Renin immunization and angiotensin converting enzyme inhibition in the normotensive marmoset.
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Angiotensin-Converting Enzyme Inhibitors↗
Biomedical subjects
P Corvol
Publications and source records attributed to P Corvol.
Immunological approach to blockade of the renin-substrate reaction.
To block the renin-substrate reaction by immunological tools is a long-standing dream. Since 1951 active immunization and the passive transfer of antirenin antisera have been successfully carried out in different species and in different experimental models of hypertension and normotension. These studies indicated that renin is a powerful immunogenic protein, capable of breaking down self-tolerance in different species. In this initial period the most significant results were obtained with hog renin. Passive transfer of antisera raised against hog renin or active immunization with hog renin was able to decrease blood pressure in renovascular or essential hypertension in dogs. Renin was semipurified and injected without adjuvant, however, since there was no method for determining plasma renin activity. Recently, complete purification of murine and human renin has allowed an extension of this approach, using the passive transfer of antirenin polyclonal antisera or monoclonal antibodies. Active immunization against pure human renin was successful in normotensive marmosets. This immunization with a nearly homologous renin in a primate model induced a significant decrease in blood pressure, associated with a complete disappearance of plasma renin activity. Unfortunately this powerful immunization was associated with an autoimmune disease that is specific for the kidney, related to self-recognition of the production site of renin by antibodies and lymphocytes. Similar results were reported with the use of mouse submandibular gland renin as an immunogen in spontaneously hypertensive rats (SHR). This manipulation decreased blood pressure in SHR to a level near that of normotensive Wistar-Kyoto control rats. However, again the animals showed a severe autoimmune disease of the kidney.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
The angiotensin converting enzyme in the kidney.
Immunohistochemical studies and experiments with microdissected nephron segments indicate that the angiotensin I converting enzyme (ACE) in the kidney is expressed in the vascular endothelial cells of the renal vessels and in the epithelial cells of the proximal convoluted tubule and the pars recta. Angiotensin converting enzyme is a membrane-bound zinc metallopeptidase and the primary structure has recently been determined by protein sequencing and molecular cloning. It is probably anchored to the cell membrane by a single, short, transmembrane domain located near the carboxy-terminal extremity. The larger, externally situated, amino-terminal part of the molecule is organized in two large, highly homologous domains, each with a putative active site. The function of the endothelial enzyme in the renal vessels is primarily related to angiotensin II (Ang II) formation. However, its level of expression in renal vessels, especially at the glomerular level, appears to be very low in the adult human kidney, and there is evidence that the conversion of angiotensin I (Ang I) may be a rate-limiting step in Ang II formation in the kidney. The vascular enzyme may also contribute to the inactivation of kinins in the peritubular circulation. In the epithelial cells of the proximal tubule, ACE is present in both the brush border and the basolateral membrane. Although the basolateral enzyme may be involved in Ang II formation in the peritubular interstitium, the function of the enzyme on the brush border is unknown. The effects of ACE inhibitors on renal function are primarily, if not exclusively, related to Ang II suppression and perhaps kinin potentiation in the renal circulation.
Endothelium, Vascular↗
Crossover design for the dose determination of an angiotensin converting enzyme inhibitor in hypertension.
