Dissociation of hypotensive and renal hemodynamic effects of an angiotensin converting enzyme inhibitor in insulin-dependent diabetic patients with incipient nephropathy

The mechanism of action of angiotensin converting enzyme (ACE) inhibitors on urinary albumin excretion (UAE) in diabetics is controversial. In order to dissociate the hypotensive and intrarenal effects, 16 insulin-dependant diabetics with permanent microalbuminuria (30-300 mg/24 h) without hypertension were given Ramipril, a long acting ACE inhibitor, at hypotensive (treatment A 5 mg/day; N = 8) and at sub-hypotensive doses (treatment B, 1.25 mg/day; N = 8) over a 6 week period in parallel double-blind study. Blood pressure, UAE, glomerular filtration renal blood flow (continuous 125I-Iodothalamate + 131I-Hippurate infusion) and converting enzyme activity (Liebermann's method), before and after treatment. In treatment group A, the blood pressure fell from 133 +/- 5/79 +/- 4 (mean +/- SE) to 125 +/- 4/77 +/- 2 mmHg (p less than 0.05 for systolic blood pressure) whereas it remained stable in treatment group B (132 +/- 7/79 +/- 4 to 128 +/- 5/80 +/- 4 mmHg). The UAE decreased in both groups: group A from an average of 74 (40-198) to 47 (5-202) mg/24 h (p = 0.07; group B, from an average of 77 (50-136) to 19 (15-120) mg/24 h (p less than 0.005), as did ACE activity: group A from 332 +/- 44 to 163 +/- 33 iu/l (p less than 0.004), group B from 423 +/- 39 to 191 +/- 28 iu/l (p less than 10-4).(ABSTRACT TRUNCATED AT 250 WORDS)     

Mineralocorticoid receptor blockade in addition to angiotensin converting enzyme inhibitor or angiotensin II receptor blocker treatment: An emerging paradigm in diabetic nephropathy: A systematic review

Blockade of the renin–angiotensin–aldosterone system (RAAS) is a standard therapeutic intervention in diabetic patients with chronic kidney disease (CKD). Concomitant mineralocorticoid receptor blockade has been studied as a novel approach to further slow down CKD progression.We used PubMed and EMBASE databases to search for relevant literature. We included in our review eight studies in patients of at least 18 years of age, with a diagnosis of type 1 or type 2 diabetes mellitus and diabetic nephropathy, under an angiotensin converting enzyme inhibitor (ACEI) and/or an angiotensin II receptor blocker (ARB) as standard treatment. A subset of patients in each study also received a mineralocorticoid receptor blocker (MRB) (either spironolactone or eplerenone) in addition to standard treatment.Combined treatment with a mineralocorticoid receptor blocker further reduced albuminuria by 23 to 61% compared with standard treatment. Estimated glomerular filtration rate values upon study completion slightly decreased under combined treatment. Blood pressure levels upon study completion were significantly lower with combined treatment in three studies. Hyperkalemia prevalence increased in patients under combined treatment raising dropout rate up to 17%.Therefore, combined treatment by an ACEI/ARB and a MRB may further decrease albuminuria in diabetic nephropathy. This effect may be due to the specific properties of the MRB treatment. Clinicians should regularly check potassium levels because of the increased risk of hyperkalemia. Available evidence should be confirmed by an adequately powered comparative trial of the standard treatment (ACEI or ARB) versus combined treatment by an ACEI/ARB and a MRB.     

Polymorphisms in the gene encoding angiotensin I converting enzyme 2 and diabetic nephropathy

Aims/hypothesis Substantial evidence exists for the involvement of the renin–angiotensin system (RAS) in diabetic nephropathy. Angiotensin I converting enzyme 2 (ACE2), a new component of the RAS, has been implicated in kidney disease, hypertension and cardiac function. Based on this, the aim of the present study was to evaluate whether variations in ACE2 are associated with diabetic nephropathy.Materials and methods We used a cross-sectional, case–control study design to investigate 823 Finnish type 1 diabetic patients (365 with and 458 without nephropathy). Five single-nucleotide polymorphisms (SNPs) were genotyped using TaqMan technology. Haplotypes were estimated using PHASE software, and haplotype frequency differences were analysed using a ²-test-based tool.Results None of the ACE2 polymorphisms was associated with diabetic nephropathy, and this finding was supported by the haplotype analysis. The ACE2 polymorphisms were not associated with blood pressure, BMI or HbA₁c.Conclusions/interpretation In Finnish type 1 diabetic patients, ACE2 polymorphisms are not associated with diabetic nephropathy or any studied risk factor for this complication. Further studies are necessary to assess a minor effect of ACE2.Electronic Supplementary Material Supplementary material is available for this article at .     

