Worldwide distribution of blood lipids and lipoproteins in childhood and adolescence: a review study.

Review and pooled analysis of the relevant worldwide literature was investigated from 1975 to 1996. Eighteen surveys out of 54 were suitable for analysis according to the selection criteria. This represents a total of 60494 observations from 26 countries all over the world. Data suggests differences as great as 76 mg/dl when comparing northern European countries to black African children. The overall curve of cholesterol with age observed in the pooled population indicates a pre-adolescent peak and then a slightly inverse change is observed for both boys and girls, from 3 to 12 years old being almost coincident absolute values. Beyond age 12, values for boys continue to slightly decrease to age 16, while for girls values tend to increase through this age-range. The curve in the late teens (16-18 years) tends to reach pre-teen levels for both sexes, although girls have consistently higher absolute values than boys. There is a great variation in the specific age-sex and race levels of cholesterol among different populations or even in the same populations over a period of time. However, an apparently universal pattern of an early rise, a fall, and a subsequent rise in mean values of total cholesterol by age from the preadolescence to late teens is observed. More data are needed on total cholesterol and lipid fractions between late school age and mid-adulthood.

Hypotensive effect of ZD7155, an angiotensin II receptor antagonist, parallels receptor occupancy in two-kidney, one-clip Goldblatt hypertensive rats.

OBJECTIVE: To examine the effect of ZD7155, an angiotensin II receptor antagonist, on blood pressure, heart rate and occupancy of tissue angiotensin II receptor in two-kidney, one-clip Goldblatt hypertensive rats. METHODS: Goldblatt hypertension was produced in Sprague-Dawley rats. ZD7155 was administered orally at 3 mg/kg and blood pressure and heart rate were monitored for up to 48 h. In a second series of experiments, the rats were administered increasing doses of ZD7155 and monitored for 1 h. For each time and dose, rats were killed and their blood and tissues were collected. Tissue angiotensin II receptor binding was assessed by quantitative autoradiography in vitro. For a separate group of rats, the pressor response to 0.1 microg/kg angiotensin II was monitored before and after the administration of 3 mg/kg ZD7155. RESULTS: After oral administration of ZD7155, blood pressure was rapidly lowered and this lowering was sustained for up to 48 h. This effect was accompanied by sustained inhibition of angiotensin II receptor binding in the aorta, kidney and adrenal gland, together with an increase in plasma renin activity. Increasing doses of ZD7155 dose-dependently reduced blood pressure and inhibited angiotensin II receptor binding in the tissues. Degrees of inhibition varied among the different tissues and had different time courses. ZD7155 inhibited the pressor response to angiotensin II remarkably for 24 h. CONCLUSIONS: ZD7155 is a potent antihypertensive agent in two-kidney, one-clip Goldblatt hypertensive rats and this effect is accompanied by sustained inhibition of tissue angiotensin II binding.

Characterization of angiotensin converting enzyme in isolated cerebral microvessels from spontaneously hypertensive and normotensive rats.

OBJECTIVE: Abnormalities in the vascular renin-angiotensin system have been hypothesized to contribute to the pathogenesis and complications of hypertension. In animal models of hypertension, there is wide variation in reported vascular angiotensin converting activity, particularly in cerebral microvessels. In this study, we sought to characterize, quantitate and compare cerebral microvessel angiotensin converting enzyme (ACE) in genetically hypertensive rats and normotensive rats. DESIGN: Brain microvascular ACE from 14-week-old spontaneously hypertensive rats (SHR) was measured and compared with ACE from brain microvessels of normotensive Wistar-Kyoto (WKY) controls. METHODS: Isolated cerebral microvascular ACE was measured using two methods, enzyme kinetic assay or radioligand binding assay. RESULTS: In SHR, cerebral microvessel ACE was of similar activity and concentration and had similar ligand binding affinities to WKY rats. Plasma ACE activity was significantly elevated in WKY rats compared with SHR. CONCLUSION: Cerebral microvascular ACE is similar in SHR and WKY rats. Microvascular ACE is unlikely to participate in the pathogenesis or complications of hypertension in this model.