In order to determine the dose regimen of new antihypertensive compounds, between-patient trials are usually performed. However, the combined use of a crossover design and a precise methodology to measure blood pressure (BP) and biological effects can provide relevant data with a minimal number of patients, if there is no carryover effect which invalidates the experiment. Such goals were successfully achieved with just 25 hypertensive patients who were randomly allocated in double-blind fashion every 2 weeks to a new angiotensin converting enzyme (ACE) inhibitor, benazepril [10 mg once a day (o.d.), 20 mg o.d., 10 mg twice a day (b.i.d.) and 20 mg b.i.d.], or a placebo. The mean BP fall [systolic (SBP)/diastolic (DBP), measured in mmHg] just before drug intake was significantly greater with benazepril: -14/-9 (10 mg o.d.); -15/-8.5 (20 mg o.d.); -22.5/-14 (10 mg b.i.d.), and -21/-13 (20 mg b.i.d.) in comparison with placebo (-3/-3). Mean active plasma renin (measured in pg/ml), assessed by an immunoradiometric assay based on two monoclonal antibodies, increased significantly in a dose-dependent manner, by +0.7 (placebo), +15.0 (10 mg o.d.), +23.4 (20 mg o.d.), +44.4 (10 mg b.i.d.) and +78.8 (20 mg b.i.d.), whereas plasma ACE decreased (by 67 and 78% after 10 and 20 mg o.d., respectively, and by 91-92% after 10 and 20 mg b.i.d.). In the clinical development of an antihypertensive drug, the earlier use of such within-patient studies, with the random insertion of one placebo period between the active periods, should help in the dose-response curve search.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Comparison of increase in the enalapril dose and addition of hydrochlorothiazide as second-step treatment of hypertensive patients not controlled by enalapril alone.
Forty-six patients were randomly allocated to two different groups of treatment if their diastolic blood pressure remained above 90 mm Hg after one month of treatment with 20 mg enalapril mg once daily. In the first group (ENA), 23 patients were given higher daily dosages of enalapril (40 mg and, when necessary, 60 mg). The second group of 23 patients (HCTZ) was given 20 mg/day enalapril and hydrochlorothiazide (25 mg/day and, when necessary, 50 mg). Blood pressure was measured by an automatic device and by the physician with a standard sphygmomanometer. Blood pressure was significantly lower in the HCTZ group, according to both the automatic device (130 +/- 9/80 +/- 8 vs. 141 +/- 5/86 +/- 8 mm Hg, p less than 0.01/p less than 0.05) and the sphygmomanometer (134 +/- 10/89 +/- 6 vs. 149 +/- 16/94 +/- 5 mm Hg, p less than 0.001/p less than 0.01). Plasma renin activity, increased by enalapril at the 20 mg dosage, rose in the HCTZ group but not in the ENA group (22.4 +/- 22 vs. 10.2 +/- 11 pmol/ml/h, p less than 0.05). Plasma aldosterone increased significantly in the HCTZ group (0.44 +/- 0.22 vs. 0.30 +/- 0.17 pmol/ml, p less than 0.05) but did not change in the ENA group (0.31 +/- 0.11 vs. 0.30 +/- 0.17 pmol/ml, NS). In the ENA group, converting enzyme activity was not reinforced (5.7 +/- 8 vs. 6.6 +/- 6 mU/ml, NS) despite an increase in plasma enalaprilat levels (172.4 +/- 108 vs. 72.1 +/- 42 ng/ml, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Angiotensinogen↗
Predictive factors of the blood pressure fall induced by intravenous nicardipine.
The effect on blood pressure of the dihydropyridine derivative nicardipine was studied in 87 essential hypertensive patients aged 25-77 years. A total cumulative dose of 8.75 mg nicardipine was administered over a 30-min period by continuous intravenous infusion. The dose was doubled every 10 min from 1.25 to 5.0 mg. The mean blood pressure fall and the heart rate rise were both dose-related. At 30 min, mean blood pressure fell by 18.9 +/- 7.5% vs. baseline values (p less than 0.001), heart rate increased by 28.0 +/- 11.8% (p less than 0.001), and the renin level by 20.7 +/- 32.5% (p less than 0.001). The blood pressure fall was correlated positively with age (r = 0.521; p less than 0.001) and negatively with the rise in heart rate (r = -0.308; p less than 0.01) and renin level (r = -0.205; p = 0.05). After eliminating the linear effects of age by the partial correlation method, blood pressure fall and the initial renin level were no longer correlated (r = -0.046, NS), whereas the positive correlation between age and blood pressure fall persisted after eliminating the effect of renin (r = 0.464; p less than 0.001). The slope of the regression line for the heart rate rise vs. the blood pressure fall was taken to reflect the baroreflex sensitivity. This sensitivity was negatively correlated to age (r = -0.515; n = 51; p less than 0.001) in the 51 of the 87 patients for whom it could be calculated.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Renin inhibition: immunological procedures and renin inhibitor peptides.
