Biomedical subjects

P Corvol

Publications and source records attributed to P Corvol.

At least 325 records · Page 18Linked to original sources

PubMed1988

[Localization of primary hyperaldosteronism].

After diagnosis of primary aldosteronism on the basis of biochemical evidence, the detection of the tumour is of crucial importance in the management of the disease. We reviewed the efficacy of CT-Scan, Iodo-Cholesterol Scintigraphy, digitalized phlebography, adrenal vein sampling for steroid measurements (AVS), and Nuclear Magnetic Resonance (NMR) in 160 hypertensive patients with primary aldosteronism. Diagnosis of Conn's adenoma (n = 96) or Adrenal Hyperplasia (n = 40) was confirmed by surgery or at least two concordant tumour localization tests. Scintigraphy gave a correct diagnosis in 53% of the 51 exams, CT-Scan in 82% of the 85 exams, and phlebography in 79% of 61 exams. Plasma Aldosterone/Cortisol ratio was 5 times higher on the side of adenoma in 55% of the 47 cases but this ratio was also present in 23% of 22 patients with adrenal hyperplasia. Each procedure exhibited few false positive and false negative cases. NMR performed in 15 patients with Conn's adenoma identified all the cases. But tumours displayed a signal close to the liver signal and identical to the normal adrenal. These results and the risk of invasive procedure (failure of catheterization of the right adrenal vein (n = 6) and adrenal haematoma (n = 2) lead us to propose a schema of exploration of patients with primary aldosteronism. The CT-Scan could be performed at the first step once the biological diagnosis confirmed. Phlebography and AVS will be performed only if tumour was less than 1 cm at the CT-Scan despite important biological abnormalities. This schema requires to be validated by a prospective evaluation.

Adenoma↗

PubMed1988

Detection and localization of renin messenger RNA in human pathologic tissues using in situ hybridization.

In order to investigate the synthesis of renin in human pathologic tissues, the authors used in situ hybridization to detect and localize renin messenger RNA (mRNA). The probe was a 35S-radiolabeled 1.1-kb length complementary DNA of human renal renin. To compare the synthesis with the presence and the storage of renin, renin antigen was assessed by immunohistochemistry in the same tissues. The human pathologic tissues were as follows: two ischemic kidneys related to renovascular hypertension; two renal juxtaglomerular cell tumors; one extrarenal renin-secreting epithelioid sarcoma of soft tissues. In ischemic kidneys, the cells containing both renin mRNA and renin protein were found in numerous juxtaglomerular apparatus and in the wall of arterioles, shown by combined in situ hybridization and immunohistochemistry. Most of the tumor cells in the juxtaglomerular cell tumors and scarce tumor cells in the epithelioid sarcoma of soft tissues were positive by in situ hybridization and immunohistochemistry. These findings demonstrate that the presence of renin in these tissues is associated with local cellular production of renin. In particular, smooth muscle cells of the wall of arterioles are definitely capable of synthesizing renin. Moreover, in these tissues, gene expression (renin synthesis) and renin storage are concordant.

Adult↗

PubMed1987

[Detection, diagnosis and localization of pheochromocytoma. 77 cases in a population of 21,420 hypertensive patients].

Phaeochromocytoma was diagnosed in 77 (0.36%) of 21,420 hypertensive patients examined in the hypertension units of the Broussais and Saint-Joseph hospitals, Paris, between 1976 and 1986. Our diagnostic strategy is to reserve biochemical examinations to cases with suspected phaeochromocytoma and to explore only those patients who have positive laboratory results. Patients suspected of harbouring a phaeochromocytoma are those who complain of headaches, palpitations and sweating (these 3 symptoms together having a 90.9% sensitivity and a 99.9% exclusion value), those who have a family history of phaeochromocytoma or who present with medullary thyroid carcinoma or phakomatosis, or those who do not respond to anti-hypertensive treatments. Altogether, these patients account for less than 10% of all cases of hypertension. The most sensitive test in this group is measurement of urinary metanephrines. Among 30 patients with phaeochromocytoma in whom urinary metanephrines and plasma noradrenaline were measured on the same day, none had urinary metanephrine values lower than 3.69 mumol/24 h (0.7 mg/24 h) while 6, who had normal blood pressure at the time of sampling, had noradrenaline levels below 3.53 nmol/l (600 pg/ml). Prior to surgery, the tumour was correctly located by urography (69% of 58 n = tumours), ultrasounds (74%, n = 38), arteriography (83%, n = 23), radioisotope scanning (91%, n = 32), computed tomography (95%, n = 40) and nuclear magnetic resonance imaging (12/12). In 28 patients who had both radioisotope scanning and computed tomography the sensitivities of these examinations were 90% and 100% respectively. A stage by stage approach to the diagnosis of phaeochromocytoma, using detection criteria followed by biochemistry then location methods, is an economical strategy with the best yield from diagnostic and imaging techniques.

