Plasma Angiotensin I-converting Enzyme Activity Research Articles

P607. Effect of Antipsychotics in the Angiotensin Converting Enzyme-1 (ACE) Activity in First-Episode Psychosis Patients and Animal Models for Schizophrenia

Angiotensin-I converting enzyme (ACE) is a key component of renin-angiotensin system (RAS), and its association with cognitive impairments in brain disorders has been recently recognized. Higher ACE activity in plasma of chronic patients with schizophrenia (SCZ) compared with healthy controls (HCs) paired by sex and age, and the relevance of ACE activity in SCZ was suggested by us. We now propose a translational analysis to understand how SCZ pharmacotherapy with antipsychotics can affect the ACE activity in clinical samples and animal model for SCZ studies.

A study in first-episode psychosis patients: does angiotensin I-converting enzyme (ACE) activity associated with genotype predict symptoms severity reductions after treatment with the atypical antipsychotic risperidone?

BackgroundOur previous studies showed increased angiotensin I-converting enzyme (ACE) activity in chronic schizophrenia patients compared with healthy control (HC) volunteers, and the relevance of combining ACE genotype and activity for predicting schizophrenia was suggested.MethodsACE activity was measured in plasma of ACE insertion/deletion (I/D) genotyped HC volunteers (n = 53) and antipsychotic-naïve first-episode psychosis (FEP) patients (n = 45) assessed at baseline (FEB-B) and also after 2 months (FEP-2M) of treatment with the atypical antipsychotic risperidone.ResultsACE activity measurements showed significant differences among HC, FEP-B, and FEP-2M groups (F = 5.356, df = 2, P = .005) as well as between HC and FEP-2M (post-hoc Tukey’s multiple comparisons test, P = .004). No correlation was observed for ACE activity increases and symptom severity reductions in FEP as assessed by total Positive and Negative Syndrome Scale (r = −0.131, P = .434). FEP subgrouped by ACE I/D genotype showed significant ACE activity increases, mainly in the DD genotype subgroup. No correlation between ACE activity and age was observed in FEP or HC groups separately (r = 0.210, P = .392), but ACE activity level differences observed between these groups were influenced by age.ConclusionsThe importance of measuring the ACE activity in blood plasma, associated with ACE I/D genotyping to support the follow-up of FEP patients, did not show correlation with general symptom amelioration in the present study. However, new insights into the influence of age and I/D genotype for ACE activity changes in FEP individuals upon treatment was demonstrated.

Mechanism of antihypertensive effect of Mucuna pruriens L. seed extract and its isolated compounds.

Background In the search of safe and effective lead molecules from natural sources, Mucuna pruriens (MP) L. (Fabaceae) seeds were utilized for exploring the antihypertensive potential. Traditionally, it is used as diuretic and hypotensive. Methods Bioassay-guided fractions were utilized for the isolation of active compounds by column chromatography. IC50 value, enzyme kinetics and inhibition mechanism were determined. In vivo time and dose-dependent hypotensive study followed by changes in mean arterial pressure (MAP) induced by angiotensin I (3 nmol/kg), angiotensin II (3 nmol/kg), and bradykinin (10 nmol/kg) in anesthetized rats was done. Plasma and tissue angiotensin I-converting enzyme (ACE) activities were also determined. Results Phytochemical analysis by spectroscopic techniques revealed the presence of known compounds like genistein, ursolic acid and L-DOPA from the ethyl acetate and water fraction, respectively. In vitro study revealed MP ethyl acetate (MPEA) fraction and genistein as the most active fraction (IC50 156.45 µg/mL) and compound (IC50 253.81 µM), respectively. Lineweaver-Burk plots revealed a non-competitive mode of inhibition. ACE protein precipitation was the suggested mechanism for inhibition. The extract showed a time- and dose-dependent decrease in MAP. Genistein was able to dose-dependently reduce the MAP, up to 53±1.5 mmHg (40 mg/kg, i.v.). As compared to control, it showed a dose-dependent decrease in plasma ACE activity of 40.61 % and 54.76 % at 10 mg/kg and 20 mg/kg, respectively. It also decreased the ACE activity in the aorta (107.67nM/ml min at 10 mg, p<0.001; 95.33nM/ml min at 20 mg p<0.001). Captopril was used as a standard for various in vitro and in vivo assays. Conclusions The study revealed the antihypertensive potential of MP seed compounds via ACE inhibition.

