Renin Activity Concentration Research Articles

Renal and endocrine effects of physiological variations of atrial natriuretic factor in normal humans

The renal and endocrine effects of incremental infusions of 3 and 6 ng.kg-1.min-1 of exogenous atrial natriuretic factor (ANF)-(99-126) or placebo were investigated in 10 normal subjects. A 90-min basal period was followed by two 2-h infusion periods with urine collection in the last 90 min of each period. Plasma ANF concentration increased by 50 and 150%, respectively, from a basal value of 6.2 +/- 3.1 pmol/l. Plasma guanosine 3',5'-cyclic monophosphate concentration increased in parallel with ANF. Blood pressure and heart rate were unchanged, whereas hematocrit was stepwise increased. 51Cr-EDTA clearance (GFR) did not change, but ANF caused an increase in Li clearance (a measure of end-proximal fluid delivery), Na clearance, and urine flow compared with time-matched control values. These excretory effects of ANF were mainly due to prevention of the 20- to 50% decreases occurring in the placebo series. Calculated values of fractional proximal and distal tubular Na reabsorption decreased significantly. ANF caused a decrease in plasma concentrations of active renin and aldosterone, whereas renin substrate, angiotensin I, and angiotensin II concentrations were unaltered. A subtle increase in plasma concentrations of norepinephrine and epinephrine was observed during the ANF infusions. These data suggest that the natriuretic effect of ANF is caused by an increased fluid delivery from the proximal tubule in addition to a fall in fractional distal Na reabsorption.

レニンＩＲＭＡパスツールキットの使用経験 肝疾患における活性型レニン濃度

We have carried out basic investigations “Renin IRMA Pasteur kit” along with investigations of active renin concentrations in liver diseases. The result of the basic investigations of this kit have proved to be satisfactory. The trend indicated in liver diseases, was low values in the chronic hepatitis group and high values in the liver cirrhosis group.

Circadian Variations of Total Renin, Active Renin, Plasma Renin Activity and Plasma Aldosterone in Clinically Healthy Young Subjects

The direct assay of total renin (TRC) and active renin concentration (ARC) is a reality due to the availability of monoclonal antibodies against human renin. Because of this, a study has been performed in order to assess the circadian rhythmicity of TRC and ARC. The study was extended to plasma renin activity (PRA) and plasma aldosterone concentration (PAC) for a more complete assessment of the renin-angiotensin-aldosterone system (RAAS). Twelve clinically healthy subjects (6 males and 6 females, age from 20 to 25 years) volunteered for this study. Time-qualified data series were analysed by means of chronobiological procedures in order to validate the circadian rhythm and to correlate the sinusoidal profiles. The circadian rhythm was validated at a high significance for TRC, ARC, PRA and at a borderline significance for PAC. The periodic oscillations were significantly correlated, demonstrating that TRC, ARC, PRA and PAC cycles oscillate in synchronism during the 24-hour span.

Effects of renin inhibition in systemic hypertension

The effect of the direct renin inhibitor enalkiren (Abbott Laboratories) was examined in 8 healthy patients with essential hypertension. With an unrestricted sodium diet, plasma renin concentration was inhibited within 10 minutes by intravenous enalkiren and remained essentially undetectable for ≥ 6 hours (11.9 ± 4 to 1.0 ± 0.6 ng angiotensin 1/ml/hour, p < 0.05). Mean arterial blood pressure declined gradually (108 ± 5 to 84 ± 4 mm Hg, p = 0.02), as did plasma aldosterone concentration (14.4 ± 3.8 to 4.4 ± 0.8 ng/dl, p = 0.03), whereas plasma immunoreactive active renin concentration increased progressively (35 ± 14 to 160 ± 60 pg/ ml, p > 0.05). Urinary excretion of the stable metabolite of prostacyclin (6-keto-prostaglandin F 1α) decreased slightly, but not significantly (42 ± 10 to 33 ± 11 ng/g creatinine, p = 0.13). The addition of a diuretic decreased baseline blood pressure and increased baseline plasma renin and aldosterone values. Blood pressure responses to enalkiren were slightly (though not significantly) greater than those observed before diuretic administration. We conclude that enalkiren is effective in decreasing blood pressure and in inhibiting the renin system, without significantly altering urinary prostacyclin excretion, in patients with essential hypertension. These results suggest that the renin system contributes to the maintenance of elevated blood pressure in some patients with essential hypertension.

