Short-term Angiotensin Converting Enzyme Inhibition Research Articles

3-Month Enalapril Treatment in Pediatric Fontan Patients With Moderate to Good Systolic Ventricular Function

Many Fontan patients with and without systolic ventricular dysfunction are being treated with angiotensin-converting enzyme (ACE) inhibitors, despite its effectiveness remaining unclear. In the present study, we evaluated the short-term effect of enalapril on exercise capacity, vascular and ventricular function in pediatric Fontan patients with moderate-good systolic ventricular function. Fontan patients between 8 and 18 years with moderate-good systolic ventricular function and without previous ACE inhibitor treatment were included and were treated with enalapril for 3 months. During the first 2 weeks, the dosage was titrated according to systolic blood pressure (SBP). Exercise tests, ventricular function assessed by echocardiography, arterial stiffness measurements, and plasma levels of N-terminal pro-B-type natriuretic peptide assessed before and after a 3-month enalapril treatment period was compared. A total of 28 Fontan patients (median age 13.9 years, 6 to 15 years after Fontan operation) completed the study with a mean dosage of 0.3 ± 0.1 mg/kg/d. A total of 6 patients (21%) experienced a significant drop in SBP and 6 others (21%) experienced other adverse events. Enalapril treatment lowered the SBP (from 110 to 104 mmHg, p=0.003) and levels of N-terminal pro-B-type natriuretic peptide (from 80 to 72 ng/L, p=0.036). However, enalapril treatment did not improve exercise capacity, ventricular function, or arterial stiffness. In conclusion, short-term ACE inhibition has no beneficial effect in Fontan patients with moderate-good systolic ventricular function.

Angiotensin converting enzyme inhibition increases ADMA concentration in patients on maintenance hemodialysis--a randomized cross-over study.

BackgroundEndothelial dysfunction occurs in patients with end-stage renal disease (ESRD) and is associated with increased cardiovascular morbidity and mortality. Asymmetric dimethylarginine (ADMA) contributes to endothelial dysfunction in ESRD. In the general population, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) decrease ADMA levels, but no study has compared the effect of these drugs in patients with ESRD on maintenance hemodialysis (MHD).MethodsWe evaluated the effect of 1-week treatment with ramipril (5 mg/d), valsartan (160 mg/d), and placebo on ADMA levels in 15 patients on MHD in a double-blind, placebo-controlled, three x three cross-over study.ResultsWe found that ADMA levels were increased at baseline and throughout the dialysis session during ramipril treatment (p < 0.001 compared to both, placebo and valsartan). Ramipril did not increase ADMA levels in a study of patients without ESRD, suggesting that factors related to ESRD or hemodialysis contribute to the ACE inhibitor-induced increase in ADMA. We have previously shown that ACE inhibition increases bradykinin (BK) levels during hemodialysis. We therefore evaluated the effect of bradykinin on ADMA production in A549 cells; a cell line that expresses BK receptors. Incubation with BK increased intracellular ADMA concentration through BK B2-receptor stimulation.ConclusionThese data indicate that short-term ACE inhibition increases ADMA in patients on MHD whereas ARBs do not. In vitro studies further suggest that this may occur through BK-mediated increase in ADMA production during ACE inhibition.Trial registrationClinicaltrials.gov NCT00732069 August 6 2008 and NCT00607672 February 4 2008Electronic supplementary materialThe online version of this article (doi:10.1186/s12882-015-0162-x) contains supplementary material, which is available to authorized users.

