Angiotensin-converting Enzyme Inhibitor Lisinopril Research Articles

Stiffness of the Arterial Wall and Central Hemodynamics During Long-Term Combination Antihypertensive Therapy

Aim of the METR study - to assess effect of antihypertensive therapy with fixed combination of angiotensin converting enzyme inhibitor lisinopril (10 mg) and calcium antagonist amlodipine (5 mg) on parameters of arterial wall stiffness and central hemodynamics in patients with stage I-II essential hypertension (EH) and functional class II-III ischemic heart disease. Combination therapy was associated with persistent lowering of central arterial pressure, decrease of augmentation index and other parameters of arterial wall stiffness, and reduction of left ventricular myocardial mass. These changes have a potential to lower risk of cardiovascular complications and improve prognosis of patients with EH.

Elucidating the Role of Mineralocorticoid Receptors in Skeletal Muscle as a Potential Therapeutic Target for Duchenne Muscular Dystrophy

Our lab identified a potential new treatment for Duchenne Muscular Dystrophy using the mineralocorticoid receptor (MR) antagonist spironolactone and ACE inhibitor lisinopril. Drug studies using dystrophic Het (utrn+/-;mdx) mice showed a dramatic improvement in both respiratory and limb muscle force and a reduction of ongoing muscle damage, in addition to preventing cardiomyopathy. We show MR is present in both skeletal muscle tissue and myogenic cultures, supporting a direct affect by MR antagonists on skeletal muscle. Global analysis of gene expression between treated and untreated dystrophic mice identified potential molecular targets to unravel the drugs' mode of action. Preliminary microarray data comparing quadriceps muscle from lisinopril and spironolactone treated het mice to untreated controls revealed changes in the expression of several gene targets with known roles in striated muscle, Gene Name Gene Symbol Fold-change (Treated/Control) Role in Striated Muscle ankyrin repeat domain 1 Ankrd1 -2.15634 Marker of skeletal muscle pathological remodeling tight junction protein 2 Tjp2 -2.02372 Important molecular target in vascular remodeling myosin VA Myo5a -2.12497 Involved in maturation of NMJs in regenerating muscle mid1 interacting protein 1 Mid1ip1 -2.48061 Potential biomarker of skeletal myopathy myosin binding protein H Mybph 2.059236 Muscle remodeling in response to injury thyroid hormone responsive SPOT14 homolog Thrsp 2.138901 Modulator of fatty acid synthesis which have been confirmed using immunofluorescence and western blot analysis. Myogenic cultures treated with MR agonists and antagonists are being used to test whether these potential downstream targets are affected in a cell autologous manner in skeletal muscle and represent bona fide MR gene targets. NIH 1 R01 NS082868; T32 NS077984

Optimal Control Strategy Allies in Blood Pressure

to review the available results of clinical trials on the efficacy and safety of a fixed combination of an angiotensin-converting enzyme (ACE) inhibitor lisinopril and the calcium antagonist amlodipine, including an analysis of the actual antihypertensive effect and organoprotective action in the russian population of patients. The main objectives of the treatment of hypertension is to achieve target blood pressure level and protection of target organs. According to the available evidence base these properties to a greater extent have only ACE inhibitors and calcium antagonists. When analyzing the results of clinical studies using a fixed combination of lisinopril and amlodipine revealed high levels of efficacy and safety in patients suffering from hypertension and related to different groups at risk of developing cardiovascular complications. The combination of lisinopril and amlodipine is a key for effective, safe control of blood pressure, organoprotection and high adherence to the treatment of patients with hypertension.

The effects of micelles of differently charged surfactants on the equilibrium between (Z)- and (E)-diastereomers of five ACE inhibitors in aqueous media

