[A reasonable pretherapeutic evaluation of the hypertensive patient].
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Biomedical subjects
Publications and source records attributed to P Corvol.
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The main physicochemical and enzymic properties of non-activated and activated human amniotic renin (EC 3.4.99.19) were studied in order to clarify the relationships between the two enzymes. Human amniotic renin was activated by dialysis against acidic buffer (pH 3.3), direct acidification or trypsin treatment. All procedures produced similar activation. The physicochemical characteristics of non-activated and activated renin were compared to those of human renal renin. Non-activated renin had a molecular weight of 45,500. A similar molecular weight was obtained by gel eluate activation and by acid treatment of renin prior to gel filtration. Similar isoelectric points were also found for non-activated and activated renin. One major renin peak focused at pH 6.6, whereas no similar renin peak was detected in extracts from normal human kidney. In addition, non-activated and activated renin forms were found to have the same optimal pH, the same Km and the same inhibiting pepstatin concentrations.
In five patients with a phaeochromocytoma, axial computerised scanner tomography made it possible to localise the tumour without ambiguity, even when intravenous urography had been interpreted as normal. Although all the tumours diagnosed were relatively large (between 3 and 9 cm), this is nevertheless a non-invasive examination, free of danger and worthy of consideration in the preoperative assessment of a case of phaeochromocytoma.
Human renin was purified from a juxtaglomerular cell tumor with a high renin content, 24.2 Goldblatt units/mg of protein. The purification procedure comprised three steps: gel filtration, DEAE-cellulose chromatography, and preparative isoelectric focusing. Five forms of renin amounting to 5.3 mg of enzyme were obtained with isoelectric points of 4.95, 5.10, 5.35, 5.55, and 5.70. They were all glycoproteins. The three major fractions had very similar specific activities, 868, 860, and 809 Goldblatt units/mg of protein. These fractions produced a single band on analytical isoelectric focusing and a single arc on immunoelectrophoresis. On polyacrylamide gel electrophoresis at pH 7.8, each fraction consisted of two renin bands with the same molecular weight, but different net charges. The molecular weight determined by gel filtration and Fergusson plot analysis on polyacrylamide gel was 38,000 to 42,000. The optimum pH determined on N-acetyltetradecapeptide substrate was 6.5, and the Km was 6.8 x 10(-6) M. These parameters were identical with those for standard human kidney renin. Antibodies raised against tumor renin completely inhibited the activity of both tumor and standard renin. Under dissociating conditions (sodium dodecyl sulfate-polyacrylamide gel electrophoresis and gel electrophoresis in the presence of 6 M urea), part of the purified enzyme dissociated into two smaller fragments (Mr = 20,000 and 25,000) containing renin activity.
The effects of acebutolol (800 mg per day for three days) on pulse rate, blood pressure, plasma noradrenaline and plasma renin activity were measured in nine patients with essential hypertension, at rest in a horizontal position, after five minutes standing upright and after walking for one hour. Acebutolol reduced pulse rate, blood pressure and plasma renin activity in all three positions. Treatment has no influence on plasma noradrenaline in a horizontal position, but significantly reduced its orthostatic stimulation. The inhibition of noradrenergic response to an orthosatic position is compatible with a central or presynaptic effect of acebutolol. This effect would not appear to be essential to its antihypertensive action since acebutolol reduced blood pressure but not plasma noradrenaline in a horizontal position. Blood pressure response to treatment was positively correlated to initial values of plasma renin activity measured after walking for one hour and plasma noradrenaline measured after five minutes in an orthostatic position. On the basis of this correlation, measurement of these two hormonal indices is of predictive value, within the limits of a short period of treatment with acebutolol and strictly defined hospital conditions.
Idiopathic edema is characterized by impaired water excretion, particularly in the upright posture. Indirect evidence has shown that antidiuretic hormone is involved in this disease. For this reason, we measured urinary arginine vasopressin by radioimmunoassay before and during water loading (15 ml/kg) in 10 normal women and in 10 subjects with idiopathic edema in both the supine and upright postures. Daily sodium intake was 100 meq. Renin and aldosterone were concomitantly investigated, and abnormally high values were observed both in the recumbent and upright postures. Basal values for urinary arginine vasopressin were identical in control subjects and in patients with idiopathic edema. The water load significantly reduced urinary arginine vasopressin in normal women in both positions, but in those with idiopathic edema only in the supine position. In those with idiopathic edema, assumption of the upright posture was accompanied by a transient decrease in glomerular filtration, a major decrease in osmolar clearance and no decrease in urinary arginine vasopressin after water loading. Significant correlations were established between urinary arginine vasopressin and osmolar or volemic parameters in normal women, but these correlations were not found in those with idiopathic edema in either position. Arginine vasopressin regulation was abnormal in idiopathic edema, and this hormone was believed to play a part in the pathogenesis of this disease.
