Eur J Clin Pharmacol. 2005 Mar 11.
Enalapril dosage in progressive chronic nephropathy: a randomised,
controlled trial.
Elung-Jensen T, Heisterberg J, Sonne J, Strandgaard S, Kamper
AL.
Departments of Nephrology and Clinical Physiology and Nuclear Medicine,
Herlev Hospital, University of Copenhagen, Denmark.
OBJECTIVE: In chronic renal failure, clearance of enalapril is reduced.
Hence, a renoprotective effect may be achieved with lower doses than conventionally
used. Since marked inter-patient variation in concentrations of enalaprilat
has been shown in patients with renal failure despite equivalent dosage
of enalapril, a direct comparison of the effect of high versus low plasma
concentrations of enalaprilat on the progression of renal failure was
undertaken.METHODS: Forty patients with a median glomerular filtration
rate (GFR) of 17 (6-35) ml/min/1.73 m(2) were studied in an open-label,
randomised trial comparing patients with a high (>50 ng/ml) with patients
with a low (<10 ng/ml) target trough plasma concentration of enalaprilat.
The dose of enalapril was titrated accordingly. The patients were followed
for 12 months or until they needed renal replacement therapy. GFR was
measured at 3-month intervals by the plasma clearance of (51) Cr-EDTA,
and the individual rates of progression of renal failure were calculated
as the slope of GFR versus time plot.RESULTS: In the high-concentration
group, the median enalaprilat trough concentration was 92.9 ng/ml (21.8-371.0
ng/ml) and in the low-concentration group it was 9.1 ng/ml (2.5-74.8 ng/ml)
at 3 months follow-up (P<0.001). The median daily doses of enalapril
were 10 mg (2.5-30 mg) and 1.88 mg (1.25-5 mg) in the high and low groups,
respectively (P<0.001). In the high-concentration group, the mean+/-SE
decline in renal function was 6.1+/-1.5 ml/min/1.73 m(2) per year and
in the low-concentration group it was 4.3+/-14.4 ml/min/1.73 m(2) per
year (P=0.48). Five patients in the high-concentration group reached end-stage
renal failure whereas none in the low-concentration group did (P=0.04).
There were no statistically significant differences in blood pressure
level, concomitant antihypertensive therapy or urinary albumin excretion.
However, the high-enalaprilat concentration group had an overall higher
plasma potassium concentration of 0.42 mmol/l than the low group (P<0.001).CONCLUSION:
In patients with moderate to severe renal insufficiency, a low concentration
of enalaprilat afforded the same degree of renoprotection, blood pressure
control and minimisation of proteinuria as a high concentration, during
12 months of follow-up. The high-dosage treatment was associated with
a more pronounced tendency to hyperkalaemia. Thus, there seems to be no
indication for increasing the daily dose of enalapril beyond what achieves
adequate blood pressure control in this group of patients.
J Pharm Biomed Anal. 2005 Mar 9;37(3):627-30. Epub 2004 Dec 25.
Quantitative analysis of enalapril by (1)H NMR spectroscopy in
tablets.
Zoppi A, Linares M, Longhi M.
Departamento de Farmacia, Facultad de Ciencias Quimicas, Universidad Nacional
de Cordoba, Ciudad Universitaria, 5000 Cordoba, Argentina.
A simple, rapid, accurate and selective (1)H NMR method was developed for quantitative determination of enalapril maleate in pharmaceutical preparations. Spectra were determined in D(2)O, using l-leucine as internal standard. Both synthetic mixtures and commercial dosage forms were assayed, and the results were compared to those obtained using the USP XXIV procedure and were both in close agreement.
Anadolu Kardiyol Derg. 2004 Dec;4(4):296-300.
Effects of enalaprilat infusion on hemodynamics and renal function
in patients undergoing cardiac surgery.
Turker H, Donmez A, Zeyneloglu P, Sezgin A, Ulucam M.
Department of Anesthesiology, University of Baskent, School of Medicine,
Ankara, Turkey.
