Plasma Renin Substrate Concentration Research Articles

Marathon run: effects on plasma renin activity, renin substrate, angiotensin converting enzyme, and cortisol.

Altogether 33 Finnish amateur runners were studied before and after a non-competitive Marathon run over the classical itinerary in Athens in 1976 (n = 8), 1977 (n = 14) and 1978 (n = 11). Plasma renin activity (PRA) rose 3-fold in all runs, whereas plasma renin substrate (RS) concentration did not change significantly. Serum angiotensin converting enzyme (ACE) activity was not changed. Serum cortisol concentration was increased 2-3 fold. The unchanged plasma RS concentration, in spite of increasing PRA, indicates that plasma RS is kept within normal limits during prolonged strenuous physical exercise. One contributing mechanism may be stimulation of RS biosynthesis by cortisol. Low PRA levels in two old runners, 65 and 83 years old, may indicate a decreased ability to respond with renin release to the stimuli of physical exercise.

Plasma renin substrate and oestrogens in normal pregnancy

Relationship between concentrations of serum oestrogens, plasma renin substrate and plasma renin activity were studied in six women throughout pregnancy. There was a significant positive correlation between serum oestradiol-17 beta and plasma renin substrate concentrations (r=0.60). Serum oestriol concentrations also correlated significantly with plasma renin substrate concentrations (r = 0.68). Correlation coefficients calculated separately for each subject throughout pregnancy were higher than those for the whole group. Also, there was much individual variation in dose-response of serum oestrogens to plasma renin substrate concentrations. There was no significant correlation between serum oestrogens and plasma renin activity. Our results support the view that oestrogens cause the increase in plasma renin substrate concentration during pregnancy, and emphasize the individual variation in response of renin substrate concentration to serum level of oestrogens.

Effects of chronic administration of captopril on blood pressure and the renin-angiotensin-aldosterone system in normotensive rats.

The chronic effects of oral administration of an angiotensin converting enzyme inhibitor (captopril, 63-80 mg/Kg/day) on blood pressure and the renin-angiotensin-aldosterone system were-studied in normotensive male Wistar rats. Blood pressure (BP), plasma renin activity (PRA), plasma renin concentration (PRC), plasma renin substrate concentration (PRS), plasma aldosterone concentration (PAC) and renal renin content (RRC) were measured after 2, 9, 19, 29 and 58 days of captopril administration. BP was determined in awake rats and blood samples were obtained by decapitation. In addition, BP responses to bolus injections of angiotensin I (AI, 80 ng/Kg), angiotensin II (AII, 80 ng/Kg) and bradykinin (BK, 10 micrograms/Kg) were examined in conscious rats which had received captopril for 20 days. The BP of the rats which had been given captopril for 9 days or longer was significantly lower than that of the control rats. PRA and PRC were markedly increased, and both PRS and PAC were decreased in the captopril-treated rats. RRC, which was reduced after 2 days of captopril administration, was substantially increased thereafter. Although the pressor responses to AII were similar in the captopril treated and the control rats, the responses to AI were reduced to 50% of those to AII in the former. The depressor responses to BK in the captopril-treated rats were 2.3 times as large as those in the control rats. Our results show that long-term use of captopril lowers BP in normotensive rats on a normal sodium intake.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies on the mechanism by which ACTH stimulates renin activity and angiotensin II formation in man.

Ten IU of ACTH (1-24) per day was infused for 34 h (starting at 7 a.m.) into 8 normal men on a constant diet containing 135 mM Na+ per day. All subjects retained between 152 and 181 mM of sodium. Potassium balance was negative. Plasma renin activity (PRA) and plasmaangiotensin II (P-A-II) started to rise in most subjects after 6 to 8 h of infusion, reached a maximum after 24 h and then tended to decline. As shown previously, the rise in PRA is not due to a rise in plasma renin substrate concentration. Systolic, but not diastolic blood pressure increased significantly on the second day of ACTH-infusion. Plasma cortisol (P-F) was continuously stimulated by ACTH. Plasma aldosterone (P-aldo) increased rapidly 1 h after ACTH administration, then tended to fall, and increased again in most subjects, roughly in parallel with PRA. No significant changes in electrolyte balance, PRA, P-A II, P-F, and P-aldo occurred in 3 subjects receiving 'sham' infusions. Additional experiments in subjects treated with propranolol or indomethacin allowed the conclusion that the effect of ACTH on PRA and P-A II is not mediated by renal beta-adrenergic receptors, but perhaps (partially?) by prostaglandins. Since the infusion rate of ACTH was not much higher than the secretion rate of ACTH in the early morning hours, it is possible that ACTH is physiologically involved in the regulation of renin secretion.

