Plasma Concentrations Of Active Renin Research Articles

624 A NEED TO RE-FOCUS ON PRECISION OF SCREENING AND DIAGNOSTIC TESTS IN PRIMARY ALDOSTERONISM

Primary aldosteronism (PA) is the commonest specifically treatable and sometimes curable cause of hypertension, and delay in diagnosis is associated with cardiovascular morbidity not explained by hypertension alone. Controversy is high regarding screening, diagnostic and sub-typing tests, and especially their “cut-off” points. This is not surprising, given biological variability of renin, aldosterone, ACTH and cortisol, based on circadian rhythms, posture and stress responses. Unfortunately, emphasis in clinical testing has shifted from precision and reliability to utility and reduced technician time, devaluing diagnostic criteria. Thus plasma concentration of active renin is currently widely preferred to plasma renin activity, but does not take into account the role of endogenous substrate in determining angiotensin II levels, leading to the need for separate normal ranges for the aldosterone/renin ratio (ARR) for men and pre-menopausal women and to changes in the ARR during phases of the menstrual cycle.1 Because most medications affect renin levels, a strong argument exists for screening for PA before commencing medications. Plasma aldosterone measurement by immunoassay (IA) has limited specificity and high-throughput mass spectrometry should gradually replace IA, and eventually angiotensin by IA also. While exciting new information on genetic bases brings the future possibility of definitive (+/-) blood tests for susceptibility to PA, until then we should critically re-examine diagnostic criteria dependent on measurements with limited precision or discriminatory power. Ahmed AH, Gordon RD, Taylor PJ, et al. Are women more at risk of false-positive primary aldosteronism screening and unnecessary suppression testing than men? J Clin Endocrinol Metab. 2011;96:E340-346.

Efficacy and Safety of a New Long-acting Drug Combination, Trandolapril/Verapamil as Compared to Monotherapy in Primary Hypertension

Objective: To evaluate the clinical efficacy and safety of a new antihypertensive drug combination of trandolapril/verapamil compared to monotherapy with verapamil or trandolapril, in patients with mild to moderate primary hypertension. Design: A multicentre, prospective, randomized, double-blind, controlled cross-over study with specific statistical considerations. Settings: Eighteen primary health care centres and out-patient hospital clinics in Sweden. Patients: Two hundred and twenty-six outpatients with uncomplicated primary hypertension with a baseline sitting diastolic blood pressure (BP) between 95 and 115 mmHg. Interventions: After a 4-week placebo period, patients were randomized to treatment for 8 weeks with trandolapril/verapamil (2 mg/180 mg) or each drug alone (verapamil 240 mg, trandolapril 2 mg) for 8 weeks. Main outcome measures: Treatment responses (blood pressure (BP) fall and rate pressure product) to the three regimens with statistical comparison and also in relation to plasma concentrations of active renin (AR). Adverse events and safety were also evaluated. Results: The mean BP fall was significantly greater with the combination (20/15 mmHg), p < 0.00054, as compared to both trandolapril (14/11 mmHg) or verapamil (13/11) mmHg. The difference between verapamil and trandolapril was not significant. Rate pressure product decreased significantly more on the combination, p < 0.001, than on trandolapril or verapamil alone. Treatment response to trandolapril was positively correlated to initial AR (r = 0.30-0.43). All treatments were well tolerated and safe. Conclusions: The new fixed drug combination trandolapril/verapamil was superior to monotherapy with either of these drugs alone regarding reduction of both BP and rate pressure product. This combination can be safely and effectively used for the treatment of mild to moderate primary hypertension.

Disruption of the relationship between renin and atrial natriuretic peptide early in the course of ventricular dysfunction.