The (Z)/(E) equilibria in water solutions of five ACE inhibitors (captopril, enalapril, lisinopril, perindopril, and ramipril) in presence and in absence of surfactants (anionic sodium dodecyl sulfate, cationic cetyltrimethyl ammonium bromide, and non-ionic 4-octylphenol poly- ethoxylate) were analyzed by reversed-phase high- performance liquid chromatography. The results showed that the (Z)/(E) equilibrium of lisinopril and captopril was the least sensitive to the effect of the examined surfactants. 4-Octylphenol polyethoxylate expressed the weakest effect on isomerization of the ACE inhibitors, while the (Z)/ (E) equilibria of enalapril, ramipril, and perindopril were the most sensitive to the presence of sodium dodecyl sul- fate and cetyltrimethyl ammonium bromide. In addition, the response of two structurally very close compounds, such as enalapril and ramipril to the presence of sodium dodecyl sulfate and cetyltrimethyl ammonium bromide was opposite, and these two ACE inhibitors had different chromatographic behavior. To provide a better insight into the reasons for the differences in order of elution of (Z)- and (E)-diastereomers and the possible molecular mecha- nism underlying their retention, (Z)- and (E)-diastereomers of enalapril and ramipril were subjected to a theoretical study optimized at the B3LYP/6-31G (d,p) level of den- sity functional theory. The Connolly solvent-excluded volume was taken as the most significant parameter that can be connected to differences in chromatographic behavior of the (Z)- and (E)-diastereomers of enalapril and ramipril. Graphical abstract

Renal function in children and adolescents with Duchenne muscular dystrophy

Improved life expectancy and the need for robust tools to monitor renal safety of emerging new therapies have fueled the interest in renal function in Duchenne muscular dystrophy (DMD) patients. We aimed to establish a methodology to accurately assess their renal function. Twenty DMD patients (5–22 years) were included in this prospective study. After obtaining medical history, all patients underwent a clinical examination, 24-hour ambulatory blood pressure monitoring, ultrasound of the kidneys, direct GFR measurement (51Cr-EDTA, mGFR), complete blood and urine analysis. Seventeen of 20 patients were treated with corticosteroids and 5/20 with angiotensin converting enzyme inhibitor (lisinopril). No patient suffered from urinary tract infections or other renal diseases. Hypertension (systolic or diastolic blood pressure >P95) was found in 9/20 patients (8/9 patients were on steroid treatment) and a non-dipping blood pressure profile in 13/20 subjects (10/13 patients were on steroid treatment). Urinary protein to creatinine ratio was elevated in 17/18 patients, whereas 24-hour urine protein excretion was normal in all subjects. Median interquartile range (IQR) mGFR was 130.4 (29.1) mL/min/1.73 m2. Hyperfiltration (mGFR >150 mL/min/1.73 m2) was found in 5/20 patients. Inverse correlation between mGFR and age was observed (R2 = 0.45, p = 0.001). Serum creatinine based estimated GFR (eGFR) equations overestimated mGFR up to 300%. eGFR based on cystatin C Filler equation was closest to the mGFR (median eGFR (IQR) of 129.5 (39.7) mL/min/1.73 m2). Our study demonstrates a high prevalence of hyperfiltration and hypertension in children and adolescents with DMD. Because the majority of hypertensive patients were under corticosteroid treatment, the iatrogenic cause of hypertension cannot be excluded. Serum or urine creatinine measurements are of no value to evaluate renal function in DMD patients due to the reduced skeletal muscle mass.

Angiotensin Blockade in Late Autosomal Dominant Polycystic Kidney Disease

BackgroundHypertension develops early in patients with autosomal dominant polycystic kidney disease (ADPKD) and is associated with disease progression. The renin–angiotensin–aldosterone system (RAAS) is implicated in the pathogenesis of hypertension in patients with ADPKD. Dual blockade of the RAAS may circumvent compensatory mechanisms that limit the efficacy of monotherapy with an angiotensin-converting–enzyme (ACE) inhibitor or angiotensin II–receptor blocker (ARB).MethodsIn this double-blind, placebo-controlled trial, we randomly assigned 486 patients, 18 to 64 years of age, with ADPKD (estimated glomerular filtration rate [GFR], 25 to 60 ml per minute per 1.73 m2 of body-surface area) to receive an ACE inhibitor (lisinopril) and placebo or lisinopril and an ARB (telmisartan), with the doses adjusted to achieve a blood pressure of 110/70 to 130/80 mm Hg. The composite primary outcome was the time to death, end-stage renal disease, or a 50% reduction from the baseline estimated GFR. Secondary outcomes included the rates of change in urinary aldosterone and albumin excretion, frequency of hospitalizations for any cause and for cardiovascular causes, incidence of pain, frequency of ADPKD-related symptoms, quality of life, and adverse study-medication effects. Patients were followed for 5 to 8 years.ResultsThere was no significant difference between the study groups in the incidence of the composite primary outcome (hazard ratio with lisinopril–telmisartan, 1.08; 95% confidence interval, 0.82 to 1.42). The two treatments controlled blood pressure and lowered urinary aldosterone excretion similarly. The rates of decline in the estimated GFR, urinary albumin excretion, and other secondary outcomes and adverse events, including hyperkalemia and acute kidney injury, were also similar in the two groups.ConclusionsMonotherapy with an ACE inhibitor was associated with blood-pressure control in most patients with ADPKD and stage 3 chronic kidney disease. The addition of an ARB did not alter the decline in the estimated GFR. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; HALT-PKD [Study B] ClinicalTrials.gov number, NCT01885559.)