Evidence for two independent effects of oestradiol benzoate on the renin-angiotensin-aldosterone system.

Abstract. Plasma renin concentrations (PRC), plasma renin substrate concentration (PRS), plasma aldosterone and cortisol concentrations as well as plama renin activity (PRA) were measured in ovariectomized subjects after im administration of 10 mg oestradiol benzoate (EB). The esterified oestrogen exerts two independent effects on the renin-angiotensin-aldosterone system. 1) 48 h after EB administration, PRS was significantly increased. Similar results were obtained for total plasma cortisol, reflecting transcortin concentration. In both cases, the increase was quantitatively related to the basal concentrations. These observations are consistent with the well known oestrogen-induced protein synthesis in the liver. 2) The elevation of PRC preceded that of PRS and was already significant 11 h after EB injection. The early rise in plasma renin activity was essentially caused by the increase in PRC, whereas an influence of the activated substrate synthesis was found later, between the 2nd and the 4th day post injection. The time course of plasma aldosterone concentration correlated well with the increased PRA. The results provide evidence that EB has two different effects on the renin-aldosterone axis: an early one by elevating renin release and a delayed one by increasing renin substrate synthesis. Whereas the second mechanism can clearly be localized in the liver, extrarenal as well as direct renal effects of EB may be responsible for the renin stimulation.

Reduction of plasma renin substrate after parturition; role of renin

Plasma renin substrate concentration, renin activity, serum sex hormone binding globulin and total protein concentration were measured sequentially in 10 women after elective caesarean section. Plasma renin substrate concentration decreased from 5406 +/- 000 micrograms AI/l (mean +/- SD) at term to 2369 +/- 726 micrograms AI/l 6 days post partum. Plasma renin activity decreased from 6.2 +/- 3.3 micrograms AI/l/h at term to 4.2 +/- 4.0 micrograms AI/l/h 6 days after delivery. Serum sex hormone binding globulin decreased more slowly than plasma renin substrate concentration. Clearance of plasma renin substrate based on plasma renin activity was calculated. This consumption by renin could explain only 12% of the decrement in plasma renin substrate concentration at the steepest part of the plasma renin substrate disappearance curve. It is concluded that metabolic clearance of plasma renin substrate may be much greater than that calculated from plasma renin activity.

Role of the renin-angiotensin system in maintaining arterial pressure in conscious pregnant rats.

The renin-angiotensin system in relation to arterial blood pressure was examined in conscious rats at various stages of pregnancy. Also, the possibility that a site other than the maternal kidney was the source of the increased plasma renin levels in late gestation was tested by examining the reninangiotensin system in nephrectomized term-pregnant rats. Conscious rats, pregnant for 9, 13, 17, and 21 days, had mean arterial pressures that were not different from those of nonbred control rats; however, infusion of the angiotensin II (A-II) antagonist, [Sar1, Ala8]A-II, resulted in significant decreases in mean arterial pressure in the 13-, 17-, and 21-day-pregnant groups. Pregnant rats had significant elevations in PRA at 13, 17, and 21 days of gestation and increases in plasma renin concentrations (PRC) at 13 and 21 days of gestation, while plasma renin substrate concentrations (PRS) were significantly increased in the 9- and 13-day-pregnant groups, but were not increased in the 17- and 21-day-pregnant gro...

Renin substrate in rat mesenteric artery.

