Rise In Plasma Renin Activity Research Articles

Divergent effects of dietary chloride restriction on aldosterone biosynthesis and the renin-angiotensin system in rats

The effects of dietary chloride restriction - alone or combined with sodium and potassium restriction - on aldosterone biosynthesis and the renin-angiotensin system were studied in rats. Treatment with a chloride-deficient diet led to a temporary decrease in the capsular adrenal conversions of corticosterone to 18-hydroxycorticosterone and aldosterone (manifest after 2 weeks but not longer apparent after 3 weeks), which was accompanied by a progressive rise in plasma renin activity and a moderate fall in plasma potassium. Combined restriction of sodium, potassium and chloride elicited a decreased activity of the enzyme(s) involved in late steps in aldosterone biosynthesis, an elevation of plasma renin activity to excessively high levels and a substantial hypokalaemia. Chloride repletion of these rats by the addition of NH4Cl or CaCl2 to their drinking fluid stimulated aldosterone biosynthesis while lowering plasma renin activity and raising plasma potassium. According to these observations, dietary chloride deficiency is another example of an experimental situation in which a high activity of the renin-angiotensin system contrasts with an unchanged or suppressed aldosterone biosynthesis. Most likely, this divergence is at least partly due to hypokalaemia which is induced during long-term chloride deficiency by a yet unknown mechanism.

Chronic effects of vasopressin on plasma renin activity in sodium-restricted dogs.

The effects of chronic (4 days) arginine vasopressin (AVP) infusion were studied in two separate groups of animals: normal Na-restricted dogs with intact renal nerves (n = 8) and renal-denervated Na-restricted dogs (n = 5). Volume expansion during AVP infusion was prevented in these studies with a sensitive servo-controlled cage-scale system. With intravenous AVP infusion (0.36 ng X kg-1 X min-1), plasma AVP levels increased from nearly 3 to 15 pg/ml, whereas total body weight remained unchanged from the control level. In renal-innervated dogs, plasma renin activity (PRA) decreased significantly (P less than 0.05) from control levels of 5.50 +/- 0.61 to an average level of 3.45 +/- 0.76 ng angiotensin I (ANG I) X ml-1 X h-1 on days 1 and 2 of AVP infusion. Thereafter, PRA tended to remain decreased on days 3 and 4, averaging 3.82 +/- 1.02 ng ANG I X ml-1 X h-1, but this was not statistically significant. Urinary Na excretion and balance, however, were not significantly altered during the 4-day AVP infusion period. In renal-denervated dogs, the rise of PRA with Na restriction was 50% that seen in normal dogs. In this group, a transient suppression of PRA was observed on day 1 of AVP infusion from 2.84 +/- 0.75 to 1.46 +/- 0.47 ng ANG I X ml-1 X h-1. Urinary Na excretion increased transiently with a small net Na loss of 4.9 +/- 1.3 meq on day 2 of AVP infusion. No significant changes occurred in average 24-h mean arterial pressure (MAP) in response to AVP in either group of dogs. Thus, in contrast to our previous observations in Na-replete dogs, elevations of plasma AVP within the physiological range result in suppression of PRA, but for periods of no longer than 1-2 days in Na-restricted dogs. This decrease of PRA occurred in the absence of measurable changes in MAP, total body weight, or plasma catecholamines. In addition, this transient AVP-induced suppression of PRA was only partially blunted by prior renal denervation. Finally, in the Na-restricted dog, AVP appears to have minimal or no long-term effects on urinary Na excretion.

Factors that determine the response of people with mild hypertension to a reduced sodium intake.

