Brain angiotensin-converting enzyme activity in experimental hypertensive rats

Angiotensin-converting enzyme (ACE) activity was measured in six areas of the brain of normotensive and experimental hypertensive rats; one-clip, one-kidney (1-c, 1-k) and one-clip, two-kidney (1-c, 2-k) Goldblatt hypertensive (GH) rats. ACE activity was consistently high in the thalamus of normotensive and both 1-c, 1-k and 1-c, 2-k GH rats. However, the enzyme activity in the hypothalamus of 1-c, 2-k GH rats was significantly higher than that of normotensive rats, while there was no significant difference in the enzyme activity between normotensive and 1-c, 1-k GH rats. These results demonstrate that in 1-c, 2-k GH rats, increased ACE activity in the brain may play a central role in the hypertension.     

Frequency of angiotensin-converting enzyme gene polymorphism in Turkish hypertensive patients

Hypertension is a multifactorial disease, in which genetic factors play an important role. This study was carried out to determine angiotensin-converting enzyme levels and angiotensin-converting enzyme gene polymorphism in Turkish hypertensive patients, and to establish whether there is an association of angiotensin-converting enzyme gene polymorphism with clinical and echocardiographic parameters. We have investigated the association among the allelic distribution of the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme gene identified by polymerase chain reaction, angiotensin-converting enzyme activity determined spectrophotometrically, cardiac morphology and function assessed by means of echocardiography. Distribution of angiotensin-converting enzyme gene I/D polymorphism and allele frequencies in hypertensive patients was not significantly different from controls. D allele frequency was 51.7% in hypertensives vs. 51.9% in controls and I allele 48.3 vs. 48.1%, respectively. The level of angiotensin-converting enzyme activity was significantly higher in the patients homozygotes for D allele (DD = 59.93 U/l) than in heterozygotes (ID = 39.49) and in homozygotes for I allele (II = 40.28 U/l). In addition to these, the level of angiotensin-converting enzyme activity was significantly lower in the ID and especially II patients receiving ACE inhibitors than the others. Also, it was determined that left atrium diameter was larger in the patients homozygotes for I allele than the others.     

Enalaprilat, an intravenous angiotensin-converting enzyme inhibitor, in hypertensive crises

The effect of enalaprilat (MK-422), a newly synthesized, intravenous, nonsulfhydryl, angiotensin-converting enzyme inhibitor, was studied in seven patients with either severe or malignant hypertension. All subjects initially received a 1 mg bolus injection of enalaprilat followed in 30 minutes by 10 mg. Five subjects received an additional 40 mg. Mean (+/- SE) pretreatment blood pressure for the group was 226 +/- 9/141 +/- 7 mm Hg. Five minutes after the 1 mg enalaprilat dose, blood pressure decreased to 211 +/- 10/131 +/- 9 mm Hg and further fell to 201 +/- 14/123 +/- 11 mm Hg at 30 minutes. The maximal reduction in blood pressure to 169 +/- 14/112 +/- 10 mm Hg occurred 30 minutes after the 10 mg dose. No further blood pressure reduction was observed in those subjects who received the additional 40 mg dose. Within the entire group, five subjects exhibited sustained blood pressure reduction. No adverse side effects or symptomatic hypotension occurred in any subject.     

Age-related underutilization of angiotensin-converting enzyme inhibitors in older hospitalized heart failure patients

BACKGROUND: The extent to which age plays a role in the underutilization of angiotensin-converting enzyme (ACE) inhibitors in heart failure patients has not been well studied. METHODS: We studied age-related variation in the use of ACE inhibitors in older Medicare beneficiaries discharged alive in Alabama with a diagnosis of heart failure with left ventricular systolic dysfunction. RESULTS: A total of 285 patients had a mean age +/- SD of 78 +/- 6.9 years; 59% were female and 21% were African American. Of the 285 patients, 181 (63%) were prescribed ACE inhibitors at discharge. Therapy with ACE inhibitors was initiated in 47% of the patients. Compared with patients 65 to 74 years, those 85 years and older had lower odds of receiving ACE inhibitors at discharge. Among patients not admitted on an ACE inhibitor, those 85 years and older also had lower odds of ACE inhibitor therapy being initiated. CONCLUSION: The overall rate of ACE inhibitor use was low, and age of 85 years and older was independently associated with lower use and initiation of ACE inhibitors. Opportunities remain to increase the use of ACE inhibitors in older patients with heart failure.     

Effect of angiotensin-converting enzyme inhibitors on glomerular eicosanoid production in normotensive and spontaneously hypertensive rats.

