[Inhibition of the renin-angiotensin system: a major breakthrough in the treatment of arterial hypertension?].
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Biomedical subjects
Publications and source records attributed to J Menard.
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An analysis of socio-professional categories was performed in 712 active hypertensive men, referred between January 1st 1976 and December 31st 1977 to the hypertension out patient clinic of the Saint-Joseph Hospital, Paris. The percentages of senior executives, middle executives and patients with liberal professions, were higher than those calculated in the whole French population. In contrast, the percentages of craftsmen, shopkeeper, employees and manual workers were lower. Furthermore, blood pressure levels obtained by history and those found at first consultation were higher in employees and manual workers than in patients from a higher socio-economic level. The social differencies which are observed may be related to known data concerning mortality, morbidity and drug consumption according to socio-professional categories. They should lead physicians and health care administrators to seek more effective and egalitarian methods of prevention.
A computerized system called ARTEMIS has been taking part in the management of a referral hypertension clinic since September 1975. From January 1, 1976 to January 1, 1979, 3,624 patients' records were set up and updated, all of them accessible on line. The mean rate of response to 17 questions with obligatory answers concerning patients' past history was 97.6 per cent. The 10 routine laboratory tests included in the initial in-hospital work-up were registered in over 92 per 100 of the 2,651 hospital records examined. Negative responses were registered with the same accuracy as positive ones, when the computerized questionnaires were appropriately drafted. Standardized collection of information insured homogeneity of the medical staff and has already made possible epidemiologic studies. ARTEMIS has detected strategical errors such as the lack of yearly programmed tests for cardiovascular risk-factors associated with hypertension. The computer has helped to achieve a high rate of patient compliance at one year (81.3 per cent), by providing patients up-dated editions of their personal summary reports as well as sending periodical letters of recall to them and to their physicians. At a total annual cost of 11 dollars per patient, the computer provides continuous information on process and outcome, for each patient and physician, and for the entire population followed up at the clinic. It facilitates physician adherence to predefined protocols and reinforces follow-up continuity by creating a communications network between the referral clinic, the patient and the general practitioner.
Renin secretion was compared in vivo and in vitro among five groups of rats, each group subjected to a different sodium balance for 10 to 14 days. The state of the renin-angiotensin system in vivo was evaluated by measuring the renal renin (RR) and the plasma renin concentration (PRC) in both anesthetized and nonanesthetized animals. The in vitro renin secretion rate (RSR) was determined in isolated perfused kidneys. RR was reduced (-48%) by sodium loading and deoxycorticosterone (DOCA) and increased (+27%) by sodium deprivation and furosemide. Sodium loading and DOCA reduced both the PRC and the RSR to less than 20% of control values. By contrast, sodium deprivation and furosemide induced a more than fourfold rise in the PRC but only a small increase in the RSR (+37%). These results indicate that changes in fractional renin release are induced by sodium balance variation, and these changes are preserved in vitro only in sodium-loaded states. The inability of sodium-deprived kidneys to maintain high renin release in vitro suggests that high plasma renin levels in these rats depend on mechanisms that are not preserved in vitro. There was no evidence supporting the participation of inactive renin secretion in the regulation of fractional renin release under varying sodium balance.
1. Physicochemical properties of renin secreted by isolated perfused rat kidney were examined and the results compared with those obtained for the renin in renal extract. 2. In renal extract, two high-molecular-weight renins (molecular weight 65 000 and 55 000) and one low-molecular-weight renin (molecular weight 39 000) were found. Their relative proportion varied depending on extraction conditions. By acidification, high-molecular-weight renins were converted into low-molecular-weight renin without marked changes in activity. 3. In renal perfusate only low-molecular-weight renin was found after renin stimulation by isoprenaline or anoxia. Inactive renin was not found. 4. Renin in renal extract and perfusate samples were both found to consist of at least four isoenzymes having different isoelectric points (pI). The pI patterns were identical in renal extract and perfusate samples: pI 5.7 (60-70%), 5.5 (15-25%), 5.3 (5-10%) and 5.0-5.2 (2-5%). 5. These results indicate that the native renin secreted by rat kidney consists entirely of the low-molecular-weight and active form comprising multiple isoenzymes with a stable pI pattern.
1. Human plasma, amniotic fluid and acidified amniotic fluid were incubated at pH 5.5 with the same concentrations of human plasma renin substrate and rat plasma renin substrate. They produced three to eight times more angiotensin I with human than with rat renin substrate. By contrast, human brain extracts generated 20 times more angiotensin I when incubated with rat plasma renin substrate than with human plasma renin substrate. 2. Serial dilutions of anti-(human renin) antibody inhibited, in a dose-dependent manner, the production of angiotension I when plasma, amniotic fluid and brain extracts were incubated with human plasma renin substrate. They also inhibited the production of angiotensin I when plasma and amniotic fluid were incubated with rat plasma renin substrate. They were ineffective on the angiotensin I generation by human brain extracts acting on rat plasma renin substrate. 3. Affinity chromatography on an haemoglobin-Sepharose gel separated the fraction of brain extract acting on human renin substrate and inhibited by anti-(human renin) antiserum; this was not retained on the gel at pH 3.3. Part of the angiotensin I-forming activity detected by rat renin substrate hydrolysis was not retained on the gel and part was eluted at pH 8.5. These angiotensin I-forming activities did not hydrolyse human renin substrate, and were not neutralized by anti-(human renin) antibody. 4. These results demonstrate that a renin, immunochemically identical with renal, plasma amd amniotic fluid renin, is present in the human brain. Other angiotensin I-forming activity, acting on an heterologous substrate at a more acidic pH, is also present in human brain.