Plasma renin activity is normal in left ventricular dysfunction in the absence of diuretic therapy. In health there is a reciprocal relationship between renin and atrial natriuretic peptide (ANP) but a positive correlation in advanced heart failure. The relationship between renin and ANP in mild left ventricular dysfunction is unknown. Patients with left ventricular dysfunction (n = 35, 18 without diuretic therapy) were compared to 20 age-matched healthy subjects. Plasma concentrations of active renin (PARC), ANP and norepinephrine were measured after 20 min rest and 45 min after an infusion of normal saline (10 ml/kg body wt.). Basal plasma ANP was increased in patients with left ventricular dysfunction compared to healthy subjects, whether or not they were receiving diuretics. PARC was similar in healthy controls and patients untreated with diuretics but was increased in diuretic treated patients. After saline loading in healthy subjects PARC fell while ANP rose. Patients with left ventricular dysfunction had a smaller decline in PARC, that did not achieve statistical significance, but had a greater increase in plasma ANP compared to healthy subjects (P<0.05). The close reciprocal relationship between PARC and ANP observed in healthy subjects before and after saline loading (r = 0.8, P<0.001 and r = 0.6, P<0.01) was weakened in those not receiving diuretics (r = 0.4, P<0.05 and r = 0.24, ns) and lost in those receiving diuretics (r = 0.1 and r = 0.08). Patients with left ventricular dysfunction have a disturbance of the normal reciprocal relationship between PARC and ANP which antedates diuretic treatment. This should be taken into account when interpreting plasma neuroendocrine measurements in patients with ventricular dysfunction.

Persistent abnormalities in plasma volume and renal hemodynamics in patients with a history of preeclampsia

OBJECTIVE: The objective was to test the hypothesis that women with a recent history of preeclampsia have abnormalities in renal hemodynamics and volume status. STUDY DESIGN: We studied a group of 26 primiparous women with history of preeclampsia and a group of 12 parous women with a history of uneventful pregnancies (control group). At least 4 months post partum we compared the following variables between these groups: effective renal plasma flow, glomerular filtration rate, plasma volume, plasma concentration of active renin, plasma concentration of angiotensin II, plasma concentration of aldosterone, and plasma concentration of atrial natriuretic peptide. RESULTS: Both plasma volume and plasma concentration of atrial natriuretic peptide were lower in the formerly preeclamptic group. Compared with the control subjects, the formerly preeclamptic group also had a lower effective renal plasma flow, a higher filtration fraction, and a higher renal vascular resistance. Intergroup differences in plasma concentration of active renin, plasma concentration of angiotensin II and plasma concentration of aldosterone were small and inconsistent. CONCLUSIONS: Women with history of preeclampsia are relatively hypovolemic and tend to have lower effective renal plasma flow and higher renal vascular resistance and filtration fraction than do control subjects. These findings support the hypothesis that otherwise healthy women with a history of preeclampsia show abnormalities in their volume status and renal hemodynamics, irrespective of their blood pressure. (Am J Obstet Gynecol 1998;179:690-6.)

Hyponatremic Hypertensive Syndrome and Massive Proteinuria in a Patient With Renin-Producing Leiomyosarcoma

We report a case of renin-producing leiomyosarcoma associated with the hyponatremic hypertensive syndrome and nephrotic-range proteinuria. Extremely high levels of active renin and, to a greater extent, of prorenin were found in plasma and tumor tissue. Immunohistochemical and in situ hybridization studies demonstrated that the neoplastic cells were the source of renin production. The hyponatremic hypertensive syndrome and proteinuria promptly responded to treatment with angiotensin-converting enzyme inhibitors, suggesting an angiotensin II dependency of these disorders. After removal of the leiomyosarcoma, plasma concentration of active renin, but not of prorenin, normalized and the hypertension, proteinuria, and electrolyte abnormalities disappeared. However, 5 months after operation, the patient presented once again with hypertension, hypokalemia, proteinuria, and markedly increased plasma levels of both active renin and prorenin that heralded the relapse of neoplastic disease.

Renal ischaemia, transient glomerular leak and acute renal tubular damage in patients envenomed by Russell's vipers ( Daboia russelii siamensis) in Myanmar

Fifty-two patients who had been bitten by Russell's vipers in Myanmar developed acute renal failure (serum creatinine exceeding 1·3 mg/dL). Thirty-four of them (65%) became oliguric, but the other 18 (35%) maintained a urine output of more than 400 mL/24 h. In oliguric patients, gastrointestinal haemorrhages, renal angle tenderness and conjunctival oedema occurred more commonly, and peak serum creatinine, blood urea nitrogen and the fractional excretion of sodium were significantly higher ( P < 0·01) than in non-oliguric patients, indicating a greater degree of renal damage. Urinary concentrations of β 2 microglobulin and retinol binding protein were raised in most of the patients indicating failure of proximal tubular reabsorption of these proteins, while high urinary N-acetyl glucosaminidase concentrations were consistent with renal tubular damage. Plasma concentrations of active renin were very high, suggesting that renal ischaemia, associated with activation of the renin-angiotensin system, was involved in the development of renal dysfunction.

