A Study of the Renin Inhibitor H142 in Man
David J. WebbPer ManhemStephen G. BallGordon C. InglisB LeckieAnthony F. LeverJames J. MortonJ. I. S. RobertsonGordon MurrayJo l M nardAllan HallettD. Michael JonesMichael Szelke
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The inhibitor of human renin, H142, was studied in nine male volunteers. On three occasions, in random order, volunteers were infused with 5% dextrose or with H142 at 1.0 or 2.5 mg/kg per h for 30 min while supine and thereafter with dextrose for 1½ h. There was a marked reduction in plasma active renin concentration as assayed by an enzyme-kinetic method, with parallel falls in the circulating concentrations of angiotensins (ANG) I and II, all of which rebounded transiently to values above basal after the H142 infusion was stopped. In contrast, total renin concentration as measured by radio-immunoassay rose while ANG I and II fell, subsiding when H142 was discontinued. There was a slight but significant increase in plasma noradrenaline as renin became inhibited; plasma adrenaline was unchanged. H142 produced a slight fall in systolic blood pressure (SBP) and a clearer, highly significant, dose-related fall in diastolic blood pressure (DBP). There was a modest but significant increase in the heart rate. These studies confirm H142 as an effective inhibitor of human renin in vivo.Keywords:
Plasma renin activity
Renin inhibitor
Supine position
Components of the renin-angiotensin system (plasma renin activity, total and inactive renin, angiotensinogen and angiotensin II) were examined in 90 patients with labile and stable essential hypertension before and after functional and pharmacologic tests. New data have been obtained on intrasystemic regulatory mechanisms of the pressor renin-angiotensin systems. Different patterns of plasma active and inactive renin variations in response to salt loading are demonstrated in patients with different "renin" variants of essential hypertension. Angiotensin II is shown to have a stimulating effect on angiotensinogen synthesis.
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Renin activity, concentration, substrate and reactivity were determined in normal subjects as well as in hypertensive subjects with suppressed and normal plasma renin activity. Renin substrate measurements were similar in all groups. Renin reactivity, a measure of circulating modifiers of the renin reaction, was significantly increased in both hypertensive groups. Reactivity was significantly greater in the normal renin hypertensive group than the low renin hypertensive group. Renin concentration was significantly suppressed in both hypertensive groups, but to a greater degree in the low renin hypertensives. These findings suggest that plasma renin concentration may be suppressed in most hypertensive subjects. Furthermore, plasma renin activity may be "normalized" in most hypertensive subjects by the effect of circulating modifiers of the renin reaction. While renin reactivity in the plasma of low-renin hypertensive subjects is accelerated to a lesser degree than that of the normal-renin hypertensives, this finding alone does not explain the low plasma renin activity.
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The enzyme renin ( M r ∼40 000) is released in an active form from the renal juxtaglomerular cells in response to physiologic factors, including sodium depletion, decreased blood volume and blood pressure, and β-adrenergic stimulation (1). Although several local angiotensin II-generating systems exist within various tissues (including the heart, brain, and adrenal glands), the concentration of active renin in plasma depends on the rate of renin secretion from the kidneys (2). Renin catalyzes the formation of angiotensin I (AngI) by cleavage of the renin substrate called angiotensinogen. Plasma renin is therefore the initiator of the renin-angiotensin-aldosterone system, which has an important role in the homeostasis of water and electrolyte balance and in the regulation of arterial pressure.
In most studies, circulating renin has been estimated by assays of plasma renin activity (PRA). PRA is measured by generating AngI from endogenous angiotensinogen, followed by measurement by RIA of the generated AngI. Although PRA measurement is convenient for estimating the biological activity of the renin system, it may not necessarily reflect the real concentration of active renin. The concentration of substrate rarely affects the PRA result, but exceptions do occur (3). More importantly, PRA depends not only on renin, but also on factors that influence the renin–renin substrate interaction.
An additional difficulty occurs in measuring low concentrations of renin. In the PRA method, prolonged incubation is needed to generate measurable AngI. This is specifically important when measuring PRA in black people because their values are often below the limit of detection of the routine PRA method. This complicates and prolongs the method and makes it impractical for large throughput for population-based studies.
Immunoassays are available to quantify renin directly with use of monoclonal antibodies. In addition, interlaboratory CVs are lower with immunoassays than with PRA assays (4).
