced systemic activity and increased kidney-specific activity of the targeted drug.