THE EFFECTS OF MENTAL STRESS AND ISOMETRIC HANDGRIP EXERCISE ON PERIPHERAL BLOOD CELL COUNTS IN PATIENTS WITH ESSENTIAL HYPERTENSION

The effects of mental stress and isometric handgrip exercise on peripheral white blood cell counts and plasma active renin concentrations were studied in 20 patients with mild essential hypertension. The increases in blood pressure and pulse rate were similar for both provocations. Mental stress increased white blood cell (10.3±2.1%), platelet (2.8±1.6%), and red blood cell counts (1.7±0.3%). Isometric exercise also increased these blood cell counts (6.2±1.2%, 1.9±0. 8%, 1.0±0.3%, respectively). The increase in white blood cell counts with mental stress was significantly greater than that in response to isometric exercise. With both provocations, the increase in white blood cell counts was significantly greater than those in platelet and red blood cell counts. There was a positive correlation between the increases in white blood cell counts and systolic blood pressure with mental stress (r = 0.49, p<0.05). Mental stress increased plasma concentrations of active renin and aldosterone, but isometric exercise did not affect these hormones. These results indicate that both white blood cell counts and concentrations of renin and aldosterone are higher in mental stress than in isometric exercise. It is possible that leukocytosis induced by mental stress damages target organ in hypertensive patients.

Angiotensin-converting enzyme inhibitors, left ventricular dysfunction, and early heart failure

A study was undertaken to examine the effects of the angiotensin-converting enzyme inhibitor lisinopril on exercise performance in 18 patients with major impairment of left ventricular systolic function. The study was a randomized, doubleblind, crossover design, and patients received treatment with either once-daily lisinopril (2.5–10 mg) or placebo for a period of 6 weeks. A total of 15 patients completed the study. Compared with placebo, lisinopril had no significant effect on supine or standing blood pressure or heart rate. Although lisinopril had no effect on exercise duration during a low-intensity exercise protocol, in patients undergoing a high-intensity exercise protocol, there was a trend toward improved exercise time and peak oxygen consumption improved significantly. In addition, treatment with lisinopril resulted in an increase in renal blood flow and a reduction in glomerular filtration rate. Moreover, administration of once-daily lisinopril 10 mg resulted in a decrease in plasma concentrations of angiotensin II, aldosterone, and atrial natriuretic peptide, and an increase in plasma concentrations of active renin.

Serum angiotensin-converting enzyme activity and active renin plasma concentrations in insulin-dependent diabetes mellitus

We report here the alterations of serum angiotensin-converting enzyme activity (S-ACE) and of active renin plasma concentrations (ARPC) in 41 insulin-dependent diabetes mellitus (IDDM) patients compared with those of 26 control subjects. The IDDM patients had S-ACE activity (54± 16 I.E.) in the upper normal range (controls, 39 ± 7). When the patients were subclassified according to their diabetic complications, a significant increase of S-ACE within the IDDM group compared to the controls was observed in patients with nephropathy (68 ± 13, P < 0.001) with persistent proteinuria and with retinopathy (63 ± 14, P < 0.001). A significant correlation was found between proteinuria and S-ACE ( r = 0.98, P < 0.001) and between retinopathy and S-ACE levels ( r = 0.64, P < 0.001). No correlation between blood pressure and S-ACE or between blood glucose and S-ACE was observed. The ARPC were within the normal range in the IDDM (21 ± 9 ng/l) and in control (19 ± 3) groups. No correlations between ARPC and blood pressure or blood glucose or the degree of diabetic complications were registered. These data show that S-ACE activity is elevated in IDDM patients with nephropathy-proteinuria and/or with retinopathy and the circulating renin may not represent the renal renin-angiotensin vascular system.

Renal sites of action of physiological increases in plasma atrial natriuretic factor concentration in essential hypertension.

