General well-being during treatment with different ACE-inhibitors: Two double-blind placebo-controlled cross-over studies in healthy volunteers

Summary Two randomised, double-blind, cross-over studies inhealthy volunteers given captopril 50 mg b. d. (n = 37; Study I) or enalapril 20 mg o. d. (n = 40; Study 2) and placebo for 2 weeks have been done to examine general well-being. Subjective experiences were evaluated using the standardised, Minor Symptoms Evaluation-profile (MSEP), which was completed during Run-in and on Days l, 4,7 and 14 in the morning.In comparison to placebo and the Run-in period, neither captopril nor enalapril affected the MSEP dimensions of Vitality, Contentment and Sleep. Captopril treatment was also assessed by applying the Quality of Life Clinical Questionnaire during Run-in and on Days 7 and 14. No improvement in the quality of life was demonstrated during treatment in comparison with the placebo or the Run-in period. Thus, no mood elevating effect of the ACE-inibitors captopril and enalapril was demonstrated in healthy volunteers.Cough, which is believed to be a common adverse effect of ACE-inhibitors, was no more frequent during the treatment with captopril or enalapril than with placebo.It is concluded, that short-term treatment with captopril or enalapril is not perceived differently by healthy volunteers than placebo or no treatment at all. Furthermore, the cough associated with ACE-inhibition may be dependent on the duration of treatment, and two weeks was apparently too short for it to emerge.     

Safety and tolerance of single oral doses of trandolapril (RU 44.570), a new angiotensin converting enzyme inhibitor

Summary The safety and tolerance of single oral doses of a new angiotensin converting enzyme (ACE) inhibitor, trandolapril have been examined in 90 healthy male volunteers, in a randomised, double blind, placebo-controlled study. The subjects were divided into 10 groups, each of 9 subjects and treatments (6 subjects on trandolapril and 3 on placebo per group) were allocated by unbalanced randomisation. Ten single, increasing oral doses were tested: 0.125, 0.25, 0.5, 1, 2, 4, 8, 16, 24 and 32 mg. The assessment criteria were clinical (monitoring of blood pressure, heart and respiratory rate, electrocardiogram, temperature and evaluation of behaviour and side effects) and routine laboratory tests.Blood pressure did not fall except for a slight drop in diastolic pressure during the first 4 h following the 32-mg dose. However, although an effect of the compound cannot be excluded, the reduction in blood pressure may have reflected intersubject variability. No orthostatic hypotension was observed. There was no change in the other vital signs, and in particular no increase in heart rate was observed. No serious adverse effect was encountered.The pharmacological activity of the compound was studied by assaying plasma ACE activity. Inhibition of ACE was linearly dose-dependant from 0 (placebo) to 2 mg, and above that dose, the inhibition was nearly total. ACE activity was markedly reduced within 30 min after administration of trandolapril, and maximal inhibition was observed from 2–4 h onwards, lasting for up to 24 h after dosing. For doses above 2 mg, inhibition was still 40% of the basal activity on Day 8 after dosing.     

The DIAB-HYCAR study

Summary Microalbuminuria and proteinuria are strong independent predictors for increased cardiovascular mortality in non-insulin-dependent diabetic (NIDDM) patients. In such patients, angiotensin converting enzyme (ACE) inhibition improves the evolution of diabetic nephropathy; however, no data are currently available on the effects of such intervention on cardiovascular morbidity and mortality. The aim of the Diab-Hycar study is to test the hypothesis that ACE inhibition with a low daily dose of 1.25 mg ramipril, which has no significant effect on blood pressure, may reduce cardiovascular morbidity and/or mortality in normotensive or hypertensive NIDDM patients with persistent albuminuria. Selected and followed by general practitioners, 4000 patients will receive their usual oral antidiabetic treatment and if necessary antihypertensive treatment (ACE inhibitors excluded). In addition in a randomized, double-blind trial they will be given either a placebo or 1.25 mg ramipril daily. The follow-up is currently scheduled to last 3 years. The efficacy of ACE-inhibition will be assessed by the following major end-points: cardiovascular death, sudden death, myocardial infarction, stroke, renal replacement therapy. The Diab-Hycar study started on 3 February 1995. By 1 September 1995, 11 000 urine samples were tested. The prevalence of persistent albuminuria was 23 %, 964 patients were initially included in the study, with 619 eligible patients included soon after. Different strategies have been developed to record cardiovascular events correctly and to minimize the number of patients lost to follow-up. [Diabetologia (1996) 39: 1662–1667]     