Measurement of angiotensin converting enzyme induction and inhibition using quantitative in vitro autoradiography: tissue selective induction after chronic lisinopril treatment.

Angiotensin converting enzyme (ACE) inhibitors lead to induction of ACE in animals and humans. This complicates the use of ACE enzymatic activity as an index of inhibition in plasma or tissues after chronic administration of ACE inhibitors. We have, therefore, developed a method for ACE measurement by in vitro autoradiography using an 125I-labelled inhibitor to quantitate total ACE and the concentration of free (not inhibited) ACE in tissues after prolonged administration of ACE inhibitors to rats. Measurements made on unprocessed tissue sections reflect residual free ACE activity in the presence of the unlabelled inhibitor. In a parallel series of adjacent sections, the ACE inhibitor is dissociated from the enzyme by reversibly denaturing the enzyme by zinc chelation. This is followed by reconstitution of the active enzyme by zinc ion replacement and measuring total enzyme concentration. This technique permits measurement of the extent of ACE inhibition and induction. This method was evaluated in tissues of rats following chronic oral administration of lisinopril (10 mg/kg per day) for 2 weeks. The pattern of ACE inhibition was similar to that seen in our previous acute studies. However, induction of ACE was found to be organ specific; plasma total ACE increased 1.75-fold and total ACE in the lung increased by 30% compared with untreated animals, but there was no demonstrable change in total ACE concentration in the kidney, adrenal or aorta. Despite this, during chronic treatment with lisinopril, ACE activity in all of these organs was inhibited with low levels of free ACE.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of angiotensin converting enzyme in the vascular effects of an endopeptidase 24.15 inhibitor.

1. We investigated the role of angiotensin converting enzyme (ACE) in the cardiovascular effects of N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate (cFP), a peptidase inhibitor selective for metalloendopeptidase (EP) E.C. 3.4.24.15. 2. In conscious rabbits, cFP (5 mg kg-1, i.v.) markedly slowed the degradation of [3H]-bradykinin, potentiated the depressor response to right atrial administration of bradykinin (10-1000 ng kg-1), and inhibited the pressor response to right atrial angiotensin I (10-100 ng kg-1). In each of these respects, the effects of cFP were indistinguishable from those of the ACE inhibitor, captopril (0.5 mg plus 10 mg kg-1h-1 i.v.). Furthermore, the effects of combined administration of cFP and captopril were indistinguishable from those of captopril alone. 3. In experimentally naive anaesthetized rats, cFP administration (9.3 mg kg-1, i.v.) was followed by a moderate but sustained fall in arterial pressure of 13 mmHg. However, in rats pretreated with bradykinin (50 micrograms kg-1) a more pronounced fall of 30 mmHg was observed. Captopril (5 mg kg-1) had similar hypotensive effects to those of cFP, and cFP had no effect when it was administered after captopril. 4. CFP displaced the binding of [125I]-351A (the p-hydroxybenzamidine derivative of lisinopril) from preparations of rat plasma ACE and solubilized lung membrane ACE (KD = 1.2 and 0.14 microM respectively), and inhibited rat plasma ACE activity (KI = 2.4 microM). Addition of phosphoramidon (10 microM), an inhibitor of a range of metalloendopeptidases, including neutral endopeptidase (E.C.3.4.24.11), markedly reduced the potency of cFP in these systems. 5. Taken together these findings suggest that the actions of cFP in vivo are attributable to inhibition of ACE rather than EP 24.15. Given that cFP is a poor inhibitor of ACE in the presence of phosphoramidon in vitro, it is likely that cFP is cleaved by a phosphoramidon-sensitive metallopeptidase in vivo to liberate N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala, a potent ACE inhibitor.

Structural constraints of inhibitors for binding at two active sites on somatic angiotensin converting enzyme.