To investigate the renal, haemodynamic and neurohormonal responses to low-dose infusions of atrial natriuretic factor (ANF) in hypertensive humans. Ten patients with mild-to-moderate essential hypertension received incremental infusions of 3 and 6 ng/kg per min ANF or vehicle alone whilst on a constant dietary sodium intake. A 90-min basal clearance period was followed by two 2-h infusion periods, with urine collection in the last 90 min of each period. In each of the three clearance periods, glomerular filtration rate (GFR), renal tubular function, and the activity of the renin-angiotensin and sympathetic nervous systems were determined. The renal sites of ANF action were established by simultaneous measurements of 51Cr-ethylenediaminetetraacetate lithium and sodium clearances. Plasma concentrations of neurohormones were measured by radioimmunoassays. Plasma ANF concentrations increased by 1.6- and 2.5-fold during the lower and higher ANF infusion rates, respectively. Plasma cyclic guanosine monophosphate concentrations increased in parallel. ANF caused no changes in supine systolic and diastolic blood pressure or in heart rate. In contrast, haematocrit values increased progressively across the study. The renal effects of ANF administration were characterized by an unaltered GFR and significant increases in the renal clearances of lithium (a marker of end-proximal fluid delivery) and sodium when compared with vehicle infusions, whereas urine flow did not change. Estimated values of fractional proximal and distal tubular sodium reabsorption decreased significantly. Plasma concentration of active renin decreased during ANF infusions, but no significant changes in plasma levels of renin substrate, angiotensin I, angiotensin II or aldosterone were observed. A subtle activation of the sympathetic nervous system was indicated by a moderate increase in plasma noradrenaline during the ANF infusions. These results indicate that even small increases in plasma ANF, as can be found during physiological conditions, induce natriuresis in patients with essential hypertension by enhancing fluid delivery from the proximal tubules, in addition to impairing distal fractional sodium reabsorption. With minor exceptions, the ANF infusions caused qualitatively and quantitatively similar renal, haemodynamic and endocrine effects in the hypertensive patients as in a previously studied group of normotensive subjects.

Renin gene expression in the adrenal and kidney of patients with primary aldosteronism.

mRNA levels for renin in the adrenal gland and kidney were measured by ribonuclease protection assay (RPA). Renin mRNA was not detected by RPA in aldosteronoma and kidney tissues obtained from two patients with primary aldosteronism (PA). In these patients, the PRA values, plasma concentrations of active renin (ARC), and total renin (TRC = ARC + prorenin) were below the assay limit (less than 0.03 ng/L.s, 2.5 ng/L, and 10 ng/L, respectively). On the other hand, renin mRNA was recognized by RPA in aldosteronoma and kidney tissues obtained from two other patients with PA treated with 50 mg/day spironolactone for more than 2 months. Their TRC values were 49.8 and 16.6 ng/L, but their PRA and ARC were undetectable. Renin mRNA content was greater in normal adrenocortical tissue and in the normal kidneys obtained from three hypertensive patients with renal cell carcinoma. In these patients, the mean values of PRA, ARC, and TRC were 0.28 +/- 0.03 (mean +/- SD) ng/L.s, 18.4 +/- 7.8 ng/L, and 110 +/- 15 ng/L, respectively. This is the first report of the lack of renin gene expression in aldosteronoma and kidney tissues obtained from untreated patients with PA. Furthermore, treatment with spironolactone resulted in an increase in the levels of renin mRNA in the aldosteronoma and kidney tissues of patients with PA.

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.

Low angiotensinogen levels are related to the severity and liver dysfunction of congestive heart failure: implications for renin measurements