Reduced glomerular filtration rate and cardiovascular damage in diabetes: a key role for abnormal albuminuria

There is general agreement that a fall rate in glomerular filtration rate (GFR) is the principal endpoint in diabetics with renal disease, and that abnormal albuminuria (including microalbuminuria) is an important intermediate end-point. The relative roles of blood pressure (BP) elevation and abnormal albuminuria in the prediction and genesis of renal disease are a matter of debate, and are further analysed in this paper. New studies show that neither genetic predisposition to hypertension (parental BP) nor parental abnormal albuminuria can be used to predict renal disease in patients with type 1 (insulin-dependent) diabetes. However, parental predisposition to proteinuria seems to be important to certain types of patients with type 2 (non-insulin-dependent) diabetes. Cross-sectional as well as follow-up studies document that GFR is generally well preserved in microalbuminuria (in both type 1 and type 2 patients), while the transition to clinical proteinuria is associated with a decline in GFR. Thus, prevention of overt proteinuria is important in clinical trials in microalbuminuric patients. In type 1 diabetes clear ultrastructural changes have been documented with microalbuminuria and a good correlation between abnormal albuminuria and structural damage is seen. Structural damage in normo- and microalbuminuric patients correlates poorly with BP. New studies in type 1 diabetes document that microalbuminuria (but not elevated BP) predicts not only clinical diabetic nephropathy but also end-stage renal failure and mortality. In type 2 diabetes microalbuminuria is the strongest predictor of mortality, whereas BP elevation is not a predictor. Several studies now document that antihypertensive treatment, especially with inhibitors of angiotensin converting enzyme, is able to reverse or reduce abnormal albuminuria, even in non-hypertensive type 1 patients, and possibly preserve GFR. Therefore, microalbuminuria may be the main indicator for starting antihypertensive treatment in these patients. With respect to organ damage in the retina, abnormal albuminuria is an important indicator of the risk of severe diabetic retinopathy. BP elevation seems not to be an initiating factor, but rather aggravates established retinopathy. Left ventricular hypertrophy has a stronger correlation with BP elevation than normoalbuminuria, suggesting that left ventricular hypertrophy is at least partially a phenomenon secondary to elevated BP in diabetic patients with abnormal albuminuria. Generally, abnormal albuminuria is a strong indicator of cardiovascular renal damage in diabetic patients and in most organs is a stronger factor than elevated BP.     

EFFECT OF ACUTE INTRAVENOUS ACE-INHIBITION ON THE INTRARENAL DOPPLER FLOW CHARACTERISTICS IN HYPERTENSIVE PATIENTS WITH AND WITHOUT UNILATERAL RENAL ARTERY STENOSIS

Assessment of intrarenal doppler signals is of particular importance in screening for renal artery stenosis. We studied the effect of acute ACE-inhibition (1,25 mg enalaprilate i.v.) on intrarenal resistive indices in 10 hypertensive patients with unilateral renal artery stenosis versus 10 patients with essential hypertension. Any changes limited to poststenotic vessels could possibly improve the diagnostic value of duplex sonography.

After ACE-inhibition a significant fall of the intrarenal Resistive Index occurred in both patient groups. In cases of unilateral renal artery stenosis we saw a tendency to an increased side difference of the Resistive Index due to a greater fall on the poststenotic side.