Renin inhibitors represent an alternative to angiotensin-converting enzyme inhibitors (ACEI) for the treatment of hypertension. They inhibit the renin-angiotensin system at its first and rate limiting step, the renin-angiotensinogen reaction. Passive administration of angiotensinogen or renin antibodies lowers blood pressure in primates to the same extent as ACEI. Chronic active immunization against renin decreases blood pressure markedly in normotensive marmosets. Renin can be inhibited by peptides derived from its prosegment. The design of compounds based on pepstatin and on angiotensinogen sequence has led to very potent and specific human renin inhibitors. Such inhibitors are active by the IV route in primates but still lack of good oral activity.
Animals↗
Inhibition of angiotensinogen production by angiotensin II analogues in human hepatoma cell line.
The aim of this study was to examine in Hep G2, a human hepatoma-derived cell line, the presence of angiotensin II (ANG II) receptors and the effect of ANG II and its analogues on angiotensinogen production. The presence of ANG II receptors was demonstrated using a long-acting ANG II analogue, 125I-labeled [Sar1]ANG II. A single class of specific binding sites was identified in these cells with a dissociation constant (Kd) of 2 nM. The number and affinity of these binding sites were not changed by [Sar1]ANG II treatment over 24 h. ANG II showed an inhibitory effect on angiotensinogen production. [Sar1]ANG II also exhibited a similar inhibitory effect as that of ANG II but to a greater extent and therefore was used throughout these studies. [Sar1]ANG II inhibited angiotensinogen production in a dose-dependent manner, exhibiting a half-maximal inhibitory concentration (IC50) of 2 nM. Other ANG II analogues showed similar effects on angiotensinogen production. In order of decreasing ability, they were [Sar1]ANG II greater than [Sar1-Ala8]ANG II greater than [Sar1-Val8]ANG II greater than [Sar1-Val5-(Br5)-Phe8]ANG II greater than [Sar1-Val5-DPhe8]ANG II. Results of these studies show that the Hep G2 cell possesses specific ANG II receptors and that [Sar1]ANG II induces a dose-dependent inhibition of angiotensinogen production in this system.
Angiotensin II↗
Angiotensinogen's role in ANG formation, renin release, and renal hemodynamics in isolated perfused kidney.
Isolated perfused rat kidneys were used to investigate the effects of the addition of pure angiotensinogen or renin-free plasma to the perfusate on angiotensin I (ANG I) and angiotensin II (ANG II) generation, renal hemodynamics, and renin release. When no angiotensinogen or plasma is added, a very small amount of angiotensinogen is initially detected in the perfusate. Whereas renin secreted by the kidney accumulates in the perfusate, angiotensinogen disappears during the perfusion and immunoreactive ANG II cannot be detected. The addition of angiotensinogen reactivates the renin-angiotensin system. ANG I, [des-Asp1] ANG I, ANG II, and [des-Asp1] ANG II are progressively generated in the perfusate. At a constant perfusion pressure, as well as at a variable perfusion pressure, a progressive fall in renal perfusate flow is observed that is significantly correlated to the level of immunoreactive ANG II. ANG II significantly blunts the rise in renin, and renin release in the perfusate is negatively correlated to immunoreactive ANG II levels. Comparison of the ANG I and ANG II levels in in vitro incubated perfusates and circulated perfusates shows that in plasma-injected perfusates the level of immunoreactive ANG II is dependent on both the production of ANG I and its conversion to ANG II by renal and perfusate converting-enzyme activity, and on ANG I and ANG II degradation by the kidney and the perfusate.
Angiotensin I↗
Response of plasma prorenin and active renin to chronic and acute alterations of renin secretion in normal humans. Studies using a direct immunoradiometric assay.