Adrenal Gland Neoplasms↗

PubMed1987

A potent radiolabeled human renin inhibitor, [3H]SR42128: enzymatic, kinetic, and binding studies to renin and other aspartic proteases.

The in vitro binding of [3H]SR42128 (Iva-Phe-Nle-Sta-Ala-Sta-Arg), a potent inhibitor of human renin activity, to purified human renin and a number of other aspartic proteases was examined. SR42128 was found to be a competitive inhibitor of human renin, with a Ki of 0.35 nM at pH 5.7 and 2.0 nM at pH 7.4; it was thus more effective at pH 5.7 than at pH 7.4. Scatchard analysis of the interaction binding of [3H]SR42128 to human renin indicated that binding was reversible and saturable at both pH 5.7 and pH 7.4. There was a single class of binding sites, and the KD was 0.9 nM at pH 5.7 and 1 nM at pH 7.4. The association rate was 10 times more rapid at pH 5.7 than at pH 7.4, but there was no difference between the rates of dissociation of the enzyme-inhibitor complex at the two pHs. The effect of pH on the binding of [3H]SR42128 to human renin, cathepsin D, pepsin, and gastricsin was also examined over the pH range 3-8. All the aspartic proteases had a high affinity for the inhibitor at low pH. However, at pH 7.4, [3H]SR42128 was bound only to human renin and to none of the other aspartic proteases. Competitive binding studies with [3H]SR42128 and a number of other inhibitors on human renin or cathepsin D were used to examine the relationships between structure and activity in these systems.(ABSTRACT TRUNCATED AT 250 WORDS)

Aspartic Acid Endopeptidases↗

PubMed1987

[Ambulatory blood pressure in normotensive subjects. Definition of reference values as a function of age by the Spacelabs instrument].

For a finer assessment, by repeated blood pressure (BP) measurements, of the cardiovascular risk associated with BP levels, new instruments have been developed which provide multiple reading during periods of activity. However, the lack of epidemiological studies makes it necessary to determine reference ambulatory BP levels by another method. Twelve-hour recordings were taken with the Spacelabs instrument in 130 volunteers (45% males) aged from 20 to 90 years during their various activities. Mean systolic and diastolic BP values +/- SD were calculated per age-groups of 10 years each. That this sample was representative of the general population was confirmed by the fact that BP fluctuations and variations according to age and sex in these 130 subjects were identical with those observed in the population of an entire town (Framingham). The concept of hypertension, as defined by ambulatory BP recordings, is discussed. This study provides, for the first time, reference ambulatory BP values according to age and sex, measured in normotensive subjects with the Spacelabs instrument. These values constitute a preliminary step indispensable to evaluate this technique in hypertensive patients.

Adult↗

PubMed1987

Efficacy and tolerance of spironolactone in essential hypertension.