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Juxtaglomerular apparatus
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Sex differences are known in several facets of cardiac electrophysiology, mostly concerning myocardial repolarisation. In this study, heart rate and heart rate variability (HRV) responses to postural provocations were compared in 175 and 176 healthy females and males, respectively (aged 33.1 ± 9.1 years). Two different postural provocative tests with position changes supine→sitting→standing→supine and supine→standing→sitting→supine (15-min standing, 10-min other positions) were performed up to 4 times in each subject. Heart rate and heart rate variability spectral indices were measured in 5-min windows before positional changes. At supine position, females had averaged heart rate approximately 5 beats per minute (bpm) faster than males and this sex difference was practically constant during the postural changes. In both sexes, change supine→sitting and supine→standing increased heart rate by approximately 10 and 30 bpm, respectively, with no statistical differences between the sex groups. At supine baseline, females had normalised high frequency components (nHF) of HRV approximately 7% larger compared to males (p < 0.001). While the same difference in nHF was found at sitting, the change to standing position lead to significantly larger nHF reduction in females compared to males (mean changes 22.5 vs 17.2%, p < 0.001). This shows that despite similar heart rate increase, females respond to standing by more substantial shifts in cardiac sympatho-vagal modulations. This makes it plausible to speculate that the differences in autonomic reactions to stress contribute to the known sex-differences in psychosocial responses to stressful situations and to the known difference in susceptibility to ventricular fibrillation between females and males.
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Hemodynamic and biochemical effects of the new renin inhibitor CGP 38560A (molecular weight 826) were tested in 15 healthy volunteers after a single-blind, randomized, placebo-controlled protocol. At a 2-week interval, groups of five subjects received a 30-minute infusion of either 5% dextrose or CGP 38560A 50, 125, or 250 micrograms/kg. Blood pressure, heart rate, plasma renin activity, active and total renin, angiotensin-(1-8)octapeptide (angiotensin II), and aldosterone were sequentially measured up to 3 hours from the onset of the infusion. There was no consistent change in blood pressure or heart rate. Plasma renin activity and angiotensin II decreased dose dependently, and peak suppression was observed at the end of the infusion of CGP 38560A and after the 250-micrograms/kg dose. Plasma renin activity fell from 1.0 +/- 0.19 (mean +/- SEM) to less than 0.05 ng/ml/hr in all five subjects (p less than 0.001), and angiotensin II fell from 7.7 +/- 1.2 to 2.6 +/- 0.9 femtomole/ml (p less than 0.01). Active renin rose fourfold from 24 +/- 1.9 to 98 +/- 14 pg/ml (p less than 0.001) at the end of the infusion of the high dose. Plasma angiotensin II returned toward its initial values much faster than plasma renin activity and active renin. In conclusion, CGP 38560A was well tolerated. It induced a dose-dependent decrease in angiotensin II and plasma renin activity and a long-lasting and dose-dependent rise in active renin. The doses used did not reduce plasma angiotensin II maximally despite reduction of plasma renin activity to unmeasurable levels.(ABSTRACT TRUNCATED AT 250 WORDS)
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AbstractHomogenates of rat aortic wall can generate angiotensin I when incubated with nephrectomised rat plasma. This renin-like activity is due to a mixture of proteolytic enzymes. Thus the capacity to generate angiotensin I is greater at pH 5.3 than pH 6.5, although the latter is the pH optimum for rat renal renin. The present work addresses itself to two questions. Is this activity derived from plasma renin? Secondly, does vascular renin-like activity play a role in blood pressure control? Plasma and aortic renin were altered by bilateral nephrectomy and modulation of salt intake. In addition four models of hypertension were studied (early and chronic Goldblatt 2-kidney 1-clip, DOC-salt and spontaneous hypertension). The results indicated that in steady state conditions, aortic and plasma renin-like activity (measured with an incubation pH of 6.5) changed in parallel. When plasma renin was altered acutely however by intravenous injection of renin into nephrectomised rats the half-life of plasma renin was much shorter than the half life of aortic renin. Under these circumstances the pressor response to renin correlated much better with aortic than with plasma renin-like activity. Whilst these studies suggest therefore that renin taken up by the arterial wall is an important determinant of blood pressure, they provide no evidence that accumulation of renin locally produces hypertension in the presence of normal or low plasma renin activity.Key Words: arterial reninrenin-like activityblood pressureGoldblatt hypertensionspontaneously hypertensive ratsdeoxycorticosterone-salt hypertension
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Plasma renin activity
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Aortic homogenates contain proteolytic enzymes which will release angiotensin I (AI) from renin substrate. Some of these are active at low pH and are probably unrelated to renin. Renin-like activity in the rat measured at the optimum pH of 6.5 is altered in parallel with plasma renin in a wide variety of situations. The two diverge only in non-steady state situations. Studies have therefore been carried out after bilateral nephrectomy and after the injection of renal renin into nephrectomized rats. In each case aortic renin-like activity was cleared much more slowly than plasma renin, and the blood pressure change was related to aortic renin-like activity rather than to plasma renin. The blood pressure response to the converting enzyme inhibitor teprotide was also related to the former rather than the latter. Immunofluorescent studies of the aorta and the intrasplenic arteries from rats injected with mouse renin showed that renin was taken up predominantly into the media and persisted at this site. Thus, the uptake of renal renin from plasma by both large and small arteries is probably an important step in the physiology of the renin-angiotensin system and mediates renin-induced changes in peripheral resistance and blood pressure. However, we have no evidence for the hypothesis that selective accumulation of renin in the resistance vessel walls causes hypertension when circulating levels of renin are normal.
