Plasma Angiotensin-converting Enzyme Concentration Research Articles

Correlation between serum angiotensin-converting enzyme (ACE) levels and intervertebral disc degeneration

Studies have shown that the renin-angiotensin system (RAS) might play an essential role in intervertebral disc degeneration (IDD). The study aimed to investigate the relationship between serum angiotensin-converting enzyme (ACE) concentration and IDD and its predictive value for severe disc degeneration. 245 patients who came to our hospital for low back pain were recruited, and blood samples were collected for routine examination. Descriptive data and demographic parameters were collected. The cumulative grade 1 was calculated by summing up the Pfirrmann grade of all lumbar discs. ACE concentration grouping was determined via tertile split. Correlation analysis and multivariable linear regression analysis were performed to determine the relationship between ACE and IDD. The receiver's degree of disc degeneration (ROC) curve determined the ACE's predictive value. Results indicated that there was no significant difference in demographic parameters among groups. Correlation analysis and multivariate linear analysis showed that ACE was an independent risk factor for IDD. The cumulative grade 1 increased significantly with the increase in ACE concentration, which was consistent with the correlation analysis. Average Pfirrmann grade < 4 indicates mild to moderate degeneration, and grade ≥ 4 indicates severe degeneration in terms of an individual disc. From L1/2 to L5/S1, the mean plasma ACE concentration was significantly higher in the severe degeneration group than in the mild to moderate degeneration group. According to the ROC curve, the cut-off value of ACE levels was 22.5. patients with ACE > 22.5 had severe degeneration. The sensitivity and specificity were 0.762 and 0.521, respectively.

Reduced blood pressure in sickle cell disease is associated with decreased angiotensin converting enzyme (ACE) activity and is not modulated by ACE inhibition.

BackgroundSickle cell disease (SCD) incurs vaso-occlusive episodes and organ damage, including nephropathy. Despite displaying characteristics of vascular dysfunction, SCD patients tend to present relatively lower systemic blood pressure (BP), via an unknown mechanism. We investigated associations between BP and renin-angiotensin-system (RAS) components in SCD and determined whether an inhibitor of angiotensin converting enzyme (ACE; often used to slow SCD glomerulopathy) further modulates BP and RAS components in a murine model of SCD.MethodsBP was compared in human subjects and mice with/without SCD. Plasma angiotensin II, ACE and renin were measured by immunoassay. BP was reevaluated after treating mice with enalapril (25 mg/kg, 5x/week) for 5 weeks; plasma and organs were stored for angiotensin II and ACE activity measurement, and quantitative real-time PCR.ResultsDiastolic BP and systolic BP were significantly lower in patients and mice with SCD, respectively, compared to controls. Reduced BP was associated with increased plasma renin and markers of kidney damage (mice) in SCD, as well as significantly decreased plasma ACE concentrations and ACE enzyme activity. As expected, enalapril administration lowered BP, plasma angiotensin II and organ ACE activity in control mice. In contrast, enalapril did not further reduce BP or organ ACE activity in SCD mice; however, plasma angiotensin II and renin levels were found to be significantly higher in enalapril-treated SCD mice than those of treated control mice.ConclusionRelative hypotension was confirmed in a murine model of SCD, in association with decreased ACE concentrations in both human and murine disease. Given that ACE inhibition has an accepted role in decreasing BP, further studies should investigate mechanisms by which ACE depletion, via both Ang II-dependent and alternative pathways, could contribute to reduce BP in SCD and understand how ACE inhibition confers Ang II-independent benefits on kidney function in SCD.

The angiotensin-converting enzyme insertion/deletion polymorphism rs4340 associates with habitual physical activity among European American adults.