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。     

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.     

First dose hypotension after angiotensin converting enzyme inhibitor captopril and angiotensin II blocker losartan in patients with acute myocardial infarction

BACKGROUND: First dose hypotension after the administration of an angiotensin-converting enzyme inhibitor in patients with acute myocardial infarction is one of the most important adverse events of this type of treatment. There is no information about first dose hypotension after angiotensin type 1-receptor blocker in this type of patient. Aim: To compare the first dose responses to low dose captopril and losartan in patients with acute myocardial infarction. METHODS: Single blind, randomised, multicentric, prospective study. Patients (n=320) with confirmed acute myocardial infarction, age >18 years, treated by direct percutaneous transluminal coronary angioplasty, thrombolysis and/or heparin, were randomised to receive a single dose of 6.25-12.5 mg captopril or 12.5-25 mg losartan within 24 h of hospital admission. Baseline laboratory and clinical examinations were performed before entering the study. Blood pressure monitoring started at hospital admission and continued for at least 8 h after the medication (second dose of captopril was given after 8 h). RESULTS: The maximal blood pressure fall appeared about 1 h after the first dose of captopril and 3.5 h after the first dose of losartan. Patients in the captopril group had significantly higher incidence of asymptomatic hypotension (38%) than patients treated with losartan (24%) (P<0.001). No difference in hypotension requiring a change in medication was observed. CONCLUSION: Low dose of losartan is safe for initiating therapy in patients with acute myocardial infarction within 24 h of hospital admission.     

血管紧张素转化酶抑制剂对糖尿病肾病早期肾小管功能的保护作用研究

目的探讨血管紧张素转化酶抑制剂（ACEI）对肾小管功能的保护作用。方法选择142例2型糖尿病合并高血压的患者，按治疗方法不同分A组（降糖的同时口服ACEI类降压药）和B组（降糖的同时口服非ACEI类降压药），检测各组尿N-乙酰-β-葡萄糖苷酶（NAG）、视黄醇结合蛋白（RBP）、α1微球蛋白（α1-MG）、IV胶原（CIV）水平，并进行统计学分析。结果组尿微量白蛋白排泄明显低于B组（P〈0．05）；肾小管功能指标中尿RBP明显低于B组（P〈0．05），而NAG、α1—MG、CIV差异无显著性意义（P〉0．05）。结论ACEI能明显减少糖尿病肾病患者尿白蛋白的排泄，而且对糖尿病肾病患者的肾小管功能有保护作用，糖尿病患者应提前使用ACEI类降压药。     

Unmasking of the hypotensive effect of nifedipine in normotensives by addition of the angiotensin converting enzyme inhibitor benazepril.

OBJECTIVE: To study the pharmacological interaction between a dihydropyridine derivative (nifedipine slow release 20 mg) and inhibition of the renin-angiotensin system (benazepril 10 mg). DESIGN: Single application at intervals of 2 weeks in an open-label three-way cross-over design. SETTING: Institutional pharmacological unit. PARTICIPANTS: Nine healthy male volunteers. MAIN OUTCOME MEASURES(S): Blood pressure and heart rate were recorded in the supine position for 24 h as well as plasma drug levels, plasma angiotensin converting enzyme activity and active plasma renin concentration. RESULTS: Nifedipine increased active plasma renin two-fold and benazepril increased it five-fold. The combination of the two drugs accelerated the increase of active renin during the first 2 h after drug intake. Whereas no hypertensive effect could be detected after nifedipine or benazepril alone, a significant fall in systolic and diastolic blood pressure was observed for up to 9 to 12 h after the combination. The increase in heart rate induced by nifedipine was minimized by the addition of benazepril. There was no interaction between the pharmacokinetics of benazeprilate and nifedipine which would explain these pharmacodynamic effects. CONCLUSION: These results demonstrate that, in normotensive volunteers, the renin-angiotensin system contributes to mask the hypotensive effect of a single oral dose of dihydropiridine. The concomitant administration of a converting enzyme inhibitor discloses the hypotensive effect and limits the baroreflex-mediated increase in heart rate secondary to vasodilation.     

Selection of the dose of angiotensin converting enzyme inhibitor for patients with diabetic nephropathy depends on the presence or absence of left ventricular hypertrophy.