Renin secretion from both kidneys was studied in eleven Wistar rats for 40 min after partial clamping of the left renal artery. 14C Inulin and 3H para aminohippuric acid clearance and the arterial and venous plasma renin concentrations were measured in each kidney during control and experimental procedures. After clamping, the arterial plasma renin concentration increased and correlated positively with the plasma renin concentration in both renal veins. However, the plasma renin concentration of the right renal vein was lower than the arterial concentration (P < 0.01). The slope correlating the two variables is significantly lower than unity (P < 0.05, n = 19). As the left kidney secreted a large amount of renin, calculation of secretion by the right kidney decreased to negative values, implying renin uptake by this kidney. These data suggest the existence of a balance between the two kidneys. Renin secretion appears to maintain an equilibrium between release by the juxtaglomerular apparatus and removal from the blood into interstitial space. Release seems to predominate in the hypoperfused kidney, and removal in the contralateral kidney. This may result from the increase of the circulating angiotensin II, since we observed a direct correlation between renin uptake and the arterial plasma renin concentration.
The use of anti-human renin antibodies made possible the intrarenal localization of renin in human kidney by immunofluorescence. In normal kidney, only some juxtaglomerular apparatus (JGA) were fluorescent. In these JGA, granular or diffuse fluorescence was only seen in afferent arterioles and was not present in all cells. In the ischemic areas of partially infarcted kidney, fluorescence was seen in all JGA and in interlobular arteries. In these arteries the most eccentric cells were often the most positive. In the nonischemic areas of the same kidneys, fluorescence was not seen in JGA, but was observed in proximal tubular cells, suggesting the reabsorption of filtered renin at this site.
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The effects of selective and nonselective beta adrenergic drugs on the renin secretion rate (RSR) in isolated perfused rat kidneys were studied. Both isoproterenol (Ipr) (nonselective agonist) and salbutamol (Salb) (beta-2 selective agonist) stimulated RSR in a dose-dependent manner. The lowest doses able to induce a significant RSR increase were 5 nM for Ipr and 50 nM for Salb. A 5-fold increase in RSR was induced by 500 nM Ipr and a 3.2-fold increase by 5 microM Salb. Renin stimulation by both agonists was suppressed by propranolol (nonselective) and by acebutolol and its derivative M&B 16,942 (beta-1 selective antagonists). Thus, renin release was stimulated or inhibited effectively by all the drugs tested, regardless of the beta selectivity of agonists and antagonists. There were no consistent relationships observed between changes in renal hemodynamics and in RSR, suggesting that the used drugs affected renin release from in vitro-perfused rat kidney through their direct effects on juxtaglomerular cells. These results indicate that renal beta adrenoreceptors involved in renin release do not fall into two distinct beta subtypes.
In order to better define the kinetics of the adrenal androgens in hyperprolactinemic states, we have studied 10 patients suspected of having a pituitary prolactinoma. Compared with the levels in 10 healthy control women (normal range: N), no significant differences in the mean (+/- standard error) plasma concentrations of cortisol (F), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DS), androstenedione (A), and testosterone (T) were found: F, 22.7 +/- 2.6 micrograms/100 ml (N = 10 to 25); DHEA, 7.5 +/- 1.4 ng/ml (N = 3.0 to 12.5); DS, 1.7 +/- 0.3 micrograms/ml (N = 1.1 to 3.6); A, 2.2 +/- 0.3 ng/ml (N = 0.5 to 3.5); T, 30.5 +/- 6.4 micrograms/100 ml (N = 20 to 80). Using constant infusions of unlabeled steroid, the metabolic clearance rates (MCR) of the adrenal androgens DHEA and DS were found to be 1282.6 +/- 342.6 liters/day and 5.6 +/- 1.4 liters/day, respectively, which were no different from the MRC of 1689.4 +/- 364.2 liters/day and 6.8 +/- 1.9 liters/day, respectively, found in the normal control women. Medical therapy with a dopaminergic agent in three of these patients reduced mean circulating levels of prolactin from 81.1 +/- 4.7 ng/ml to less than 15 ng/ml but did not change any of our results. It is concluded that, in the study group, hyperprolactinemia exerted minimal trophic effects on the production rates of adrenal androgens.
The authors present a computer system for hypertension control in a specialized department in Paris. The hypertension clinic performs the initial evaluation of the disease in ambulatory care or during a short hospitalization period. The general practitioner (GP) is mainly in charge of the long term follow-up. The objective of the system is to improve the communication between the patient, the clinic and the GP. Data are collected during each visit at the clinic. The computer is used to produce evolutive summary reports for each patient and to control the appointment system. Thus, the data processing system improves the quality of the individual follow-up and, at the same time, a medical data bank is available for epidemiological and pharmacovigilance studies.
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.
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.
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.
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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.