1. This study was designed to examine the production of certain eicosanoids (prostaglandin E2), prostacyclin (as 6-keto-prostaglandin F1 alpha) and thromboxane A2 (as thromboxane B2) by glomeruli isolated from normotensive Wistar-Kyoto and spontaneously hypertensive rats both before and after the administration of one of three angiotensin-converting enzyme inhibitors, captopril, enalapril or fosinopril, for 10 days. 2. Measurements of glomerular eicosanoid production were made under basal conditions and in the presence of excess exogenous arachidonic acid. 3. The production of prostaglandin E2, 6-keto-prostaglandin F1 alpha and thromboxane B2 was greater by glomeruli from untreated spontaneous hypertensive rats (prostaglandin E2 2.24 +/- 0.41, 6-keto-prostaglandin F1 alpha 1.20 +/- 0.13 and thromboxane B2 2.75 +/- 0.43 ng 10 min-1 mg-1 of protein) than by those from Wistar-Kyoto rats (prostaglandin E2 1.41 +/- 0.28, 6-keto-prostaglandin F1 alpha 0.98 +/- 0.11 and thromboxane B2 1.29 +/- 0.24 ng 10 min-1 mg-1 of protein) under basal conditions. However, these differences only achieved statistical significance for thromboxane B2 (P less than 0.01). Similar strain-related differences were noted in the presence of arachidonic acid. 4. The ratio of glomerular (prostaglandin E2 + prostacyclin)/thromboxane A2 production was significantly lower in spontaneously hypertensive rats than in their normotensive counterparts under basal conditions with values of 1.3 +/- 0.18 and 2.2 +/- 0.20, respectively (P less than 0.01). 5. Angiotensin-converting enzyme inhibitors induced significant changes in the glomerular production of some eicosanoids, which differed both between strains and with the nature of the inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of sodium intake on brain angiotensin-converting enzyme activity in spontaneously hypertensive rat

The effect of sodium intake on angiotensin-converting enzyme activity in five areas of the brain (the cerebral cortex, midbrain, striatum, thalamus and hypothalamus) was studied in normotensive, spontaneously hypertensive and stroke-prone spontaneously hypertensive rats. The enzyme activity was significantly higher in the hypothalamus than in other areas of the brain of spontaneously hypertensive rats. Sodium intake resulted in a significant rise of the enzyme activity in the midbrain of spontaneously hypertensive rats and also in the midbrain and the striatum of stroke-prone spontaneously hypertensive rats. In normotensive rats, however, there was no significant difference in the enzyme activity in any area of brain between the control and the salt-treated group. It is likely therefore that a high circulating sodium level increases angiotensin-converting enzyme content of the brain in spontaneously hypertensive rats, and it is suggested that the increased converting-enzyme activity may play a role in development of hypertension induced by sodium loading.     

The effect of angiotensin-converting enzyme polymorphism on hemodynamic response to endotracheal intubation in hypertensive patients

Endotracheal intubation elicits a hemodynamic response associated with increased heart rate and blood pressure that is influenced by the angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) genetic polymorphism which may be of importance also for the pressure response to anesthesia. A total of 337 patients underwent abdominal surgery in general anesthesia and 16% were D/D-homozygotes, 45% were I/D heterozygotes and 39% of the patients were I/I homozygotes. Before surgery most patients were in treatment for arterial hypertension. Systolic and diastolic pressure, heart rate and concentrations of catecholamines in blood were determined before and after induction of anesthesia and for up to 10?minutes following endotracheal intubation. Anesthesia decreased blood pressure and for patients presenting ID and DD, blood pressure and heart rate reached similar levels but compared to II-homozygotes, D-carriers demonstrated significantly higher levels for systolic pressure and heart rate before and after intubation (p?相似文献   

Angiotensin converting enzyme 2 polymorphisms and postexercise hypotension in hypertensive medicated individuals