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The response of renin release to the administration of renin inhibitors cannot be studied with conventional enzymatic methods used to measure plasma renin. In the present experiments, a novel multirange enzyme-linked immunosorbent assay for human and primate renin was used to investigate the changes in plasma immunoreactive renin after renin inhibition. A potent and long-acting statine-containing renin inhibitor, CGP 29 287, was injected in conscious marmosets after mild or severe sodium depletion. In mildly sodium-depleted marmosets, CGP 29 287 (0.1 mg/kg i.v.) reduced mean arterial blood pressure and completely inhibited plasma renin activity for up to 30 minutes. This response was associated with a transient increase in plasma immunoreactive renin concentration. After a dose of 1.0 mg/kg i.v., the reduction of mean arterial pressure and the complete inhibition of plasma renin activity persisted for up to 120 minutes. These effects were accompanied by a sustained increase in plasma immunoreactive renin concentration. In severely sodium-depleted marmosets, CGP 29 287 (1.0 mg/kg i.v.) induced a marked fall in systolic blood pressure and complete inhibition of plasma renin activity within 30 minutes of injection. Plasma immunoreactive renin levels increased to 257% of pretreatment values. The converting-enzyme inhibitor enalaprilat (2 mg/kg i.v.) induced a fall in systolic blood pressure of similar magnitude, which was accompanied by an increase in plasma renin activity. Levels of plasma immunoreactive renin increased to 210% of pretreatment values. Hydralazine (0.2 mg/kg i.v.) did not increase plasma renin activity or plasma immunoreactive renin levels despite a comparable hypotensive effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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Plasma active renin (PAR), plasma inactive renin (PIR), and plasma renin activity (PRA) were determined after intravenous bolus injection of the renin inhibitor SR 42128, in sodium repleted and sodium depleted macacas. The kit renin of Pasteur Diagnostics allows determination of PAR after renin inhibition by SR 42128. PAR and total plasmatic renin (TPR) were determined before and after treatment of plasma using trypsin. IR = TPR-PAR. ARP was measured by RIA of angiotensin I. Sodium depletion induced a dramatic increase of PAR (1,678 + 11.5 pg/ml compared to 94.4 + 11.5, n = 6). PIR rose from 322.1 + 34.3 pg/ml to 1,137 + 206 (n = 6). In sodium repleted macacas, SR 42128 (3 mg/kg and 9 mg/kg) induced a PRA inhibition of 90 to 100 p. 100, for 4 h post-injection. PAR increased to reach maximal level after 90 min and remained constant up to 4 h post-injection (increase of 420 p. 100 at 3 mg/kg and 620 p. 100 at 9 mg/kg). PIR increased more slowly for 4 h (maximum increase of 250 p. 100). PRA was also inhibited in sodium depleted macacas by SR 42128 at the doses of 3 mg/kg and 9 mg/kg ARP was inhibited. PIR increased more slowly, but significantly at 9 mg/kg. We conclude that the activity of SR 42128 on PAR and PIR levels is the sole consequence of the inhibition of the Renin Angiotensin system.
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