Association of insertion/deletion polymorphism of angiotensin-converting enzyme gene among Malay male hypertensive subjects in response to ACE inhibitors.

Several studies show that the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene has been associated with hypertension in various populations. The present study sought to determine the association of the I/D gene polymorphism among Malay male essential hypertensive subjects in response to ACE inhibitors (enalapril and lisinopril). A total of 72 patients with newly diagnosed hypertension and 72 healthy subjects were recruited in this study. Blood pressure was recorded from 0 to 24 weeks of treatment with enalapril or lisinopril. Genotyping of the I/D polymorphism was carried out using a standard PCR method. Statistically significant association of the D allele of the ACE gene was observed between the case and control subjects (p < 0.01). There was a decrease in blood pressure in the patients carrying the DD genotype (SBP=18.5±8.1 mmHg, DBP=15.29±7.1 mmHg) rather than the ID (SBP=4.1±3.3 mmHg, DBP=9.1±3.5 mmHg) and II genotypes (SBP= 3.0±0.2 mmHg, DBP 0.11±6.1 mmHg) of the ACE gene. Patients carrying the DD genotype had higher blood pressure-lowering response when treated with ACE inhibitors enalapril or lisinopril than those carrying ID and II genotypes, suggesting that the D allele may be a possible genetic marker for essential hypertension among Malay male subjects.

Chronic infusion of lisinopril into hypothalamic paraventricular nucleus modulates cytokines and attenuates oxidative stress in rostral ventrolateral medulla in hypertension

The hypothalamic paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM) play a critical role in the generation and maintenance of sympathetic nerve activity. The renin–angiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. This study was designed to determine whether inhibition of the angiotensin-converting enzyme (ACE) in the PVN modulates cytokines and attenuates oxidative stress (ROS) in the RVLM, and decreases the blood pressure and sympathetic activity in renovascular hypertensive rats. Renovascular hypertension was induced in male Sprague–Dawley rats by the two-kidney one-clip (2K1C) method. Renovascular hypertensive rats received bilateral PVN infusion with ACE inhibitor lisinopril (LSP, 10μg/h) or vehicle via osmotic minipump for 4weeks. Mean arterial pressure (MAP), renal sympathetic nerve activity (RSNA), and plasma proinflammatory cytokines (PICs) were significantly increased in renovascular hypertensive rats. The renovascular hypertensive rats also had higher levels of ACE in the PVN, and lower level of interleukin-10 (IL-10) in the RVLM. In addition, the levels of PICs, the chemokine MCP-1, the subunit of NAD(P)H oxidase (gp91phox) and ROS in the RVLM were increased in hypertensive rats. PVN treatment with LSP attenuated those changes occurring in renovascular hypertensive rats. Our findings suggest that the beneficial effects of ACE inhibition in the PVN in renovascular hypertension are partly due to modulation cytokines and attenuation oxidative stress in the RVLM.

Unilateraal angio-oedeem van de tong en de mondbodem door ACE-remmers

An 80-year-old woman who was medically compromised had recurrent diffuse unilateral swelling of the tongue and the floor of the mouth. The clinical working diagnosis of angioedema as a result of the use of ACE-inhibitors (lisinopril) was made. In consultation with the cardiologist in charge of her case and the general practitioner, the ACE-inhibitor was discontinued. The patient's complaints subsequently ceased.