Short-term ACE inhibition confers long-term protection against target organ damage

Angiotensin converting enzyme (ACE) inhibitors reduce left ventricular (LV) hypertrophy and cardiovascular-renal fibrosis. Experimentally, changes in the LV and kidney persist even after cessation of treatment. The present study investigates whether brief ACE inhibition in spontaneously hypertensive rats (SHR) provides long-term protection against the LV and kidney damage induced by the nitric oxide synthase inhibitor N-ω-nitro-L-arginine-methyl ester (L-NAME). SHR received the ACE inhibitor enalapril (n = 36) or tap water (n = 36). In all, 12 control and treated SHR were sacrificed after 2 weeks and remaining rats were taken off-treatment. After a 2-week washout, 12 controls or previously treated SHR were sacrificed and remaining rats were treated with L-NAME ((control (Con)+L, enalapril (Enal)+L) for 10 days. At sacrifice, blood pressure was recorded via carotid artery cannulation in anesthetized rats, and blood, the kidney and LV were isolated for analysis. LV mass and arterial pressure were significantly reduced by enalapril. LV mass showed a persistent reduction throughout the study. In LV, prior enalapril treatment provided significant (P<0.05) protection against L-NAME-induced increases in proliferating cells (Con+L: 11 ± 10.0 mm(2) vs. Enal+L: 4 ± 4.4 mm(2)), interstitial fibrosis (Con+L: 3 ± 2.5% vs. Enal+L: 1 ± 1.0%) and tissue macrophages (Con+L: 12 ± 9 mm(2) vs. Enal+L: 5 ± 3.6 mm(2)). In the kidney, prior enalapril treatment protected against L-NAME-induced interstitial fibrosis and vascular injury. There was no difference in glomerular size or glomerulosclerosis regardless of prior treatment. Plasma creatinine and urea were significantly increased in L-NAME treated rats. This study suggests that brief ACE inhibition confers protection against future heart and kidney injury, even in the absence of continued antihypertensive treatment.

ACE Inhibition Reduces Infarction in Normotensive but Not Hypertensive Rats: Correlation with Cortical ACE Activity

Angiotensin-converting enzyme (ACE) inhibition can reduce stroke risk by up to 43% in humans and reduce the associated disability, and hence understanding the mechanism of improvement is important. In animals and humans, these effects may be independent of the blood pressure-lowering effects of ACE inhibition. Normotensive (Wistar-Kyoto (WKY)) and hypertensive (spontaneously hypertensive rat (SHR)) animals were treated with the ACE inhibitors ramipril or lisinopril for 7 or 42 days before 2 hours of transient middle cerebral artery occlusion (MCAo). Blood pressure, serum ACE, and blood glucose levels were measured and stroke infarct volume was recorded 24 hours after stroke. Despite greater reductions in blood pressure, infarct size was not improved by ACE inhibition in hypertensive animals. Short-term ACE inhibition produced only a modest reduction in blood pressure, but WKY rats showed marked reductions in infarct volume. Long-term ACE inhibition had additional reductions in blood pressure; however, infarct volumes in WKY rats did not improve further but worsened. WKY rats differed from SHR in having marked cortical ACE activity that was highly sensitive to ACE inhibition. The beneficial effects of ACE inhibition on infarct volume in normotensive rats do not correlate with changes in blood pressure. However, WKY rats have ACE inhibitor-sensitive cortical ACE activity that is lacking in the SHR.

Short-term angiotensin converting enzyme inhibition reduces basal tone and dilator reactivity in skeletal muscle arterioles

Alterations in resting tone, maximum diameter, and dilator reactivity to acetylcholine (ACH) and sodium nitroprusside (SNP) were assessed in cremaster muscle microvessels of Sprague-Dawley rats receiving angiotensin converting enzyme (ACE) inhibition with captopril for 4 days and in untreated time-control rats. The transilluminated in situ cremaster muscle was superfused with physiologic salt solution (PSS) and viewed via television microscopy; arteriolar diameter was measured using a videomicrometer. Before agonist challenge, resting arteriolar diameter was significantly increased in captopril-treated rats. Although maximum arteriolar diameter (determined during superfusion of the cremaster muscle with Ca 2+-free PSS containing 10 −4 mol/L adenosine) was not altered with ACE inhibition, the maximum possible arteriolar dilation was reduced in captopril-treated rats. Captopril administration reduced both ACH- and SNP-induced dilation of cremasteric arterioles compared with responses in control rats, although this was partially a function of the reduced capacity for dilation, primarily to SNP. These observations indicate that short-term ACE inhibition reduces both resting tone and agonist-induced dilator responses of skeletal muscle arterioles.