The long-term efficacy and tolerance of spironolactone in essential hypertension was evaluated among 20,812 patients referred to the Broussais and St. Joseph systemic hypertension clinics between 1976 and 1985 by using information prospectively collected in the computerized ARTEMIS data bank. In 182 patients (51 men, 131 women) treated with spironolactone alone during a mean follow-up period of 23 months, a mean dose of 96.5 mg decreased systolic and diastolic blood pressure (BP) by 18 and 10 mm Hg, respectively, below pretherapeutic levels. The BP decrease was greater with doses of 75 to 100 mg (12.4% and 12.2%) than with doses of 25 to 50 mg (5.3 and 6.5%, p less than 0.001), but no additional decrease was found with doses above 150 mg. Plasma creatinine level increased modestly (8.3 mumol/liters), as did plasma potassium level (0.6 mmol/liters) (both p less than 0.001); uric acid level increased, but not significantly (10.5 mumol/liter). Fasting blood glucose and total cholesterol levels did not change, triglyceride levels increased slightly (0.1 mmol/liter, p less than 0.05). These changes were similar in both sexes and were not influenced by length of follow-up. Among the 699 men prescribed spironolactone alone or in association with another antihypertensive treatment, 91 cases of gynecomastia developed (13%). Gynecomastia was reversible and dose-related; at doses of 50 mg or less the incidence was 6.9%, but 52.2% for doses of 150 mg or higher. Despite limitations inherent in the interpretation of data banks, it is concluded that spironolactone administered in daily practice reduced BP without inducing adverse metabolic adverse effects and that in patients with essential hypertension, doses should be kept below 100 mg.

Aged↗

PubMed1987

Comparative enzymatic studies of human renin acting on pure natural or synthetic substrates.

Some of the essential structural requirements for the enzymatic reaction of pure human renin acting on pure human and rat angiotensinogen and on their synthetic tetradecapeptide substrates were investigated. The five carboxy terminal amino acids of synthetic tetradecapeptides played a significant role in substrate recognition and/or hydrolysis by human renin. Kinetic constants Km, Kcat and kcat/Km of the various human renin assays were different according to the substrate used. The presence of either an asparagine or a threonine residue in the S'4 renin subsite did not affect significantly the kinetic constant values. A tyrosine residue, rather than a histidine residue, in the S'3 renin subsite gave the best synthetic substrate studied. When tyrosine residue was present in the S'2 renin subsite an important decrease in kcat was observed. Human angiotensinogen was hydrolysed by human renin with lower Km and kcat values than those measured with human and porcine synthetic substrates, suggesting that the 3-dimensional structure of human angiotensinogen plays a key role in the hydrolysis. This finding was supported by assays performed with rat angiotensinogen, which was cleared by human renin with the same kcat value as rat tetradecapeptide, but with a 49-fold lower Km. Between human and rat angiotensinogen a kcat/Km value of only 2-fold higher has been found in the renin assay using human substrate.

Amino Acid Sequence↗

PubMed1987

Production and characterization of human renin antibodies with region-oriented synthetic peptides.

Polyclonal and monoclonal antibodies were raised against pure human renin, but nothing was known about the regions against which they were directed. Using a three-dimensional model of mouse submandibular renin, we selected seven peptide sequences as belonging to potential epitopes. The main criteria for their choice were the location of the peptide sequences near the catalytic region and on the surface of the renin molecule and their hydrophilicity. After transposition of the regions to the 340-amino acid sequence of human renin, the seven peptides (corresponding to amino acids 50-60, 63-71, 81-90, 118-126, 162-169, 247-255, and 287-295) were synthesized, coupled to bovine serum albumin, and injected into rabbits. Five of these peptides elicited antibodies, and 50-68% binding of the corresponding iodinated peptide was obtained with a 1:25 dilution of antiserum. The antisera titers ranged from 1:5,000 to 1:100,000 when tested by enzyme-linked immunosorbent assay. The same antisera bound 15-65% of labeled pure human renin at a final dilution of 1:2.5, the highest percentage being obtained with peptide 81-90 antiserum. At a 1:5 dilution, the five antisera inhibited renin activity by 23-68% in human plasma with a high renin activity (40 ng of angiotensin I/h/ml). At a final dilution of 1:50, peptide 81-90 antiserum was still capable of producing 25% inhibition. Purified IgG (0.6 mg) from this antiserum inhibited pure human renin activity by up to about 40%, as measured by its reaction with pure synthetic human tetradecapeptide substrate. Antigenic peptides that mimic a part of the human renin sequence, especially peptide 81-90 representing the "flap" covering the cleft between the two renin lobes, constitute promising tools for the development of a synthetic antirenin vaccine.