The concentration of renin substrate (RS) was measured in rat mesenteric artery tissue. The concentration of this substrate both in arterial tissue and in plasma was markedly higher in rats 1 day after bilateral nephrectomy than in sham-operated controls, the percentage difference being higher in plasma than in arterial RS. Conversely, the decrease apparently induced 3 days after adrenalectomy (i.e., the difference in RS concentration from sham-operated rats) was greater in arterial tissue than in plasma. This finding may be explained by changes in RS concentrations induced by the sham operation. Sham surgery itself increased plasma RS after 1 day (but not after 3 days) and arterial RS after 3 days (but not after 1 day). There was a positive correlation between arterial and plasma renin substrate concentration for the overall results but not within individual groups. As renin and angiotensin-converting enzyme activity are also present in arterial tissues, all the necessary components for local generation of angiotensin II have now been shown to be present within the wall of resistance vessels.

Captopril combined with thiazide lowers renin substrate concentration: implications for methodology in renin assays.

1. We have measured plasma concentrations of renin, renin substrate and angiotensins I and II as well as plasma renin activity in nine patients with severe or malignant hypertension during treatment with captopril, hydrochlorothiazide and propranolol. 2. On captopril and hydrochlorothiazide the plasma concentrations of renin substrate and angiotensin II decreased markedly, while renin and angiotensin I levels were increased. 3. The changes in renin substrate concentration suggest a consumption of substrate induced by an increased renin release. Further, the positive feedback of angiotensin II on hepatic renin substrate synthesis may be inhibited. 4. The sequential changes in renin release during captopril treatment should be monitored by measuring plasma renin concentration since plasma renin activity measurements will be profoundly influenced by the marked changes in plasma renin substrate concentration.

Effects of angiotension II, thyroxine and estrogen on plasma renin substrate concentration and renin substrate production by the liver.

The effects of angiotensin II, thyroxine and 17 beta estradiol on plasma renin substrate concentration in rats and renin substrate production by perfused rat livers were investigated. The addition of angiotensin II (1-10 microgram) to the perfusion system did not affect the synthesis of renin substrate. After treatment with thyroxine (2.5 mg/kg/day), plasma renin substrate concentration, plasma renin activity, plasma aldosterone concentration and the rate of renin substrate synthesis were all significantly increased. 17 beta estradiol (2 mg) raised both plasma renin substrate concentration and the amount of renin substrate production by the liver. Isoelectric focusing profiles of renin substrate of liver perfusate and of plasma from estrogen-treated rats were different from that of liver perfusate from normal rats. But the profile of renin substrate in plasma was essentially similar to those to liver perfusates both in normal and estrogen-treated rats.

Age dependence of human plasma renin substrate.

Renin substrate (angiotensinogen) was measured with an assay employing exhaustive incubation of plasma with purified human kidney renin and radioimmunoassay of the angiotensin I (AI) generated. Plasma renin substrate concentration was higher at the age of 3 days (females: 2028 +/- 551, males: 1951 +/- 565 micrograms AI/l, mean +/- SD) than in age group 0-15 years (females: 1513 +/- 555, males: 1263 +/- 392 micrograms AI/l). Plasma renin substrate concentration at the age over 15 years (females: 1780 +/- 464, males 1752 +/- 321 micrograms AI/l) was higher than in children 0-15 years. Expectedly, high concentrations of plasma renin substrate were found in pregnant women at term (4127 +/- 1961 micrograms AI/l).

Effects of prostaglandins on renin substrate production by the liver.

1. The effects of prostaglandin (PG) E1, PGE2 and PGF2 alpha on plasma renin substrate concentration in rats and renin substrate production by perfused rat liver were investigated. 2. After bilateral nephrectomy, both plasma renin substrate concentration and renin substrate production were remarkably elevated. 3. The increase in plasma renin substrate level and production of renin substrate by the liver after nephrectomy was markedly suppressed by the treatment with PGE1 or PGE2. 4. In contrast PGF2 alpha had no suppressive effect on renin substrate synthesis. 5. These findings suggest that PGE1 and PGE2 might be inhibitory factors in the regulation of renin substrate synthesis.