To investigate the possible direct effect of two aldosterone antagonists (Canrenoate-K and Prorenoate-K) upon mineralocorticoid biosynthesis a perifusion system technique has been developed. Frog interrenal tissue was selected for its ability to secrete huge amounts of aldosterone (twice as much as corticosterone in resting conditions). Throughout the experiment, secretion of aldosterone was measured every ten minutes by means of a sensitive and highly specific radioimmunoassay method. Increasing concentrations of both Canrenoate-K and Prorenoate-K (ranging from 10(-4)M to 10(-3)M) caused a dose-related inhibition of aldosterone output. At a dose of 3.16 x 10(-4)M, Prorenoate-K appeared to be somewhat more potent (57.8% inhibition) than Canrenoate-K (47.8% inhibition). Infusion of both Canrenoate-K and Prorenoate-K at a dose of 5 x 10(-4)M during 1 or 2 hours induced a similar sharp decrease in mineralocorticoid secretion. Thus, it appears that Canrenoate-K and Prorenoate-K beside their well known effects at renal tubular receptor sites do also inhibit aldosterone biosynthesis. These results indicate that in vivo administration of aldosterone antagonists may first involve a transient decrease in aldosterone secretion. Furthermore, they suggest that mineralocorticoid biosynthesis might be regulated by a short loop feedback mechanism.
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1. The presence of high-affinity sites for [3H]-aldosterone was shown in the normal human renal tissue. 2. [3H]Aldosterone and [3H]dexamethasone binding were studied in human renal adenocarcinoma and in uninvolved external cortex, in 22 patients undergoing nephrectomy for renal adenocarcinoma. Tissue incubations were performed with either [3H]aldosterone (5 x 10(-10) mol/l; 5 x 10(-9) mol/l in the presence of unlabelled glucocorticoids) or [3H]dexamethasone (5 x 10(-9) mol/l). 3. Cytosol [3H]aldosterone binding was six- to seven-fold lower (P less than 0.001) in neoplastic than normal tissue. [3H]Dexamethasone binding was about twofold higher in neoplastic than in normal tissue. This difference was not significant. 4. Nuclear uptake experiments showed that, both in cytosol fractions and nuclei, [3H]aldosterone binding was lower in adenocarcinoma than in normal cortex. 5. The very low binding of [3H]aldosterone suggests that mineralocorticoid receptors are absent in renal adenocarcinoma, an hypothesis in line with the proximal origin of these tumours.
1. Highly specific antibodies to human renin were prepared in rabbits and used for the preparation of a renin-free substrate, the direct radioimmunoassay of renin in plasma and kidneys, and the localization of renin with fluoresceinated antibodies. 2. In a patient with a partially infarcted kidney, plasma renin activity was increased, and could be activated by acid. The direct measurement of plasma renin by radioimmunoassay gave identical values before and after acidification. 3. In the ischaemic part of the kidney, renin content was high, both by the enzymatic and the direct method of measurement. It was low in the non-ischaemic part of the kidney. 4. All afferent and some interlobular arteries of the obsolescent glomeruli were stained with fluoresceinated anti-renin antibodies. In the non-ischaemic area, the juxtaglomerular appratus did not stain. 5. Renin can now be measured in human plasma and kidney as an entity, by a specific radioimmunoassay. A direct investigation of this intrarenal hormone is now possible at the renal tissue level.
In 2 patients with phaeochromocytoma, effective beta-blockade was obtained with propranolol (40 mg twice a day for 3 days) or acebutolol (400 mg twice a day for 3 days) without any effect on the blood pressure. In both patients the excretion of noradrenaline predominated over that of adrenaline, a picture found in most cases of phaeochromocytoma. A hypertensive response to beta-blockade might be expected in patients with an adrenaline-secreting tumour. It cannot be a regular event or constitute a diagnostic test in patients with suspected phaeochromocytoma.
Two new aldosterone antagonists, K-prorenoate [potassium 3(17 beta-hydroxy-6 beta, 7 beta-methylen-3-oxo-4-androsten-17 alpha-yl)propionate] and prorenone [3(17 beta-hydroxy-6 beta, 7 beta-methylen-3-oxo-4-androsten-17 alpha-yl) propionic acid gamma-lactone], its lactonic form, were studied in rat kidney using in vitro systems. Study of [3H]prorenone binding by a recently developed computer method indicated a high affinity, low capacity class of sites which are, seemingly, mineralocorticoid receptors. In competition experiments performed on [3H]aldosterone- and [3H]dexamethasone-binding sites, prorenone appeared to be a good competitor for mineralocorticoid-binding sites and a poor competitor for glucocorticoid-binding sites. The specificity of this molecule was further confirmed by its poor ability to displace [3H]dihydrotestosterone from rat prostate androgenic receptors compared to spironolactone [3-(3-oxo-7 alpha-acetylthio-17 beta-hydroxy-4-androsten-17 alpha-yl) propionic acid gamma-lactone]. In the same experiments, K-prorenoate demonstrated a very low affinity for the two types of receptors. The behavior of [3H]prorenone cytosolic complex was also studied in kidney mince experiments, which showed that the [3H]prorenone complex was not able to translocate into the nucleus. Prorenone inhibited the binding of [3H]aldosterone to the receptor and, consequently, the nuclear binding of aldosterone was not observed.
Antibodies were raised in rabbit against pure human renin. The antisera obtained are highly specific for human renin versus hog, dog and rat renin. They do not cross-react with acid proteases such as pepsin and human cathepsin D. A direct radioimunoassay is described for human renin in plasma and kidney extracts. 30 to 50 pg of enzyme (2.5 to 4 x 10(-5) Goldblatt units) are detected.
Of the metabolic precursors of the catecholamines fixed by the adrenal medulla, 131I marked thyrosine was chosen as a radio-tracer. 6 positive results out of 11 pheochromocytomas confirmed at surgery were obtained in a series of 23 patients. This result is comparable with the results of arteriography but there are more false positives, reflecting the insecurity of this technique which is otherwise quite innocuous.
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