OBJECTIVE: This study was undertaken to evaluate the effect of enalaprilat infusion on hemodynamics and renal function during cardiopulmonary bypass (CPB). METHODS: Thirty adults undergoing CPB were randomly allocated into 2 groups. All patients received the same anesthetic protocol and same dopamine infusion protocol (2 mg/kg(-1)/min(-1)) during the study. In addition to dopamine infusion 15 patients received enalaprilat infusion (0.06 mg/kg(-1)/hr(-1)) during CPB. Blood creatinine, urea levels, and creatinine clearance (CLcr) were measured and cardiac output (CO) was calculated by echocardiography preoperatively and on the 6th postoperative day. Mean arterial pressure (MAP), central venous pressure (CVP), systemic vascular resistance (SVR) measurements were recorded during the operation and during postoperative 24 hours. RESULTS: In the control group postoperative blood creatinine and urea levels were significantly higher and CLcr measurements were significantly lower than the preoperative values (p<0.05). These values did not change in the enalaprilat group. Mean arterial pressure was similar in both groups (p>0.05), but SVR was lower (p<0.05) and CVP was higher (p<0.05) in the enalaprilat group than in the control group. In the enalaprilat group postoperative CO measurements were higher than the preoperative values (p<0.05). CONCLUSION: Our results demonstrate that enalaprilat infusion during CPB improves renal function and CO measurements in the early postoperative period.
JAMA. 2004 Nov 10;292(18):2217-25.
Effect of antihypertensive agents on cardiovascular events in
patients with coronary disease and normal blood pressure: the CAMELOT
study: a randomized controlled trial.
Nissen SE, Tuzcu EM, Libby P, Thompson PD, Ghali M, Garza D,
Berman L, Shi H, Buebendorf E, Topol EJ; CAMELOT Investigators.
Department of Cardiovascular Medicine, Cleveland Clinic Lerner School
of Medicine, Cleveland, Ohio, USA.
CONTEXT: The effect of antihypertensive drugs on cardiovascular events in patients with coronary artery disease (CAD) and normal blood pressure remains uncertain. OBJECTIVE: To compare the effects of amlodipine or enalapril vs placebo on cardiovascular events in patients with CAD. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized, multicenter, 24-month trial (enrollment April 1999-April 2002) comparing amlodipine or enalapril with placebo in 1991 patients with angiographically documented CAD (>20% stenosis by coronary angiography) and diastolic blood pressure <100 mm Hg. A substudy of 274 patients measured atherosclerosis progression by intravascular ultrasound (IVUS). INTERVENTIONS: Patients were randomized to receive amlodipine, 10 mg; enalapril, 20 mg; or placebo. IVUS was performed at baseline and study completion. MAIN OUTCOME MEASURES: The primary efficacy parameter was incidence of cardiovascular events for amlodipine vs placebo. Other outcomes included comparisons of amlodipine vs enalapril and enalapril vs placebo. Events included cardiovascular death, nonfatal myocardial infarction, resuscitated cardiac arrest, coronary revascularization, hospitalization for angina pectoris, hospitalization for congestive heart failure, fatal or nonfatal stroke or transient ischemic attack, and new diagnosis of peripheral vascular disease. The IVUS end point was change in percent atheroma volume. RESULTS: Baseline blood pressure averaged 129/78 mm Hg for all patients; it increased by 0.7/0.6 mm Hg in the placebo group and decreased by 4.8/2.5 mm Hg and 4.9/2.4 mm Hg in the amlodipine and enalapril groups, respectively (P<.001 for both vs placebo). Cardiovascular events occurred in 151 (23.1%) placebo-treated patients, in 110 (16.6%) amlodipine-treated patients (hazard ratio [HR], 0.69; 95% CI, 0.54-0.88 [P = .003]), and in 136 (20.2%) enalapril-treated patients (HR, 0.85; 95% CI, 0.67-1.07 [P = .16]. Primary end point comparison for enalapril vs amlodipine was not significant (HR, 0.81; 95% CI, 0.63-1.04 [P = .10]). The IVUS substudy showed a trend toward less progression of atherosclerosis in the amlodipine group vs placebo (P = .12), with significantly less progression in the subgroup with systolic blood pressures greater than the mean (P = .02). Compared with baseline, IVUS showed progression in the placebo group (P<.001), a trend toward progression in the enalapril group (P = .08), and no progression in the amlodipine group (P = .31). For the amlodipine group, correlation between blood pressure reduction and progression was r = 0.19, P = .07. CONCLUSIONS: Administration of amlodipine to patients with CAD and normal blood pressure resulted in reduced adverse cardiovascular events. Directionally similar, but smaller and nonsignificant, treatment effects were observed with enalapril. For amlodipine, IVUS showed evidence of slowing of atherosclerosis progression.