BackgroundThe angiotensin‐converting enzyme (ACE) insertion/deletion (I/D) polymorphism (rs4340) (ACE DIP) accounts for half of the variability in plasma ACE concentrations. ACE has been widely studied for its influence on sports performance; however, research on its influence in physical activity is limited and inconsistent. We examined the influence of the ACE DIP on physical activity among 461 European Americans.MethodsSubjects completed the Paffenbarger Physical Activity Questionnaire for weekly walking distance. Multivariate analysis of covariance (MANCOVA) tested log‐transformed differences in weekly walking distance among ACE DIP genotypes (II, ID, DD) with gender as a fixed factor, and age and body mass index (BMI) as covariates. Because we found a significant ACE DIPxBMI interaction (P = 0.03), we categorized the sample by normal weight (NW: BMI<25.0 kg/m2) and overweight (OW: BMI ≥25.0 kg/m2) and repeated the MANCOVA with multiple comparison adjustments.Results NW adults with ACE II walked 15.8 ± 11.1 km/week, ID 13.2 ± 10.6 km/week, and DD 17.9 ± 13.0 km/week, with ID walking less than II (P = 0.03) and DD (P = 0.01). OW adults with ACE II walked 16.7 ± 12.6 km/week, ID 13.8 ± 11.6 km/week, and DD 9.7 ± 9.0 km/week, with DD walking less than II (P = 0.02). Weekly walking distance was 8.2 ± 2.4 km/week less among OW adults with ACE DD than NW (P = 0.02).Conclusion BMI interacted with ACE DD such that OW walked ~8.2 km/week less than NW, potentially equating to a body weight differential of ~3.5 kg annually.

ACE Phenotyping as a Guide Toward Personalized Therapy With ACE Inhibitors.

Angiotensin-converting enzyme (ACE) inhibitors (ACEI) are widely used in the management of cardiovascular diseases but with significant interindividual variability in the patient's response. To investigate whether interindividual variability in the response to ACE inhibitors is explained by the "ACE phenotype"-for example, variability in plasma ACE concentration, activity, and conformation and/or the degree of ACE inhibition in each individual. The ACE phenotype was determined in plasma of 14 patients with hypertension treated chronically for 4 weeks with 40 mg enalapril (E) or 20 mg E + 16 mg candesartan (EC) and in 20 patients with hypertension treated acutely with a single dose (20 mg) of E with or without pretreatment with hydrochlorothiazide. The ACE phenotyping included (1) plasma ACE concentration; (2) ACE activity (with 2 substrates: Hip-His-Leu and Z-Phe-His-Leu and calculation of their ratio); (3) detection of ACE inhibitors in patient's blood (indicator of patient compliance) and the degree of ACE inhibition (ie, adherence); and (4) ACE conformation. Enalapril reduced systolic and diastolic blood pressure in most patients; however, 20% of patients were considered nonresponders. Chronic treatment results in 40% increase in serum ACE concentrations, with the exception of 1 patient. There was a trend toward better response to ACEI among patients who had a higher plasma ACE concentration. Due to the fact that "20% of patients do not respond to ACEI by blood pressure drop," the initial blood ACE level could not be a predictor of blood pressure reduction in an individual patient. However, ACE phenotyping provides important information about conformational and kinetic changes in ACE of individual patients, and this could be a reason for resistance to ACE inhibitors in some nonresponders.

ACE genotype, phenotype and all-cause mortality in different cohorts of patients with type 1 diabetes