purpose: To compare the determination of plasma renin activity (PRA) and the direct measurement of active renin by immunoradiometric assay (IRMA) as methods of assessing the renin system in patients with congestive heart failure. patients and methods: The status of the renin-angiotensin system in congestive heart failure was assessed by measuring the plasma renin substrate concentration, PRA, and plasma concentration of active renin in 37 patients with mild to severe congestive heart failure. Natremia and plasma levels of atrial natriuretic factor (ANF) were determined as biologic indexes of the severity of heart failure, and concentrations of prealbumin and retinol-binding protein were used as indexes of liver dysfunction. results: The PRA and the concentrations of active renin and ANF were markedly higher in patients with New York Heart Association class IV heart failure than in patients with class II to III heart failure, while natremia and the concentrations of renin substrate, prealbumin, and retinol-binding protein were markedly lower in the class IV patients than in the class II to III patients. Plasma renin substrate concentration was negatively correlated with active renin concentration (n = 37, r = −0.45, p = 0.005), and positively related to natremia (r = 0.56, p <0.0005), prealbumin (r = 0.54, p <0.001), and retinolbinding protein (r = 0.60, p <0.0001). conclusions: Low levels of plasma renin substrate can be considered as an indirect index of the severity of heart failure that reflects both the high level of circulating active renin and the decrease in hepatic protein output. In patients with class IV heart failure, low levels of renin substrate led to a marked underestimation of active renin concentration from measurements of PRA. In contrast, direct IRMA of active renin measures the true plasma active renin concentration, independent of plasma renin substrate, and closely reflects renin secretion.

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)

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.

Effects of aging on human plasma renin: simultaneous multiple assays of enzyme activity and immunoactivity of plasma renin

The effects of aging on plasma renin in normotensive volunteers were evaluated by conventional indirect RIA of angiotensin I and a newly developed direct RIA. Plasma renin activity and the plasma concentration of active renin measured by radiometric assay with monoclonal antibody were significantly lower in 14 subjects over 60 years than in 15 subjects under 60 years (plasma renin activity: 0.5 +/- 0.1 vs 1.7 +/- 0.4 nmol.1-1.h-1, P less than 0.01; plasma active renin: 0.50 +/- 0.05 vs 0.87 +/- 0.13 pmol/l, P less than 0.01, means +/- SEM), whereas neither the total renin activity nor the total plasma renin concentration measured by the newly developed immunometric assay were different in the two groups. In another study, the plasma renin concentration, total renin concentration and immunoreactive total renin concentration measured by direct RIA with polyclonal antibody were determined in 17 young (less than 60 years) and 12 elderly (greater than or equal to 60 years) subjects. Plasma renin concentration was significantly lower in the elderly subjects (1.7 +/- 0.2 nmol.l-1.h-1) than in young subjects (3.2 +/- 0.7 nmol.l-1.h-3, P less than 0.05), but the total renin concentration and immunoreactive total renin concentrations in the two groups were not significantly different. These results indicate that the total renin content of the plasma does not change, whereas the active renin content decreases with age in normal subjects, and suggest that activation of prorenin to active renin may be impaired in elderly subjects.

Haemodynamic, hormonal and renal effects of adrenocorticotrophic hormone in sodium-restricted man

The effect of a dietary sodium restriction (15 mmol/day) on the development of adrenocorticotrophic hormone (ACTH) hypertension was examined in six normal male subjects. When ACTH (1 mg/day) was given for 5 days to subjects on a sodium-restricted diet, systolic blood pressure rose (116 +/- 4 to 125 +/- 4 mmHg, P less than 0.001), while diastolic blood pressure was unchanged. There was a modest antinatriuresis (cumulative Na+ balance, 59 +/- 2 mmol) which was reflected in a small rise in exchangeable body sodium (65 +/- 15 mmol); plasma concentrations of active renin and angiotensin II both fell during ACTH treatment. Plasma volume rose (2.8 +/- 0.2 to 3.6 +/- 0.16 l, P less than 0.01) while extracellular fluid volume was unchanged. Plasma concentration of atrial natriuretic peptide (ANP) rose to more than twice basal. Glomerular filtration rate (inulin clearance) increased (111 +/- 9 to 131 +/- 7 ml/min, P less than 0.001), renal plasma flow, measured as the rate of para-aminohippurate (PAH) clearance, was unaltered and calculated filtration fraction rose. Dietary sodium restriction did not, therefore, prevent an ACTH-induced increase in blood pressure. The increase in plasma volume with ACTH is not dependent on renal sodium retention and is associated with increased concentrations of ANP. When these data are compared with findings previously reported in subjects given the same dose of ACTH when on normal or high sodium intakes, it is clear that, although the action of ACTH in raising blood pressure is not dependent on exogenous sodium or extracellular fluid volume expansion, sodium retention can modify the level of blood pressure attained.