Effects of di-isopropylfluorophosphate and isopropanol on the measurement of plasma renin activity

Since the protease inhibitor, di-isopropylfluorophosphate (DFP), inhibits the cryoactivation of inactive renin, its addition to stored plasma should prevent unintended renin activation and thereby minimize this source of inaccuracy in the assay of plasma renin activity. However, we have found that 6 mmol/1 DFP in stored frozen plasma actually reduced plasma renin activity from 4.89 ± 0.13 (S.D.) to 2.48 ± 0.17 ng · ml −1 · h −1 ( p < 0.001). This effect did not occur if DFP was added immediately before assay, suggesting that the decreased renin activity reflected an action of DFP on components of the renin system during storage rather than any interference with the assay method itself. The organic solvent isopropanol, which is required to dilute the DFP, appeared responsible for this phenomenon, for when the isopropanol alone, in concentrations of 20 and 40 μl/ml, was added to stored frozen plasma it decreased plasma renin activity from 3.6 ± 0.3 to 2.2 ± 0.1 and 0.6 ± 0.1 ng · ml −1 · h −1, respectively ( p < 0.001 in each case). Correspondingly, plasma renin substrate concentrations were decreased to 71% and 6% of control, indicating that the renin activity reductions produced by isopropanol were due to its denaturation of substrate. Moreover, addition of exogenous sheep renin substrate (1400 ng/ml) immediately before assay restored plasma renin activity to control. Thus, although DFP effectively prevents inadvertent renin activation in stored frozen plasma, it would seem important that subsequent assays for plasma renin activity be performed in the presence of added exogenous substrate.

The effect of chronic low-dose infusion of ACTH (1-24) on renin, renin-substrate, aldosterone and other corticosteroids in sodium replete and deplete man.

Abstract. Low-dose infusions of ACTH 1-24 (5 U/day) of 4 days duration were performed in 2 healthy young men on a normal sodium diet and in 2 on a low sodium diet, in order to study the mechanism of the transient effect of ACTH on aldosterone secretion described by other authors using larger doses of ACTH. Cortisol secretion was continuously stimulated by ACTH. Plasma aldosterone (P-Al) and its urinary metabolites increased during the first two days of infusion and returned to control or below control levels subsequently. Plasma renin activity (PRA) was also transiently stimulated by ACTH. Changes in PRA were not caused by changes in plasma renin substrate concentration. The correlation between PRA and P-Al (r = + 0.78; n = 52) was highly significant (P &lt; 0.01). Plasma levels of deoxycorticosterone (DOC), 18-OH-DOC and corticosterone were also transiently stimulated in subjects on a normal sodium diet, while the stimulation was better maintained in those on a low sodium diet. The results suggest that the transient effect of low-dose ACTH infusion on aldosterone secretion may in part be mediated by changes in the renin-angiotensin-system. Changes in plasma levels of angiotensin II, which controls early and late steps in the mineralocorticoid biosynthetic pathway, may determine the extent to which chronically elevated ATCH levels stimulate the release of aldosterone and, perhaps, even the release of DOC and corticosterone. On the normal sodium diet, sodium retention and a slight fall in serum potassium levels towards the end of ACTH infusion may have contributed to the depression of aldosterone release.

Postnatal development of the renin-angiotensin system in rats.

The purpose of this investigation was to correlate the development of the various enzyme activities associated with the renin-angiotensin system with age-related differences in the steady-state concentrations of angiotensin I (AI) and II (AII). Angiotensin was quantified by radioimmunoassay. Plasma renin activity and concentration increased between birth and 3 wk of age, and declined thereafter to adult values. Renal renin content, on the other hand, increased throughout the first 6 wk of postnatal life. The concentration of AII in plasma also increased following birth; however, maximum concentrations were not attained until 5 wk of age. In contrast, plasma AI did not increase between 3 and 6 wk of age. These data suggest that the steady-state concentration of AII in neonatal rat plasma may be partially limited by the low plasma renin substrate concentration. The increase in AII between 3 and 6 wk of age may reflect the increasing converting enzyme activity.