Differing effects of enalapril and losartan on renal medullary blood flow and renal interstitial hydrostatic pressure in spontaneously hypertensive rats.

To determine the effect of short-term angiotensin converting enzyme inhibition (enalapril) or angiotensin II AT1 receptor blockade (losartan) on medullary hemodynamics in the spontaneously hypertensive rat (SHR). Laser-Doppler flowmetry allowed for the characterization of medullary blood flow (MBF) over a wide range of renal arterial pressure (RAP), and was used for comparison among treatment groups. Renal interstitial hydrostatic pressure (RIHP) was also determined over a wide range of RAP. Enalapril or losartan was given to male 12-13-week-old SHR for 3 days (25 mg/kg per day in drinking water). Rats were anesthetized with Inactin, renal function was measured at resting levels of RAP and then RAP was varied over a range of 50-150 mmHg in 25 mmHg steps. MBF and RIHP were determined at each pressure. Resting mean arterial pressure (MAP) (mmHg +/- SE) for enalapril- and for losartan-treated SHR [114 +/- 3 (n = 18) and 124 +/- 3 (n = 20), respectively] were both significantly lower than for untreated SHR [159 +/- 5 (n = 20)]. Renal function at resting levels of MAP was not significantly different among groups. Enalapril and losartan both increased MBF by 30% at levels of RAP of 125 mmHg and over. Enalapril did not alter the relation between RAP and RIHP, but losartan shifted the RAP versus RIHP curve by approximately 40 mmHg to lower levels of RAP. Acute administration of the B2 kinin receptor antagonist HOE 140 [20 microg/kg intravenous (i.v.) bolus, then 10 microg/kg per h i.v.] did not significantly alter MAP in any group. HOE 140 did not significantly alter MBF or RIHP in the untreated or losartan-treated SHR. MBF in enalapril-treated rats receiving HOE 140 was not significantly different from that of the enalapril-only group; however, the relation between RAP and RIHP was shifted to lower levels of RAP by approximately 45 mmHg. Both enalapril and losartan increase MBF in SHR, suggesting that the medullary circulation of SHR is influenced by endogenous levels of angiotensin II. The failure of enalapril to increase RIHP in parallel with MBF appears to be due to an enhanced effect of kinins.

Short-term ACE inhibition has no effect on sodium and water excretion during PEEP ventilation

The short-term effect of intravenous (i.v.) angiotensin converting enzyme (ACE) inhibitor enalaprilat in 10 critically ill patients, being ventilated with positive end-expiratory pressure (PEEP), on sodium and water excretion was investigated. Mean arterial pressure (MAP) decreased. Heart rate and central venous pressure (CVP) did not change. Glomerular filtration rate (GFR), urine volume (V) and sodium excretion (UNaV) decreased in two patients with reduced MAP. GFR, V and UNaV increased in two patients with decreased MAP. No relation between changes in MAP and excretion was observed in six patients. ACE decreased in all patients. Plasma renin activity increased, aldosterone decreased, while atrial natriuretic peptide as well as antidiuretic hormone did not change. Enalaprilat did not facilitate sodium and water excretion during ventilation with PEEP. Decreased MAP indicates that the investigated patients were very dependent on their renin-angiotensin system to maintain systemic perfusion pressure. Base-line MAP and CVP values were no predictors of haemodynamic and excretory changes following acute ACE inhibition.