The renin‐angiotensin aldosterone system (RAAS) is associated with diverse physiological responses and adaptations to exercise. The angiotensin converting enzyme (ACE) 2 has vasodilatory effects, which might be associated with the blood pressure (BP) responses to acute exercise. The aim of this study was to investigate the role of ACE2 polymorphisms in postexercise hypotension (PEH). Thirty‐four medicated hypertensive (61·3 ± 1·7 years, 76·1 ± 2·7 kg, 160 ± 1·6 cm) men (n = 12) and women (n = 22), participated in a control and a moderate intensity exercise session in a randomized order. After both experimental sessions, they left the laboratory wearing an ambulatory BP device for 24‐h monitoring. ACE2 polymorphisms (Int‐1 and Int‐3) were assessed by polymerase chain reaction. Over the course of 5‐h monitoring, we observed a significant reduction in SBP and DBP following exercise in the AA/AG of the Int‐1 polymorphism (p‐interaction = 0·02 and 0·001, respectively), whereas this could not be found in the individuals homozygous G (p‐interaction = 0·76 and 0·51, respectively). With regard to Int‐3 polymorphism, individuals AA/AG showed a significant reduction in SBP following exercise (p‐interaction <0·0001) but not for DBP (p‐interaction = 0·06) whereas GG individuals showed only a significant reduction in DBP following exercise (p‐interaction = 0·02). Our results suggest that ACE2 polymorphism could affect PEH; however, larger trials are needed to confirm our findings.     

Aldosterone escape during angiotensin-converting enzyme inhibitor therapy in essential hypertensive patients with left ventricular hypertrophy

Continuous angiotensin-converting enzyme (ACE) inhibitor therapy does not necessarily produce significant decreases in plasma aldosterone levels (aldosterone escape). We examined the role of aldosterone escape in 75 essential hypertensive patients treated with an ACE inhibitor (enalapril maleate [34 patients], imidapril hydrochloride [24 patients] or trandolapril [17 patients]) for 40 weeks. With treatment, blood pressure decreased and plasma renin activity increased, while plasma aldosterone concentrations did not change. Aldosterone escape was observed in 38 of the 75 patients and in 17 of 37 patients with left ventricular hypertrophy before treatment. Left ventricular mass index did not change in patients with aldosterone escape but decreased significantly in patients without aldosterone escape. The present study demonstrated a high incidence of aldosterone escape in patients with essential hypertension despite the use of ACE inhibitors. The results also suggest that aldosterone escape may reverse the beneficial effects of an ACE inhibitor on left ventricular hypertrophy.     

Different patterns of angioedema in patients with and without angiotensin-converting enzyme inhibitor therapy

BACKGROUND: There is convincing evidence for a causal relationship between angiotensin converting enzyme inhibitor (ACEI) therapy and angioedema, but the clinical features of the patients remain unclear. The aim of the study was to compare patterns of angioedema in patients under ACEI therapy and those without ACEI therapy. METHODS: One hundred and seventeen consecutive patients with angioedema treated in the emergency department of a 2000-bed tertiary care university hospital were included. A retrospective cohort study was performed, the exposure being ACEI therapy. The pattern of location of angioedema was the primary outcome measure. RESULTS: Of 117 patients with angioedema, 25 (21%) received ACEI therapy. In a multivariate logistic regression model, angioedema of the cheeks, eyelids or nose was independently negatively associated with ACEI therapy [adjusted odds ratio 0.13 (95% confidence interval 0.03 to 0.49), p = 0.003]. Higher age was also significantly associated with ACEI therapy [adjusted odds ratio 1.85 (95% confidence interval 1.23 to 2.80), p = 0.003]. Furthermore, a trend towards an independent negative association between a history of allergies and angioedema under ACEI therapy was seen. CONCLUSION: Patients with angioedema under ACE inhibitor therapy differ significantly from those receiving no ACEI therapy in terms of patterns of angioedema and age. The applicability of this observation as a tool for deciding whether to continue or terminate ACEI therapy requires prospective evaluation.     

A rapid fluorometric assay of angiotensin-converting enzyme.

A rapid, simple and sensitive method is described for the fluorometric assay of angiotesin-converting enzyme using Fluorescamine. The critical factors such as optimal pH, incubation time, chloride ion, and inactivation by EDTA and 8-hydroxyquinoline were examined. The Km value for hippuryl-L-histidyl-L-leucine was 0.5 mM. This method was applied to the assay of angiotensin-converting enzyme in the rat serum and the reproducible values were obtained with a 10 mul of the rat serum.     