Amino Acid Sequence↗

PubMed1987

Earliest renin containing cell differentiation during ontogenesis in the rat. An immunocytochemical study.

The differentiation of renin containing cells was studied by immunocytochemistry in normal rat fetuses by the use of highly specific renin, angiotensin I and II antisera. Renin synthesizing cells were detectable as early as the 15th day of gestation outside the nephrogen territories within the walls of mesonephrotic-gonadic and renal arteries. Intrarenal differentiation began at the 17th day and progressed along the intrarenal arterial tree. AII immunostaining appeared concomitantly in the renin containing cells and developed considerably during ontogenesis, suggesting intracellular biosynthesis. It can be suggested that in the fetus newly synthesized AII may contribute to the early systemic and renal blood pressure regulation.

Angiotensin II↗

PubMed1987

Treatment of mild to moderate hypertension with or without the converting enzyme inhibitor enalapril. Results of a six-month double-blind trial.

A group of 205 patients with mild to moderate essential uncomplicated hypertension was chosen from 3,183 hypertensive patients referred to a hypertension clinic for the first time, and was asked to participate in a six-month double-blind parallel trial. A single physician was in charge of all the patients. After a two-week single-blind placebo period, the patients were randomly assigned to regimens of either enalapril (20 mg per day) or placebo. Both groups were then followed up every two weeks, and increasing doses of hydrochlorothiazide (25 and 50 mg), oxprenolol (160 and 320 mg), and dihydralazine (50 and 100 mg) were added until the diastolic blood pressure was lower than 90 mm Hg. After a six-month follow-up, the enalapril group showed lower systolic and diastolic blood pressures than the control group (129/82 +/- 12/6 mg Hg versus 135/86 +/- 10/5 mm Hg; p less than 0.001). The number of daily tablets of active drugs was 2.7 +/- 1.8 in the enalapril group and 4.4 +/- 2.4 in the control group (p less than 0.01). The mean plasma potassium level was 4.16 +/- 0.4 mmol/liter in the enalapril group versus 3.92 +/- 0.4 mmol/liter in the control group (p less than 0.001), despite more frequent use of amiloride (p less than 0.001). This difference is explained by the lower dose of hydrochlorothiazide used in the enalapril group by comparison to the control group, and a lower excretion of urinary aldosterone in the enalapril group than in the control group (11.6 +/- 7.4 versus 19.8 +/- 11.8 micrograms per 24 hours, p less than 0.001). Drug withdrawal was necessary in eight patients in the enalapril group and in 16 patients in the control group (p less than 0.05). These results show that first-step treatment of mild to moderate uncomplicated essential hypertension with enalapril permits better blood pressure control than the standard treatment, requires fewer tablets to be taken daily, and involves a smaller risk of hypokalemia.

Adult↗

PubMed1987

Isolated clinical syndrome of primary aldosteronism in four patients with adrenocortical carcinoma.

Adrenocortical carcinoma is a rare disorder that can be revealed by an isolated syndrome of mineralocorticoid excess. In a retrospective study of 137 patients referred to our hypertension clinic in the past 10 years for primary aldosteronism, four cases of adrenocortical carcinoma were identified. The clinical presentation of these patients was similar to that of patients with Conn's adenoma, but preoperatively, malignant tumoral primary aldosteronism was suspected because of profound hypokalemia, marked elevation in plasma aldosterone levels, and enlarged size and weight of an heterogenous adrenal tumor with internal calcifications. Malignancy was confirmed by the histologic features. No prognostic criteria could be established and two patients died despite specific surgery, which was performed in all cases. More recent developments in the use of mitotane led to the addition of adrenocorticolytic therapy in the remaining two patients, who are still alive at the time of this report.

Adolescent↗

PubMed1987

Active immunization against renin in normotensive marmoset.