Therefore a clear advantage of duplex scanning after acute ACE-inhibition due to a limited effect of enalaprilate on poststenotic vessels was not found. The results suggest that the vascular resistance and not only the degree of renal artery stenosis is of significance for the characteristics of the doppler signal.     

Systemic and renal haemodynamic effects of angiotensin converting enzyme inhibition by zabicipril in young and in old normal men

Summary Zabicipril is a recently introduced angiotensin converting enzyme (ACE) inhibitor, which has been observed in experimental animals to increase diuresis, natriuresis, glomerular filtration rate (GFR) and renal plasma flow (RPF). We have investigated the acute effects of zabicipril on systemic and renal haemodynamics in two groups of 8 sodium-replete normal men, aged 23 to 30 y and 65 to 74 y. Zabicipril 0.5 mg, 1 mg or 2.5 mg and a placebo were administered orally, at one week intervals, in a random order and in a double blind fashion. Haemodynamic measurements were performed at base line and every hour for 4 hours after intake of drug or placebo. Cardiac output (Q) was measured by Doppler echography, and RPF and GFR by the constant infusion technique using I¹²³ iodohippurate and Cr⁵¹ EDTA, respectively.In the young men zabicipril did not affect Q, heart rate (HR), systemic arterial pressure (AP) or GFR, but it did increase RPF at the 4th hour after the highest dose (from 540 to 653 ml · min^–1 · m^–2). In the old men zabicipril had similar actions, but the effect of the highest dose on RPF (from 355 to 415 ml · min^–1 · m^–2) was less marked than in the young men. In the young and old men the inhibition of ACE peaked at about of 90% or more from the 2th to the 4th hour after the highest dose of zabicipril.We conclude that, in normal men, zabicipril increases the renal fraction of cardiac output in the absence of a concomitant change in systemic haemodynamics. This specific effect of zabicipril on the kidney may be less important with advancing age.     

Chickpea Peptide: A Nutraceutical Molecule Corroborating Neurodegenerative and ACE-I Inhibition

Chickpea seeds are the source of proteins in human nutrition and attribute some nutraceutical properties. Herein, we report the effects of chickpea seed bioactive peptide on albumin, insulin, lactoglobulin and lysozyme amyloid fibril formation. Employing thioflavin T (ThT) assays and circular dichroism (CD), amyloid structural binding transition was experimented to analyze the inhibition of amyloid fibril formation. The purified active peptide with a molecular mass of 934.53 Da was evaluated in vitro for its ACE-I inhibitory, antibacterial, antifungal and antidiabetic activities. Further, in vivo animal studies were carried out in wistar rats for blood pressure lowering action. In hypertensive rats, chickpea peptide decreased 131 ± 3.57 mm of Hg for systolic blood pressure and 86 ± 1.5 mm of Hg for diastolic blood pressure after 8 h intraperitoneal administration. Additionally, the peptide suppressed the fibrillation of amyloid and destabilized the preformed mature fibrils. Data emphasize efficacy of chickpea peptide vis-a-vis ACE-Inhibitory, antibacterial, antifungal, antidiabetic and anti-amyloidogenic activities, allowing us to propose this novel peptide as a suitable candidate for nutraceutical-based drugs and seems the first kind of its nature.     

Intracoronary enalaprilat during angioplasty for acute myocardial infarction: alleviation of postischaemic neurohumoral and inflammatory stress?