Stimulation of Active Renin Release in Normal and Hypertensive Pregnancy

1. Active plasma renin concentration but not total renin concentration is reduced in women with pregnancy-induced hypertension compared with normotensive pregnant women. This study was conducted to determine whether women with pregnancy-induced hypertension are able to stimulate release of active renin. 2. Active plasma renin concentration was measured as the generation of angiotensin I at physiological pH in the presence of excess renin substrate, and total renin concentration was determined in the same way after trypsin activation. Inactive plasma renin concentration was calculated as the difference between total renin and active plasma renin concentrations. 3. Resting active plasma renin concentration was significantly greater in third-trimester primigravidae compared with normotensive non-pregnant women and active plasma renin and total renin concentrations rose significantly without a fall in inactive plasma renin concentration in both groups after 2 h ambulation, suggesting increased release of active plasma renin and not conversion of circulating inactive to active renin. These responses were blunted in women taking oral contraceptives. 4. Although the active plasma renin concentration was significantly reduced in third-trimester primigravidae with pregnancy-induced hypertension, total renin concentration was not significantly different compared with normotensive women of similar gestation and in both groups 30 min 60 degrees head-up tilt increased active but not inactive plasma renin concentration. 5. These studies show that in normal pregnancy active plasma renin concentration can be stimulated to a similar extent as in non-pregnant women, despite a higher resting level. This appears to be due to increased secretion of active plasma renin rather than conversion of circulating inactive to active renin.(ABSTRACT TRUNCATED AT 250 WORDS)

Measurement of Plasma Active Renin by Solid Phase Radioimmunoassay Using Monoclonal Antibodies

A direct radioimmunoassay (RIA) for plasma active renin concentration (ARC) was evaluated by using plasma samples obtained from hospitalized normal volunteers and hypertensive patients. The direct renin RIA was performed by using a pair of anti-renin monoclonal antibodies and a sandwich method. It is suggested that an agitator should be used during the incubation, because the magnetic solid phase was precipitated and could not be suspended well in plasmas. Further, the thawed reagents should not be used for the assay. A highly significant correlation (r = 0.96, p less than 0.01) was found between ARC and enzymatic activity of renin (PRA) in plasma samples obtained from hypertensive patients. The mean values of ARC were 22.8 +/- 3.6 pg/ml in normal subjects, 22.5 +/- 5.3 in patients with EH having medium levels of PRA, 113.7 +/- 11.7 in patients with renovascular hypertension, and undetectable in patients with primary aldosteronism. The results indicated good and reliable performance of the direct renin RIA, which is clinically useful to investigate the renin-angiotensin system.

The Atriopeptidase Inhibitor UK 69,578 Increases Atrial Natriuretic Factor and Causes a Natriuresis in Normal Humans

The endopeptidase EC 3.4.24.11 (atriopeptidase) degrades atrial natriuretic factor (ANF). Intravenous administration of UK 69,578 (0.025 to 10.0 mg/kg), a new specific atriopeptidase inhibitor, in 16 normal volunteers produced a two- to three-fold rise in endogenous ANF. Peak levels were reached within 2 h declining to control values by 8 h. The rise in ANF was associated with an increase in urine volume and mean urinary sodium excretion rose from 64.9 mmoles/8 h after placebo to 116.1 mmoles/8 h after 10 mg/kg UK 69,578. Despite the natriuresis, plasma active renin concentration was suppressed for up to 8 h. We conclude that inhibition of the endopeptidase EC 3.4.24.11 in humans elevates endogenous ANF and causes a natriuresis and may offer a novel therapeutic approach to the treatment of hypertension and cardiac failure.