Primate renins (human and monkey) are very similar. We used pure human renin to immunize marmosets (Callithrix jacchus) and thereby produce a chronic blockade of the renin-angiotensinogen reaction. After a control period of 2 months, five male marmosets, on their usual sodium-poor diet, were immunized against pure human renin by three subcutaneous injections of 30 micrograms each, with complete and then incomplete Freund's adjuvant. Three marmosets were injected with adjuvant only and served as controls. Blood sampling and blood pressure measurements were performed weekly. After the third injection, the five marmosets immunized against renin developed a high titer of renin antibodies (50% binding of 125I-labeled human renin at a dilution of greater than or equal to 1:10,000). The antibodies inhibited the enzymatic activity of both marmoset and human renins. At the same time, systolic blood pressure decreased significantly from 125 +/- 13 mm Hg to 87 +/- 8 mm Hg (mean +/- SD; 1 mm Hg = 133 Pa). Plasma renin enzyme activity was undetectable in three animals. Plasma aldosterone decreased significantly. After 1-4 months with low blood pressure, a normal urinary output, and a normal plasma creatinine, the five marmosets became sick and died within one month. At autopsy an immunological renal disease, characterized by the presence of immunoglobulin and macrophage infiltration colocalized with renin, was found. Granulomatous formations, probably due to Freund's adjuvant, could be seen in the lungs and in the kidney. No immunoglobulin was detectable in extrarenal vessels or in other organs. These experiments demonstrate that, in this primate, a chronic blockade of the renin-angiotensin system can be achieved by active immunization against homologous renin, but this blockade is associated with the development of an autoimmune disease localized in the kidney.

Animals↗

PubMed1987

Angiotensin I-converting enzyme in a suprasellar germinoma.

High levels of angiotensin I-converting enzyme (ACE) were found by both direct radioimmunoassay and enzyme activity evaluation in a patient's plasma that had suprasellar germinoma. ACE levels returned to normal values after surgery, suggesting the tumor was the cause of the elevated plasma ACE. ACE was found in the tumor, and ACE activity was measured in a tumor extract. With the use of specific antihuman ACE antibodies, ACE was localized by immunohistochemistry in the tumoral germinal cells. Because ACE was also found in testicular germinomas, it appears to be a possible marker for germ cell tumors.

Aged↗

PubMed1987

Evaluation of slow release nicardipine in essential hypertension by casual and ambulatory blood pressure measurements. Effects of acute versus chronic administration.

We conducted a randomized placebo-controlled double-blind study in 40 hypertensive subjects to assess the antihypertensive effect of a new galenic form of nicardipine administered at a dosage of 50 mg twice daily for 3 weeks. Regardless of whether blood pressure was measured by standard mercury sphygmomanometer, non-ambulatory automatic oscillometry or a Remler ambulatory blood pressure recorder, it dropped by a significantly larger amount in the nicardipine group than in the placebo group. In the control group, a placebo effect was observed with the ambulatory diastolic blood pressure recording, whereas it was not observed with hospital blood pressure measurements, especially when using the serial measurements performed for 30 min by an automatic recorder. The fall in blood pressure measured with the Remler recorder was correlated with the fall measured 10-20 min during one acute intravenous nicardipine perfusion before the trial, although the correlation coefficients do not suggest clinically relevant predictability of nicardipine efficacy at the individual level. The present findings support the need for controlled double-blind trials with careful office blood pressure measurements.

Administration, Sublingual↗

PubMed1987

Binding of a tritiated pepstatin analog to human renin.

The interaction between human renin and a potent pepstatin analog, SR 42128, has been investigated using binding studies. Binding and enzymatic assays were performed at pH 5.7 and pH 7.4. We found one specific inhibitor binding site per molecule of renin at both pH's. The dissociation constant (KD) obtained at equilibrium was 14-fold lower at pH 5.7 than at pH 7.4, showing a pH effect on binding of [3H]SR 42128. A similar decrease was measured in enzymatic studies. In nonequilibrium conditions, we demonstrated that only association kinetic constants have been affected by pH variations. Radioligands provided interesting tools to investigate enzyme-inhibitor relationships.

Humans↗

PubMed1987

Effects of transdermal clonidine in young and elderly patients with mild hypertension: evaluation by three noninvasive methods of blood pressure measurement.