Regression of left ventricular hypertrophy with moexipril, an angiotensin-converting enzyme inhibitor, in hypertensive patients

Left ventricular hypertrophy (LVH) is a common complication of essential hypertension and an independent risk factor for the development of cardiovascular disease. Therefore, antihypertensive treatment should decrease blood pressure (BP) and reverse LVH. However, antihypertensive drugs have been shown to have different effects on LVH despite similar effects on BP reduction. Although lowering BP produces a beneficial effect on LVH per se, meta-analyses of clinical trials have indicated that angiotensin-converting enzyme (ACE) inhibitors decrease left ventricular mass (LVM) to a greater extent than do some other antihypertensives. The aim of this study was to evaluate the effect of a 24-week treatment with the ACE inhibitor moexipril (15 mg once daily) on the regression of LVH in hypertensive patients. This was a multicenter, international, single-blind, single-group, nonrandomized study. After a wash-out placebo period of 2 weeks, 15 mg moexipril once daily was administered for 24 weeks followed by a 2-week follow-up placebo period. Subjects with mild to moderate essential hypertension were screened; those with LVH [defined as an LVM indexed for body surface area (LVMIs) >111 g/m in men and LVMIs >106 g/m in women] were eligible to participate in this study. Echocardiograms were recorded on videotape and sent to a centralized laboratory for reading by 2 independent experts blinded for treatment, center, and visit; the mean values of these readings were calculated and used for analysis. Valid echocardiographic data were obtained from 72 patients (50 males, 22 females) with a mean age of 49 +/- 11 years. Analysis showed significant decrease of LVMIs (121 +/- 20 versus 103 +/- 17 g/m; P < 0.001) and BP (152 +/- 12/96 +/- 9 versus 140 +/- 13/86 +/- 9 mm Hg; P < 0.001) with moexipril. For patients who met LVMI inclusion criteria after centralized, blinded readings, the decrease from baseline in LVMIs was 23.4 g/m. The decrease in LVMIs was independent from the regression to the mean phenomenon as observed from the follow-up placebo period. Moexipril 15 mg once daily administered for 24 weeks resulted in a significant reversal of LVH in patients with essential hypertension. The result compares favorably with results previously obtained in trials of similar duration with other ACE inhibitors.     

A fluorogenic substrate for angiotensin-converting enzyme in plasma.

A simple, sensitive, and reproducible assay for angiotensin-converting enzyme is described. It is based on the hydrolysis of the minimally fluorescent substrate p-nitrobenzyloxycarbonylglycyl-L-tryptophylglycine to the products p-nitrobenzyloxycarbonylglycine and the highly fluorescent L-tryptophylglycine. The L-tryptophylglycine was analyzed by fluorometry (lambda excitation = 285 nm; lambda emission = 350 nm). The mean value for human plasma (serum) is 16.5 nmol of substrate hydrolyzed per minute per milliter of plasma under the described assay conditions.     

Clinical significance of serum angiotensin-converting enzyme levels in sarcoidosis.

Determinations of SACE activity were performed in 80 patients with sarcoidosis, 55 normal controls, and 29 patients with asthma, by the spectrophotometric method of Cushman and Cheung. SACE levels were significantly higher in both untreated and steroid-treated patients with sarcoidosis than in normal controls: 46.2 +/- 20.6 (S.D.), nm/min/ml, 38.1 +/- 23.1, and 26.8 +/- 1.8, respectively. There were no significant differences between steroid-treated and untreated patient groups. However, an inverse correlation was observed between SACE levels and steroid dose, suggesting the possibility of a dose dependency for steroid-induced depression of SACE. Elevated SACE levels (2 S.D. above mean controls) were present in 67% of untreated sarcoidosis patients. The prevalence of elevated SACE levels was not significantly higher when the patient population was examined with respect to duration of disease, radiological stage, and the presence of abnormality in pulmonary function tests. When patients were divided according to the frequency of clinical criteria of disease activity, the presence of two or more criteria was associated with elevated SACE levels in 88% of patients. But SACE levels were elevated in 32% of patients judged to have dormant disease by clinical criteria. SACE levels had an 81% accuracy in prediction of disease activity and a 79% accruacy for prediction of inactivity. It was concluded that SACE elevations have definite diagnostic value in sarcoidosis and are helpful in establishing the presence of disease activity but are not sufficient to fully separate active from inactive disease groups.     

Enhanced angiotensin-converting enzyme activity and impaired endothelium-dependent vasodilation in aortae from hypertensive rats: evidence for a causal link.