We employed a novel immunoradiometric assay to measure plasma levels of active renin and prorenin in physiologic and pharmacologic studies designed to characterize renin biosynthesis and processing in response to both chronic and acute stimuli of renin secretion in normal human subjects. Stimulation of renin secretion with prolonged dietary sodium restriction or amiloride resulted in marked increases in the plasma levels of prorenin, active renin, and plasma renin activity (PRA); suppression of renin secretion with indomethacin resulted in parallel decreases in prorenin, active renin, and PRA. In contrast, acute stimulation with upright activity or administration of an angiotensin-converting enzyme inhibitor, which increased active renin and PRA from 2- to 15-fold, had no effect on prorenin levels. Based on studies in cultured human juxtaglomerular tumor cells, it has been proposed that prorenin is secreted constitutively whereas active renin is stored in and released from secretory granules through a regulated pathway. Our studies are consistent with such a model: the parallel changes in active renin and prorenin with experimental maneuvers of long duration suggest that both the constitutive and regulated pathways are altered under these conditions. The increase in active renin levels in the absence of a change in prorenin that occurs in response to acute stimuli presumably represents the release of preformed active enzyme that is stored in secretory granules.
Adult↗
The application of molecular genetics to the study of familial arterial hypertension.
The hereditary nature of familial hypertension has been clearly established by a number of clinical studies. Most of the present work has been concentrated on the correlation between various phenotypic traits and the level of blood pressure. The development of molecular genetics allow now to establish a link between high blood pressure and specific phenotypes. As analyzed in this paper, several strategies can be used for the genetic study of arterial hypertension: linkage studies in informative families, population association studies, analysis of subjects with contrasted predisposition to high blood pressure, affected sib-pair method. The identification of the loci implicated in blood pressure regulation and which contribute to the development of arterial hypertension can then be performed in this clinical material by two main approaches. One is based on the study of candidate genes, genes whose products are known to participate in blood pressure regulation, such as those of the renin-angiotensin system which are examplified. The other involves testing a series of markers distributed randomly throughout the genome in order to establish a link between increased blood pressure and a particular region of the genome.
Female↗
Measurement of angiotensin II concentration in rat plasma: pathophysiological applications.
A very reliable isocratic reverse phase high performance liquid chromatography (HPLC) system has been developed to separate angiotensins, which combined with a very sensitive radioimmunoassay, provided precise measurements of the endogenous angiotensin II (AII) concentration in the rat plasma in different experimental circumstances. The overall recoveries of AII were 95.2 +/- 15.8% (means +/- SD) when 10 pg of this peptide was added to 1 ml of human plasma. The coefficient of variation for within-assay precision was 10% (n = 6). The plasma AII, measured by this method, of normal male pentobarbital-anesthetized rats was 53.0-141.6 pg/ml (mean: 103.9 +/- 29.7 pg/ml). The plasma AII of rats fed a sodium deficient diet was 300.0 +/- 100.6 pg/ml, while that of rats given oral Enalapril, an angiotensin converting enzyme (ACE) inhibitor, for 1 week was 35.7 +/- 28.0 pg/ml. The plasma AII of bilaterally nephrectomized rats was 2.7 +/- 2.9 pg/ml 24 hours after nephrectomy and below the detection limit 48 hr after nephrectomy. This method, therefore, can be used to study AII in different pathophysiological states or after treatment with renin-angiotensin system inhibitors.
Analysis of Variance↗
Circulating and tissular renin-angiotensin systems.
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Animals↗
The peculiar characteristics of the amino acid sequence of angiotensin I-converting enzyme, as determined by cDNA cloning of the human endothelial enzyme.
The angiotensin-I converting enzyme (ACE) is a membrane bound zinc metallopeptidase of the vascular endothelial cell. Recently, the complete amino-acid sequence of human ACE has been determined by protein sequencing and cDNA cloning in endothelial cell libraries. The ACE is encoded from a 4.3 kb transcript and comprises 1,306 amino acids. The molecule comprises a signal peptide of 29 residues cleaved off during maturation. It is most likely anchored by a short transmembrane domain situated near the carboxyterminal extremity. Interestingly, the molecule presents a high degree of internal homology between two large peptidic domains. Each of these domains contains short sequences identical to zinc binding and active site sequences of other zinc metallopeptidases and therefore bears a putative active site. The ACE gene results probably from duplication and fusion of a more ancestral gene, coding for a putative nonduplicated enzyme. However, despite the duplicated structure of ACE, it has been reported that there is only one zinc atom bound per molecule. Competitive inhibitors seem to interact with a unique high affinity binding site. Therefore, there is only one active site in ACE whose location remains to be determined.