The coexistence of hypertension increases cardiovascular risks and the rate of deterioration of renal function for diabetic patients. For patients with left ventricular hypertrophy (LVH), the use of an angiotensin converting enzyme (ACE) inhibitor is known to be effective and well tolerated and to be protective against chronic renal insufficiency (CRI). However, serious adverse reactions to ACE inhibitors, such as the rapid deterioration of renal function, have been reported, making physicians hesitant to use these agents. To resolve this dilemma, we compared changes in renal function and left ventricular function and the safety and effectiveness of benazepril, an ACE inhibitor, in patients with diabetic nephropathy, with or without LVH. The age, sex, duration of diabetes, levels of blood pressure and blood glucose and rates of creatinine clearance (CrCl) were compared between 36 diabetic patients with LVH and 36 matched diabetic patients without LVH. The rates of CrCl in all patients were between 14 and 35 ml/min, and all patients received an ACE inhibitor before enrollment. The group comprised 43 men and 29 women, with a mean age of 56 +/- 4 years. These patients were divided into three groups, each of which was subdivided into a group with and a group without LVH. Group I (without LVH) or I-L (with LVH) received a half dose of benazepril (2.5 mg daily), Group II (without LVH) or II-L (with LVH) received a normal daily dose of 5 mg benazepril, and Group III (without LVH) or III-L (with LVH) discontinued the administration of the ACE inhibitor. The follow-up period was 1 year and, during the study, blood pressure was maintained at less than 140/90 mmHg. If the blood pressure control was not satisfactory, benidipine, a calcium antagonist, and/or furosemide, a loop diuretic, and/or guanabenz, a central acting antihypertensive agent, were administered. In the diabetic patients with LVH, the administration of a normal dose of benazepril inhibited the decline of renal function and cardiac function (CrCl: 24.2 +/- 1.5 to 22.0 +/- 2.5 ml/min; EF (ejection fraction): 56 +/- 3 to 54 +/- 6%) compared to the other two groups. In patients without LVH, a half dose of benazepril preserved renal function (23.4 +/- 2.6 to 22.0 +/- 3.1 ml/min; EF: 54 +/- 3 to 56 +/- 3%). Discontinuation of the administration of ACE inhibitor led to the further progression of renal dysfunction and decreases in EF in patients with or without LVH. Our results provide some indications for the use of ACE inhibitors in diabetic patients when renal dysfunction and/or cardiac hypertrophy are present.     

Angiotensin converting enzyme genotype influences the response to the angiotensin II receptor antagonist losartan in patients with hypertension.

To examine whether the response to the angiotensin II receptor antagonist losartan varies depending on the angiotensin converting enzyme (ACE) genotype, we prospectively studied the effect of losartan in 42 hypertensive patients (20 men, 22 women; mean age: 60.4 years). After a 4-week observation period, losartan was administered at 50 mg/day and blood pressure was measured every 2 to 4 weeks for 12 weeks. Among the 42 patients, 19, 11, and 12, respectively, had the II, ID, and DD ACE genotypes. The baseline plasma ACE activity in patients with the ID or DD genotype was significantly higher than that in patients with the II genotype (13.8 +/- 4.2 vs. 9.6 +/- 2.3 IU/l; p = 0.0002). However, age, gender, baseline systolic and diastolic blood pressure (SBP/DBP), and body mass index (BMI) were not different among the groups. After 12 weeks of treatment with losartan alone, DBP in the ID+DD group was significantly higher than that in the II group (85.0 +/- 9.0 vs. 77.8 +/- 9.6 mmHg, p = 0.018), while the percent reduction in DBP in the ID+DD group was significantly smaller than that in the II group (7.9 +/- 8.8 vs. 14.3 +/- 10.1%, p = 0.035). Multiple regression analysis showed that the significant predictors of the DBP at 12 weeks were age (p = 0.030), ACE genotype (p = 0.029) and baseline DBP (p = 0.0001). The ACE genotype may be a determinant of the response to losartan in hypertensive patients.     