Clin Ther. 2004 Sep;26(9):1419-26.
Efficacy and safety of delapril plus manidipine compared with
enalapril plus hydrochlorothiazide in mild to moderate essential hypertension:
results of a randomized trial.
Mugellini A, Dobovisek J, Planinc D, Cremonesi G, Fogari R.
Department of Internal Medicine and Therapeutics, Clinica Medica II, IRCCS
Policlinico San Matteo, University of Pavia, Pavia, Italy.
BACKGROUND: The use of combination therapy is required to achieve blood pressure targets in 40% to 75% of patients with hypertension. There have been few studies comparing the efficacy and tolerability of the new fixed combination of the angiotensin-converting enzyme (ACE) inhibitor delapril 30 mg and the calcium channel antagonist manidipine 10 mg with those of a standard combination of another ACE inhibitor and a diuretic. OBJECTIVE: The aim of this study was to compare the antihypertensive efficacy and tolerability of delapril 30 mg given alone or with manidipine 10 mg with those of enalapril 20 mg given alone or with hydrochlorothiazide (HCTZ) 12.5 mg in patients with mild to moderate essential hypertension. METHODS: This was a multicenter, active-controlled, parallel-group trial. After an initial 2-week placebo run-in period, patients aged 18 to 75 years with diastolic blood pressure (DBP) > or =90 and < or =109 mm Hg were randomized in a 2:1 ratio to receive delapril or enalapril for 8 weeks. After the initial 8 weeks, nonresponders (DBP > or =85 mm Hg) received an additional 8 weeks of treatment with a fixed combination of delapril + manidipine or enalapril + HCTZ; patients whose DBP was normalized continued their initial monotherapy through the end of the study. The primary efficacy variable was the change in sitting DBP at the end of treatment. Secondary efficacy variables were the percentage of patients whose DBP was normalized (DBP Z:85 mm Hg) and the percentage of responders (> or =10-mm Hg reduction in DBP or DBP <85 mm Hg). RESULTS: One hundred sixty patients (84 men, 76 women) were randomized to receive delapril (n = 106) or enalapril (n = 54). After 16 weeks of treatment, the mean (SD) reduction in DBP was similar with the 2 treatments (delapril, -14 [8] mm Hg; enalapril, -15 [8] mm Hg). In the delapril and enalapril groups, DBP was normalized in a respective 55 (51.9%) and 29 (53.7%) patients, and 77 (72.6%) and 38 (70.4%) were responders; there was no significant difference between groups. Tolerability was also similar in both groups--10 (9.4%) patients in the delapril group and 5 (9.3%) in the enalapril group experienced adverse events that were judged related to treatment. CONCLUSIONS: The results of this study suggest that delapril alone or combined with manidipine is well tolerated and as effective as enalapril alone or combined with HCTZ in lowering blood pressure in patients with mild to moderate essential hypertension.
Am Heart J. 2004 Nov;148(5):889-94.
Impact of angiotensin-converting enzyme gene polymorphism on neurohormonal
responses to high- versus low-dose enalapril in advanced heart failure.
Tang WH, Vagelos RH, Yee YG, Fowler MB.
Kaufman Center for Heart Failure, Department of Cardiovascular Medicine,
Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
BACKGROUND: The impact of angiotensin-converting enzyme (ACE) gene polymorphism on neurohormonal dose response to ACE inhibitor therapy is unclear. METHODS: ACE Insertion (I) or Deletion (D) genotype was determined in 74 patients with chronic heart failure who were randomly assigned to receive either high-dose or low-dose enalapril over a period of 6 months. Monthly pre-enalapril and post-enalapril neurohormone levels (serum ACE activity (sACE), plasma angiotensin II (A-II), plasma renin activity (PRA), and serum aldosterone (ALDO) were compared between genotype subgroups and between patients who received high- or low-dose enalapril within each genotype subgroup. RESULTS: At baseline, predose/postdose sACE and postdose PRA were significantly higher in the DD genotype. At 6-month follow-up, postdose sACE was reduced in a dose-dependent fashion in all three genotypes (P < .05). However, predose and postdose ALDO and A-II levels did not differ between each genotype subgroup at baseline or by enalapril dose within each genotype subgroup. ALDO escape and A-II reactivation were not affected by ACE genotype or enalapril dosage. CONCLUSIONS: Predose sACE were consistently higher in the DD genotype when compared with ID or II subgroups. Despite a dose-dependent suppression of sACE, there were no observed statistically significant differences in ALDO and A-II suppression or escape with escalating doses of enalapril within each subgroup.
