Brief angiotensin converting enzyme inhibitor treatment in young spontaneously hypertensive rats reduces blood pressure long-term

Our study examines the long-term cardiovascular effects after a brief period of angiotensin converting enzyme (ACE) inhibitor treatment in young spontaneously hypertensive rats (SHR). SHR were treated with perindopril (3 mg/kg/day) by gavage from 2 to 6, from 6 to 10, or from 2 to 10 weeks of age. Systolic blood pressure was measured in the tail weekly until 25 weeks of age. Corresponding control groups received distilled water for the same periods. In each treatment group blood pressure was reduced significantly during treatment, rose when treatment stopped, but plateaued significantly below control SHR thereafter. This difference in blood pressure at 25 weeks of age was due to reduced total peripheral resistance as determined by microsphere methods, but plasma renin activity and angiotensin II concentrations were not different. Cardiac hypertrophy was also reduced in treated SHR. In a separate experiment, perindopril treatment from 6 to 10 weeks of age resulted in a significant reduction in the media/lumen ratios of mesenteric resistance vessels at 32 weeks of age. Concomitant administration of angiotensin II with perindopril from 6 to 10 weeks of age not only prevented the long-term effects on blood pressure seen with perindopril treatment alone but was associated with cardiovascular hypertrophy in excess of untreated control SHR. Finally, perindopril given for a shorter period (6 to 7 weeks) or later in life (20 to 24 weeks) had no significant long-term effects on blood pressure. These results demonstrate that a 4-week period of ACE inhibitor treatment in young SHR is sufficient to prevent the full expression of genetic hypertension and cardiovascular hypertrophy and that angiotensin II might be important in the development of hypertension in this model, its role in later life being less important.     

Angiotensin converting enzyme gene polymorphism predicts blood pressure response to angiotensin II receptor type 1 antagonist treatment in hypertensive patients

OBJECTIVES: To determine whether polymorphisms in the renin-angiotensin system can predict blood pressure-lowering response to antihypertensive treatment; more specifically, in response to treatment with irbesartan or atenolol. DESIGN AND METHODS: Eighty-six patients with hypertension were randomized to double-blind treatment with either the angiotensin II type 1 receptor antagonist irbesartan or the beta1 adrenergic receptor blocker atenolol and followed for 3 months. We analysed angiotensinogen T174M and M235T, angiotensin converting enzyme (ACE) I/D and angiotensin II type 1 receptor A1166C polymorphisms and related them to blood pressure reduction. RESULTS: The mean reductions in blood pressure were similar for both treatments. In the irbesartan group, individuals homozygous for the ACE gene I allele showed a greater reduction in diastolic blood pressure, exceeding those with the D allele (-18 +/- 11 SD versus -7 +/- 10 mmHg, P = 0.0096). This was not the case during treatment with atenolol, and the interaction term between type of treatment and ACE II genotype was significant (P = 0.0176). The angiotensinogen and angiotensin II type 1 receptor polymorhisms were not related to the response to treatment. CONCLUSIONS: ACE genotyping predicted the blood pressure-lowering response to antihypertensive treatment with irbesartan but not atenolol. Thus, specific genotypes might predict the response to specific antihypertensive treatment.     

Interaction between an angiotensin converting enzyme inhibitor, perindopril, and a thiazide diuretic in the spontaneously hypertensive rat.

Fifty adult male spontaneously hypertensive rats were randomly allocated to receive daily oral treatment with placebo, hydrochlorothiazide (HCTZ 10 mg/kg) and three different dosages of perindopril (S9490-30.1, 0.3 and 1 mg/kg) administered alone or in combination with HCTZ for two eight-day treatment periods separated by a therapeutic washout period of 13 days. Effect of order of treatment was evaluated in rats receiving perindopril plus HCTZ. Time course of changes in systolic blood pressure, heart rate, 24 h urine volume and urinary excretion of sodium, potassium and chloride were studied and compared for all groups. HCTZ alone and lower dosages of perindopril (0.1 mg/kg, 0.3 mg/kg) were ineffective in lowering elevated systolic blood pressure of the spontaneously hypertensive rat, and there were no significant intergroup differences in urine volume and electrolytes. However, antihypertensive efficacy of lower dosages of perindopril was significantly (P less than 0.01) enhanced when administered in combination with HCTZ. The combined treatment also induced significant (P less than 0.01) diuresis and urinary chloride excretion. No significant effect was seen in heart rate. The dose-effect relationship of the combination confirmed the existence of synergistic antihypertensive action between HCTZ and perindopril in the spontaneously hypertensive rat.     