Renoprotective effects of low-dose valsartan in type 2 diabetic patients with diabetic nephropathy

It is unknown whether the angiotensin receptor antagonist valsartan exerts a renoprotective effect on patients with type 2 diabetes and diabetic nephropathy independent of its hypotensive effects. Forty patients with type 2 diabetes participated in this study. All patients received valsartan 40 mg, a dose with no clinical effect on blood pressure levels. Blood pressure, urinary albumin excretion (UAE), and creatinine clearance were determined at baseline and at the end of the 6-month treatment period. Antihypertensive and/or antidiabetic drugs, including insulin, were permitted throughout the study. After 6 months of valsartan therapy, mean UAE decreased from 86.8 +/- 196 to 46.9 +/- 97 microg/min (n = 37). In addition, a significant decrease was observed in the UAE of the subgroup of patients displaying diabetic nephropathy (UAE > 20 microg/min, n = 14), from 219.4 +/- 275 to 102.7 +/- 141 microg/min, (P < 0.01). Changes in UAE for valsartan correlated significantly with UAE at baseline (r = -0.935, P < 0.0001). Serum creatinine levels and creatinine clearance remained stable before and after treatment with valsartan. No significant differences were observed between pre- and post-treatment body mass index, glycosylated hemoglobin, or systolic and diastolic blood pressure. In type 2 diabetic patients with diabetic nephropathy, 6 months of treatment with low dose valsartan, an angiotensin-II receptor antagonist, thus reduced UAE with no reduction in systemic blood pressure. The drug may be safely administered in this subset of type 2 diabetic patients. The long-term benefits in terms of risk reduction must still be evaluated in further trials.     

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)     

Renoprotective effect of diltiazem in hypertensive type 2 diabetic patients with persistent microalbuminuria despite ACE inhibitor treatment

The aim of the study was to evaluate the effects of the non-dihydropyridine calcium antagonist (NDCA) diltiazem on the development of urinary albumin excretion (UAE) in type 2 hypertensive diabetic patients with persistent microalbuminuria despite ACE inhibitor treatment. Thirty-six type 2 diabetic hypertensive patients with microalbuminuria persisting after at least 1 year of treatment with ACE inhibitors were randomized to receive captopril (n=22) or combined therapy with captopril and 120 mg diltiazem (n=14) for 2 years. Captopril dose was individualized according to blood pressure. Changes in UAE, blood pressure, and metabolic control were monitored to analyze the influence of the addition of diltiazem on progression of diabetic nephropathy. In patients treated with captopril and diltiazem, absolute UAE did not change during the study (baseline: 101 mg/24 h, range 39-298; 2 years after randomization: 74 mg/24 h, range 12-665). In contrast, UAE increased in patients treated with captopril monotherapy (baseline: 118 mg/24 h, range 32-282; 2 years after randomization: 164 mg/24 h, range 15-1161, p<0.05). In addition, fewer patients in the captopril/diltiazem group progressed to macroalbuminuria (eight patients in captopril group and one in captopril/diltiazem group, p<0.05). The beneficial effects of the addition of diltiazem were independent of blood pressure and metabolic control. We suggest that the combination of ACE inhibitors and NDCA should be considered in type 2 microalbuminuric patients at high risk for progression to established diabetic nephropathy.     

Long-term treatment of chronic heart failure by an inhibitor of angiotensin converting enzyme

We studied the hemodynamic, echocardiographic, phonomechanographic and hormonal changes during acute (25 mg) and chronic (6 months--75 to 225 mg/day) treatment of 10 patients with congestive cardiac failure due to cardiomyopathy with dilatation with SQ 14 225 (Captopril). The following changes were observed after the single dose: an increase in cardiac output (p less than 0,001), in stroke volume (p less than 0,01), a reduction in heart rate (p less than 0,01), in peripheral resistance (p less than 0,001) and pulmonary capillary pressure (p less than 0,001). There were no significant changes in end systolic or end diastolic left ventricular internal diameter. Plasma renin activity increased (p less than 0,001); there was a concurrent fall in serum aldosterone (NS): the plasma concentration of converting enzyme decreased (p less than 0,001). There was a correlation between the increase in peripheral resistance under basal conditions and the basal plasma renin activity (R = 0,72, p less than 0,02). The decrease in peripheral resistance after captopril also correlated with basal plasma renin activity (R = 0,89, p less than 0,01). After six months continuous therapy, the hemodynamic effect was sustained and was accompanied by a significant symptomatic improvement. Left ventricular internal end systolic and end diastolic diameters decreased (p less than 0,01 and p less than 0,01 respectively). The pre-ejectional period decreased (p less than 0,05). Serum aldosterone fell significantly (p less than 0,001) as did plasma renin activity (p less than 0,01); the serum level of converting enzyme remained low with respect to its initial value. These results show that captopril may be useful in severe cardiac failure without tolerance during long-term administration. No renal or hematological toxicity was observed in this group of patients.     