An experimental study on the effects of the chronic administration of an angiotensin converting enzyme inhibitor (captopril) on blood pressure and the renin-angiotensin-aldosterone system (author's transl)

The chronic effects of the oral administration of an angiotensin converting enzyme inhibitor (captopril, 63-80 mg/kg/day) on blood pressure and the renin-angiotensin-aldosterone system were studied in normotensive male Wistar rats. The blood pressure (BP), plasma renin activity (PRA), plasma renin concentration (PRC), plasma renin substrate concentration (PRS), plasma aldosterone concentration (PAC), and renal renin content (RRC) were measured 2, 9, 19, 29 and 58 days after the administration of the agent. Blood pressure was determined in unanesthetized rats, and blood samples were obtained by decapitation. Furthermore, blood pressure responses to bolus injections of angiotensin II (AII, 80 ng/kg), angiotensin I (AI, 80 ng/kg) and bradykinin (BK, 10 micrograms/kg) were examined in unanesthetized rats which had been given the agent for 20 days. The BP of the rats which had been given captopril for 9 days or more was significantly lower than in the control rats. The reduction in heart weight in the captopril rats reached a statistically significant level 58 days after the administration of the agent. The PRA and the PRC markedly increased, and the PRS and the PAC both decreased in the captopril rats. The RRC which was reduced after 2 days of captopril administration markedly increased thereafter. In the captopril rats, significant negative correlations were observed between PRC and PRS (r=-0.43, p<0.01), and between BP and PRC (r=-0.60, p<0.001). The PRC significantly correlated with the RRC in the control rats (r=-0.44, p<0.01) while such a relationship did not exist in the captopril rats. Although the pressor responses to AII were similar in the captopril and the control rats, the responses to AI were reduced to 50% of the responses to AII in the captopril rats. The blood pressure reduction in response to BK in the captopril rats was 2.3 times as great as that in the control rats. Thus, it is suggested that the increases in PRA, PRC and RRC in the captopril rats may be related to both the blood pressure reduction and interruption of the negative feedback inhibition of renin synthesis and release by AII, and that the decrease in PRS in the captopril rats is due to the increased consumption and probably to the decreased rate of substrate production in the liver which is secondary to the decrease in plasma AII. The lack of significant positive correlation between PRC and RRC in the captopril rats seems to demonstrate that captopril may modify the relationship between them. The results also show that the chronic administration of captopril lowers blood pressure in normotensive animals. The blood pressure reduction by captopril may be related to the decreased kininase activity which is suggested by the enhanced depressor responses to BK, as well as the lowered plasma level of AII.

Effect of ethinyl estradiol on renin activity and on the concentrations of renin substrate and aldosterone in plasma of ovariectomized women.

The effect of high doses of ethinyl estradiol (0.4 mg/day) on renin substrate concentration, renin activity and aldosterone concentration in plasma was studied in eight ovariectomized women. Plasma renin substrate (angiotensinogen) increased already within 24--48 h, reaching a maximum on the third to fifth day after starting estrogen treatment. Thereafter, renin substrate concentration remained relatively constant in a range which was fourfold above the baseline levels. The increase of plasma renin activity was less pronounced and showed considerable between-patient variability; this increase was statistically significant only after 48 hours of estrogen intake. A rise in plasma aldosterone concentration was observed in two of four subjects examined. In one patient treated with 5 mg estradiol benzoate intramuscularly, plasma renin activity increased without any measurable change in renin substrate concentration. Only in one subject treated with ethinyl estradiol did plasma renin activity increase before plasma renin substrate concentration; the results presented do not preclude factors other than the stimulation of renin substrate synthesis in the liver from contributing to the activation of the renin-aldosterone axis during treatment with ethinyl estradiol.