Gonadectomy-induced reduction of antihypertensive action of angiotensin converting enzyme inhibitor and its role of central renin activity in spontaneously hypertensive rats]

Gonadectomy induced a significant retardation of systolic blood pressure (BP) in male and female spontaneously hypertensive rats (SHR). Captopril (5 mg/kg, i.p.), an angiotensin converting enzyme (ACE) inhibitor, significantly decreased BP in all groups, except that the antihypertensive action was significantly inhibited by gonadectomy in both sexes. The plasma ACE activity was increased in orchiectomized males, but this effect did not appear in females. Neither plasma renin activity nor its concentration were changed by gonadectomy in either sex. Aorta ACE activity was not changed by gonadectomy in either sex, while the renin activity was increased only in gonadectomized females. Diencephalon ACE activity was not changed by gonadectomy in either sex, but the renin activity was decreased in these groups. These results suggested that the decrease of BP by gonadectomy in both sexes SHR was closely related to the decrease of renin activity in diencephalon by androgen deprivation with gonadectomy.     

Diurnal monitoring of blood pressure and the renin-angiotensin system in hypertensive patients on long-term angiotensin converting enzyme inhibition

The temporal blood pressure course and the diurnal profile of the renin-angiotensin system were examined in 13 patients with essential hypertension receiving hydrochlorothiazide and enalapril once daily. Blood samples were taken and blood pressure was measured before the habitual morning dose of hydrochlorothiazide and enalapril (at 8.00 a.m.) and at seven time points over the next 24 h. During the period of maximal effect of enalapril (from 11.00 a.m. to 2.00 p.m.), the increase in plasma renin concentration ranged from no change to an 800% increase. A negative correlation was observed between an increase in plasma renin and a decrease in immunoreactive plasma angiotensin II concentration (Spearman rank-order correlation coefficient = 0.83). Notably, the greatest changes in plasma renin and angiotensin II concentrations after enalapril were seen in those patients whose blood pressure fell most during the day. We conclude that hypertensive patients on long-term therapy with enalapril once daily vary widely in their between-dose biochemical response to the drug, and that there is a significant association between the responsiveness of the plasma renin-angiotensin system and the effect on 24 h blood pressure.     

Valsartan, a new angiotensin II antagonist; blood pressure reduction in essential hypertension compared with an angiotensin converting enzyme inhibitor, enalapril

OBJECTIVE: To compare the blood pressure reduction induced by valsartan, a new angiotensin II receptor antagonist, with that induced by enalapril, an angiotensin converting enzyme (ACE) inhibitor in essential hypertension. METHODS: In total 189 adult outpatients with uncomplicated essential hypertension participated in this double-blind study. Patients were allocated randomly in equal numbers to be administered 80 mg valsartan or 20 mg enalapril daily for 12 weeks. Patients whose blood pressure had not been controlled adequately despite 8 weeks of monotherapy were administered additional therapy with 12.5 mg hydroclorothiazide (HCTZ) daily thereafter. Patients were assessed aftger 4, 8 and 12 weeks of therapy. The primary efficacy variable was the change from baseline in mean sitting diastolic blood pressure (SDBP) after 8 weeks of therapy. Other variables analyzed included the change in sitting systolic blood pressure and percentage responses after 8 weeks of therapy. RESULTS: Valsartan and enalapril were both effective at lowering the blood pressure. Similar falls were induced in the two groups with a similar time course of blood pressure reduction. The mean decreases in SDBP after 8 weeks of therapy were 13.2 mmHg for valsartan and 12.0 mmHg for enalapril. There was no significant difference between the treatments [P = 0.475, 95% confidence interval of the estimated difference (SBP after therapy - SDBP before therapy) -3.5 to 1.6 mmHg]. After 8 weeks of therapy 60.6% had responded to valsartan and 52.6% to enalapril (P = 0.267). Both treatments were tolerated well. Three patients administered enalapril and one patient administered valsartan discontinued their treatment because it made them cough. CONCLUSION: The data show that 80 mg valsartan is as effective as 20 mg enalapril in the treatment of moderate hypertension and that it is tolerated well.     