The efficiency of the clonidine transdermal therapeutic system was assessed in a group of patients under 35 years of age and in another group of patients over 60 years of age. The patients in both groups had mild uncomplicated hypertension. Blood pressure (BP) was measured by the three following methods: by the physician; by an automatic device at the outpatient clinic; and by the patient at home. Seventeen young patients (mean age, 26 years) and 18 elderly patients (mean age, 68.5 years) were included in a double-blind crossover study comprising four periods of 2 weeks each, during which patients were given, weekly, either placebo or one and then two transdermal clonidine patches containing 2.5 mg of the drug. In the younger group, the average systolic and diastolic BPs measured by the physician after administration of two clonidine patches were, respectively, 4.9 and 5.9 mm Hg lower than after placebo (p less than 0.05). The absolute drop was more significant in the older group (9.3 and 6.0 mm Hg; p less than 0.01). In the young group, placebo markedly reduced systolic BP (9.8 mm Hg; p less than 0.01), and comparison of the three methods of BP measurement demonstrated their great reactivity to the physician's presence. Nine young and eight elderly patients received clonidine treatment for an average duration of 9 +/- 5 months. Six cases of skin reactions occurred and limited the usefulness of the clonidine transdermal system used in this study.

Administration, Cutaneous↗

PubMed1987

Converting-enzyme inhibition buffers the counter-regulatory response to acute administration of nicardipine.

1. To investigate the interaction of angiotensin-converting-enzyme (ACE) inhibitor and calcium antagonist, we conducted a double-blind randomized, placebo-controlled crossover study of a new ACE inhibitor (CGS 14824 A, 20 mg) during intravenous administration (i.v.) of nicardipine in eight normotensive healthy subjects. Nicardipine was infused to give cumulative doses of 1.25, 3.75, and 8.75 mg after 10, 20 and 30 min. 2. ACE inhibition was demonstrated 24 h after the first CGS 14 824 A intake (61%). Three hours after the second dose this inhibition was more marked (98%). 3. I.v. nicardipine administration induced a significant and similar fall in systolic or diastolic blood pressure with and without ACE activity (-3/-6 vs -2/-8%), while tachycardia was significantly decreased by CGS 14 824 A (+14 vs +30%, P less than 0.02). The increase of plasma noradrenaline was also significantly blunted (+1.8 +/- 0.3 vs +3.1 +/- 0.7 pmol ml-1, P less than 0.05). 4. Active and total plasma renin increased at the end of nicardipine infusion in the presence or absence of ACE inhibition. Inactive renin did not increase after nicardipine infusion under placebo. It was higher 3 h after the second intake of CGS 14 824 A and then increased after nicardipine infusion. 5. The rise in plasma aldosterone during i.v. calcium antagonist infusion was diminished after ACE inhibition (126 +/- 39 vs 277 +/- 120 pmol l-1, P less than 0.02). 6. In conclusion, converting-enzyme inhibition buffers the rise in heart rate, plasma noradrenaline and plasma aldosterone induced by acute calcium blockade.

Adult↗

PubMed1987

Renin secretion from malignant pulmonary metastatic tumour cells of vascular origin.

1. A pulmonary chemodectoma/glomangiosarcoma that had metastasized from the thigh was studied after removal from a 22 year old Algerian patient with hypertension, high plasma prorenin and signs of secondary aldosteronism. 2. Renin and renin mRNA were localized in sections of the tumour tissue using monoclonal anti-human renin antibody and human renin cDNA probe, respectively. 3. The cells grew prolifically in culture, but, even though their renin content was similar to that of transfected human juxtaglomerular cell tumour cells (approximately 1 pg/microgram DNA), their rate of secretion of renin was much lower (0.05-0.15 cf. 0.5-1.5 pg/h per microgram DNA). 4. Forskolin (10 mumol/l for 24 h) increased secretion of renin from 1.9 +/- 0.36 to 4.1 +/- 0.64 pg/ml per h of culture (P less than 0.001, n = 11), consistent with cAMP being a second messenger in the secretory mechanism. 5. The cells should provide valuable information about intracellular mechanisms for the regulation of renin synthesis and secretion.

Adolescent↗