Short-term ACE inhibition may influence exercise-induced changes in haemostasis in healthy subjects

Summary Experimental studies have indicated that the renin-angiotensin system may regulate plasminogen activation and fibrinolysis and that angiotensin-converting enzyme (ACE) inhibitors are able to reduce the rate of myocardial infarction, possibly by interfering with haemostatic system. However, no data are available on the effect of ACE inhibition on haemostasis in healthy subjects. The aim of this study was to evaluate the effects of short-term ACE inhibition on haemostasis, both in baseline conditions and after a standardized exercise stress test in healthy subjects. Ten male control subjects (age 25–40 years) were enrolled in a randomized, double blind, placebo-controlled crossover study. They assumed enalapril 20 mg or placebo once daily for 7 days, then, after a 15-day washout period, treatments were crossed. Treadmill stress test was performed before and after each 7-day treatment period. Blood sampling for fibrinolysis and coagulation studies were performed before exercise and after maximal exercise. The exercise-induced decrease in ELT and plasminogen activator inhibitor-1 and the increase in tissue plasminogen activator were more marked after enalapril than after placebo. No differences were seen in signs of exercise-induced clotting activation. These data indicate that a short-term treatment with enalapril in healthy subjects is able to affect fibrinolysis response to a physiological stimulation such as physical effort. These results may be of help in the study of complex relationships among ACE inhibition, haemostasis and reduction in myocardial infarction.

Acute but not chronic angiotensin-converting enzyme inhibition induces enzyme synthesis in the glomerulus of the spontaneously hypertensive rat.

1. Treatment with angiotensin-converting enzyme (ACE) inhibitors slows the rate of progression of nephropathy in the spontaneously hypertensive rat (SHR) with streptozotocin-induced diabetes. Paradoxically, however, chronic ACE inhibitor therapy has been reported to be associated with induction of ACE in the plasma. We sought to determine whether induction also occurred in the glomerulus. 2. Seven days after induction of diabetes rats were randomized to receive perindopril (4 mg/kg per day) in the drinking water or water alone. Blood glucoses were maintained 6-10 mmol/L by daily ultralente insulin. Rats were killed after 1 and 12 weeks of ACE inhibitor therapy and the kidneys were harvested. Angiotensin-converting enzyme activity was determined in isolated glomeruli before and after removal of perindopril and reconstitution with zinc sulphate. 3. After 1 week of ACE inhibitor therapy, glomerular ACE was significantly greater after removal of perindopril than either before its removal (P < 0.025) or in the untreated controls (P < 0.025). After 12 weeks of therapy, ACE activity was significantly lower in the perindopril-treated group than in the untreated controls (P < 0.025). There was no increase in ACE activity following removal of perindopril. 4. These studies suggest that short-term ACE inhibition is associated with induction of ACE in the glomerulus. However, there was no increase in ACE activity after removal of perindopril, suggesting that induction of synthesis of this enzyme in the glomerulus does not occur during chronic ACE inhibition.

Impaired renal haemodynamic response to amino acid infusion in essential hypertension during angiotensin converting enzyme inhibitor treatment.

To determine whether hyperfiltration induced by amino acid infusion can be influenced by angiotensin converting enzyme (ACE) inhibition. We studied the acute effects of ramipril in 12 healthy control subjects and in 14 patients with essential hypertension. We studied also the effects of 2 months' treatment with ramipril inn 12 patients with essential hypertension and performed a time-control study without amino acids infusion with 12 control subjects. The glomerular filtration rate (GFR), renal plasma flow (RPF), fractional excretion of sodium (FENa) and fractional excretion of lithium (FELi) were determined during 6 clearance periods of 30 min each and amino acids infusion was administered during the last four periods. Plasma concentrations of angiotensin II, aldosterone, atrial natriuretic peptide (ANP), arginine vasopressin, insulin and glucagon were determined. Both the GFR and the RPF increased markedly in healthy subjects after amino acid infusion both with (GFR 7%, RPF 7%) and without ramipril (GFR 7%), RPF 8%), both P < 0.05. Ramipril administered acutely to essential hypertensives prevented the amino acid-induced increase in RPF [with ramipril 5% (NS), without ramipril 9% (P < 0.05)]. The GFR increased equally with (5%) and without (8%) ramipril (P < 0.20). ACE inhibition after 2 months' treatment of essential hypertension blunted the amino acid-induced increase both in GFR and in RPF [with ramipril GFR 5% and RPF 3% (NS), without ramipril GFR 12%, RPF 11% (P < 0.05)]. The FENa did not change in all four experiments. The FELi, insulin and glucagon increased to the same extent in the first three experiments. ANP increased (P < 0.05) in control subjects both with and without ramipril; angiotensin II and aldosterone decreased significantly in control subjects without ramipril. The renal haemodynamic response both after acute and after short-term ACE inhibition is attenuated in essential hypertension. Presumably, this treatment makes the arterioles at the glomeruli unresponsive to subsequent amino acid infusion. This inhibition of hyperfiltration might be an important mechanism for the renal protective effect of ACE inhibition in some renal diseases.