Angiotensin converting enzyme active sites from rat plasma, lung, kidney and testis were assessed by comparative radioligand binding studies under physiological chloride conditions. Displacement of [125I]Ro 31-8472 from somatic and plasma angiotensin converting enzyme by angiotensin converting enzyme inhibitors of different structure indicated two binding sites (perindoprilat: high affinity carboxyl site, KDC 18 +/- 6 pM), and a single high affinity binding site on testis angiotensin converting enzyme (KDC 20 +/- 1 pM). Displacement of [125I]351A from plasma, somatic and testis angiotensin converting enzyme occurred at a single high affinity binding site. Reduction in affinity at the amino binding site of somatic angiotensin converting enzyme was related to an increased side chain size (lung KDA (pM): Ro 31-8472 175 +/- 38, lisinopril 2205 +/- 1832, and 351A 2271 +/- 489), or hydrophobicity of the competing unlabelled angiotensin converting enzyme inhibitor (lung KDA (pM): quinaprilat 1267 +/- 629 and perindoprilat 824 +/- 6). This trend was reversed at the carboxyl binding site of plasma, somatic and testis angiotensin converting enzyme. Bradykinin hydrolysis by lung angiotensin converting enzyme was inhibited in a similar manner by cilazaprilat or quinaprilat (F = 0.64, F-test based on the extra sum-of-squares principle; P > 0.05), indicating the angiotensin converting enzyme carboxyl active site predominates in bradykinin cleavage. The data demonstrate that the two binding sites on native plasma and somatic angiotensin converting enzyme are of potentially different functional and structural nature, suggesting they may have different substrate specificities.

Characterization and localization of bradykinin B2 receptors in the guinea-pig using a radioiodinated HOE140 analogue.

The potent bradykinin B2 receptor antagonist analogue, [125I]HPP-HOE140, ([125I]-3-4-hydroxyphenyl-propionyl-D-Arg0-[Hyp3, Thi5,D-Tic7, Oic8]bradykinin), was used to localize and characterize guinea-pig tissue bradykinin B2 receptors. Analysis of competition for the radioligand binding, using membrane preparations of lung, ileum and uterus, revealed the presence of a high- and low-affinity binding site: at the high-affinity site, the apparent Ki for the various bradykinin B2 receptor ligands ranged from 0.26 to 2.13 nM for HPP-HOE140, from 0.25 to 1.45 nM for HOE140, from 129 to 625 nM for D-Arg0[pHyp3,Phe7]bradykinin and from 0.05 to 1.11 nM for bradykinin. At the low-affinity site, the apparent Ki values ranged from 4.90 to 10.5 nM, from 1.23 to 1.90 nM, 4760 nM and from 2.01 to 62.1 nM, respectively. By contrast, the bradykinin Bi receptor antagonist, des-Arg9[Leu8]bradykinin did not compete for [125I]HPP-HOE140 binding from membrane preparations at concentrations up to 1 microM. Using in vitro autoradiography on tissue sections, intense binding was observed in the lamina propria of the villi of ileum and the arteriolar smooth muscle cells in lung. In the uterus, dense binding was found in the inner third of the myometrium and over epithelial cells of the glandular endometrium, while diffuse binding was observed throughout the endometrial stroma. In the brain, intense binding was observed in the nucleus of the solitary tract, spinal trigeminal tract and area postrema of the hindbrain, the middle cerebral arteries, and the choroid plexus of the third and lateral ventricles. Moderate binding was observed in the CA3 region of the hippocampus and posterior and ventroposterior thalamic nuclei. In the spinal cord, high-density binding occurred in the laminae I and II of the dorsal horn. Unlike previous autoradiographic localization studies of the bradykinin B2 receptor using radiolabeled bradykinin, the radiolabeled antagonist HPP-HOE140 did not bind to bradykinin-degrading peptidases, such as angiotensin-converting enzyme, and displayed subtype specificity. Therefore, binding studies with [125I]HPP-HOE140 offers high sensitivity and specificity for characterization, quantitation and localization of subtypes of bradykinin B2 receptors in tissues, and offers new information on uterine and brain bradykinin B2 receptors.