Selective Hypoaldosteronism with Hyperreninemia in a Diabetic Patient

A 62-yr-old diabetic woman exhibited low plasma and urinary aldosterone levels in the face of markedly elevated PRA during the course of nonketoacidotic hyperglycemic precoma with dehydration, hyponatremia, and hyperkalemia, for which she was hospitalized. Studies performed after her recovery from precoma revealed hyperreninemic hypoaldosteronism with normal adrenoglucocorticoid function. While the patient was supine, PRA on a 256-meq sodium intake was at or above the upper limit of the normal range for a 200-meq sodium intake; furthermore, after sodium depletion with furosemide and 4 h of ambulation, PRA markedly increased. No increases in plasma inactive renin were found. Plasma renin substrate concentration was normal. Plasma levels and urinary excretion of aldosterone were low and increased slightly during sodium restriction with insulin treatment, accompanied by hyperkalemia and sodium loss, despite markedly elevated PRA. Repository ACTH administration induced sodium retention and potassium loss with a normal increase in urinary 17-hydroxycorticosteroids. Plasma levels of deoxycorticosterone, corticosterone, and 18-hydroxycorticosterone were normal, while plasma aldosterone was low. Levels of these mineralocorticoids remained unchanged during angiotensin II infusion on both 256-meq and 100-meq sodium intakes. Rapid ACTH administration produced normal increases in plasma deoxycorticosterone and corticosterone but caused a subnormal increase in plasma aldosterone. These results suggest adrenal insensitivity to angiotensin II, possibly a defect in adrenal angiotensin II receptors, as the cause of hypoldosteronism with hyperreninemia in this patient.

Hypertension and aldosterone overproduction without renin suppression in Cushing's syndrome from an adrenal adenoma

Adrenal steroids and components of the renin-angiotensin system were measured before and after adrenalectomy in a woman with Cushing's syndrome and hypertension from a functioning adrenocortical adenoma. Aldosterone, deoxycorticosterone and cortisol were produced in excess by the adenoma, and were measured in tumor tissue. High plasma renin substrate concentrations, and normal basal and furosemide-stimulated plasma renin activities and plasma renin concentrations which were present before surgery, decreased after adrenalectomy, and the hypertension diminished. The inappropriately normal levels of renin and potassium in this patient, despite autonomous aldpsterone overproduction, suggest an ineffective mineralocorticoid action of aldosterone, possibly from interaction with her other adenoma-produced steroids. The decrease in components of the renin-angiotensin system suggests a partial renin-dependence of her hypertension.

Serial renin-angiotensin studies in spontaneously hypertensive and Wistar-Kyoto normotensive rats. Transition from normal- to high-renin status during the established phase of spontaneous hypertension.

To characterize the renin-angiotensin system in the Aoki-Okamoto spontaneously hypertensive rat (SHR) more fully, serial measurements of plasma renin activity (PRA), plasma renin concentration (PRC), renin reactivity (as relative index of circulating modifiers of the renin reaction) and renin substrate concentration were made in 6- to 64-week-old SHR and in age-matched Wistar-Kyoto normotensive rats (WKY). In the evolving phase of SHR hypertension (6 and 13 weeks of age), PRA was comparable to WKY control values, whereas mature SHR with established hypertension developed, between 13 and 35 weeks of age, a high-PRA state persisting through 64 weeks of age. In 64-week-old SHR, increased plasma volume (3.54 +/- 0.91 in SHR vs. 3.18 +/- 0.90 ml/100 g body weight in WKY, p less than 0.025), together with increased PRA (24.9 +/- 3.8 in SHR vs. 13.1 2.2 ng AI/ml plasma/hr in WKY, p less than 0.025), suggest that volume decrease cannot explain increased PRA. In 42-week-old SHR, PRA was incompletely suppressed by deoxycorticosterone acetate plus 1% saline orally for 4 days: 4.9 +/- 1.2 in SHR vs. 0.6 +/- 0.8 ng angiotensin I/ml plasma/hr in WKY, p less than 0.001. Modestly increased renin reactivity of plasma was observed in SHR at all ages studied, supporting the ubiquity of increased circulating accelerators (or decreased inhibitors) of the renin reaction in hypertensive states. However, elevated renin reactivity did not account for the transition from normal to high PRA observed in mature SHR, nor did renin substrate concentration, which was consistently lower in SHR than in age-matched WKY. Temporal patterns of, and strain differences in PRA were closely paralleled by variations in PRC but not by other reaction components. Significant elevation of serum creatinine in old SHR support the presence of renal injury. We conclude that PRA and PRC are normal in evolving SHR hypertension and progress to abnormally elevated levels after hypertension is established. We postulate that "high-renin" hypertension may develop as a consequence of the hypertensive state per se, perhaps due to nephrosclerotic vascular disease.