794-2 Angiotensin Converting Enzyme Inhibition in Adults with Cyanotic Congenital Heart Disease

Adult patients (pts) with cyanotic congenital heart disease (CCHD) and elevation (↑) in pulmonary vascular resistance (PVR) may have a marked decrease in exercise capacity (EX) and quality of life due to intravascular volume overload, ventricular dysfunction and cyanosis-related morbidity. Concerns of increasing right-to-left shunting and cyanosis have limited characterization of the safety and effects of angiotensin converting enzyme inhibition (ACEI) in these pts. We evaluated ACEI in 7 symptomatic adults (ages 29–36 yrs) with CCHD and ↑PVR from 6/92 to 6/94. Intracardiac shunting was present at the ventricular level (single ventricle, double outlet right ventricle) in 3 pts, at the atrial septum (Ebstein's malformation, peripheral pulmonary stenoses) in 2 pts, and at both levels (AV canal defect) in 2 pts. All pts had marked exercise incapacity; 6/7 were candidates for heart-lung transplantation. Baseline serum hemoglobin (Hgb) oxygen saturation (O2sat) and 6 minute walking capacity (6 min) were compared before and after 6 weeks of ACEI. Baseline Hgb was ≥6 gm/dl (19.3 ± 1.7) and O2sat was ≤90% (79 ± 4) in all pts. ACEI caused no decrease in O2sat or increase in Hgb in any pt. When compared to baseline, EX increased ≥30% (6 min: 326 ± 129 vs 441 ± 160 yds) with ACEI in 5/5 pts (p = 0.01). All pts noted subjective functional improvement with ACEI; during treatment 3/6 pts removed themselves from consideration for organ transplantation and remain well. Our preliminary findings suggest that short-term ACEI is safe and may improve exercise capacity and quality of life in adult pts with CCHD and ↑PVR. Further investigation is required to elucidate the mechanisms of these benefits and to determine the long-term effects of ACEI in this cohort.

Renal response to angiotensin after short-term angiotensin converting enzyme inhibition.

In 13 normotensive subjects on a normal sodium diet, we studied hormonal, blood pressure, and renal vascular changes and dextran sieving profiles induced by infusion of exogenous angiotensin II (Ang II) (5 ng.kg-1.min-1). during baseline conditions and after 5 days of administration of the angiotensin converting enzyme inhibitor cilazapril. Cilazapril induced a renal vasodilative effect without affecting supine blood pressure and glomerular filtration rate. Fractional dextran clearances were significantly decreased for dextran of effective radius ranging from 3.0 to 4.0 nm. This shift was primarily related to an increase in glomerular capillary plasma flow, because no change was observed in the transcapillary glomerular pressure gradient, the ultrafiltration coefficient, or the membrane parameters. Ang II elicited a slight pressor response accompanied by hormonal, antinatriuretic, and renal hemodynamic changes that were similar during and before short-term angiotensin converting enzyme inhibition. Dextran sieving curves were unchanged by a low dose of Ang II. However, the transcapillary glomerular pressure gradient and the ultrafiltration coefficient were computed to increase by 19.4% and to decrease by 44.2%, respectively, whereas membrane parameters were unaffected. When superimposed onto short-term angiotensin converting enzyme inhibition, glomerular response to this unique dose of Ang II was similar to that induced by Ang II alone. These findings indirectly suggest that most, if not all, of the renal effects of cilazapril are mediated through suppression of Ang II formation.