Inhibition of the Metabolism of Atrial Natriuretic Factor Causes Diuresis and Natriuresis in Chronic Heart Failure

Atrial natriuretic factor (ANF) is a peptide hormone secreted by the heart that is degraded in vivo by endopeptidase 24:11 (atriopeptidase). UK 69,578 is a novel atriopeptidase inhibitor that raises plasma levels of ANF in animals and normal volunteers, with associated diuresis and natriuresis. This study examines the effects of UK 69,578 in patients with mild heart failure. UK 69,578 was administered as an intravenous infusion over 20 min in a placebo-controlled, cross-over study to six patients with stable (NYHA Class 2) chronic heart failure. The atriopeptidase inhibitor was well tolerated and no side effects were encountered. Mean baseline plasma ANF was elevated at 88 pg/mL (normal less than 50), and increased 2- to 5-fold after UK 69,578 administration. Plasma ANF did not change significantly following placebo. There was a marked diuresis after UK 69,578 compared to placebo. Urinary sodium excretion doubled for 4 to 6 h, but there was no significant rise in potassium excretion. There was no increase in plasma active renin concentration during the study period. Noninvasive hemodynamic monitoring revealed no significant changes in heart rate, systemic arterial blood pressure, or echocardiographic left ventricular dimensions. However, invasive measurements using a Swan-Ganz catheter demonstrated falls in mean right atrial and pulmonary artery wedge pressures after UK 69,578. There was no change in cardiac output. Thus, inhibition of endopeptidase 24:11 by UK 69,578 results in significant elevation of plasma ANF, with associated diuresis, natriuresis and venodilatation. The compound was well tolerated in these patients with mild chronic heart failure.

β‐ADRENOCEPTOR MEDIATED SECRETION OF ACTIVE AND INACTIVE RENIN IN CONSCIOUS SHEEP

1. Beta-adrenoceptor linked regulation of plasma active and inactive renin was investigated in sheep with indwelling artery, vein and bladder catheters. Concurrent changes in renal function were also monitored. 2. The beta-adrenoceptor agonist isoprenaline (bolus intravenous (i.v.) dose 0.5 mg/kg, 0.05 microgram/kg per min) increased plasma active renin concentration within 15 min and reached a plateau increase of 306%. Initially plasma inactive renin remained unchanged but after 105 min it decreased. 3. The non-selective beta-adrenoceptor antagonist propranolol (bolus i.v. dose 4 mg/kg, 40 micrograms/kg per min) did not significantly alter basal plasma active renin but selectively reduced inactive renin. The absence of any change in active renin may reflect the relatively low level of stress-induced sympathetic activation in these conscious animals compared to equivalent studies carried out on human subjects. 4. Using the same dose schedules, propranolol completely blocked the isoprenaline-induced increases in plasma active renin secretion even though it had no effect on the basal active renin levels. 5. The selective beta 1-adrenoceptor antagonist atenolol (bolus i.v. dose 5 mg/kg) decreased basal plasma active renin by 24% (+ 135 min) but reduced plasma inactive renin by 75% compared to control. 6. Therefore, both a beta-adrenoceptor agonist (isoprenaline) and two beta-adrenoceptor antagonists (propranolol and atenolol) decreased plasma inactive renin concentration in conscious sheep. 7. These results are discussed in relation to the accompanying changes in arterial blood pressure and aspects of renal function.

Activation of the renin-angiotensin system during ritodrine treatment in preterm labor

Plasma renin activity, active renin concentrations, and total renin concentrations were measured serially in 15 women in preterm labor treated with ritodrine. All three parameters showed rapid increases during treatment that depended on ritodrine doses and paralleled changes in maternal pulse rate. The slope of the correlation between plasma renin activity and active renin concentrations suggested an increase in both active renin and renin substrate during ritodrine treatment. In contrast, levels of inactive renin remained unchanged for several hours during ritodrine infusion, showing only a late and much smaller response than that of either total or active renin concentrations. Thus ritodrine treatment results in further activation of an already activated renin-angiotensin system in pregnancy. This activation relates to an increase in both renin enzyme and its substrate. It may be responsible for the disturbance in water balance and the risk of pulmonary edema associated with beta-sympathomimetic drug treatment in preterm labor.