Antihypertensive effect of fermented skim camel (Camelus dromedarius) milk on spontaneously hypertensive rats.

Hypertension is one of the most common diseases in worldwide, thus prevention of hypertension is important in reducing the risks of cardiovascular disease. Milk contains bioactive peptides released during milk fermentation which lead to exhibit angiotensin I converting enzyme (ACE) inhibitory. The aim of this study was to investigate the antihypertensive effect of fermented skim camel milk on rats and compared with unfermented skim camel milk as control. The antihypertensive effect of fermented skim camel milk on thirty six male spontaneously hypertensive rats (SHR) was carried out for (short-term) and (long-term) using different doses (80, 240 and 1200 mg/kg body weight). Angiotensin converting enzyme (ACE) activity was also measured using ACE Kit. The blood pressure (systolic and diastolic) of spontaneously hypertensive rats (SHR) in short term administration (24 hours) of 1200 mg/kg body weight fermented skim camel milk decreased significantly (p < 0.05) from 22 to 36 mmHg and 28 to 32 mmHg, respectively, at four and eight hour of post administration. On the other hand, the blood pressure of fermented skim camel milk for long-term (20 days) decreased and affected the heart rate (beats/min). The lowest record of systolic (41 mmHg) and diastolic blood pressure (19 mmHg) were at dose of 1200 mg/kg body weight of fermented skim camel milk at 15 days of administration. Likewise, ACE activity in plasma of SHR administered fermented skim camel milk decreased significantly (p < 0.05) compared with the control group. The hypotensive effect of fermented skim camel milk by L. helveticus and S. thermophillus in SHR rats depends on the high dose of fermented skim camel milk in short and long-term. The ACE activity inhibitory was clear with fermented skim camel milk.

Angiotensin converting enzyme activity is positively associated with IL-17a levels in patients with schizophrenia

Previous studies of our group showed increased plasmatic Angiotensin-I Converting Enzyme (ACE) activity in schizophrenia (SCZ) patients compared to healthy controls, which was also associated to poor cognitive functioning. The ACE main product angiotensin II (Ang-II) has pro-inflammatory properties. Activated immune-inflammatory responses in SCZ and their association with disease progression and cognitive impairments are also well-described. Therefore, we examined here the association of plasma ACE activity and inflammatory mediators in 33 SCZ patients and 92 healthy controls. Non-parametric correlations were used to investigate the association of the enzyme activity and the peripheral levels of immune inflammatory markers as interleukins, tumor necrosis factor (TNF-α), and interferon (IFN-γ). Although no significant correlations could be observed for ACE activity and measured cytokines levels in healthy controls, a significant positive correlation for ACE enzymatic activity and IL-17a levels was observed in SCZ patients. Correcting for gender did not change these results. Moreover, a significant association for ACE activity and IFN-γ levels was also observed. To our knowledge, this is the first study to show a significant association between higher ACE activity and the levels of cytokines, namely IL-17a and IFN-γ, in patients with SCZ.

Association of insertion–deletion polymorphism of ACE gene and Alzheimer’s disease in Egyptian patients

IntroductionAlzheimer’s disease (AD) is a progressive, neurodegenerative disease. Many studies proposed an association of the insertion (I)/deletion (D) polymorphism (indel) in intron 16 of the gene for angiotensin I-converting enzyme (ACE) on chromosome 17q23 with Alzheimer’s disease. ACE indel and related haplotypes associated with AD risk have reduced plasma ACE whereas protective genotypes have elevated ACE. ObjectTo investigate whether there is a correlation between polymorphisms of the ACE I/D locus gene and AD in Egyptian patients and to determine whether there is a difference in ACE activity in the plasma of clinically diagnosed AD patients. MethodsSubjects of this study are 84 dementia patients diagnosed as having Alzheimer’s disease, 45 males and 39 females aged 65±7years from the Geriatric Department at Ain-Shams University Hospitals and 86 individuals as non dementia controls, 44 males and 42 females aged 63±6years.All subjects were genotyped for the common insertion/deletion polymorphisms for ACE gene locus, and ACE plasma activity assay was measured for AD patients. ResultsThere was statistically significant difference in the frequency of the ACE insertion/deletion alleles between the cases and controls where the I allele distribution in AD cases and controls was 74% vs. 15%, and the I/I genotype frequency was 60% vs. 5%, respectively. They both reached a statistical significance range (I allele frequency: OR=3.714, 95% CI 1.311–10.523, p<0.01; I/I genotype frequency: OR=3.18 95% CI 2.33–4.33, p<0.01). But no significant difference in ACE plasma level was found between different genotypes in our AD patients. ConclusionsOur present study supports the hypothesis of implication (I allele) of ACE gene polymorphism in the development of AD. On the other hand, we did not find significant difference in plasma ACE activities when compared with different studied genotypes.