Carrying the D-allele of the angiotensin-converting enzyme (ACE) I/D polymorphism and high ACE activity are prognostic factors in diabetic nephropathy, which predicts mortality in type 1 diabetes. We studied the association between the ACE D-allele and ACE phenotype and long-term all-cause mortality in three single-institution outpatient cohorts. Genotype-based analyses were performed in 269 patients from Hillerød Hospital (HIH) (follow-up: 12 years) and in 439 patients with diabetic nephropathy and 437 patients with persistent normoalbuminuria from the Steno Diabetes Center (SDC) (follow-up: 9.5 years). Patients not on renin-angiotensin system (RAS)-blocking treatment were included in analyses of serum ACE activity (HIH: n = 208) and plasma ACE concentration (SDC: n=269). In the HIH cohort, carrying a D-allele was associated with excess mortality (hazard ratio (HR) = 4.0 (95% confidence interval (CI) 1.0-16)), but not in the SDC cohorts. At HIH, serum ACE activity was associated with excess mortality (HR=1.04 (95% CI 1.0-1.1 per unit increase)), but in the SDC cohort plasma ACE concentration was not. In unselected patients with type 1 diabetes, carrying the ACE D-allele and high spontaneous serum ACE activity were associated with 12-year excess mortality. These findings could not be reproduced in two other cohorts with persistent normoalbuminuria or diabetic nephropathy.

Angiotensin-converting enzyme gene 2350 G/A polymorphism and susceptibility to atrial fibrillation in Han Chinese patients with essential hypertension

OBJECTIVE:The angiotensin-converting enzyme gene is one of the most studied candidate genes related to atrial fibrillation. Among the polymorphisms of the angiotensin-converting enzyme gene, the 2350 G/A polymorphism (rs4343) is known to have the most significant effects on the plasma angiotensin-converting enzyme concentration. The aim of the present study was to investigate the association of the angiotensin-converting enzyme 2350 G/A polymorphism with atrial fibrillation in Han Chinese patients with essential hypertension.METHODS:A total of 169 hypertensive patients were eligible for this study. Patients with atrial fibrillation (n = 75) were allocated to the atrial fibrillation group, and 94 subjects without atrial fibrillation were allocated to the control group. The PCR-based restriction fragment length polymorphism technique was used to assess the genotype frequencies.RESULTS:The distributions of the angiotensin-converting enzyme 2350 G/A genotypes (GG, GA, and AA, respectively) were 40.43%, 41.49%, and 18.08% in the controls and 18.67%, 46.67%, and 34.66% in the atrial fibrillation subjects (p = 0.037). The frequency of the A allele in the atrial fibrillation group was significantly greater than in the control group (58.00% vs. 38.83%, p = 0.0007). Compared with the wild-type GG genotype, the GA and AA genotypes had an increased risk for atrial fibrillation. Additionally, atrial fibrillation patients with the AA genotype had greater left atrial dimensions than the patients with the GG or GA genotypes (p<0.01 and p<0.05, respectively).CONCLUSIONS:The results obtained in this study indicate that the angiotensin-converting enzyme 2350 G/A polymorphism is associated with atrial fibrillation and that the A allele shows an increased risk for atrial fibrillation in Han Chinese patients with essential hypertension.

Association of angiotensin-converting enzyme gene 2350 G/A polymorphism with diabetic retinopathy in Chinese Han population

The angiotensin-converting enzyme (ACE) gene is one of the most studied candidate genes related to diabetic retinopathy (DR). ACE 2350 G/A polymorphism (rs4343) is known among the polymorphisms of this gene to have the most significant effect on plasma ACE concentrations. The aim of the present study was to investigate the relationship between 2350 G/A polymorphism of ACE gene and the susceptibility of DR in Chinese Han population. A case-control study for 145 type 2 diabetes mellitus (DM) patients, including 63 type 2 DM without DR (NDR) and 82 type 2 DM with DR (DR), and 90 subjects of age, gender matched normal controls (NC group) was performed. ACE 2350 G/A genotypes were identified by polymerase chain reaction and restriction digestion in all study participants. The distribution of the ACE 2350 G/A genotypes (GG, GA, and AA) was 35.56, 45.55, and 18.89 % in the NC group, 28.57, 46.03, and 25.40 % in the NDR group, and 15.85, 46.34, and 37.81 % in the DR group, respectively. There were no significant differences in either genotype frequency distribution (P = 0.5266) or allele frequency distribution (P = 0.2425) between the NC group and NDR group. However, the distribution of genotype frequency (P = 0.0026) and allele frequency (P = 0.0003) in the DR group showed a significant difference when compared to that of NC group (P = 0.0075). Moreover, there was statistical difference in allele frequency distribution (P = 0.0328) between the DR group and the NDR group. No statistical differences were observed between ACE 2350 G/A polymorphism and the diabetes duration or types of DR. Results obtained in this study indicate that ACE 2350 G/A polymorphism is associated with DR in Han Chinese patients with type 2 DM.