Renin-angiotensin system: oral contraception and exercise in healthy female subjects

The effect of oral contraception and of exercise on the renin-angiotensin system was studied in 20 highly trained athletes, of whom 10 were ingesting oral contraceptives (users) and 10 were not (nonusers), and in 24 sedentary age-matched healthy female subjects, of whom 13 were users and 11 were nonusers. No training-related effects were observed with the exception of renin substrate, which was significantly higher in the athletes. The plasma concentrations of active renin and of trypsin-activatable prorenin were significantly lower in the subjects taking oral contraceptives. Renin substrate, however, was significantly higher in the oral contraceptives group. No difference in plasma renin activity (PRA) was observed between users and nonusers. The results demonstrate the well-known estrogen-induced stimulation of renin substrate synthesis by the liver and suggest a decreased secretion of renin by the kidney. Exhaustive exercise of short duration, performed by the trained athletes only, stimulated the renin-angiotensin system. An increase in PRA and in active renin concentration was observed. The prorenin concentration did not change significantly. The magnitude of the exercise-induced changes was considerably influenced by oral contraceptive medication. Nonusers showed a significantly greater increase in PRA and active renin and total renin concentration than users. Renin substrate decreased significantly during exercise in the nonusers only. These results demonstrate that oral contraceptives have a suppressive effect on renin secretion at rest, an effect that becomes more prominent during exercise, i.e., physiological stimulation.

Enalapril in Treatment of Hypertension with Renal Artery Stenosis: Changes in Blood Pressure, Renin, Angiotensin I and II, Renal Function, and Body Composition

The converting enzyme inhibitor enalapril, in single daily doses of 10 to 40 mg, was given to 20 hypertensive patients with renal artery stenosis. The decrease in blood pressure six hours after the first dose of enalapril was significantly related to the pretreatment plasma concentrations of active renin and angiotensin II, and to the concurrent decrease in angiotensin II. Blood pressure decreased further with continued treatment; the long-term decrease was not significantly related to pretreatment plasma renin or angiotensin II levels. At three months, 24 hours after the last dose of enalapril, blood pressure, plasma angiotensin II, and converting enzyme activity remained low, and active renin and angiotensin I high; six hours after dosing, angiotensin II had, however, decreased further. The increase in active renin during long-term treatment was proportionately greater than the increase in angiotensin I; this probably reflects the diminution in renin substrate that occurs with converting enzyme inhibition. Long-term enalapril treatment increased renin secretion by more than 10-fold, and renal venous and peripheral plasma renin concentration by more than 20-fold; however, the mean renal venous renin ratio was not changed. Enalapril caused a reduction in effective renal plasma flow via the affected kidney but a marked and consistent increase on the contralateral side, where renal vascular resistance decreased. The overall increase in effective renal plasma flow was significantly related to the decrease in angiotensin II. Overall glomerular filtration rate was lowered, and serum creatinine and urea increased. Enalapril alone caused a long-term reduction in exchangeable sodium, with slight but distinct increases in serum potassium. In five patients with bilateral renal artery lesions, enalapril given alone for three months did not cause renal function to deteriorate. Enalapril was well tolerated and provided effective long-term control of hypertension; only two of the 20 patients studied required concomitant diuretic treatment.

Enalapril in the treatment of hypertension with renal artery stenosis.

The converting enzyme inhibitor enalapril, in single daily doses of 10-40 mg, was given to 20 hypertensive patients with renal artery stenosis. The blood pressure fall six hours after the first dose of enalapril was significantly related to the pretreatment plasma concentrations of active renin and angiotensin II and to the concurrent fall in angiotensin II. Blood pressure fell further with continued treatment; the long term fall was not significantly related to pretreatment plasma renin or angiotensin II concentrations. At three months, 24 hours after the last dose of enalapril, blood pressure, plasma angiotensin II, and converting enzyme activity remained low and active renin and angiotensin I high; six hours after dosing, angiotensin II had, however, fallen further. The rise in active renin during long term treatment was proportionally greater than the rise in angiotensin I; this probably reflects the fall in renin substrate that occurs with converting enzyme inhibition. Enalapril alone caused reduction in exchangeable sodium, with distinct increases in serum potassium, creatinine, and urea. Enalapril was well tolerated and controlled hypertension effectively long term; only two of the 20 patients required concomitant diuretic treatment.