慢性心力衰竭治疗中血管紧张素转换酶抑制剂的应用

慢性心力衰竭传统的治疗主要是针对心脏的血流动力学异常,采用“强心、利尿、扩血管”的治疗方案。然而大规模、多中心、随机双盲、安慰剂对照的临床试验结果却表明正性肌力药和单纯的血管扩张剂虽可产生短期的血流动力学效应,但长期治疗却增加病死率和病残率。随着对“心室重构是心衰发生、发展机制”认识的逐步深入,以及神经内分泌拮抗剂——血管紧张素转换酶抑制剂(ACEI)和β-受体阻滞剂等成功地降低心     

Successful treatment of severe hypertension with the combination of angiotensin converting enzyme inhibitor and angiotensin II receptor blocker.

Three patients who suffered from congestive heart failure caused by severe hypertension were treated with a combination therapy consisting of angiotensin converting enzyme inhibitor (ACEI) and angiotensin II receptor blocker (ARB). Before initiation of treatment, all three patients showed elevations of serum creatinine concentration (sCr), plasma renin activity (PRA), and plasma aldosterone concentration (PAC), which indicated insufficient blood supply to the kidney during exacerbation of hypertension. All three cases successfully recovered from hypertensive heart failure with the combination therapy. sCr gradually decreased during continuation of the therapy, although one patient showed an increase in sCr at an early stage of the combination therapy. Blockade of the renin-angiotensin-aldosterone system (RAAS) by the combination of ACEI and ARB was well tolerated in patients with severe hypertension with renal damage and showed a beneficial effect in protecting against further renal damage. This result suggests that combination therapy with ACEI and ARB should be considered as a candidate treatment in cases of severe hypertension.     

血管紧张素转换酶抑制剂对2型糖尿病患者肾小球高滤过的影响

2型糖尿病患者早期存在肾小球高滤过 (ＨＧＦＲ) 〔1,2〕。血管紧张素转换酶抑制剂 (ＡＣＥＩ)能使糖尿病肾病 (ＤＮ)患者的全身血压和肾小球毛细血管内压降低 ,从而延缓ＤＮ的进展。但ＡＣＥＩ对正常白蛋白尿排泄率 (ＵＡＥＲ)伴ＨＧＦＲ的 2型糖尿病患者研究却报告甚少。本研究对新诊断的 30例 2型糖尿病伴ＨＧＦＲ的患者进行为期 14个月的随机、双盲、安慰剂对照研究 ,以观察ＡＣＥＩ对其肾功能的影响。现将结果报告如下。一、对象和方法1.研究对象 :2型糖尿病患者 30例 (男 2 2 ,女 8) ,平均年龄 48岁 (30～ 6 0岁 )。入选要求 :(1)肾小…     

Combined treatment of severe essential hypertension with the new angiotensin converting enzyme inhibitor ramipril

Ramipril is a newly synthesized angiotensin converting enzyme inhibitor without a sulfhydryl group in the molecule but with a prolonged duration of action. Efficacy, tolerance and safety of this drug were evaluated in 10 patients with severe essential hypertension. After a treatment period of at least 4 weeks with the conventional antihypertensive drug combination of a diuretic and a beta-blocking agent with the vasodilator dihydralazine, their systolic and diastolic blood pressures averaged 161 +/- 6 and 111 +/- 2 mm Hg, respectively. Because diastolic blood pressure during this drug regimen was still greater than 105 mm Hg in all patients, the patients received ramipril initially at single daily doses of 5 mg in addition to their previous medication. The first dose of 5 mg ramipril resulted in a moderate but significant decrease in systolic and diastolic blood pressure in 9 of the 10 patients to 142 +/- 5 and 104 +/- 4 mm Hg (p less than 0.01), respectively, between 3 and 6 hours after drug administration. In 1 patient blood pressure was unresponsive to ramipril and 1 patient complained of nausea and vomiting within the first week of treatment with ramipril. Within the following 8-week treatment period with a once-daily intake of 5 or, if necessary, 10 mg of ramipril, diastolic blood pressure normalized in the remaining 8 patients to less than 90 mm Hg. Systolic and diastolic blood pressure averaged 130 +/- 5 and 83 +/- 2 mm Hg, respectively, at the end of the 8-week treatment period with ramipril. Severe hypotension and reflex tachycardia were not observed.(ABSTRACT TRUNCATED AT 250 WORDS)