Association of Angiotensin-Converting Enzyme Gene 2350G&gt;A Polymorphism With Myocardial Infarction in a Chinese Population

Angiotensin-converting enzyme (ACE) gene 2350G>A polymorphism has the most significant effect on plasma ACE concentrations. But the association between this polymorphism and myocardial infarction (MI) is presently unknown. We carried out a case-control study in the Chinese Han population. ACE2350G>A genotypes of 231 patients with MI and 288 healthy controls were detected by PCR-RFLP. Differences in frequencies of ACE genotypes and alleles and their associations with clinical features were assessed. The distribution of the ACE2350G>A genotypes (GG, GA, and AA) was 20.78%, 51.08%, and 28.14% in the MI group and 31.60%, 46.53%, and 21.87% in controls, respectively (P = .0167).The frequency of the A allele in the MI group was significantly higher than that in controls (53.68% vs 45.14%, P = .0062). The A allele carriers (GA + AA genotypes) had approximately 2-fold increased risk of MI when compared with the GG genotype (odds ratio = 1.76; 95% confidence interval = 1.24-3.52). There were no significant differences among the 3 genotypes in plasma levels of lipids, apolipoproteins, high-sensitivity C-reactive protein, and soluble CD40 ligand in either the MI group or the control group (P > .05). No statistical difference was observed between ACE2350G>A polymorphism and severity of the coronary lesions (P > .05). These results suggest that ACE2350G>A polymorphism is associated with acute MI, and A allele carrier is an independent risk factor for acute MI in the Chinese Han population.

Investigation of association between angiotensin-converting enzyme gene insertion/deletion polymorphism frequency and plasma angiotensin-converting enzyme concentration in patients with idiopathic dilated cardiomyopathy

Investigation of association between angiotensin-converting enzyme gene insertion/deletion polymorphism frequency and plasma angiotensin-converting enzyme concentration in patients with idiopathic dilated cardiomyopathy

Angiotensin-Converting Enzyme Gene 2350 G/A Polymorphism Is Associated with Left Ventricular Hypertrophy but Not Essential Hypertension

The angiotensin-converting enzyme (ACE) gene (ACE) is one of the most studied candidate genes related to essential hypertension (EH) and left ventricular hypertrophy (LVH). ACE rs4343 synonymous coding polymorphism (2350 G/A) is known among the polymorphisms of this gene to have the most significant effect on plasma ACE concentrations. The aim of the present study was to investigate the association of this polymorphism with EH and LVH in 440 subjects (246 EH patients and 194 controls) from a Chinese Han population. In this study, 2350 G/A genotypes were identified by polymerase chain reaction and restriction digestion in all study participants, and left ventricular mass was assessed by 2-mode echocardiography in 178 untreated EH patients. There was no significant difference in either genotype distribution (p=0.3659) or allele frequency (p=0.1453) between EH and control groups. In addition, the 2350 G/A polymorphism had no effect on blood pressure in either controls or untreated EH patients. The distribution of genotypes differed significantly when patients with LVH were examined, i.e., 14.71% GG, 54.41% GA, and 30.88% AA patients had this complication, and 36.36% GG, 42.73% GA, and 20.91% AA patients did not (p=0.0070). The LVH patients had a higher A allele frequency (58.09%) than patients without LVH (42.27%) (p=0.0037). Logistic regression analysis revealed that the association between the A allele and LVH was independent of age, blood pressure, and body mass index. The relative risk of LVH in patients bearing the A allele (GA+AA group) compared with that of GG hypertensive patients was 3.31 (95% confidence interval [CI]: 1.43 to 7.68). These findings suggest an association between LVH and the 2350A allele in hypertensive patients.