N Engl J Med. 2004 Nov 4;351(19):1952-61.
Angiotensin-receptor blockade versus converting-enzyme inhibition
in type 2 diabetes and nephropathy.
Barnett AH, Bain SC, Bouter P, Karlberg B, Madsbad S, Jervell
J, Mustonen J; Diabetics Exposed to Telmisartan and Enalapril Study Group.
Division of Medical Sciences, University of Birmingham and Birmingham
Heartlands and Solihull National Health Service Trust (Teaching), Birmingham,
United Kingdom.
BACKGROUND: Few studies have directly compared the renoprotective effects of angiotensin II-receptor blockers and angiotensin-converting-enzyme (ACE) inhibitors in persons with type 2 diabetes. METHODS: In this prospective, multicenter, double-blind, five-year study, we randomly assigned 250 subjects with type 2 diabetes and early nephropathy to receive either the angiotensin II-receptor blocker telmisartan (80 mg daily, in 120 subjects) or the ACE inhibitor enalapril (20 mg daily, in 130 subjects). The primary end point was the change in the glomerular filtration rate (determined by measuring the plasma clearance of iohexol) between the baseline value and the last available value during the five-year treatment period. Secondary end points included the annual changes in the glomerular filtration rate, serum creatinine level, urinary albumin excretion, and blood pressure; the rates of end-stage renal disease and cardiovascular events; and the rate of death from all causes. RESULTS: After five years, the change in the glomerular filtration rate was -17.9 ml per minute per 1.73 m2 of body-surface area, where the minus sign denotes a decrement, with telmisartan (in 103 subjects), as compared with -14.9 ml per minute per 1.73 m2 with enalapril (in 113 subjects), for a treatment difference of -3.0 ml per minute per 1.73 m2 (95 percent confidence interval, -7.6 to 1.6 ml per minute per 1.73 m2. The lower boundary of the confidence interval, in favor of enalapril, was greater than the predefined margin of -10.0 ml per minute per 1.73 m2, indicating that telmisartan was not inferior to enalapril. The effects of the two agents on the secondary end points were not significantly different after five years. CONCLUSIONS: Telmisartan is not inferior to enalapril in providing long-term renoprotection in persons with type 2 diabetes. These findings do not necessarily apply to persons with more advanced nephropathy, but they support the clinical equivalence of angiotensin II-receptor blockers and ACE inhibitors in persons with conditions that place them at high risk for cardiovascular events. Copyright 2004 Massachusetts Medical Society.
Pediatr Int. 2004 Oct;46(5):576-9.
Combined therapy of enalapril and losartan attenuates histologic
progression in immunoglobulin A nephropathy.
Tanaka H, Suzuki K, Nakahata T, Tsugawa K, Konno Y, Tsuruga K,
Ito E, Waga S.
Department of Pediatrics, Hirosaki University School of Medicine, Hirosaki,
Japan.