One hundred and eighty-six males who had had 3 run-in visits entered the study with a supine diastolic BP 95-110 mm Hg. This was followed by 3 pretreatment and 3 post-treatment visits. One hundred and sixty patients were given advice to reduce sodium intake after visit 3, and twenty-six patients served as control. In the control group there were relatively insignificant changes between the pre and post visits. In the diet group blood pressure fell by 13/9 mm Hg; urine sodium from 168 to 85 mmol/day and plasma renin activity rose from .50 to .77 ng AI/ml/h. Regression analysis showed that the only cross-sectional correlations were PRA with age, urine sodium and plasma potassium. There were highly significant correlations between the change in urinary sodium and the change in blood pressure and between the changes in blood pressure and plasma renin activity. Multiple Regression Analysis indicated that the final diastolic blood pressure achieved depended upon the initial diastolic blood pressure, the fall in sodium intake, and was reduced by the rise in plasma renin activity. Patients who responded to sodium restriction had a lower initial renin value than other patients. This study emphasises the importance of the interaction between sodium, potassium and renin in the determination of blood pressure levels.

Cardiovascular Effects of the New Angiotensin-Converting-Enzyme Inhibitor, Cilazapril, in Anesthetized and Conscious Dogs

Cilazapril is a new angiotensin-converting-enzyme inhibitor. In conscious renal-hypertensive dogs, cilazapril (2 X 10 mg/kg/day p.o.) caused a long-lasting (greater than 24 h) decrease in systolic arterial blood pressure, the magnitude of which was potentiated by pretreatment with furosemide. A maximal fall in systolic blood pressure of 39 +/- 6 mm Hg (from 145 +/- 5 to 106 +/- 7 mm Hg) was recorded. The antihypertensive effect did not decline with repeated administration and was accompanied by only a slight increase in heart rate. Cilazapril also reduced systolic blood pressure in furosemide-pretreated normotensive dogs. Hemodynamic studies in anesthetized dogs revealed that cilazapril (0.03-1 mg/kg i.v.) caused a fall in mean arterial and left ventricular systolic pressures. At the highest dose of 1 mg/kg i.v., the blood-pressure-lowering effect (-27%) was due to a decrease in total peripheral resistance (-12%) and cardiac output (-16%). Intravenous administration of cilazapril to anesthetized dogs resulted in a rise in plasma renin activity and a significant fall in plasma angiotensin II levels. In conscious normotensive dogs, cilazapril (0.3-10 mg/kg p.o.) exerted diuretic and saluretic effects, which were accompanied by a significant increase in renal plasma flow (46%), but only a slight rise in the glomerular filtration rate. These results characterize cilazapril as an effective and long-lasting antihypertensive drug, with diuretic activity and, possibly, preload- as well as afterload-reducing properties.

Pharmacological studies on stress-induced renin and prolactin secretion: Effects of benzodiazepines, Naloxone, propranolol and diisopropyl fluorophosphate

Stress-induced renin and prolactin secretion was investigated using a conditioned emotional response paradigm. Three minutes after placement in a chamber the rats received an electric shock to their feet via the grid floor, then were immediately returned to their home cage. This procedure was repeated for 3 consecutive days. On the fourth day, instead of receiving an electric shock, they were removed after 3 min and sacrificed by decapitation. Control rats were treated identically with the exception that shock was not administered at any time. There was a significant increase in plasma renin activity and prolactin level in the stressed rats. The administration of the antianxiety drugs chlordiazepoxide (10 mg/kg i.p.) or midazolam (0.125–2 mg/kg i.p.) blocked the stress-induced increase in prolactin levels but not the stress-induced rise in plasma renin activity. Administration of the β-blocker propranolol (1 mg/kg i.p.) inhibited, but did not completely block, stress-induced rise in plasma renin activity and had no effect on stress-induced prolactin secretion. The opiate antagonist naloxone (0.1–10 mg/kg i.p.) and the acetylcholinesterase inhibitor diisopropyl fluorophosphate (0.5 mg/kg i.p.) did not block stress-induced renin of prolactin secretion. It is concluded that stress-induced prolactin secretion is regulated by a benzodiazepine-mediated mechanism and that stress-induced renin but not prolactin secretion is mediated in part via β-receptors.