Inhibition of angiotensin converting enzyme (ACE) by normal solutes of human plasma

Human plasma ACE concentration is ~4 nM, yet net ACE activity is <1 nM. Inhibition is evident on assaying ACE of increasing dilutions of plasma. Here, means are defined for computing net ACE activity of undiluted plasma, total ACE and % inhibition. Under first order kinetics, the Michaelis-Menten equation is v/s = Vmax/(Km (1 + i/Ki)), where i is inhibitor concentration; v/s is called apparent (app) (Vmax/Km). The inverted equation describes a straight line: app(Km/Vmax) = Km/VmaxKi(i) + Km/Vmax. When i, fractional concentration (fr conc) of plasma, is plotted against app(Km/Vmax), the y-intercept is true (Km/Vmax). The x-intercept is the fr conc of plasma for inhibition of ACE by half. Net ACE activity of undiluted plasma is computed for i = 1.0; 1/x is units of inhibitory activity. Plasmas of 37 healthy adults, 23 – 57 y.o., were assayed in fr conc of 0.2 – 0.00625 using [3H]hippuryl-His-Leu, 40 nM, in Hepes buffer, pH 8.0, plus NaCl and sodium sulfate, at 37oC. Results (mean±SD): Vmax/Km 0.3755±0.098/min, app(Vmax/Km) 0.0442±0.003/min, inhibitor units 7.29±2.0, inhibition 88.2±5.0%. Thus, <12% of plasma ACE is active. Inhibition, relieved by dialysis, is attributable to arginine, lysine, ornithine, cysteine, Cys-Gly and glutathione. Following a meal, their concentrations can double and increase inhibition, which raises the question, Is ACE activity physiologically modulated by food intake?

Association study of the angiotensin-converting enzyme (ACE) gene G2350A dimorphism with myocardial infarction.

The angiotensin converting enzyme (ACE) is a strong candidate gene for myocardial infarction (MI). Insertion-deletion dimorphism in intron 16 of this gene has been inconclusively found to be associated with it. Several new polymorphisms in the ACE gene have been identified and among these, a dimorphism in exon 17, ACE G2350A, has a significant effect on plasma ACE concentrations. To assess the value of genotyping the ACE G2350A dimorphism in a genetically homogeneous population, we carried out a case-control study of dimorphism G2350A for a putative association with MI among Pakistani nationals. We investigated a sample population of 370 Pakistanis, comprising 163 controls, and 207 patients with clinical diagnosis of acute MI (AMI). ACE G2350A alleles were visualized by assays based on polymerase chain reaction and restriction endonuclease analysis. Frequencies of G alleles were 0.68 among controls and 0.72 among AMI patients. The ACE G2350A dimorphism showed no significant association with MI (chi2 = 0.90, 2 df, P = 0.64), plasma levels of homocysteine (P = 0.52) or with serum levels of folate (P = 0.299). The results indicate that ACE G2350A polymorphism is not associated with risk of myocardial infarction in the Pakistani population investigated here.

Association of the angiotensin-converting enzyme (ACE) gene G2350A dimorphism with essential hypertension.