Sympathetic alterations after sodium restriction and short-term captopril administration

Objectives. The purpose of this study was to examine the effects of short-term captopril therapy during sodium restriction on several markers of the sympathetic nervous system, including plasma norepinephrine, neuropeptide Y, beta-adrenergic receptors and cortisol.Background. Recent studies suggest that the therapeutic effects of converting enzyme inhibitors involve not only the renin-angiotensin and prostaglandin systems but also the sympathetic system.Methods. Twelve hypertensive and 20 normotensive men were studied after 25-day hospital stays during which they consumed a 10-mEq sodium diet and received captopril (25 mg twice daily) or placebo in a double-blind crossover study.Results. Captopril decreased neuropeptide Y (p < 0.05) and angiotensin II (p < 0.01) and increased isoproterenol-stimulated cyclic adenosine monophosphate (AMP) in lymphocytes (p < 0.03), plasma norepinephrine (p < 0.02), Cortisol (p < 0.05) and renin (p < 0.001) in both hypertensive and normotensive subjects. Hypertensive subjects had an increased beta-adrenergic receptor density (p < 0.02) and a greater decrease in diastolic blood pressure compared with normotensive subjects (p < 0.02).Conclusions. The results of this study suggest that the short-term therapeutic effects of captopril may involve concerted changes in key components of the sympathetic nervous system. These findings, such as decreased neuropeptide Y combined with increased norepinephrine and beta-adrenergic receptors, are compatible with the observation of increased cardiac output and decreased peripheral resistance after short-term angiotensin-converting enzyme inhibition.

Contrasting peripheral short-term and long-term effects of converting enzyme inhibition in patients with congestive heart failure. A double-blind, placebo-controlled trial.

To discover the underlying mechanisms involved in the beneficial long-term effects of angiotensin converting enzyme (ACE) inhibitors, we investigated the systemic and peripheral effects of short- and long-term ACE inhibition in patients with chronic heart failure. After assessing the short-term effects and dose titration with cilazapril, a new long-acting ACE inhibitor, 21 patients were randomized to receive either placebo or the ACE inhibitor. Seventeen patients completed the 3-month treatment. Central hemodynamic output, femoral blood flow (measured by thermodilution), oxygen saturation, and lactate and norepinephrine levels were determined simultaneously in the femoral vein and radial artery during treatment and after a 3-month rest and during symptom-limited bicycle exercise. Short-term ACE inhibition improved rest and exercise hemodynamic output, but it did not alter peak femoral blood flow, calculated leg oxygen consumption, or systemic oxygen uptake during exercise, despite significant reduction in femoral norepinephrine extraction and arterial angiotensin levels during exercise. In contrast, long-term ACE inhibition further improved exercise cardiac output and increased leg blood flow (from 2.3 to 2.9 l/min, p less than 0.05), leg oxygen consumption (from 277 to 403 ml/min, p less than 0.05), and systemic oxygen uptake (from 1,133 to 1,453 ml/min, p less than 0.05), whereas these variables remained unchanged with placebo treatment (p less than 0.02 between groups). Moreover, a moderate but significant increase in femoral oxygen extraction occurred after long-term therapy (ACE inhibitor: from 76% to 83%, p less than 0.05; placebo: from 75% to 74%, NS; p less than 0.01 between groups). We conclude that long-term ACE inhibition is clinically beneficial in that it improves blood flow to skeletal muscle during exercise over time. The long-term effects of ACE inhibition are, in part, probably related to peripheral (vascular) mechanisms, for example, by reversing the inability of peripheral vessels to dilate and by improving oxygen utilization.