Endothelial vasomotor function is impaired in a variety of disorders representing both early and late stages of atherosclerosis. There is experimental evidence for enhanced vascular angiotensin-converting enzyme (ACE) activity in these disorders. We explored whether enhanced vascular ACE activity accounts for endothelial dysfunction in experimental hypertension. Hypertension was induced in rats by coarctation of the aorta. At 2 weeks post-operation, the animals were randomly divided into groups receiving the ACE inhibitor quinapril (2.0 mg.kg(-1).day(-1)), the angiotensin type-1 receptor antagonist losartan (3.0 mg.kg(-1).day(-1)), the B(2) kinin receptor antagonist icatibant (0.4 mg.kg(-1).day(-1)), quinapril plus icatibant, losartan plus icatibant, or no drug. Analyses were performed 4 weeks post-operation. None of the drug treatments had any significant effect on blood pressure. ACE activity was nearly doubled in aortae from untreated hypertensive rats as compared with sham-operated rats. Quinapril reduced ACE activity in aortae from hypertensive rats by 75%, losartan caused a 40% decrease, and icatibant had no effect. Endothelium-dependent, nitric oxide-mediated vasodilator responses studied in vitro were impaired by 40% in aortae from untreated hypertensive rats as compared with sham-operated rats. Both quinapril and losartan restored endothelial vasomotor function in aortae from hypertensive rats. Co-applied icatibant negated the effects of quinapril, but not those of losartan. The level of endothelial NO synthase (eNOS) mRNA determined by competitive RNA PCR was decreased by half in aortae from untreated hypertensive rats as compared with sham-operated rats. Quinapril induced an increase in the eNOS mRNA level of 350% in aortae from hypertensive rats, which was negated by co-applied icatibant. Losartan restored eNOS mRNA expression in aortae from hypertensive rats to normal levels, and this effect was not modified by co-applied icatibant. These findings suggest that enhanced vascular ACE activity accounts for endothelial vasomotor dysfunction by impairing the bioavailability of endothelium-derived NO. Both enhanced formation of angiotensin II and enhanced metabolism of bradykinin might account for a vascular deficiency of bioactive NO.     

Effects of angiotensin-converting enzyme (ACE) inhibitors on water-salt homeostasis in hypertensive patients living in Far North

The aim of the study was evaluation of ACE inhibitors (captopril and ramipril) effect on water-salt homeostasis in the treatment of patients with arterial hypertension (AH) living in the Far North of Russia. 100 male patients with mild and moderate AH were examined 2 weeks, 3 and 6 months after administration of captopril or ramipril. The drugs are shown to correct water-salt metabolism. This is explained by better renal function due to speeding up glomerular filtration and increased sodium excretion with urine, and by activity of humoral mechanisms (inhibited activity of plasma renin, low plasma concentration of aldosterone and its 24-h excretion). Comparison of captopril versus ramipril demonstrates advantages of prolonged ramipril in respect to regulation of water salt metabolism in the treatment of essential hypertension in the Far North.     

Automated determination of angiotensin-converting enzyme in serum

This is an adaptation of the Fujirebio "ACEcolor" kit for automated measurement of angiotensin-converting enzyme (EC 3.4.15.1) in serum with the Cobas Fara centrifugal analyzer. The linear range extends to an activity of 110 U/L. Results obtained by the present method and by the manual method were identical, and correlated closely (r = 0.983) with those by Cushman's modified method. The reference interval for 77 adult blood-bank donors was 9-25 U/L (mean 17, SD 4 U/L). Within-run and between-run CVs are 1.7 and 4.0%, respectively. The present method permits rapid, precise, and economical measurement of the enzyme and allows users of a Cobas Fara centrifugal analyzer to introduce a fully automated assay for angiotensin-converting enzyme into their clinical laboratory.     

Role of angiotensin-converting enzyme in Bacille Calmette-Guérin-induced granulomatous inflammation. Increased angiotensin-converting enzyme levels in lung lavage and suppression of inflammation with captopril.

Lung lavage levels of angiotensin-converting enzyme (ACE)-like activity were increased in C57BL/6 mice with Bacille Calmette-Guérin (BCG)-induced chronic granulomatous pulmonary inflammation and splenomegaly. Contrariwise, ACE activity was not increased in lung lavage fluids of CBA mice that developed only minimal pulmonary inflammation in response to BCG. ACE-like activity correlated with the intensity of inflammation and Captopril, a specific competitive inhibitor of ACE activity, markedly suppressed the induction and maintenance of the BCG-induced inflammatory response in both lungs and spleen. It was necessary, however, to provide sustained treatment with large doses of Captopril in order to reduce the inflammatory response. After a single intraperitoneal injection of Captopril, ACE levels in lung lavage of BCG-injected mice were reduced but returned to preinjection levels or greater within 24 h. The highest dose of Captopril was more effective in reducing the lung fluid level of ACE in BCG-inflamed lungs. This suggests that sustained daily injections of Captopril were necessary to maintain reduced ACE levels. In vitro studies indicated that high concentrations of Captopril did not affect macrophage mobility or chemotactic activity for macrophages. Thus, ACE may act as a molecular mediator of BCG-induced granulomatous inflammation in the lung.