Although the angiotensin converting enzyme (ACE) is a strong candidate gene for hypertension, the extensively studied insertion-deletion dimorphism in intron 16 was not found to be associated with it. Several new polymorphisms in the ACE gene were identified, among which a dimorphism in exon 17, ACE G2350A, has a significant effect on plasma ACE concentrations. To assess the value of genotyping the ACE G2350A dimorphism in a genetically homogeneous population, we carried out a retrospective, case-control study of dimorphism G2350A for a putative association with essential hypertension (EH) in a Gulf population (Emirati)--an ethnic group characterized by no alcohol intake and no cigarette smoking. We investigated a sample population of 254 Emirati, comprising 136 normotensive controls, and 118 patients with clinical diagnoses of EH. ACE G2350A alleles were visualized by assays based on polymerase chain reaction and restriction endonuclease analysis. The ACE G2350A dimorphism showed an association with EH (chi2=6.71, 2 df, P=0.05). Further analysis revealed that the ACE G/G 2350 genotype was positively associated (OR=1.06-3.07, P=0.02) with EH. This is the first association study of the ACE G2350A dimorphism with EH, and the positive result might indicate that ACE could be a QTL for EH as originally thought.

Effect of ACE gene I/D polymorphism on hypertension-related traits in french-canadian families

Angiotensin-converting enzyme (ACE) gene is a well known blood pressure candidate gene as demonstrated by previous studies, where its insertion/deletion (I/D) polymorphism has been shown to be associated with hypertension and coronary artery disease, and plasma ACE concentrations have been found to be associated with plasma triglyceride and total cholesterol levels. The aim of this study was to determine the effect of the I/D polymorphism on hypertension-related traits in French-Canadian families. 125 French-Canadian families were selected on the basis of having at least one sib pair affected by early-onset (<55 years) hypertension and dislipidemia. From these, 542 individuals were genotyped for I/D marker and a sib pair linkage analysis (SIBPAL, from S.A.G.E. package) adapted to familial structures was performed for seventy hypertension-related traits. In this population, allelic frequency was: allele I = 42.5%, allele D = 57.5%. The genotypic distribution was: I/I = 17.7%, I/D = 49.6% and D/D = 32.7%. The linkage analysis was significant for NaLi countertransport (p=0.03) in male sib pairs, for plasma levels of vasopressin (p=0.002) and of glucose (p=0.007) in female sib pairs and of ANP (p=0.003) in mixte sib pairs. Microalbumin excretion (p=0.037) was significantly linked in hypertensive sib pairs, whereas volume of total body water (p=0.005) and of intracellular water (p=0.012) correlated with the marker in normotensive sib pairs. No significative effect of the Ace locus was found for the systolic or diastolic blood pressures, left ventricular hypertrophy, wake or sleep heart rates, BMI, cholesterol or triglyceride levels in neither hypertensive nor normotensive gender specific groups. In French-Canadian population, the effect of Ace gene I/D marker on hypertension-related traits varies depending on hypertension status and gender. Results of the present genetic study underline the importance of Ace locus in the pathogenesis of hypertension, with a distinct effect on some previously suggested linkages.

Involvement of renin-angiotensin system in pressure-flow relationship: role of angiotensin-converting enzyme gene polymorphism.

The renin-angiotensin system is involved in blood pressure regulation. The insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene is known to be associated with variation of plasma and cellular ACE concentrations. Furthermore, changes in arterial function have been suggested to be associated to the DD genotype. The aim of the study was to investigate the arterial vascular response to a physiologic stimulus (i.e., flow) according to the I/D ACE gene polymorphism. Sixty patients scheduled for coronary artery bypass grafting (n = 24) or valve surgery (n = 36) under normothermic cardiopulmonary bypass were genotyped in a blind manner by polymerase chain reaction. Mean arterial pressure was measured at pump flows ranging from 1 to 3 l x min(-1) x m (-2) by 0.25 l x min(-1) x m(-2) step each 15 s, to obtain a pressure-flow relation. Independent factors associated with the variation of the slope of the pressure-flow relation curve were assessed by multivariate analysis. We found a D allelic frequency of 0.54. Patients were separated in two groups (DD, n = 16; ID/II, n = 44). There were no significant difference with regard to preoperative and intraoperative data between the two groups. DD patients had their pressure-flow relation curves shifted upward (with higher pressures as flow increased), indicating a lesser decrease in vascular resistance. Furthermore, DD genotype was the only independent predictor of the slope of the curves (21.5 +/- 4.2 vs. 18.1 +/- 5 mmHg/[l x min(-1) x m(-2)] for DD and ID/II, respectively; P = 0.02; values are mean +/-SD). These results show that vasomotor properties are influenced by the I/D polymorphism of the ACE gene.