Gender difference in the response to an angiotensin-converting enzyme inhibitor and a diuretic in hypertensive patients of African descent

BACKGROUND: The efficacy of angiotensin-converting enzyme (ACE) inhibitors in decreasing blood pressure in African patients is controversial. OBJECTIVE: We examined the ambulatory blood pressure (ABP) response to a diuretic and an ACE inhibitor in hypertensive patients of East African descent and evaluated the individual characteristics that determined treatment efficacy. DESIGN: A single-blind randomized AB/BA crossover design. SETTING: Hypertensive families of East African descent from the general population in the Seychelles. PARTICIPANTS: Fifty-two (29 men and 23 women) out of 62 eligible hypertensive patients were included.Main outcome measures ABP response to 20 mg lisinopril (LIS) daily and 25 mg hydrochlorothiazide (HCT) daily given for a 4-week period.Results The daytime systolic/diastolic ABP response to HCT was 4.9 [95% confidence interval (CI) 1.2-8.6]/3.6 (1.0-6.2) mmHg for men and 12.9 (9.2-16.6)/6.3 (3.7-8.8) mmHg for women. With LIS the response was 18.8 (15.0-22.5)/14.6 (12.0-17.1) mmHg for men and 12.4 (8.7-16.2)/7.7 (5.1-10.2) mmHg for women. The night-time systolic/diastolic response to HCT was 5.0 (0.6-9.4)/2.7 [(-0.4)-5.7] mmHg for men and 11.5 (7.1-16.0)/5.7 (2.6-8.8) mmHg for women, and to LIS was 18.7 (14.2-22.1)/15.4 (12.4-18.5) mmHg for men and 3.5 [(-1.0)-7.9]/2.3 [(-0.8)-5.4] mmHg for women. Linear regression analyses showed that gender is an independent predictor of the ABP responses to HCT and to LIS. CONCLUSIONS: Hypertensive patients of African descent responded better to LIS than to HCT. Men responded better to LIS than to HCT and women responded similarly to both drugs.     

血管紧张素转换酶基因多态性和动态血压关联性的初步探讨

探讨血压和位于人染色体１７ｑ２３的血管紧张素转换酶（ＡＣＥ）基因第１６内含子的一个２８７片段的插入／缺失多态性的关联性。在６０例６０岁以上的高血压病患者中，测量了偶测血压（ＣＢＰ）和动态血压（ＡＢＰ）；观察三种基因型之间的血压差异。结果显示：在三种基因型之间，未发现ＣＢＰ的明显差异（Ｐ＞０．０５），然而，其间的多个２４小时动态血压参数之间存在明显的不同（Ｐ＜０．０５）。本研究提示：ＡＣＥ基因的Ｉ／Ｄ多态性对血压有影响；ＡＢＰ较ＣＢＰ敏感。     

First dose response and 24-hour antihypertensive efficacy of the new once-daily angiotensin converting enzyme inhibitor, ramipril

The reduction in blood pressure (BP) after the first dose and after 8 weeks of treatment with a new once-daily angiotensin converting enzyme (ACE) inhibitor, ramipril, was examined in 12 untreated hypertensive patients, using ambulatory intraarterial BP monitoring. The first period of monitoring began 24 hours before the first dose was given, and continued for 24 hours afterwards. A second 24-hour period of monitoring was carried out after 8 weeks of treatment, commencing immediately after the morning dose. Angiotensin II levels and serum drug levels were measured at 0, 2, 6 and 24 hours after the acute dose. BP decreased progressively from the first hour after the first dose, reached a maximum in the fifth hour (p less than 0.001) and then the effect diminished. The maximum reduction of systolic BP in any patient was 64 mm Hg, the minimum 4 mm Hg. Blood pressure was significantly (p less than 0.05) reduced throughout the 24 hours after dosing, with a mean daytime reduction of 13/12 mm Hg, and a mean nighttime reduction of 15/7 mm Hg. Angiotensin II levels were significantly (p less than 0.02) and maximally reduced by 2 hours after administration, but the reduction was no longer significant after 24 hours. Serum drug levels were also maximal 2 hours after administration. The trial population could be clearly divided into groups of good and poor responders on the basis of BP reduction. The angiotensin II levels were higher before treatment, and decreased further, in all patients with a good response than in those with a poor response.(ABSTRACT TRUNCATED AT 250 WORDS)     

Beta-blocker versus diuretic for control of the blood pressure response to stress in hypertensive patients