Normal renal tubular response to changes of sodium intake in hypertensive man

In a comparative study the influence of changes in dietary sodium intake on blood pressure, renal function, extracellular fluid volume, the renin-angiotensin-aldosterone system and plasma concentrations of arginine vasopressin, atrial natriuretic factor and cyclic guanosine monophosphate (GMP) was investigated in 12 patients with essential hypertension and in 10 normotensive controls. The subjects were studied after 4 days on a low (50 mmol/day), medium (180 mmol/day) or high (380 mmol/day) sodium intake. Renal sodium handling was assessed by simultaneous measurements of 51Cr-ethylenediaminetetraacetic acid (EDTA), lithium and sodium clearances. Identical values for the extracellular fluid volume, glomerular filtration rate and proximal and distal tubular resorption rates of sodium and water were found in the hypertensive patients and the controls at all three levels of sodium intake. In both groups, raising the sodium intake from low to high significantly increased 51Cr-EDTA and lithium clearance (an indirect measure of end-proximal fluid delivery), with intermediate values for the medium-sodium diet. The estimated values of fractional proximal and distal sodium resorption decreased when sodium intake was raised; the absolute proximal sodium resorption rate did not change, whereas the absolute distal sodium resorption rate as well as the extracellular fluid volume and sodium clearance increased. Blood pressure and the heart rate were unaffected by sodium intake. In both hypertensives and controls, plasma concentrations of active renin, angiotensin II and aldosterone decreased with increasing sodium intake, arginine vasopressin did not change, and atrial natriuretic factor and cyclic GMP increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma Active and Inactive Renin Concentrations in Children

Plasma active and inactive renin concentrations (PARC and PIRC) were measured by immunoradiometric assay. Age-related changes in PARC, PIRC and the ratio of PARC/PIRC were studied in 78 normal children, age 1 month to 15 years. The effects of upright position for 15 min were also investigated in 7 postmenarcheal girls. PARC and PIRC in infants were significantly higher than in older children and their ratio of PARC/PIRC was significantly lower than in prepubertal children. During puberty, PARC, PIRC and their ratio were higher in premenarcheal girls than in postmenarcheal girls. In the upright position, PARC, PIRC and the ratio were increased significantly. These finding suggest that: (1) the production of inactive renin is increased but the activation of renin may be lowered in infants; (2) the activation of renin is affected by the menstrual cycle, and (3) the production and activation of renin are increased during short term standing.

Roles of the Kidney in Activation and Release of Plasma Inactive Renin in the Rat

Plasma inactive as well as active renin is supposed to originate from the kidney, though there is little direct evidence. As we have previously reported (Sakanaka et al., Folia Endocrinol. Jap., 63: 961-977, 1987; Miyazaki et al., J. Hypertension 4 (Suppl 6): S453-S455, 1986; Miyazaki et al., J. Hypertension 6: 33-40, 1988), the submandibular gland, but not the kidney, is thought to play an crucial role in releasing plasma inactive renin in the rat. In the present acute studies, we attempted to elucidate the roles of the kidney in the release mechanisms of plasma inactive renin. Adult male rats maintained on a regular rat chow (Na: 260 mg/100g) were uninephrectomized, and vessel clips were placed on the renal pedicles of the contralateral kidneys to make completely ischemic and non-filtered kidneys. In the first protocol, the renal pedicles were occluded for 2 h, followed by the removal of the vessel clips. During the occlusion for 2 h, plasma active renin concentration (PAC) in the peripheral blood obtained from the femoral cannulae decreased, while plasma inactive renin concentration (PIC) along with plasma total renin concentration (PTC) increased as in the case of total nephrectomy, which supports our previous studies. Then, declipping resulted in the rapid rise in PAC with the peak values at 2 min, which was followed by its gradual decrease with time during the experimental period (30 min). On the other hand, PIC decreased gradually toward control levels with no rise after declipping. In the second protocol, blood trapped in the kidney was collected through the renal venous cannulae at 0, 60, 120 and 240 min after the pedicle occlusion in the different groups of rats. The renal blood levels of PAC increased by more than three times at 240 min compared to the control values, while PIC decreased to one third of the control values. PTC increased at 120 and 240 min. Renal tissue levels of renin were also measured at 0 and 120 min in the second protocol in the kidneys of rats which were maintained on a regular rat chow. Inactive renin concentration increased, while active renin concentration decreased. These were compatible with the results obtained in plasma. In the last protocol, the second protocol was in part repeated in salt-depleted rats which were kept on a low salt diet (Na: 11.3 mg/100g) for 2 weeks.(ABSTRACT TRUNCATED AT 400 WORDS)