Preventive and treatment effects of a hemp seed (Cannabis sativa L.) meal protein hydrolysate against high blood pressure in spontaneously hypertensive rats

This work determined the ability of hemp seed meal protein hydrolysate (HMH)-containing diets to attenuate elevated blood pressure (hypertension) development in spontaneously hypertensive rats (SHRs). Effects of diets on plasma levels of renin and angiotensin I-converting enzyme (ACE) in the SHRs were also determined. Defatted hemp seed protein meal was hydrolyzed using simulated gastrointestinal tract digestion with pepsin followed by pancreatin, and the resulting HMH used as a source of antihypertensive peptides. The HMH was substituted for casein at 0.5 and 1.0% levels and fed to young growing rats for 8 weeks (preventive phase) or adult rats for 4 weeks (treatment phase). Feeding of young growing SHRs with HMH resulted in attenuation of the normal increases in systolic blood pressure (SBP) with an average value of ~120 mmHg when compared to the casein-only group of rats (control) with a maximum of 158 mm Hg (p < 0.05). Feeding adult rats (SBP ~145 mmHg) with same diets during a 4-week period led to significant (p < 0.05) reduction in SBP to ~119 mmHg in comparison with 150 mmHg for the control rats. Plasma ACE activity was significantly (p < 0.05) suppressed (0.047-0.059 U/mL) in HMH-fed rats when compared to control rats (0.123 U/mL). Plasma renin level was also decreased for HMH-fed rats (0.040-0.054 μg/mL) when compared to control rats that were fed only with casein (0.151 μg/mL). The results suggest that HMH with strong hypotensive effects in SHRs could be used as a therapeutic agent for both the prevention and treatment of hypertension.

Quantitative Variation in Plasma Angiotensin‐I Converting Enzyme Activity Shows Allelic Heterogeneity in the ABO Blood Group Locus

Angiotensin-I converting enzyme (ACE) occupies a pivotal role in cardiovascular homeostasis. Major loci for plasma ACE have been identified at ACE on Chromosome 17 and at ABO on Chromosome 9. We sought to characterise the genetic architecture of plasma ACE at finer resolution in two populations. We carried out a GWAS in 1810 individuals of Japanese ethnicity; this identified signals at ACE and ABO that together accounted for nearly half of the population variability of the trait. We conducted measured haplotype analysis at the ABO locus in 1425 members of 248 British families using haplotypes of three SNPs, which together tagged the alleles responsible for the principal blood group antigens A1, A2, B and O. Type O alleles were associated with intermediate plasma ACE activity compared to Type A1 alleles (in whom plasma ACE activity was ∼36% lower) and Type B alleles (in whom plasma ACE activity was ∼36% higher). We demonstrated heterogeneity among A alleles: A2 alleles were associated with plasma ACE activity that was very similar to the O alleles. Variation at ACE accounted for 35% of the trait variance, and variation at ABO accounted for 15%. A further 10% could be ascribed to polygenic effects.

Clinical impact of an angiotensin I-converting enzyme insertion/deletion and kinin B2 receptor +9/-9 polymorphisms in the prognosis of renal transplantation

There is a consensus in the scientific literature that supports the importance of the kallikrein kinin and renin angiotensin systems in renal physiology, but few studies have investigated their importance after renal transplantation. The aim of this study was to investigate the clinical effects of the insertion/deletion polymorphism in the angiotensin I-converting enzyme (ACE) gene and the +9/-9 polymorphism in the kinin B2 receptor (B2R) gene in kidney-transplanted patients (n=215 ACE, n=203 B2R) compared with 443 healthy individuals. Demographic results showed that there is a higher frequency of the D allele (high plasma ACE activity) and +9 allele (lower B2R expression) in transplant patients compared with control individuals. We also observed a higher frequency of these alleles in patients who had an elevated level of plasma creatinine. At day 7 post-transplantation, we found a higher prevalence of individuals with the DD genotype with elevated plasma creatinine level. Furthermore, individuals with the DD genotype had a higher chronic allograft dysfunction and graft loss compared with the II patient genotype, which showed no loss of graft. Taken together, our data suggest that the DD genotype is an indicator of an unfavorable prognosis following renal transplantation and could be related to kinin modulation.