To compare the antihypertensive effects of beta-blockers and diuretics on the blood pressure increase to stress, a randomized single-blind crossover study was performed in 27 patients with mild or moderate hypertension. At the initial examination and after two subsequent periods of therapy with 100 mg atenolol or with a combination of 50 mg hydrochlorothiazide and 5 mg amiloride hydrochloride, once a day, blood pressure and heart rate were measured at rest, during mental arithmetic, sustained handgrip and cycloergometric test. Both treatment significantly decreased supine and standing systolic and diastolic pressure at rest, during and immediately after mental stress and isometric exercise, with the reduction of diastolic pressure significantly greater after atenolol. During dynamic exercise, systolic and diastolic pressures were significantly decreased by diuretics at the lowest work-load only, whereas beta-blocker caused significant and greater blood pressure reductions throughout the exercise. The combination of two classes of drug normalized resting blood pressure in 8 of 9 subjects in which the monotherapy had failed to obtain values less than 140/90 mmHg and gave a better control of systolic and diastolic pressures throughout all the stress tests. It is concluded that atenolol is more effective than diuretics during stress, suggesting that beta-blocking drugs are the first choice treatment for mild to moderate hypertension and that when the antihypertensive effect of a single agent is insufficient, a combination of beta-blockers and diuretics is also effective during stress.     

Effect of losartan on nocturnal blood pressure in patients with stroke: comparison with angiotensin converting enzyme inhibitor

BACKGROUND: Treatment of nocturnal hypertension has been reported to be beneficial for primary and secondary prevention of stroke. We compared the effects of angiotensin II antagonist (losartan) and angiotensin converting enzyme inhibitor (quinapril) on nocturnal blood pressure (BP) and sympathetic nervous activity in patients with hypertension and stroke. METHODS: According to a prospective, randomized, cross-over design, 30 hypertensive patients with a previous history of stroke (25 hemorrhage, 5 infarction) were assigned randomly to receive losartan (50 mg) or quinapril (10 mg) once daily for 4 weeks. The patients were switched to the alternative regimen for an additional 4-week period. In the last week of each treatment, 24-h ambulatory BP monitoring was performed every 30 min, and 24-h urine was collected for the measurement of catecholamine. RESULTS: Neither systolic nor diastolic BP during daytime differed between losartan and quinapril treatments, but those during nighttime were lower with losartan treatment than with quinapril treatment. The nocturnal decreases in systolic and diastolic BP were both greater with losartan treatment than with quinapril treatment (systolic BP: 6.1% +/- 5.9% v 2.5% +/- 6.9%, diastolic BP: 6.4% +/- 6.5% v 3.3% +/- 7.8%, both P <.05). The nocturnal decrease in urinary norepinephrine excretion was greater with losartan treatment than with quinapril treatment (52.8% +/- 9.7% v 42.8% +/- 17.2%, P <.05). CONCLUSIONS: Losartan enhances the nocturnal decrease in ambulatory BP compared with that of quinapril in patients with a previous history of stroke presumably by way of the suppression of nocturnal sympathetic nervous activity.     

Angiotensin-converting enzyme gene polymorphism predicts the time-course of blood pressure response to angiotensin converting enzyme inhibition in the AASK trial

OBJECTIVE: It has yet to be determined whether genotyping at the angiotensin-converting enzyme (ACE) locus is predictive of blood pressure response to an ACE inhibitor. METHODS: Participants from the African American Study of Kidney Disease and Hypertension trial randomized to the ACE inhibitor ramipril (n = 347) were genotyped at three polymorphisms on ACE, just downstream from the ACE insertion/deletion polymorphism (Ins/Del): G12269A, C17888T, and G20037A. Time to reach target mean arterial pressure (相似文献   

Effects of angiotensin I converting enzyme inhibitor (SQ 14,225) on the responses of blood pressure and steroid hormone to angiotensin II and ACTH infusion in hypertensive subjects

The effects of the converting enzyme inhibitor, SQ 14,225, on the renin-angiotensin system, adrenal function and blood pressure were investigated in 14 hypertensive patients, i.e., 10 with essential hypertension (EH) and 4 with renovascular hypertension (RVH). The mean blood pressure (MBP) and plasma aldosterone showed significant decreases in the EH with normal renin (NR) group and in the RVH group but no significant changes in the EH with low renin (LR) group. Plasma renin activity (PRA) increased significantly in the EH and NR group and in the RVH group but showed no significant change in the EH with LR group. Significant correlations were found between the fall in MBP after SQ 14,225 treatment and the pretreatment levels of PRA or plasma aldosterone. In an ACTH infusion study, the response of plasma aldosterone to ACTH revealed significant decreases after SQ 14,225 administration. In an angiotensin II (A II) infusion study, the response of plasma aldosterone was unchanged after SQ 14,225 administration. However, the pressor responses to A II infusion with SQ 14,225 were significantly higher than those without SQ 14,225. From these findings, it is concluded that the antihypertensive mechanism of SQ 14,225 may be due mainly to the decrease in levels of endogenous A II and that the reduction in plasma aldosterone after SQ 14,225 were significantly higher than those without SQ 14,225. From these findings, it is concluded that the antihypertensive mechanism of SQ 14,225 administration may be due to reduction of endogenous A II levels by converting enzyme inhibition.     