BACKGROUND: It has been reported that combined therapy of angiotensin converting enzyme inhibitor and angiotensin receptor blocker significantly decreases proteinuria in immunoglobulin A (IgA) nephropathy. However, histologic alterations following the therapy have not been reported. METHODS: A total of nine Japanese children with severe proteinuric IgA nephropathy who received a prompt immunosuppressive therapy were enrolled the study, four of whom received a combined therapy of angiotensin converting enzyme inhibitor, enalapril and angiotensin receptor blocker, losartan (Group A), while the remaining five did not (Group B). All underwent renal biopsy before and approximately 12 months after the first renal biopsy. RESULTS: At presentation, urine protein excretion and the histologic indices of mean activity index, mean chronicity index and tubulointerstitial scores did not show a statistical difference between the two groups: Group A (2.6 +/- 0.6 g/day; mean activity index, 5.0 +/- 1.0; mean chronicity index, 5.0 +/- 1.0; tubulointerstitial scores, 4.3 +/- 1.0) and Group B (2.2 +/- 0.6 g/day; mean activity index, 4.8 +/- 0.8; mean chronicity index, 4.8 +/- 1.3; tubulointerstitial scores, 3.6 +/- 0.5, respectively). All had normal blood pressure and renal function. Urine protein excretion and the activity index decreased at the second renal biopsy, while the chronicity index and the tubulointerstitial scores slightly increased or remained unchanged. In comparison with Group B, a significant suppression in increasing the chronicity index and the tubulointerstitial scores obtained at the second renal biopsy were observed in Group A [Group A: 4.3 +/- 1.2 and 3.0 +/- 0.0, respectively, vs Group B: 6.0 +/- 0.7 and 4.4 +/- 0.9, respectively (P < 0.05)]. One patient in Group B developed chronic renal insufficiency thereafter. CONCLUSIONS: Although only a small number of patients were examined, these clinical findings suggest that a combined therapy of enalapril and losartan may attenuate histologic progression in at least a proportion of patients with severe proteinuric IgA nephropathy.
Clin Ther. 2004 Aug;26(8):1292-304.
Randomized, controlled, parallel-group comparison of ambulatory
and clinic blood pressure responses to amlodipine or enalapril during
and after treatment in adult chinese patients with hypertension.
Tomlinson B, Woo J, Thomas GN, Chau YM, Critchley JA.
Department of Medicine and Therapeutics, Chinese University of Hong Kong,
Shatin, Hong Kong.
BACKGROUND: Few studies have examined the relative efficacy and tolerability of antihypertensive drug classes in Chinese populations. OBJECTIVE: This study compared the efficacy, tolerability, and duration of antihypertensive effect of amlodipine besylate and enalapril in Chinese patients with hypertension, including elderly patients with isolated systolic hypertension. METHODS: This randomized, double-blind, double-dummy, parallel-group dose-titration study was conducted at the Department of Medicine and Therapeutics, Chinese University of Hong Kong. Chinese patients aged 18 to 80 years with primary hypertension were enrolled. After a 4-week placebo run-in period, patients were randomly assigned to receive active oral, once-daily treatment with amlodipine (5 mg) or with enalapril (5 mg) for 14 weeks. Treatment doses were titrated at weeks 4 and 8 if necessary according to blood pressure (BP) response and if the dose had been tolerated. Patients also underwent 24-hour ambulatory BP monitoring (ABPM) at the end of the placebo run-in, after the first and last doses of active treatment, and 48 hours after discontinuation of treatment to determine the duration of drug action and to mimic the effect of 2 missed doses. RESULTS: Eighty patients were recruited for the study (26 men, 54 women; mean [SD] age, 60.5 [11.6] years) (40 patients per group). Thirty-seven patients in each group completed the active treatment phase. Baseline trough BPs were similar: 167.7 (15.0)/94.6 (9.7) mm Hg in the amlodipine group and 168.6 (11.9)/93.4 (9.5) mm Hg in the enalapril group. After 14 weeks of treatment, amlodipine (mean [SD] final dose, 6.3 [2.3] mg) produced greater reductions than enalapril (mean [SD] final dose, 13.3 [6.6] mg) in trough BP (-20.8 [13.2]/-9.2 [9.0] vs -5.5 [14.9]/-3.2 [10.6] mm Hg, respectively; P < or = 0.01). Most of the effect of amlodipine persisted for 72 hours after the last dose (-18.9 [14.6]/-11.1 [11.7] mm Hg), but enalapril had no significant antihypertensive effect at 72 hours (-1.3 [12.3]/-1.8 [9.1] mm Hg). Similar observations were found with ABPM recordings. Cough was reported in 5 patients (12.5%) and 13 patients (32.5%) in the amlodipine and enalapril groups, respectively, but was thought to be treatment related in only 6 patients (15.0%), all in the enalapril group. One of the patients in the enalapril group withdrew from the study because of cough, and 1 patient in the amlodipine group withdrew because of ankle edema.