[Non-compacted cardiomyopathy: clinical characteristics, evolution and prognostic data in childhood. Results of a multicenter study]. / Miocardiopatía no compactada: características clínicas, evolutivas y pronósticas en edad pediátrica. Resultados de un estudio multicéntrico.

INTRODUCTION: Non-compaction of the ventricular myocardium (NCVM) is a rare congenital heart disease. Heightened awareness has resulted in increased detection of the morphological features of NCVM in routine clinical practice. PATIENTS AND METHODS: Multicentre study including paediatric patients affected by NCVM according to the echocardiographic criteria of Chin and Jenni. RESULTS: A total of 29 patients were included, 15 female and 14 male, the median age at diagnosis was 5 years and 7 months (birth to 17 years). Sixteen patients (55%) presented as an isolated lesion, 8 (27.5%) had a ventricular septal defect, one of them associated with aortic coarctation, 3 (10%) had an inborn error of metabolism, 1 (3.5%) had Juvenile Idiopathic Arthritis and 1 (3.5%) has a syndrome being studied. The location of the trabeculae has been predominantly at the apex, but also affected the left ventricle free wall in 11 patients (40%) and right ventricle in 2 (7%). No complications were present in 12 patients (41%), with cardiac failure in 12 patients (41%), an implantable cardioverter defibrillator was placed for ventricular arrhythmias in 2 patients (7%), stroke, 1 patient (3,5%) and death, 2 patients (7%), both of them less than 6 months of age (P<.05). Median follow up was 12 months (2 months to 8 years). Current treatment includes carvedilol, ACEI's and ASA, and one patient is waiting for a cardiac transplantation. CONCLUSIONS: Early onset of symptoms is associated with a poor prognosis. Clinical and prognostic heterogeneity is described.

Attenuated response to purified protein derivative in patients with rheumatoid arthritis: study in a population with a high prevalence of tuberculosis.

BACKGROUND: The purified protein derivative (PPD) skin test is the only widely used method which detects latent tuberculosis infection (LTBI) and is dependent on a normal T cell function. In rheumatoid arthritis (RA) the T cell function is altered, which may result in an inability to develop an adequate PPD reaction. OBJECTIVES: To evaluate the response to PPD in patients with RA and to compare it with that of control subjects. METHODS: 112 patients with RA and 96 healthy controls were studied. PPD 5 U was applied using the Mantoux method, and skin reaction was measured at 72 hours. The reaction was considered negative for PPD <5 mm. RESULTS: There were no significant differences in age, sex, history of bacille Calmette-Guerin vaccination, or tuberculosis contact between the two groups. The median size of the PPD induration in the patients with RA was significantly less than that in the control group (4.5 v 11.5 mm, p<0.01). 79 (70.6%) patients with RA compared with 25 (26%) of the control group had a negative reaction to PPD (p<0.01), a response not influenced by disease activity or duration of disease in the patients with RA. CONCLUSION: A PPD skin test is not an appropriate test for recognising LTBI in patients with RA in our population.

Mesenteric resistance and brain microvascular angiotensin-converting enzyme in the spontaneously hypertensive rat.