Renal adaptation and gut hormone release during sodium restriction in ileostomized man.

The renal excretion of water, electrolytes, aldosterone and kallikrein was monitored in 12 ileostomized patients before and during sodium deprivation. Changes in plasma renin activity (PRA), plasma aldosterone and plasma arginine vasopressin (AVP) concentrations were measured, together with aldosterone in ileal fluid. The pattern of gut peptide release in response to a test meal was also examined to assess whether a circulating gut peptide might be involved in the renal adaptation to sodium restriction, and compared with healthy normal subjects who were under no dietary constraint. In each patient renal sodium excretion fell within 8-12 h of sodium deprivation and was associated with a prompt and significant rise in PRA; much later increases in plasma aldosterone concentration and renal aldosterone excretion occurred, and were established by day 2 of sodium restriction. No consistent change in renal kallikrein excretion was found. Ileal sodium loss was little changed by sodium deprivation, but ileal potassium concentration rose steadily and became significantly correlated with PRA, and to a lesser extent with renal aldosterone excretion. Of the gut peptides measured in plasma, only the insulin profile was altered by sodium deprivation, with an increase in the test meal response; insulin has previously been shown to have a significant antinatriuretic action at physiological concentrations. Plasma levels of pancreatic polypeptide and motilin were increased in ileostomized patients when compared with normal subjects, but were unaffected by the change to a low sodium diet. An early increase in urine flow and water diuresis occurred during sodium deprivation, following a cyclical pattern with peaks each evening.(ABSTRACT TRUNCATED AT 250 WORDS)

Absent aldosterone response to metoclopramide in patients with high spinal cord transection: Evidence that metoclopramide stimulates aldosterone secretion through central pathways

This study evaluates dopaminergic regulation of aldosterone secretion in 6 patients with high spinal cord transections. Administration of the dopamine antogonist metoclopramide resulted in a marked rise in plasma aldosterone and 18-hydroxycorticosterone levels in 12 normal individuals, but no change in plasma levels of these zona glomerulosa corticosteroid products in spinal cord patients. Spinal cord transected patients also did not have the rise in plasma renin activity that was observed in normals following metoclopramide administration. Basal levels of aldosterone, 18 hydroxycorticosterone, corticosterone and renin activity as well as the aldosterone responses to graded dose infusion of adrenocorticotropin were similar in the spinal cord patients and the normals. These data suggest that dopaminergic regulation of adrenal zona glomerulosa corticosteroid and renal renin secretion is absent in patients with high spinal cord transections, suggesting that intact neural pathways from the central nervous system are necessary for metoclopramide stimulation of aldosterone and renin secretion in men. Since basal plasma aldosterone levels were normal in spinal cord transected patients, it appears that the absence of dopaminergic control does not result in elevated secretion.

The influence of captopril, the nitrates and propranolol on apparent liver blood flow.

Indocyanine green estimated apparent liver blood flow was measured in normal volunteers following glyceryl trinitrate, propranolol, isosorbide mononitrate and captopril. Glyceryl trinitrate and propranolol significantly reduced apparent liver blood flow. Isosorbide mononitrate did not alter apparent liver blood flow or produce an additional reduction in apparent liver blood flow when combined with propranolol. Captopril did not alter apparent liver blood flow despite a significant fall in mean arterial pressure and rise in plasma renin activity. Captopril and isosorbide mononitrate if shown to reduce portal pressure, do so without a fall in apparent liver blood flow.