Amino Acid Sequence↗
Circulating and tissue renin-angiotensin system: present and future.
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Animals↗
[New therapeutic perspectives in the inhibition of the renin-angiotension system].
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Angiotensin II↗
[Detection of silent ischemia in hypertensive subjects with high vascular risk using continuous electrocardiogram in real time].
UNLABELLED: To assess the prognostic value of ECG repolarisation abnormalities (negative T wave and/or ST downslopping (STD) less than 0.1 mV) in systemic hypertension, we compared the frequency of STD greater than or equal to 0.1 mV and greater than 40 s (Qmed real-time ambulatory ECG system) in asymptomatic high-risk hypertensive men with or without ST-T abnormalities on resting ECG (less than or equal to 0 T wave and less than 1 mm ST downslopping). Among 68 hypertensive patients in the upper quintile of risk distribution according to the Paris prospective study, 32 were R+ and 36 R-. Mean age (R+ 53, R- 53 yrs), blood pressure (R+ 180/106, R- 175/102 mmHg), body-mass index (R+ 27, R- 28 kg/m2) risk score (R+ 5.8, R- 5.4), and Sokolow index (R+ 2.7, R- 2.5 mV) were similar in both groups. Left ventricular mass index was different (R+ 152, R- 118 gr/m2, p less than 0.02). Mean recording duration was 35 hours. Eighty-nine episodes of STD were detected in 7 R+ patients (lasting 3 to 136 mn) and one R- patient (lasting 60 s), p less than 0.001. Echographic LVH was present in the 7 positive patients of the group R+. 6 patients underwent thallium scanning and/or coronary angiography: thallium was positive in 4 patients; coronary artery angiography was performed in 3 patients, showing bitroncular stenosis in 1 patient. CONCLUSION: in the present group of high-risk asymptomatic hypertensive patients, the frequency of STD was higher (p = 0.05) in the presence of repolarisation abnormalities on the resting ECG. STD suggests silent ischemia and could account for the excess of cardio-vascular mortality connected with ST-T abnormalities in hypertension.
Adult↗
[Iodo-methyl norcholesterol scintigraphy in the localization of primary hyperaldosteronism].
UNLABELLED: The aim of the study was to investigate the accuracy of iodomethyl norcholesterol, a new adrenal isotopic scanning agent, in the strategy of aldosteronism localization. Among 1499 patients examined in the clinic in 1987, 49 presented with primary aldosteronism. Nine were explored by adrenal scintigraphy (SCI). Mean age was 50 +/- 10 ans, blood pressure was 188 +/- 26/110 +/- 17 mmHg. Initial serum kalemia was 3.2 +/- 0.4 mMol/l, urinary potassium 67 +/- 39 mMol/d; standing plasma active renin was 9.9 +/- 5.0 pg/ml (20 less than N less than 50), supine plasma aldosterone was 316 +/- 200 pg/ml (50 less than N less than 150) and aldosterone excretion rate was 49 +/- 27 microgr/day (N less than 17). Adrenal CT-scan correctly predicted unilateral adenoma in 7 patients (size from 5 to 15 mm). CT-scan was negative twice. Adrenal vein aldosterone sampling and phlebography confirmed adenoma in the 8th patient. 7 patients underwent surgery, with pathological confirmation of the diagnosis. The diagnosis of adrenal hyperplasia (AH) was made in the 9th patient. (table; see text) When compared to CT-scan, SCI is unuseful if a tumor (greater than or equal to 10 mm) is detected on CT-scan (2 SCI false-negative/5 CT-scan tumors). At the opposite, when CT-scan is negative, SCI localizes 2 tumors in 4 patients (2 adenomas). CONCLUSION: SCI should not be used as first step diagnosis procedure in the localization of primary aldosteronism.
19-Iodocholesterol↗