Clin Cardiol. 2004 Sep;27(9):523-7.
Effects of cyclooxygenase inhibition on endothelial function in
hypertensive patients treated with angiotensin-converting enzyme inhibitors.
Yamanari H, Nakamura K, Kakishita M, Ohe T.
Department of Cardiovascular Medicine, Okayama University Medical School,
Okayama, Japan.
BACKGROUND: Cyclooxygenase inhibition restores endothelium-dependent vasodilatation in hypertension, but it is unknown whether it restores endothelial function in hypertensive patients treated with angiotensin-converting enzyme (ACE) inhibitors. HYPOTHESIS: The purpose of the present study was to evaluate the effects of cyclooxygenase inhibition on endothelial function in hypertensive patients treated with ACE inhibitors. METHODS: Endothelium-dependent flow-mediated dilatation (FMD) and endothelium-independent glyceryl trinitrate-induced dilatation were investigated in 10 patients treated with enalapril (ACE group), 11 patients treated with manidipine and metoprolol (non-ACE group), and 12 normotensive control subjects. After administration of 1000 mg of aspirin, FMD was investigated once again. Plasma cyclic guanosine monophosphate (cGMP) and eicosanoids were also measured during reactive hyperemia before and after aspirin administration. RESULTS: Flow-mediated dilatation was more impaired in the non-ACE group than in the ACE group (8.3 +/- 3.8%, 5.7 +/- 1.7%, respectively, p<0.04). Glyceryl trinitrate-induced dilatation was similar in the ACE group, the non-ACE group, and in the control subjects. In the ACE group, FMD was reduced after administration of aspirin (5.3 +/- 4.2%, p<0.05). The percent change in FMD after administration of aspirin correlated significantly with percent change in cGMP (r=0.77, p<0.03; y-intercept, -62.1%, p<0.01). After aspirin administration, levels of thromboxane B2 and 6-keto-prostaglandin(1alpha) were significantly decreased compared with those before aspirin administration in all groups. CONCLUSIONS: Cyclooxygenase inhibition may reduce the beneficial effect on endothelium-dependent vasodilatation induced by ACE inhibitors. The results suggested that prostacyclin in addition to nitric oxide plays a significant role in the restoration of endothelial function in hypertensive patients treated with ACE inhibitors.
Int J Exp Pathol. 2004 Oct;85(5):287-94.
The effect of enalapril on the cardiac remodelling in ovariectomized
spontaneously hypertensive rats.
Santos WV, Pereira LM, Mandarim-de-Lacerda CA.
Laboratory of Morphometry & Cardiovascular Morphology, Biomedical
Centre, Institute of Biology, State University of Rio de Janeiro, Rio
de Janeiro, Brazil.
Angiotensin-converting enzyme inhibitors reduce the blood pressure (BP) and inhibit the generation of the angiotensin II from the inactive angiotensin I. Ten 28-week-old spontaneously hypertensive rats (SHRs) had their ovaries bilaterally removed and five rats were left intact and studied for 7 additional weeks: intact group, ovariectomized group (ovx SHRs) and ovariectomized + enalapril group (ovx + en). BP was higher in ovx SHRs and lower in treated ovx SHRs. Left ventricular (LV) mass index was greater in untreated ovx SHRs and smaller in ovx + en group. The LV cardiomyocyte (cmy) mean cross-sectional area, measured by stereology, was greater in ovx SHRs and smaller in both intact and ovx + en SHRs. Ovx significantly decreased the density of intramyocardial blood vessels (ive), but administration of enalapril was able to restore the density of the ive to that seen in intact group. The worst ive:cmy ratio was found in untreated ovx SHRs, the intact group showed a 90% greater ratio, and the treated ovx group showed a 150% greater ratio than the untreated ovx group. In conclusion, ovariectomy, in SHRs, causes cardiac hypertrophy and an unfavourable myocardial remodelling. Of the spectrum of changes seen, the major effect of enalapril appears to be mediated via an increase in the density of ive.
Mol Cell Biochem. 2004 Jun;261(1-2):271-8.