Immunoradiometric Assay of Active Rerun versus Determination of Plasma Renin Activity in the Clinical Investigation of Hypertension, Congestive Heart Failure, and Liver Cirrhosis

We compared the determination of plasma renin activity (PRA) and the direct immunoradiometric measurement of active renin (AR) as ways of assessing the activity of the renin-angiotensin system in normal volunteers and in patients with hypertension, heart failure, or liver failure. The levels of plasma renin substrate, angiotensinogen, and the ratio of PRA to AR concentration did not differ in the normal volunteers and the patients with essential or renovascular hypertension. However, compared to the volunteers, patients with severe heart or liver failure had markedly reduced plasma renin substrate levels, which led to a considerable underestimation of AR concentration when it was measured by PRA.

Assays to measure nanomolar levels of the renin inhibitor CGP 38 560 in plasma.

A radioinhibitor binding assay and an enzyme inhibition assay have been developed to measure plasma levels of CGP 38 560, a potent human renin inhibitor. The detection limit of the assays was between 0.5 and 1 pmol/ml. There was a good correlation (r = 0.989) between the two assays for the measurement of human plasma spiked with CGP 38 560 in concentrations from 1.9 nM to 12 microM. Intra-assay variability was 6.1-17.3% and 4.4-27.2% for the radioinhibitor binding assay and the enzyme inhibition assay, respectively. Interassay variability was 6.0-28.2% and 3.8-28.4% for the radioinhibitor binding assay and the enzyme inhibition assay, respectively. Blood samples were collected during a pharmacological study performed in normotensive human volunteers on an unrestricted diet who were infused during a 30-minute period with CGP 38 560 A (50 micrograms/kg). Similar values for the concentrations of renin inhibitor in plasma were obtained with the radioinhibitor binding assay and the enzyme inhibitor assay, and there was a significant correlation between values obtained with the two different methodologies (r = 0.94). The plasma levels of renin inhibitor reached a maximum at the end of infusion and then decreased rapidly, indicating a short plasma half-life. The changes in biochemical parameters, plasma renin activity, and plasma concentration of active renin could be related to the concentrations of CGP 38 560 measured in the plasma.

Arterial Hypertension as a Paraneoplastic Phenomenon in Hepatocellular Carcinoma

Three South African blacks with hepatocellular carcinoma and arterial hypertension are described. Plasma angiotensinogen (renin substrate) concentrations were increased eightfold to 10-fold in the two patients in whom these concentrations were measured. One of these two patients also showed a 34-fold rise in plasma inactive, active, and total renin concentrations, and an elevated plasma renin activity (2.73 ng.L-1.s-1 angiotensin l/mL/h). Inactive renin (prorenin) constituted 90% of the total plasma renin concentration. In the third patient only plasma renin activity was measured, and this was considerably raised (6.05 ng.L-1.s-1; angiotensin l/mL/h). Thus, the arterial hypertension that rarely complicates hepatocellular carcinoma may be caused either by a combination of eutopic synthesis of excessive quantities of angiotensinogen and ectopic production and secretion of active renin by malignant hepatocytes, or by eutopic production of angiotensinogen alone.