The non-benzodiazepine anxiolytic buspirone inhibits stress-induced renin secretion and lowers heart rate

The non benzodiazepine drug, buspirone, produces a dose-dependent biphasic effect on plasma renin activity in non-stressed rats. Low doses (0.1 - 2.0 mg/kg i.p.) decrease while high doses (10.0 - 50.0 mg/kg i.p.) increase plasma renin activity. The maximal decrease in plasma renin activity produced by buspirone (1.0 mg/kg i.p.) was observed 30 minutes post-injection. In addition, buspirone (0.5 and 2.0 mg/kg i.p.) blocked the stress-induced rise in plasma renin activity. This effect of buspirone is in contrast to the previously observed failure of the benzodiazepine anxiolytics to alter the effect of stress on plasma renin activity. Administration of buspirone (0.5 mg/kg i.p.) produced a sustained reduction (15%) in heart rate but did not affect mean arterial pressure. The present data support the view that the mechanism of the anxiolytic action of buspirone is different from that of the benzodiazepines.

Converting-enzyme inhibitor administration lowers urinary free 19-nor-deoxycorticosterone levels.

19-Nor-deoxycorticosterone (19-nor-DOC) is a human mineralocorticoid. The regulation of its secretion is poorly understood, as renin angiotensin II (ANG II) stimulation has minimal effects on 19-nor-DOC. This study sought to determine if ANG II inhibition would decrease 19-nor-DOC production. Six normal subjects on fixed electrolyte intake were admitted to a metabolic unit. After a 5-day control period to establish electrolyte balance, enalapril, p.o., 10 mg/day, was administered for 28 days. This treatment resulted in ANG II inhibition, which was reflected by a rise in plasma renin activity, a blunting of the postural plasma aldosterone increment, and a decrease in aldosterone secretion rate (ASR). Levels of urinary free (UF) 19-nor-DOC progressively decreased from 294 +/- 108 ng/day on Day 0 to 164 +/- 70 on Day 3, 141 +/- 62 on Day 7, 101 +/- 38 on Day 14, 68 +/- 18 on Day 21, and 106 +/- 31 on Day 28. The decrease in 19-nor-DOC levels was synchronous with the fall in ASR (R = 0.94, n = 5, p less than 0.005), but it was of greater magnitude (71% decrease in 19-nor-DOC levels versus 41% decrease in ASR). In addition, the decrease in 19-nor-DOC levels correlated with a fall in urinary potassium and an increase in both urinary sodium and chloride (R = 0.68, -0.79, -0.87 respectively; n = 6, p less than 0.05). The fall in ASR, on the other hand, was not significantly correlated with the changes in these urinary electrolyte levels (R = 0.65, 0.64, 0.57 respectively; n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)

Percutaneous transluminal renal artery dilatation for fibromuscular dysplasia with special reference to the acute effects on the renin-angiotensin-aldosterone-system and blood pressure.

Twelve hypertensive patients (mean age 46.6 years, range 37-55 years) with fibromuscular dysplasia of the renal artery were treated with percutaneous transluminal renal angioplasty (PTRA) and the effects on the renin-angiotensin-aldosterone system and blood pressure were studied in the acute phase. The technical result of PTRA measured by angiography and reduction of PRA and aldosterone excretion was satisfactory in 11 patients. In spite of this only three patients were cured of their hypertension and two patients were improved at six months follow-up. During PTRA an immediate rise in plasma renin activity was noted in patients without beta-receptor blockade but not in patients treated with beta-receptor blocking agents suggesting a beta-receptor mediated release. This peak in renin release was not accompanied by any rise in systemic blood pressure. The blood pressure response in the acute phase did not show any regular pattern. We conclude that PTRA can serve as a model for studying effects of ‘clamping’...

Effects of enalapril maleate (MK-421) on renovascular hypertension.