Renin-angiotensin blockade attenuates cardiac myofibrillar remodelling
in chronic diabetes.
Machackova J, Liu X, Lukas A, Dhalla NS.
Institute of Cardiovascular Sciences, St. Boniface General Hospital Research
Centre; Department of Physiology, Faculty of Medicine, University of Manitoba,
Winnipeg, Manitoba, Canada.
Previous studies have shown that the renin-angiotensin system (RAS) is
activated in diabetes and this may contribute to the subcellular remodelling
and heart dysfunction in this disease. Therefore, we examined the effects
of RAS blockade by enalapril, an angiotensin-converting enzyme inhibitor,
and losartan, an angiotensin receptor AT1 antagonist, on cardiac function,
myofibrillar and myosin ATPase activity as well as myosin heavy chain
(MHC) isozyme expression in diabetic hearts. Diabetes was induced in rats
by a single injection of streptozotocin (65 mg/kg; i.v.) and these animals
were treated with and without enalapril (10 mg/kg/day; oral) or losartan
(20 mg/kg/day; oral) for 8 weeks. Enalapril or losartan prevented the
depressions in left ventricular rate of pressure development, rate of
pressure decay and ventricular weight seen in diabetic animals. Both drugs
also attenuated the decrease in myofibrillar Ca2+-ATPase, Mg2+-ATPase
and myosin ATPase activity seen in diabetic rats. The diabetes-induced
increase in beta-MHC content and gene expression as well as the decrease
in alpha-MHC content and mRNA levels were also prevented by enalapril
and losartan. These results suggest the occurrence of myofibrillar remodelling
in diabetic cardiomyopathy and provide evidence that the beneficial effects
of RAS blockade in diabetes may be associated with attenuation of myofibrillar
remodelling in the heart.
Jpn Heart J. 2004 Jul;45(4):623-35.
A double blind randomized trial to compare the effects of eprosartan
and enalapril on blood pressure, platelets, and endothelium function in
patients with essential hypertension.
Leu HB, Charng MJ, Ding PY.
Division of Cardiology, Taipei Veterans General Hospital and National
Yang-Ming University, Taiwan, ROC.
The renin-angiotensin system is the major contributor to development of hypertension, atherosclerosis, and many other cardiovascular diseases. Angiotensin II, one of the main effectors of this system, contributes to the pathogenesis of hypertension and plays an important role in monocyte, platelet, and endothelium interactions. The effects on platelet and endothelial function, either by angiotensin converting enzyme inhibitors or angiotensin receptor antagonists, are still not well understood. A double-blind, randomized, prospective trial of either enalapril (10-20 mg daily) or eprosartan (400-800 mg daily) over a 10-week period was conducted in 42 patients (27 males, 15 females). Platelet activation was evaluated by measuring platelet factor 4 (PF-4), beta-thromboglobulin (beta-TG), the ratio of platelet factor 4 to beta-thromboglobulin, and endothelial function by measuring total plasma nitrate levels, von Willebrand factor (vWF) levels, and blood flow using venous occlusive plethysmography. After a 10-week treatment with enalapril or eprosartan, the sitting blood pressure in both the enalapril group (from 152.2 +/- 18.7 mmHg to 141.9 +/- 23.5 mmHg, P < 0.05) and eprosartan group (from 151 +/- 10.0 mmHg to 142.3 +/- 12.9 mmHg, P < 0.05) was significantly reduced. Significant diastolic blood pressure (DPB) reduction (from 94 +/- 8.7 to 84.5 +/- 9.6 mmHg, P < 0.05) and a greater DBP reduction response were found in the eprosartan group (63% in eprosartan versus 25% in enalapril). Additionally, dose-dependent reductions in the indices of platelet activation and endothelial dysfunction were observed in patients administered high dose treatments of eprosartan and enalapril, and the beneficial effects of these agents were not correlated with the reduction of blood pressure using both agents. Eprosartan is effective and well-tolerated in the treatment of mid-to-moderate hypertension, and the DBP response reduction to eprosartin was better than that to enalapril. A high dose of either eprosartan or enalapril significantly decreased the indices of platelet activation and endothelial dysfunction in hypertensive patients. The benefits of both agents cannot be explained solely by their antihypertensive effects and possibly may be mediated through their unique effect on angiotensin blockade. Copyright 2004 American Chemical Society
Am J Cardiol. 2004 Sep 1;94(5):564-9.