Effects of nabumetone,celecoxib, and ibuprofen on blood pressure control in hypertensive patients on angiotensin converting enzyme inhibitors

Nonsteroidal anti-inflammatory drugs interfere with certain antihypertensive therapies. In a double-blind study, 385 hypertensive patients stabilized on an angiotensin converting enzyme inhibitor were treated with nabumetone, celecoxib, ibuprofen, or placebo for 4 weeks. Ibuprofen caused significantly greater increases in systolic (P < .001) and diastolic (P < .01) blood pressures (BPs) compared to placebo, but not nabumetone or celecoxib. The proportion of patients with systolic BP increases of clinical concern at end point was significantly higher (P < .001) for the ibuprofen group (16.7%; 15 of 90), but not for the nabumetone group (5.5%; 5 of 91) or the celecoxib group (4.6%; 4 of 87) compared to the placebo group (1.1%; 1 of 91).     

心房颤动患者心房组织的血管紧张素转换酶2表达及血管紧张素转换酶抑制剂干预的影响

目的 探讨心房颤动（房颤）患者心房肌组织中血管紧张素转换酶2（ACE2）的表达和血管紧张素转换酶抑制剂（ACEI）干预的影响及可能的信号传导途径。方法 选取接受开胸手术的风湿性心脏病患者47例,手术中取右心耳处心房肌标本。采用RT-PCR法检测心房肌ACE2和ACEmRNA水平,采用Western blot法检测ACE、ACE2、细胞外信号调节激酶1／2（ERK1／2）和磷酸化的细胞外信号调节激酶1／2（pERK1／2）蛋白表达水平,应用放射免疫法检测心房肌组织血管紧张素Ⅱ（AngⅡ）水平。结果 与窦性心律组相比,持续性房颤组心房肌组织中ACE2表达显著减少（P〈0．05）,而ACE的表达和AngⅡ含量显著增加（P〈0．05）。ERK1／2的活化水平在持续性房颤组较窦性心律组明显增加（P〈0．05）。与持续性房颤组相比,ACEⅠ干预组ACE2表达水平显著增加（P〈0．01）,ERK1／2的活化水平显著降低（P〈0．05）,而ACE表达和AngⅡ含量差异无统计学意义。结论 房颤患者心房肌组织中ACE2表达下调,ACE／ACE2平衡失调;ACEⅠ对房颤的长期临床效应可能与其上调ACE2、抑制有丝分裂素激活蛋白激酶信号途径有关。     

Dry cough in the elderly patients treated with angiotensin converting enzyme inhibitor

Since dry cough has recently been recognized as a side effect of angiotensin converting enzyme (ACE) inhibitors employed in the treatment of hypertension or congestive heart failure, the incidence of dry cough in elderly patients receiving ACE inhibitors was investigated. There were 237 out-patients on either captopril, enalapril, or delapril, in August and November 1989. Questionnaires concerning dry cough and smoking were completed by 184 patients. Patients either less than 50 years of age, or with chronic pulmonary disease were excluded. The remaining 168 patients, 63 males, 105 females, with a mean age of 73 years were analyzed for the incidence of a dry cough in relation to age, sex, smoking, and type of drugs. The overall incidence of a dry cough was 21/168 (12.5%), 7/63 (11.1%) for males and 14/105 (13.3%) for females, and was less frequent with advancing age; in the 51-60 age group 4/11 (36.4%), in the 61-70 age group 5/39 (12.8%), in the 71-80 age group 9/75 (12.0%), in the 81-90 age group 3/40 (7.5%), in the 91- age group 0/3 (0%). Enalapril showed significantly higher incidence of dry cough than captopril (16/93, 17.2% vs 7/88, 8.0%, p less than 0.05). Delapril showed an incidence 4/11, 36.4%, however, 9 out of the 11 patients who were given delapril had had a history of a dry cough with captopril or enalapril, and in 4 out of these 9 patients the dry cough disappeared by replacement of captopril or enalapril by delapril.(ABSTRACT TRUNCATED AT 250 WORDS)