Hypertension-attenuating effect of whey protein hydrolysate on spontaneously hypertensive rats

The angiotensin I-converting enzyme (ACE)-inhibitory activity and antihypertensive effect of whey protein hydrolysate (WPH) after single oral administration (short term) or continuous administration for 20 d (long term) were investigated. In the case of short term administration, the systolic and diastolic blood pressure of spontaneously hypertensive rats (SHRs) in captopril and WPH-supplemented groups significantly decreased from 6 to 8 h post-administration compared to the negative control group. In the case of long term administration, WPH supplementation lowered the blood pressure and affected the heart rate of SHRs in a dose-dependent manner, the lowest systolic blood pressure was obtained at the dose of 240 mg WPH/kg b.w. Furthermore, the ACE activity in plasma, lung, kidney and abdominal aorta of the WPH-administered groups decreased in a dose-related manner, and was significantly lower than that of the negative control group. These results suggest that WPH with an ACE-inhibitory activity could potentially suppress the development of hypertension in SHRs.

No association betweenACEolymorphism and risk of nasopharyngeal carcinoma

Emerging evidence has shown that angiotensin I-converting enzyme (ACE) plays pivotal roles not only in the regulation of cardiovascular homeostasis but also in the process of tumorigenesis. A common ACE I/D polymorphism has been found to be functional, with the D allele displaying a higher plasma ACE level and ACE activity. The purpose of this study was to investigate whether the ACE I/D polymorphism was related to the risk of nasopharyngeal carcinoma (NPC). The study included 175 patients with NPC and 279 age- and sex-matched control subjects. The ACE I/D polymorphism was identified by a polymerase chain reaction analysis. No association was found between the ACE I/D polymorphism and risk of NPC (ID vs. II: odds ratio [OR] = 0.77, 95% confidence interval [CI] 0.51-1.17; DD vs. II: OR = 0.98, 95%CI 0.56-1.72, respectively). This finding indicates that the ACE I/D polymorphism may not play a role in susceptibility to NPC. Further studies are warranted to confirm this finding, especially in ethnically disparate populations.

Effects of two training protocols on Angiotensin I-converting enzyme (ACE) activity in horses

Studies in man have shown a correlation between Angiotensin I-converting enzyme (ACE) genetic polymorphisms, ACE activity in the blood and superior athletic performance in sports requiring endurance. It has been hypothesised that the same correlation occurs in horses. There is no information in the literature concerning the effects of training on ACE activity in equine plasma. Exercise training influences the activity of circulating ACE and the response observed is dependent on the exercise protocol. Thirteen horses of mixed breeds were randomly allocated 2 different training protocols to be carried out for a period of 15 weeks. Blood samples were collected from each horse before the beginning of training to determine baseline values. Subsequent sampling took place every 15 days throughout the training phase and for 8 weeks of paddock rest. Angiotensin I-converting enzyme activity was determined by automated spectrophotometry. Training for 15 weeks significantly increased plasma ACE activity, irrespective of training protocol. Differences observed in ACE activity pattern between the 2 training protocols were not statistically significant. Increase in ACE activity peaked with maximum workload. As soon as training was interrupted, ACE levels significantly decreased. Exercise training affects levels of ACE activity in equine plasma. The mechanism for this is not yet elucidated, but cardiovascular adaptation to exercise and blood pressure changes might be involved in this regulation. Exercise training produced a gradual increase in enzymatic activity and might warrant the use of ACE as a tool for fitness monitoring. Angiotensin I-converting enzyme enzymatic activity in the plasma might be directly correlated to a change in genetic expression and that variability must be taken into account when evaluating results from horses undergoing a physical training programme.