AIM: Reperfusion after myocardial ischaemia is associated with a distinct ischaemia/reperfusion injury. Since ACE-inhibition, beyond its influence on cardiac angiotensin II formation and kinin metabolism, has been shown to be cardioprotective by decreasing leucocyte adhesion and endothelin-1 (ET-1) release, we investigated the effects of intracoronary (i.c.) enalaprilat during primary angioplasty in acute myocardial infarction. METHODS AND RESULTS: Twenty-two patients were randomized to receive i.c. enalaprilat (50 micro g) or placebo immediately after reopening of the infarct-related artery (IRA). Plasma concentrations of soluble L-selectin, P-selectin, intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), ET-1 and nitric oxide metabolite concentrations (NOx) were measured in pulmonary arterial blood. Coronary blood flow was assessed using corrected thrombolysis in myocardial infarction (TIMI) frame counts (CTFC). During reperfusion, there was a significant increase in sL-selectin, sP-selectin and ET-1 in the placebo group, which was greatly diminished by enalaprilat. Levels of sVCAM-1 and sICAM-1 were not affected in either group. CTFC in the placebo group remained higher than normal in both the IRA and nonculprit vessels, whereas myocardial blood flow improved with enalaprilat. CONCLUSION: Enalaprilat as adjunct to primary angioplasty might be a protective approach to prevent leucocyte adhesion and the release of ET-1, thereby improving coronary blood flow.     

Antihypertensive medications and differences in muscle mass in older persons: the Health, Aging and Body Composition Study

OBJECTIVES: To evaluate whether older persons using angiotensin-converting enzyme (ACE) inhibitors have a larger lower extremity muscle mass (LEMM) than users of other antihypertensive drugs. DESIGN: Cross-sectional analysis of data from the Health, Aging and Body Composition (Health ABC) Study. SETTING: University of Tennessee, Memphis, and University of Pittsburgh clinics. PARTICIPANTS: A community-based sample of 2,431 well functioning participants of the Health ABC, aged 70 to 79, who were free of heart failure, were selected according to use of antihypertensive medications: ACE inhibitors (n=197), beta-blockers (n=169), thiazides (n=216), calcium-channel blockers (n=340), or none (n=1,509). MEASUREMENTS: LEMM, assessed using dual-energy x-ray absorptiometry, compared by index drug in analysis of variance models unadjusted and adjusted for demographics, study site, height, body fat, physical activity, blood pressure, coronary artery disease, diabetes mellitus, and chronic pulmonary disease. RESULTS: LEMM significantly differed across the study groups, being larger in users of ACE inhibitors than in users of other drugs (unadjusted and adjusted models). LEMM was comparable in users of ACE inhibitors and no drug users. A trend toward larger LEMM was also observed in sex- and ethnicity-stratified analyses and in the subgroup of noncoronary hypertensive participants. CONCLUSION: In older persons, use of ACE inhibitors is associated cross-sectionally with larger LEMM. This finding suggests a possible explanation of the benefits of ACE inhibitors in wasting syndromes. If confirmed in longitudinal studies, this pharmacological action might have important implications for the prevention of physical disability in older patients with hypertension.     

The Carvedilol and ACE-Inhibitor Remodelling Mild Heart Failure EvaluatioN trial (CARMEN)--rationale and design

Inhibition or reversal of ventricular remodelling in heart failure patients is regarded as of prime importance in the treatment of heart failure and in determining long term outcome. Recent studies have demonstrated that the addition of carvedilol to Angiotensin Converting Enzyme (ACE) inhibitors and other routine heart failure therapy results in a valuable improvement in the clinical status and life expectancy of mild, moderate and severe heart failure patients. ACE inhibitors have become the cornerstone of heart failure therapy. Also, carvedilol in combination with standard therapy (including ACE inhibitors) has demonstrable beneficial effects on left ventricular remodelling. Each new treatment has to be added, this quickly leads to polypharmacy, which may not be necessary and even unwanted in the individual patient, as the pharmacological profile of carvedilol compares favourably to ACE inhibitors, this suggests that it could challenge ACE inhibitors as first-line treatment for heart failure.The CARMEN trial (Carvedilol and ACE-Inhibitor Remodelling Mild Heart Failure EvaluatioN) was designed to compare the effects of carvedilol alone and of carvedilol plus an ACE inhibitor (enalapril) with the effect of an ACE inhibitor alone on different parameters of left ventricular remodelling as well as morbidity and mortality in patients with chronic mild heart failure, thereby allowing conclusions on whether combination therapy may be replaced by the multiple action adrenergic inhibitor carvedilol in the future.