Angiotensinergic neurotransmission in the paraventricular nucleus of the hypothalamus modulates the pressor response to acute restraint stress in rats

We tested the hypothesis that the angiotensinergic neurotransmission, specifically in the paraventricular nucleus of the hypothalamus (PVN), is involved in the cardiovascular modulation during acute restraint stress (RS) in rats. The intravenous pretreatment with the angiotensin AT1 receptor antagonist losartan (5mg/kg) inhibited the pressor response to RS, but did not affect the concomitant RS-evoked tachycardiac response. Because similar effects were observed after the PVN pretreatment with CoCl2, and considering the high density of angiotensin receptors reported in the PVN, we studied the effect of the pretreatment of the PVN with either losartan or the angiotensin-converting enzyme (ACE) inhibitor lisinopril on the RS-evoked cardiovascular response. The bilateral microinjection of losartan (0.5nmol/100nL) or lisinopril (0.5nmol/100nL) into the PVN inhibited the RS-related pressor response without affecting the tachycardiac response, suggesting that the PVN angiotensinergic neurotransmission modulates the vascular component of the stress response. Finally, to exclude the possibility that centrally injected drugs could be leaking to the circulation and acting on peripheral vascular receptors, we tested the effect of the intravenous pretreatment with either losartan (0.5nmol/animal) or lisinopril (0.5nmol/animal), assuming the hypothesis of a total spread of drugs from the CNS to the peripheral circulation. When animals were pretreated with such doses of either losartan or lisinopril, the cardiovascular RS-evoked response was not affected, thus indicating that even if there were a complete leakage of the drug to the periphery, it would not affect the cardiovascular response to RS. This observation favors the idea that the effect of the intravenous injection of 5mg/kg of losartan on the RS-related cardiovascular response would be explained by an action across the blood–brain barrier, possibly in the PVN. In conclusion, the results suggest that an angiotensinergic neurotransmission in the PVN acting on AT1-receptors modulates the vascular component of the RS-evoked cardiovascular response.

Lisinopril in the composition of calcium phosphate nanoparticles as a promising antiglaucoma agent

A method of preparing calcium phosphate particles containing the angiotensin-converting enzyme inhibitor lisinopril has been suggested. The influence of the conditions of preparation of the particles on their characteristics (size, ζ-potential values, and structure) has been determined. It has been demonstrated that, at a reduced temperature (4°C) of preparation, particles with hydrodynamic radii 40–100 nm with a hollow porous structure and high degree of crystallinity are formed, while at high temperatures (40°C), amorphous particles with hydrodynamic radii 60–230 nm are formed. A decrease of the pH value of a medium from 7.5 to 5.8 resulted in the appearance of only large particles with mean hydrodynamic radius of approximately 400 nm. Replacing the potential-determining Na+ ions with K+ resulted in a higher absolute value of the ζ potential (−15 ± 2 mV compared to −6 ± 1 mV). It has been demonstrated in the experiments in vivo that lisinopril incorporated in the calcium phosphate particles caused a significantly stronger (approximately 2 times) and prolonged decrease of the intraocular pressure when compared to the same inhibitor used in the form of an aqueous solution.

Pharmacokinetic evaluation of lisinopril-tryptophan, a novel C-domain ACE inhibitor

Angiotensin-converting enzyme (ACE, EC 3.4.15.1) is a metallopeptidase comprised of two homologous catalytic domains (N- and C-domains). The C-domain cleaves the vasoactive angiotensin II precursor, angiotensin I, more efficiently than the N-domain. Thus, C-domain-selective ACE inhibitors have been designed to investigate the pharmacological effects of blocking the C-terminal catalytic site of the enzyme and improve the side effect profile of current ACE inhibitors. Lisinopril-tryptophan (LisW-S), an analogue of the ACE inhibitor lisinopril, is highly selective for the C-domain. In this study, we have analysed the ex vivo domain selectivity and pharmacokinetic profile of LisW-S. The IC50 value of LisW-S was 38.5nM in rat plasma using the fluorogenic substrate Abz-FRKP(Dnp)P-OH. For the pharmacokinetics analysis of LisW-S, a sensitive and selective LC–MS/MS method was developed and validated to determine the concentration of LisW-S in rat plasma. LisW-S was administered to Wistar rats at a dose of 1mg/kg bodyweight intravenously, 5mg/kg bodyweight orally. The Cmax obtained following oral administration of the drug was 0.082μM and LisW-S had an apparent terminal elimination half-life of around 3.1h. The pharmacokinetic data indicate that the oral bioavailability of LisW-S was approximately 5.4%. These data provide a basis for better understanding the absorption mechanism of LisW-S and evaluating its clinical application.