ANTIHYPERTENSIVE EFFECT OF MUNG BEAN SPROUT EXTRACTS IN SPONTANEOUSLY HYPERTENSIVE RATS

ABSTRACT We investigated the efficacy of mung bean sprout in reducing hypertension. Different dosages of raw sprout extract (RSE) or dried sprout extracts (DSE) and enzyme-digested sprout extracts were used in a single intragastric administration test to examine the short-term effect in spontaneously hypertensive rats. Results indicated that high doses (600 mg peptide/kg body weight) extracts significantly reduced systolic blood pressure (SBP) of the rats after administration for 6–9, 3–6 and 3–9 h, respectively. Plasma angiotensin I-converting enzyme activities in the treated rats also decreased. A long-term (1 month) intervention study that consists of treatment groups of fresh sprout powder, dried sprout powder and concentrated extracts of the sprouts (RSE and DSE, respectively) was carried out. Results indicated that the sprout powders were not as efficacious as concentrated sprout extracts. SBP of the rats in the RSE and DSE groups were significantly reduced during the intervention period from week 1–4 and week 2–4, respectively. PRACTICAL APPLICATIONS The results suggested that although fresh and low doses of mung bean sprout or sprout extracts did not have apparent antihypertensive effects, high doses of sprout extracts significantly decreased blood pressure in the experimental animals. Therefore, concentrated mung bean sprout juice has potential applications in the preventive management of hypertension. It might be utilized for physiologically functional food with antihypertensive activity.

Determination of angiotensin I-converting enzyme activity in equine blood: lack of agreement between methods of analysis

Angiotensin-I converting enzyme (ACE) is a key regulator of blood pressure, electrolytes and fluid homeostasis through conversion of angiotensin I into angiotensin II. Recently, a genetic polymorphism of the ACE gene, which accounts for 47% of the variation of ACE activity in blood, has been advocated as a biomarker of athletic aptitude. Different methods of analysis and determination of ACE activity in plasma have been used in human and equine research without a consensus of a "gold standard" method. Different methods have often been used interchangeably or cited as being comparable in the existing literature; however, the actual agreement between assays has not been investigated. Therefore, in this study, we evaluated the level of agreement between three different assays using equine plasma obtained from 29 horses. Two spectrophotometric assays using Furylacryloyl-phenylalanyl-glycyl-glycine as substrate and one fluorimetric assay utilizing o-aminobenzoic acid-FRK-(Dnp)P-OH were employed. The results revealed that the measurements from the different assays were not in agreement, indicating that the methods should not be used interchangeably for measurement of equine ACE activity. Rather, a single method of analysis should be adopted to achieve comparable results and critical appraisal of the literature is needed when attempting to compare results obtained from different assays.

Leptin regulates ACE activity in mice

Leptin is a hormone related to metabolism. It also influences blood pressure, but the mechanisms triggered in this process are not yet elucidated. Angiotensin-I converting enzyme (ACE) regulates cardiovascular functions and recently has been associated with metabolism control and obesity. Here, we used ob/ob mice, a model lacking leptin, to answer the question whether ACE and leptin could interact to influence blood pressure, thereby linking the renin-angiotensin system and obesity. These mice are obese and diabetic but have normal 24 h mean arterial pressure. Our results show that plasma and lung ACE activities as well as ACE mRNA expression were significantly decreased in ob/ob mice. In agreement with these findings, the hypotensive effect produced by enalapril administration was attenuated in the obese mice. Plasma renin, angiotensinogen, angiotensin I, bradykinin, and angiotensin 1-7 were increased, whereas plasma angiotensin II concentration was unchanged in obese mice. Chronic infusion of leptin increased renin activity and angiotensin II concentration in both groups and increased ACE activity in ob/ob mice. Acute leptin infusion restored ACE activity in leptin-deficient mice. Moreover, the effect of an ACE inhibitor on blood pressure was not changed in ob/+ mice during leptin treatment but increased four times in obese mice. In summary, our findings show that the renin-angiotensin system is altered in ob/ob mice, with markedly reduced ACE activity, which suggests a possible connection between the renin-angiotensin system and leptin. These results point to an important interplay between the angiotensinergic and the leptinergic systems, which may play a role in the pathogenesis of obesity, hypertension, and metabolic syndrome.