1. Angiotensin-converting enzyme (ACE) concentration was measured in mesenteric and brain microvessels from spontaneously hypertensive rats (SHR) and compared with normotensive controls using a specific radioligand binding assay. 2. Plasma angiotensin-converting enzyme activity was similar in SHR (n = 15) and normotensive controls (n = 21; 58 +/- 1 nmol HL/mL per min, vs 64 +/- 6 nmol HL/mL per min). 3. There was no significant difference between the mesenteric vascular angiotensin-converting enzyme radioligand binding site density (Bmax, fmol/mg protein) of SHR and normotensive controls (954 +/- 77 vs 890 +/- 56, P = 0.5, unpaired Student's t-test), despite significant differences in systolic blood pressure (220 +/- 8 mm Hg vs 120 +/- 6 mm Hg respectively, P less than 0.01) and increased mesenteric wet weight to bodyweight ratio in the hypertensive rats (0.28 +/- 0.02 mg/g, n = 5 vs 0.16 +/- 0.02 mg/g, n = 7, P less than 0.01). 4. Brain vascular angiotensin-converting enzyme radioligand binding site density (Bmax, fmol/mg protein) was also similar in SHR and normotensive controls (467 +/- 62, n = 5 vs 497 +/- 64, n = 5, P = 0.7, unpaired Student's t-test). 5. These results demonstrate that vascular angiotensin-converting enzyme concentration is not altered in the SHR and that vascular ACE is not increased in this form of vascular hypertrophy or regulated by the blood pressure level.

Variation in angiotensin-converting enzyme (ACE) inhibitor affinity at two binding sites on rat pulmonary ACE: influence on bradykinin hydrolysis.

1. ACE from rat lung and testis was characterized by radioligand binding studies using [125I]-Ro 31-8472, the radioiodinated hydroxy derivative of the potent ACE inhibitor cilazaprilat. 2. Analysis of the displacement of [125I]-Ro 31-8472 from ACE by ACE inhibitors of different structure by the LIGAND program was best fitted by a two binding site model for lung ACE and a one binding site model for testis ACE. 3. There was marked variation in ACE inhibitor binding affinity at the two binding sites of lung ACE across the panel of ACE inhibitors studied (equilibrium dissociation constant; Kd; pmol/L) for site one vs site two: cilazaprilat 40 +/- 3 vs 430 +/- 92*; lisinopril 25 +/- 1 vs 848 +/- 107**; and quinaprilat 4 +/- 1 vs 1869 +/- 720; *P less than 0.05; **P less than 0.005, t-test, n = 3). Reduction in binding affinity at site two of lung ACE was related to an increase in ACE inhibitor side chain length or complexity of carboxyl terminal moiety. ACE inhibitor binding affinity at the testis ACE binding site resembled site one of lung ACE. 4. Inhibition of bradykinin hydrolysis by lung ACE in the presence of increasing concentrations of cilazaprilat or quinaprilat was similar (F = 0.64; P greater than 0.05), suggesting that bradykinin cleavage predominates at ACE active site one. 5. The differences in ACE inhibitor affinity at the two ACE active sites has implications in physiological substrate selectivity, and may influence the pharmacodynamic effects of different ACE inhibitors.

Cross sectional subcostal echocardiography: atrioventricular septal defects and the short axis cut.

A short axis echocardiographic cut of the heart from the subcostal approach was used to study the atrioventricular junction in 47 infants and children with congenital heart disease and 20 with normal hearts. Examination of the diastolic openings of both atrioventricular valves was able to establish normal developments of the valves and annuli even when this was found in cases of complex congenital heart disease. In 30 patients with atrioventricular septal defects the technique distinguished between a partial defect (when the two atrioventricular valves were linked transseptally) and a complete defect (when there was only one atrioventricular valve). A range of atrioventricular attachments was seen in these patients. Short axis echocardiography from the subcostal approach reliably identifies different forms of atrioventricular septal defects by defining the anatomy of the atrioventricular valves during maximal diastolic expansion.

Increased cardiac angiotensin-converting enzyme in rats with chronic heart failure.