Acute responses to urapidil in hypertensive persons

Urapdil is a new antihypertensive agent involving both a peripheral and a central mode of action. To evaluate the acute effects of this drug on renal vascular tone and on pressor systems a randomized placebo-controlled crossover study was conducted in 10 patients with uncomplicated essential hypertension. Each subject received, on 2 separate days 1 week apart, an intravenous injection of either placebo or urapidil (25 or, if necessary, 50 mg). Before and after this injection blood pressure and heart rate (Dinamap ®), renal plasma flow ( 125I-hippuran), active plasma renin concentration, angiotensin II, aldosterone and catecholamines in plasma were measured. The results show that urapidil, when compared with placebo, greatly reduced Mood pressure, while increasing heart rate, renal blood flow, and noradrenaline and adrenaline levels. However, dopamine levels were suppressed. Whereas renin and angiotensin II were only mildly stimulated, aldosterone levels increased significantly. It is concluded that urapidil, given intravenously, has an immediate blood pressure-lowering effect associated with a decrease in renal vascular tone and an increase in renal perfusion. Consequently, both the sympathetic and renin-angiotensin systems are stimulated, although the latter only to a mild degree. The increase in aldosterone may be partially related to the decrease in dopamine levels.

Immunoreactive renin variations during fertile and infertile hyperstimulated cycles with in-vitro fertilization and embryo transfer or gamete intra-fallopian transfer.

The concentrations of prorenin (PR) and active renin (AR) were determined sequentially during ovarian hyperstimulated cycles for in-vitro fertilization-embryo transfer or gamete intra-Fallopian transfer. AR and PR increased during the early luteal phase and PR was highly correlated with the progesterone concentration. In fertile cycles, AR increased more rapidly after HCG injection and AR and PR levels were significantly higher during the late luteal phase. These results confirm the role of the renin angiotensin system in ovarian physiology.

Processing of one-chain to two-chain renin in the mouse submandibular gland is influenced by androgen.

In the male CD-1 mouse submandibular gland (SMG) renin activity increases markedly with puberty. We have reported that this is, in part, due to an androgen-mediated increase in renin gene transcription. In this study, we examined whether posttranslational processing is also influenced by androgen. We studied secretion and processing of active renin in the CD-1 male mouse SMG which secretes primarily the Ren-2 renin isozyme before and after puberty and also compared findings with the adult female CD-1 mouse. Maturation increases renin level and secretion rate in the male SMG but much less in the female. In addition, Western blot analysis of molecular forms of renin in SMG tissue and media shows a predominance of 1-chain intermediate form of renin before puberty but of the 2-chain mature form thereafter. Adult female SMG contains and secretes much less active renin than the male organ. Administration of testosterone to the female CD-1 mouse induces an adult male level and pattern of secretion, with high concentrations of active 2-chain renin being secreted. These data suggest that SMG renin is androgen regulated, in part by an androgen-responsive enzyme that processes 1-chain renin to the 2-chain form.

Comparison of plasma renin and prorenin in healthy infants and children as determined with an enzymatic method and a new direct immunoradiometric assay.

We compared plasma active and inactive renin (prorenin) concentrations and activities in infants and children, as measured with a newly available direct immunoradiometric assay kit for active renin and a widely used enzymatic renin assay (plasma renin activity). The study was performed in 57 healthy infants and children under steady-state conditions and in eight subjects after orthostatic stimulation. Our study; (i) reports concentrations for active and inactive renin determined by the immunoradiometric assay in normal infants and children; (ii) confirms, by use of the immunoradiometric assay, the previously described decrease in plasma active and inactive renin, as measured by the enzymatic assay, with increasing age; and (iii) shows close correlations between the results obtained by immunoradiometric and enzymatic assays for active and inactive renin in normal infants and children.