Plasma Kallikrein and Angiotensin I-converting enzyme N- and C-terminal domain activities are modulated by the insertion/deletion polymorphism

Angiotensin I-converting enzyme (ACE) is recognized as one of the main effector molecules involved in blood pressure regulation. In the last few years some polymorphisms of ACE such as the insertion/deletion (I/D) polymorphism have been described, but their physiologic relevance is poorly understood. In addition, few studies investigated if the specific activity of ACE domain is related to the I/D polymorphism and if it can affect other systems. The aim of this study was to establish a biochemical and functional characterization of the I/D polymorphism and correlate this with the corresponding ACE activity. For this purpose, 119 male brazilian army recruits were genotyped and their ACE plasma activities evaluated from the C- and N-terminal catalytic domains using fluorescence resonance energy transfer (FRET) peptides, specific for the C-domain (Abz-LFK(Dnp)OH), N-domain (Abz-SDK(Dnp)P-OH) and both C- and N-domains (Abz-FRK(Dnp)P-OH). Plasma kallikrein activity was measured using Z-Phe-Arg-AMC as substrate and inhibited by selective plasma kallikrein inhibitor (PKSI). Some physiological parameters previously described related to the I/D polymorphism such as handgrip strength, blood pressure, heart rate and BMI were also evaluated. The genotype distribution was II n=27, ID n=64 and DD n=28. Total plasma ACE activity of both domains in II individuals was significantly lower in comparison to ID and DD. This pattern was also observed for C- and N-domain activities. Difference between ID and DD subjects was observed only with the N-domain specific substrate. Blood pressure, heart rate, handgrip strength and BMI were similar among the genotypes. This polymorphism also affected the plasma kallikrein activity and DD group presents high activity level. Thus, our data demonstrate that the I/D ACE polymorphism affects differently both ACE domains without effects on handgrip strength. Moreover, this polymorphism influences the kallikrein-kinin system of normotensive individuals.

ACE Insertion/Deletion gene polymorphism and genomic sequence in Diabetic nephropathy

Insertion/deletion polymorphism of the angiotensin I converting enzyme (ACE) genetically determines most of the plasma ACE activity. Modulation of ACE gene activity might have an important bearing on the rate of progression of renal disease, though its exact role in the nephropathy of type 2 diabetes (T2DM) is far from clear. This prospective, cross-sectional, observational study was designed to study the correlation between insertion/deletion polymorphism of ACE gene in diabetic nephropathy. T2DM cases (n=30) were evaluated, regarding duration, onset and degree of albuminuria, renal insufficiency and hypertension. All patients underwent detailed clinical and biochemical evaluation. Genomic DNA intron 16 of the ACE gene was amplified by polymerase chain reaction (PCR) followed by sequencing. The mean age of this study group was 45.21±2.34 yrs. PCR amplification of ACE gene fragments revealed insertion/insertion (I/I, n =8); insertion/deletion (I/D, n = 18) and deletion/deletion (D/D, n = 4) alleles. All three groups were matched age-wise. Micro- and macro-vascular complications were more prevalent in DD type (p=0.012). The majority (75%) of patients with II allele took a longer time to develop overt albumiuria, having lesser hypertension, renal dysfunction, and dyslipidemia than ID and DD allele (p<0.005). On the other hand, urinary albumin excretion, systemic and diastolic blood pressures, triglycerides, serum creatinine and low density lipoprotein-C were significantly higher (p<0.005), in patients of DD type than II and ID groups. This finding suggests that patients with DD allele of the ACE gene are more likely to have progressive diabetic nephropathy with micro- and macro-vascular complications.

The Role of Inflammatory Markers in the Cardioprotective Effect of L-Carnitine in L-NAME-Induced Hypertension

The mechanism(s) underlying the effects of L-carnitine (beta-hydroxy-gamma-N-trimethylammonium-butyrate; LC) in cardiovascular diseases are not well clarified. Previous studies have demonstrated that oxidative stress and inflammation contribute to arterial hypertension, and antioxidant and/or anti-inflammatory therapies have been proposed. We hypothesized that LC might attenuate the hypertensive status through an inhibition of inflammation process. Heart mRNA expression and plasma levels of inflammatory markers, interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha), were measured in rats that were made hypertensive with N(omega)-nitro-L-arginine methyl ester (L-NAME) and subjected to a simultaneous administration of LC. To clarify the role of the renin-angiotensin system (RAS) in this effect of LC, the activity and expression of angiotensin I-converting enzyme (ACE) as well as the expression of angiotensin II type I receptor (AT1R) in the heart were also determined. LC produced a significant, but not complete, reduction of blood pressure in L-NAME-treated rats. Plasma levels and heart expression of IL-1 beta, IL-6, and TNF-alpha showed an increase in the L-NAME group, which was reversed by LC treatment. The plasma ACE activity was not modified between normotensive and hypertensive rats although LC treatment produced a reduction of these values in the latter. Finally, protein and mRNA expression of ACE and AT1R was enhanced in the heart of L-NAME-treated animals, and LC reversed these values. The chronic administration of LC reduces blood pressure and attenuates the inflammatory process associated with arterial hypertension. LC might produce a partial inactivation in the RAS resulting in a reduction in the production and effects of angiotensin II.