In Vitro modeling of angiotensin-converting enzyme inhibitor's absorption with chromatographic retention data and selected molecular descriptors

Set of nine angiotensin-converting enzyme inhibitors (enalapril, quinapril, fosinopril, lisinopril, cilazapril, ramipril, benazepril, perindopril and moexipril) were studied to evaluate the correlation between their intestinal absorption and salting-out thin-layer chromatography hydrophobicity parameters (RM(0) or C0) obtained by ascending technique applying four different salts, (NH4)2SO4, NH4NO3, NH4Cl and NaCl as mobile phases. The best correlations between KOWWIN logP and both hydrophobicity parameters, RM(0) and C0, (R(2)>0.850) were observed for NaCl (1.0-3.0M) while the lowest R(2) was obtained for (NH4)2SO4 (0.649 and 0.427, respectively) due to highest salting-out effect of (NH4)2SO4. The effect of selected inorganic salts in the salting-out mobile phases, on the solutes solubility and retention was evaluated. The topological polar surface area should be selected as independent variable (only this molecular descriptor showed low correlation with chromatographic hydrophobicity parameters) for multiple linear regression analysis, to obtain reliable correlation between angiotensin-converting enzyme inhibitor's intestinal absorption data and salting-out thin-layer chromatograpic hydrophobicity parameters. These correlations provide R(2)=0.823 for RM(0) or R(2)=0.799 for C0 indicating good relationship between predicted and literature available intestinal absorption (ranged from 22% to 70%) of investigated angiotensin-converting enzyme inhibitors. The proposed in vitro model was checked with three in addition experimentally analyzed drugs, zofenopril, trandolapril and captoril. The satisfactory absorption prediction was obtained for zofenopril and trandolapril, while divergence established for captopril resulted from considerably different structure.

Renoprotective Effect of Ace Inhibitor-Lisinopril and Heme Oxygenase-1 Inducer-Hemin Combination against Streptozotocin Induced Advanced Diabetic Nephropathy in Rats

Renoprotective Effect of Ace Inhibitor-Lisinopril and Heme Oxygenase-1 Inducer-Hemin Combination against Streptozotocin Induced Advanced Diabetic Nephropathy in Rats

FACILE AND MANIFEST RPHPLC METHOD FOR THE DETERMINATION OF CAPTPRIL, LISIOPRIL, ENALPRIL AND DICLOFENAC SODIUM: ITS APPLICATIONS IN DOSAGE FORMULATIONS AND IN HUMAN SERUM

A simple, rapid, isocratic, high-performance liquid chromatography (RP-HPLC) method has been developed for the first time for simultaneous determination of ACE inhibitors (captopril, lisinopril and enalapril) and diclofenac sodium in bulk drugs, pharmaceutical products and human serum.

CHOICE OF LISINOPRIL FOR TREATMENT OF HYPERTENSION IN PATIENTS WITH CONCOMITANT DISEASES

Rationale and benefits of the use of the ACE inhibitor lisinopril in the clinical practice as an antihypertensive drug are considered. Special attention is paid to the organ protective effects of lisinopril and its application in some clinical situations (combination of hypertension with chronic obstructive pulmonary disease, elderly patients, and concomitant liver diseases).

Concurrent determination of Metformin and some ACE inhibitors: Its application to Pharmacokinetics

This study illustrates development and validation of a simple high performance liquid chromatographic method for the simultaneous determination of metformin hydrochloride and angiotensin-converting enzyme inhibitors (captopril, lisinopril, and enalapril) in bulk dosage form and their application in pharmacokinetic studies. The quality resolute chromatogram was obtained by using a Purospher® Star RP-18 endcapped (250×4.6mm id) column as stationary phase while acetonitrile-water 50:50 (v/v) as mobile phase, adjusted to pH 3.0 with phosphoric acid. Effluent was monitored at a flow rate of 1mLmin−1 at room temperature (25°C), detector was set at 218nm. The method was validated according to ICH guidelines. The linearity was studied over the concentration range of 10–10,000ngmL−1 for metformin and 30–10,000ngmL−1 for captopril, lisinopril, and enalapril, demonstrating good linearity with minimum r=0.9964, respectively. The developed method was successfully applied to pharmacokinetic studies of metformin, lisinopril, captopril and enalapril.