1. Chronic heart failure was induced in rats by ligation of the left coronary artery to produce a left ventricular myocardial infarct. 2. Cardiac angiotensin-converting enzyme (ACE) was estimated by radioligand binding in myocardial homogenates and by autoradiography studies of radioligand binding to ACE in heart sections. 3. Radioligand binding studies demonstrated an increase in binding sites in animals with myocardial infarction, compared with sham operated animals. Mean increases were 457% in right atrium, 295% in left atrium, 326% in right ventricle, 187% in left ventricle and 530% in the region of the left ventricular infarct, compared with the sham left ventricle. 4. Autoradiography studies confirmed tissue homogenate binding studies, demonstrating (i) a marked increase in ligand binding in the infarct area and (ii) an increase in binding density in the hypertrophied myocardium of right and left atrium, and right and left ventricle. 5. The induction of cardiac ACE in the myocardium of rats with chronic heart failure may participate in the pathophysiology of cardiac hypertrophy.

Characterisation of angiotensin converting enzyme from different rat vascular beds.

The tissue renin angiotensin system may play a role in cardiovascular pathophysiology. Angiotensin converting enzyme in tissues is now a target for pharmacological inhibition. It is therefore important to determine whether ACE is evenly distributed throughout the vascular tree and whether the enzyme has the same characteristics in different vascular beds. We have thus measured angiotensin converting enzyme density in three functionally different vascular beds with three different methods: the enzyme kinetic assay, a radioligand binding assay and in vitro autoradiography. All three methods demonstrated a significantly higher binding density and activity of ACE in resistance arteries from the mesenteric vascular bed of rats than in microvessels from the brain, or in a conduit artery, the aorta. The dissociation constant (Kd) of the enzyme-radioligand complex was the same in the three functionally different vessel types. Radioligand displacement studies for ACE from plasma and the mesenteric vessels in vitro utilizing a panel of different ACE inhibitors have shown a similar rank order of inhibitory potency suggesting that catalytic sites of ACE were the same in plasma and the mesenteric microvessels. In vivo, the enzyme inhibition in plasma, mesenteric and brain vessels measured by enzyme kinetic and radioligand binding assay were well correlated. There was a similar degree of inhibition between different vessels and tissues (mesenteric vessels, aorta, kidney, left ventricle and coronaries) measured by in vitro autoradiography.

Angiotensin-converting enzyme in macro- and microvessels of the rat.

1. Angiotensin-converting enzyme (ACE) was measured in the aorta, cerebral and mesenteric microvessels of Wistar-Kyoto rats using a specific radioligand assay. 2. Ligand binding studies revealed a four-fold increase in concentration of ACE in mesenteric microvessels, compared with aorta or brain microvessels. The dissociation constant (Kd) was similar in all tissues. 3. The effects of oral administration of the ACE inhibitor S9650 on vascular ACE in vivo were measured. 4. S9650 produced a dose-dependent inhibition of vascular ACE from brain and mesenteric microvessels.

The tissue renin-angiotensin system and its functional role.

1. The components of the renin-angiotensin system exist in many cardiovascular tissues (heart vessels, kidneys, adrenal glands). 2. Angiotensin-converting enzyme (ACE) is similar in somatic cells from all these sites. 3. ACE contains two catalytic sites that have different conformation requirements. This suggests that each site may have different substrates and that specific inhibitors could be developed for each site. 4. The cardiovascular functions of tissue ACE may include the regulation of regional blood flow, modulation of local sympathetic activity, stimulation of hyperplasia and hypertrophy and the mediation of inflammation.

Acute and chronic effects of angiotensin-converting enzyme inhibitors on tissue angiotensin-converting enzyme.

1. The effects of angiotensin-converting enzyme (ACE) inhibitors on the tissue ACE were assessed by quantitative in vitro autoradiography after acute and chronic administrations of the drugs. 2. Following acute administration of lisinopril, perindopril or benazepril, ACE was markedly inhibited in the lung, kidney and blood vessels but not in the testis. In the brain, ACE was inhibited mainly in structures with a deficient blood brain barrier. 3. High doses of perindopril progressively inhibited ACE in other brain structures. Tissue ACE inhibition persisted after serum levels of the enzyme had returned to control levels. In the case of perindopril, the time course of tissue ACE inhibition correlated with the inhibition of the pressor responses to exogenous angiotensin I. 4. After chronic administration of lisinopril or perindopril for 14 days, a similar pattern of ACE inhibition was observed in the kidney, lung and blood vessels. In the lung, however, lisinopril was found to increase total ACE by 30%, while plasma ACE was increased two-threefold by both lisinopril and perindopril. Testicular ACE remained unaltered by chronic lisinopril treatment. 5. Overall, the changes in tissue ACE after the administration of inhibitors more closely parallel the drugs' biological effects than changes in plasma ACE or drug levels. ACE in the testis and brain is protected by permeability barriers that limit access of the drugs.