Role of cortisol in the ontogenic control of pulmonary and renal angiotensin‐converting enzyme in fetal sheep near term

1. This study examined the ontogeny of angiotensin-converting enzyme (ACE) concentration in the lungs and kidneys of fetal, newborn and adult sheep, and investigated the effects of cortisol infusion on tissue and plasma ACE in the chronically catheterised ovine fetus. 2. Pulmonary and renal ACE in utero increased from 113 days of gestation towards term; peak tissue ACE concentrations were observed in fetuses studied at 143 days (term, 145 +/- 2 days). The high level of ACE seen in the fetal lungs close to term was maintained in the lambs and adult ewes whereas renal ACE decreased immediately after birth and rose to a maximal value in the adult ewes. In all groups of animals studied, higher mean concentrations of ACE were observed in the kidneys than in the lungs. Ontogenic increments in pulmonary and renal ACE in utero were coincident with the prepartum cortisol surge. In untreated and saline-infused fetuses, plasma cortisol correlated with both pulmonary (r = 0.83, P < 0.0001) and renal (r = 0.53, P < 0.01) ACE concentrations, irrespective of gestational age. 3. An intravenous infusion of cortisol (2-3 mg kg-1 day-1) at either 113 or 129 days raised plasma cortisol to the level seen near term and caused an increase in pulmonary ACE at both gestational ages. Pulmonary ACE concentration in the cortisol-infused fetuses at 129 days, but not at 113 days, was similar to that observed in the fetuses near term. In contrast, cortisol infusion had no effect on renal ACE concentration at either 113 or 129 days of gestation. Plasma ACE concentration was also increased by exogenous cortisol at 129 days. 4. Therefore, these findings suggest that the ontogenic rise in ACE concentration observed in the lungs of the sheep fetus near term is induced, at least in part, by the prepartum cortisol surge.

How often are angiotensin II and aldosterone concentrations raised during chronic ACE inhibitor treatment in cardiac failure?

OBJECTIVEAngiotensin II (AII) and aldosterone are not always fully suppressed during chronic angiotensin converting enzyme (ACE) inhibitor treatment. In congestive heart failure (CHF) such failure of hormonal suppression is associated...

Sustained antihypertensive actions of a dual angiotensin-converting enzyme neutral endopeptidase inhibitor, sampatrilat, in black hypertensive subjects

Our objective was to evaluate the safety and antihypertensive efficacy of sampatrilat, a novel dual inhibitor of both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), in subjects poorly responsive to ACE inhibitor monotherapy. The ability of sampatrilat (50 to 100 mg daily) (n = 28) to lower blood pressure was compared with that of the ACE inhibitor lisinopril (10 to 20 mg daily) (n = 30) using a double-blind, randomized, parallel group study design over a 56-day treatment period in black hypertensives. Changes in systolic (SBP) and diastolic (DBP) blood pressure were determined using repeated ambulatory blood pressure (ABP) monitoring. Both sampatrilat and lisinopril decreased plasma ACE concentrations after 28 and 56 days. The decrease in plasma ACE concentrations (U/L) was greater after lisinopril ( −9.33 ± 0.52) as compared with sampatrilat ( −6.31 ± 0.70) ( P = .0001) therapy. Lisinopril, but not sampatrilat, increased plasma renin activity. Lisinopril produced a transient decrease in mean 24-h ABP (mm Hg) at 28 days (SBP = −9.0 ± 2.3, DBP = −5.7 ± 1.3; P < .01), which returned to pretreatment values by 56 days of therapy. Alternatively, sampatrilat produced a sustained decrease in mean ABP over the 56-day treatment period (day 28: SBP = −7.3 ± 1.8, DBP = −5.2 ± 1.2; P < .01: day 56: SBP = −7.8 ± 1.5; DBP = −5.2 ± 0.95; P < 0.01) with a greater treatment effect on DBP than that of lisinopril at day 56 ( P = .05). Treatment-emergent adverse events were noted to be similar between both treatment groups. We conclude that the antihypertensive actions of ACE/NEP inhibitor monotherapy in black subjects offers a novel therapeutic approach to patients otherwise resistant to the sustained antihypertensive actions of ACE inhibitor monotherapy.