The Effects of Anionic, Cationic, and Nonionic Surfactants on Acid–Base Equilibria of ACE Inhibitors

The pKa values of ACE inhibitors captopril, cilazapril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, and zofenopril were determined by potentiometry. Because to the presence of single or several ionizable groups (carboxyl, thiol, primary and secondary amino groups) these substances represent acids and ampholytes. Determinations of pKa values were performed at 25 °C and constant ionic strength of 0.1 M (NaCl), in the absence and in the presence of surfactants, anionic sodium dodecyl sulfate (SDS), cationic cetyltrimethyl ammonium bromide (CTAB), and nonionic 4-octylphenol polyethoxylate (TX 100). A computer program Hyperquad was used to derive pKa values from the data obtained by potentiometric titrations. The observed shift of pKa values from +1.90 to −1.54 pK units demonstrated a significant effect of the surfactants on ionization of ACE inhibitors. It has been observed that the carboxyl group was more susceptible to the effect of the above surfactants than the amino group. Also, among the three surfactants employed, SDS expressed the most prominent effect on acid–base equilibria. On the basis of the shifts of pKa values in the presence of the applied surfactants different ACE inhibitor–micelle interactions were suggested.

Risk of Hospitalized Gastrointestinal Bleeding in Persons Randomized to Diuretic, ACE‐Inhibitor, or Calcium‐Channel Blocker in ALLHAT

Calcium channel blockers (CCBs) are an important class of medication useful in the treatment of hypertension. Several observational studies have suggested an association between CCB therapy and gastrointestinal (GI) hemorrhage. Using administrative databases, the authors re-examined in a post-hoc analysis whether the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants randomized to the CCB amlodipine had a greater risk of hospitalized GI bleeding (a prespecified outcome) compared with those randomized to the diuretic chlorthalidone or the angiotensin-converting enzyme inhibitor lisinopril. Participants randomized to chlorthalidone did not have a reduced risk for GI bleeding hospitalizations compared with participants randomized to amlodipine (hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.92-1.28). Those randomized to lisinopril were at increased risk of GI bleeding compared with those randomized to chlorthalidone (HR, 1.16; 95% CI, 1.00-1.36). In a post-hoc comparison, participants assigned to lisinopril therapy had a higher risk of hospitalized GI hemorrhage (HR, 1.27; 95% CI, 1.06-1.51) vs those assigned to amlodipine. In-study use of atenolol prior to first GI hemorrhage was related to a lower incidence of GI bleeding (HR, 0.69; 95% CI, 0.57-0.83). Hypertensive patients on amlodipine do not have an increased risk of GI bleeding hospitalizations compared with those taking either chlorthalidone or lisinopril.

Mortality and Morbidity During and After Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial

To determine whether an angiotensin-converting enzyme inhibitor (lisinopril) or calcium channel blocker (amlodipine) is superior to a diuretic (chlorthalidone) in reducing cardiovascular disease incidence in sex subgroups, we carried out a prespecified subgroup analysis of 15 638 women and 17 719 men in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Total follow-up (active treatment + passive surveillance using national administrative databases to ascertain deaths and hospitalizations) was 8 to 13 years. The primary outcome was fatal coronary heart disease or nonfatal myocardial infarction. Secondary outcomes included all-cause mortality, stroke, combined cardiovascular disease (coronary heart disease death, nonfatal myocardial infarction, stroke, angina, coronary revascularization, heart failure [HF], or peripheral vascular disease), and end-stage renal disease. In-trial rates of HF, stroke, and combined cardiovascular disease were significantly higher for lisinopril compared with chlorthalidone, and rates of HF were significantly higher for amlodipine compared with chlorthalidone in both men and women. There were no significant treatment sex interactions. These findings did not persist through the extension period with the exception of the HF result for amlodipine versus chlorthalidone, which did not differ significantly by sex. For both women and men, rates were not lower in the amlodipine or lisinopril groups than in the chlorthalidone group for either the primary coronary heart disease outcome or any other cardiovascular disease outcome, and chlorthalidone-based treatment resulted in the lowest risk of HF. Neither lisinopril nor amlodipine is superior to chlorthalidone for initial treatment of hypertension in either women or men. Clinical Trial Registration— clinicaltrials.gov ; Identifier: NCT00000542.