[Characteristics of insulin secretion in persons with glucose tolerance disorders and in patients with type II diabetes mellitus]. / Kharakteristika sekretsii insulina u lits s narushennoi tolerantnost'iu k gliukoze i u bol'nykh sakharnym diabetom II tipa.

Insulin secretion was studied in comparison with the glucose level in persons with disturbed glucose tolerance and in patients with type II diabetes mellitus using a glucose tolerance test and with regard for an obesity degree (the body weight index). The hyperinsulinism incidence in these groups was determined versus that of the controls. The correlation between a high insulin response and the glucose level was absent. Insulin-red blood cell binding was studied in patients with hyperinsulinism and disorder of this process was demonstrated. The hyperinsulinism rate decreased after the body weight index and the glucose level returned to normal.

Inhibition of angiotensin-converting enzyme (ACE) in plasma and tissue.

Inhibition of angiotensin-converting enzyme (ACE) in rat plasma and tissue was studied after administration of quinapril, a new orally active ACE inhibitor with an intermediate duration of action. Tissue and plasma ACE was assessed by a radioinhibitor-binding assay and by in vitro autoradiography using [125I]351A as the radioligand. Individual tissues in rats were differentially inhibited in time and degree. The highest ACE inhibition in plasma and in tissues occurred within the first 2 h after gavage treatment with quinapril, 0.3 mg/kg. After 24 h, ACE was still inhibited by 25% in plasma, by 30% in the aorta, by 35% in the kidneys, and by more than 40% in cardiac atria and ventricles. Plasma and kidney tissues showed increasing ACE inhibition in a dose-dependent manner after oral dosing with quinapril. In the brain, only the structures outside the blood-brain barrier were inhibited after the administration of 0.1 mg/kg of quinapril. Similarly, testicular ACE was unaffected by quinapril. These results demonstrate a prolonged effect of quinapril on tissue ACE and suggest that ACE inhibition in the heart, vasculature, and kidneys may be of particular importance in pathologic states such as hypertension or heart failure.

Haemodynamic, renal and hormonal responses to enalkiren in four patients with post-surgical oliguria.

1. The haemodynamic and hormonal responses of four patients with acute post-surgical oliguria (urine output < 0.5 mL/kg per h) were measured in response to the renin inhibitor enalkiren. Enalkiren was infused at 0.01 up to 0.1 mg/kg per h for up to 4 h. 2. Enalkiren infusion was associated with a progressive fall in blood pressure, clinically significant in three of the four patients. Systemic vascular resistance fell in proportion to blood pressure fall. Cardiac output and pulse rate remained unchanged. Effective renal plasma flow rose in all four cases (236 +/- 19 to 327 +/- 38). There was no change in urine flow rate, or urinary sodium excretion. 3. Plasma renin activity (ng angiotensin I/mL per h) fell from 1.9 +/- 0.5 to 0.02 +/- 0.01 (P < 0.04), plasma angiotensin II (pg/mL) fell from 104 +/- 93 to 7.7 +/- 1.5, and plasma aldosterone (ng/dL) fell from 32 +/- 8 to 21 +/- 9 (P = 0.03) at the highest infusion dose. 4. Enalkiren inhibited plasma renin activity with reduced plasma angiotensin II and aldosterone concentrations. This was associated with vasodilation, reduced blood pressure and maintained cardiac output. There was no beneficial effect on renal function in these patients with post-surgical oliguria.