Angiotensin-converting enzyme gene polymorphism: is there a link to nephropathy in patients with type 1 diabetes?

To evaluate the association between the angiotensin-converting enzyme (ACE) gene polymorphism and diabetic nephropathy in patients with type 1 diabetes. Citations were selected using the MEDLINE database. Only those citations involving human subjects and available in English were selected. Key search words included angiotensin-converting enzyme (ACE), polymorphism, nephropathy, and type 1 diabetes. Selection criteria consisted of all MEDLINE-referenced clinical trials, review articles, and editorial comments assessing the potential link between the ACE gene polymorphism and diabetic nephropathy in insulin-dependent diabetes mellitus published between January 1990 and February 1998. Because diabetic nephropathy is a serious complication of type 1 diabetes, focus has been placed on the early identification of and intervention with patients genetically susceptible to this complication. Because the ACE gene polymorphism has an effect on plasma ACE concentration variations among individuals, it has been investigated as a potential genetic marker for diabetic nephropathy. The best studies to date are reviewed in order to assess the utility of the ACE polymorphisms as a genetic marker of diabetic nephropathy in patients with type 1 diabetes, and to determine what implications this holds for drug treatment. Although the ACE gene polymorphism's potential link to diabetic nephropathy in patients with type 1 diabetes has been debated, the most definitive studies show that an association exists. Large epidemiologic studies must now be conducted to determine the implications this polymorphism holds for the best treatment strategies in the care of these patients.

Determination of Angiotensin-Converting Enzyme Gene Polymorphisms: Stepdown PCR Increases Detection of Heterozygotes

The angiotensin-converting enzyme (ACE) gene product plays an important role in cardiovascular homeostasis. An insertion/deletion (I/D) polymorphism in intron 16 of the ACE gene, with insertion polymorphism containing three more Alu-repeat sequences, was reported to be a determining factor of the plasma ACE concentration, and the D polymorphism has been found to be associated with certain cardiovascular diseases (1)(2)(3)(4)(5). Controversy exists, however, regarding the strength of the association. The diversity of conclusions has been attributed to methodological and technical variations in detection of the polymorphisms (6)(7). The preferential amplification of the D allele of the ACE gene by the PCR reported by Rigat et al. (8) was thought to be one cause. This PCR method occasionally mistyped ID heterozygotes as DD homozygotes (9). The probability of this mistyping has been estimated to be ∼5–10% (6)(7). A confirmatory PCR method, which requires an additional third PCR primer inside the Alu sequence of the I allele, was proposed to minimize the mistyping of the I allele as a D allele (9). Although this PCR technique was reported to be 100% in the typing of ACE gene polymorphisms, problems with the preferential amplification of multiplexed PCR are not entirely excluded with this method (10)(11). A stepdown PCR method, modified from touchdown PCR, has recently been used in several molecular studies (12). This method involves initial PCR annealing temperatures higher than the melting point of the primers, followed by annealing temperatures reduced stepwise to the melting point. This method should result in higher amplification specificity and greater yield. We compared the stepdown PCR with the conventional method from Rigat et al. (8) and with confirmatory PCR in the amplification efficiency of the ACE gene. We collected blood samples from …