Effect of enalapril and losartan on cytokines in patients with
stable angina pectoris awaiting coronary artery bypass grafting and their
interaction with polymorphisms in the interleukin-6 gene.
Trevelyan J, Brull DJ, Needham EW, Montgomery HE, Morris A, Mattu
RK.
Department of Cardiology, University Hospitals of Coventry and Warwickshire,
Coventry, United Kingdom.
Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may have anti-inflammatory actions, an effect that could explain some of their beneficial effects on cardiovascular events in clinical trials. Coronary artery bypass grafting (CABG) is associated with a systemic inflammatory response and provides a convenient model to examine the effects of such agents. Genetic polymorphisms may be important in influencing the expression of cytokines, such as interleukin-6 (IL-6). We randomized men awaiting CABG to treatment with enalapril, losartan, or control for 2 months before surgery. Systemic IL-6, IL-8, IL-10, and IL-1 receptor agonists were measured before and after surgery, and genotypes for the -174 G/C and -572 G/C IL-6 gene polymorphisms were determined. Total release of the IL-1 receptor agonist was decreased 29% by enalapril and 31% by losartan (adjusted p = 0.041). IL-6 was decreased 17% by enalapril and 20% by losartan. Subjects possessing the -174 GG genotype produced 20% more IL-6 (adjusted p = 0.029). In these high producers of IL-6, release of IL-6 was decreased 51% by enalapril (adjusted p = 0.001) and 32% by losartan (adjusted p = 0.068). Release of IL-10 was nonsignificantly decreased 26% by enalapril and 21% by losartan, whereas IL-8 was not detected. In conclusion, enalapril and losartan significantly decreased release of the IL-1 receptor agonist after CABG. Enalapril produced a highly significant decrease of 51% in the release of IL-6 in patients identified as high producers of IL-6 by the -174 G/C polymorphism, whereas losartan has a similar but less marked effect. The production of IL-6 in this setting is influenced by the -174 G/C polymorphism. Copyright 2004 Excerpta Medica, Inc.
Am Heart J. 2004 Jun;147(6):1061-5.
Enalapril treatment and hospitalization with atrial tachyarrhythmias
in patients with left ventricular dysfunction.
Alsheikh-Ali AA, Wang PJ, Rand W, Konstam MA, Homoud MK, Link
MS, Estes NA 3rd, Salem DN, Al-Ahmad AM.
Tufts-New England Medical Center, Department of Medicine, Division of
Cardiolgy, Boston, Mass, USA.
BACKGROUND: Experimental and clinical evidence suggests a preventive
role for agiotensin-coverting enzyme (ACE) inhibitors on the development
of atrial fibrillation. However, the effect of ACE inhibition on hospitalization
with atrial tachyarrhythmias in patients with left ventricular (LV) dysfunction
is not known. We sought to determine whether enalapril treatment reduced
hospitalizations with atrial tachyarrhythmias in patients with LV dysfunction.
METHODS: We performed a retrospective analysis of the Studies of Left
Ventricular Dysfunction (SOLVD) trial. Hospitalizations with atrial tachyarrhythmias
were noted. RESULTS: A total of 192 hospitalizations with atrial tachyarrhythmias
occurred in 158 patients during a follow-up period of 34 months. The time
to first hospitalization with atrial tachyarrhythmias or death was significantly
lower in the enalapril group (P =.005). In a multivariate analysis adjusting
for the presence of atrial fibrillation at study entry, enalapril treatment
was associated with a reduction in the rate of hospitalization with atrial
tachyarrhythmias or death (RR, 0.87; 95% CI, 0.79-0.96; P =.007). The
incidence of hospitalization with atrial tachyarrhythmias was 7.9 hospitalizations
per 1000 patient-years of follow-up in the enalapril group, compared with
12.4 per 1000 patient-years in the placebo group (RR, 0.64; 95% CI, 0.48-0.85;
P =.002). CONCLUSION: Enalapril is associated with a decreased incidence
of hospitalization with atrial tachyarrhythmias in patients with LV dysfunction.