Propofol Attenuates Endotoxin-Induced Endothelial Cell Injury, Angiotensin-Converting Enzyme Shedding, and Lung Edema

Acute lung injury (ALI) is a frequent complication in septic patients. Previously, we found that propofol, a highly lipid-soluble anesthetic, attenuates ischemia-reperfusion and oxidative lung injury in the isolated perfused rat lung. In the present study, we evaluated the effect of propofol on endotoxin-induced ALI and endothelial dysfunction. The effect of propofol on endotoxin-induced lung endothelial injury was evaluated by plasma and lung tissue homogenate angiotensin I converting enzyme (ACE) activity, pulmonary vascular anti-ACE monoclonal antibody binding, and lung wet weight to body weight ratio (LW/BW). When injected IV into rats, endotoxin produced endothelial cell injury and lung edema, as indicated by: 1) an increase in plasma ACE activity, 2) a decrease in lung ACE activity and anti-ACE monoclonal antibody binding, and 3) an increase in LW/BW. Monoclonal antibody 1A2 was up to 1.8 times more sensitive than other anti-ACE monoclonal antibodies in detecting the decrease in ACE in lungs of endotoxin-treated rats. Pretreatment of rats with a bolus of propofol before endotoxin injection significantly inhibited the increase in ACE activity in the blood, the decrease in ACE activity in the lung, the decrease in anti-ACE monoclonal antibody binding in the lung, and the increase in LW/BW ratio. Importantly, propofol also significantly increased the survival rate of endotoxin-treated animals. The protective effect of propofol in endotoxin-treated animals in vivo was confirmed in vitro, i.e., propofol decreased endothelial cell injury and ACE shedding from endothelial cells in culture. These results suggest that propofol offers significant protection against endotoxin-induced pulmonary microvessel endothelial cell injury and that anti-ACE monoclonal antibody 1A2 is a sensitive probe for monitoring endothelial dysfunction and ALI during sepsis.

Reduced plasma levels of angiotensin-(1-7) and renin activity in preeclamptic patients are associated with the angiotensin I- converting enzyme deletion/deletion genotype

The relationship between preeclampsia and the renin-angiotensin system (RAS) is poorly understood. Angiotensin I-converting enzyme (ACE) is a key RAS component and plays an important role in blood pressure homeostasis by generating angiotensin II (Ang II) and inactivating the vasodilator angiotensin-(1-7) (Ang-(1-7)). ACE (I/D) polymorphism is characterized by the insertion (I) or deletion (D) of a 287-bp fragment, leading to changes in ACE activity. In the present study, ACE (I/D) polymorphism was correlated with plasma Ang-(1-7) levels and several RAS components in both preeclamptic (N = 20) and normotensive pregnant women (N = 20). The percentage of the ACE DD genotype (60%) in the preeclamptic group was higher than that for the control group (35%); however, this percentage was not statistically significant (Fisher exact test = 2.86, d.f. = 2, P = 0.260). The highest plasma ACE activity was observed in the ACE DD preeclamptic women (58.1 +/- 5.06 vs 27.6 +/- 3.25 nmol Hip-His Leu(-1) min(-1) mL(-1) in DD control patients; P = 0.0005). Plasma renin activity was markedly reduced in preeclampsia (0.81 +/- 0.2 vs 3.43 +/- 0.8 ng Ang I mL plasma(-1) h(-1) in DD normotensive patients; P = 0.0012). A reduced plasma level of Ang-(1-7) was also observed in preeclamptic women (15.6 +/- 1.3 vs 22.7 +/- 2.5 pg/mL in the DD control group; P = 0.0146). In contrast, plasma Ang II levels were unchanged in preeclamptic patients. The selective changes in the RAS described in the present study suggest that the ACE DD genotype may be used as a marker for susceptibility to preeclampsia.