The effects of enalapril maleate (MK-421), a new angiotensin converting enzyme inhibitor, were studied on 5 patients with renovascular hypertension (RVH) due to unilateral renal artery stenosis. The therapeutic dosage was increased when the blood pressure (BP) was not controlled for more than 3 days. Blood sampling was performed before, and 5 hr and 24 hr after the first administration, and on the 3rd day with each dosage. The BP was normalized on 5 mg/day in 1 case, 10 mg in 1 case, 20 mg in 2 cases, and 40 mg plus mefruside in 1 case. Plasma renin activity (PRA) was significantly increased after 5 hr and recovered after 24 hr with 2.5 mg of the enalapril maleate, when the BP was not affected. This indicates that the increase in PRA is likely due to the reduced negative feedback of angiotensin II. When the blood pressure was lowered, PRA was increased and plasma aldosterone concentration (PAC) was decreased significantly. This rise of PRA may depend not only on the reduced negative feedback but also on the fall of BP. It is also considered that the PAC was decreased through the decrease in plasma angiotensin II. A fall of the glomerular filtration rate in one case and also a fall of the perfusion of the kidney of the stenotic side in another case were observed by radioisotope renograms. MK-421 administration was a useful treatment for RVH, and clearly normalized the BP of all the patients studied. However, there was a risk of a fall of renal function on the stenotic side due to the decrease in perfusion pressure.

Captopril Versus Enalapril Maleate

Summary: The antihypertensive effects of captopril and enalapril maleate were studied over a 10-week period in 24 hypertensive patients randomized into captopril or enalapril treatment groups. Prestudy blood pressure was 171 ± 4/109 ± 1 mm Hg and after 4 weeks of hydrochlorothiazide 160 ± 4/103 ± 1 (p < 0.05). With the addition of converting enzyme inhibitor to hydrochlorothiazide the blood pressure decreased at 3 h to 132 ± 3/87 ± 2 in the subjects. The diastolic blood pressure decreased acutely more with captopril (− 24) than with enalapril (− 17) (p < 0.05). After 10 weeks of combined therapy the depressor response was maintained (134 ± 3/83 ± 1) and there was no difference between the diastolic blood pressure in the two groups treated with captopril and enalapril. Acute and chronic responses of plasma renin activity, plasma aldosterone, and converting enzyme to the angiotensin-converting enzyme inhibitor were determined. There was a significant correlation between the acute fall in diastolic blood pressure and rise in plasma renin activity in patients treated with captopril but not with enalapril. In conclusion, there is an acute depressor response with converting enzyme inhibition which is more pronounced with captopril than with enalapril and which correlates with an increase in plasma renin activity. With more prolonged treatment, the two drugs show equivalent efficacy in reducing blood pressure, inhibiting angiotensin-converting enzyme, reducing aldosterone, and stimulating plasma renin activity.

Captopril Versus Enalapril Maleate

The antihypertensive effects of captopril and enalapril maleate were studied over a 10-week period in 24 hypertensive patients randomized into captopril or enalapril treatment groups. Prestudy blood pressure was 171 +/- 4/109 +/- 1 mm Hg and after 4 weeks of hydrochlorothiazide 160 +/- 4/103 +/- 1 (p less than 0.05). With the addition of converting enzyme inhibitor to hydrochlorothiazide the blood pressure decreased at 3 h to 132 +/- 3/87 +/- 2 in the subjects. The diastolic blood pressure decreased acutely more with captopril (-24) than with enalapril (-17) (p less than 0.05). After 10 weeks of combined therapy the depressor response was maintained (134 +/- 3/83 +/- 1) and there was no difference between the diastolic blood pressure in the two groups treated with captopril and enalapril. Acute and chronic responses of plasma renin activity, plasma aldosterone, and converting enzyme to the angiotensin-converting enzyme inhibitor were determined. There was a significant correlation between the acute fall in diastolic blood pressure and rise in plasma renin activity in patients treated with captopril but not with enalapril. In conclusion, there is an acute depressor response with converting enzyme inhibition which is more pronounced with captopril than with enalapril and which correlates with an increase in plasma renin activity. With more prolonged treatment, the two drugs show equivalent efficacy in reducing blood pressure, inhibiting angiotensin-converting enzyme, reducing aldosterone, and stimulating plasma renin activity.

Percutaneous transluminal renal artery dilatation for fibromuscular dysplasia with special reference to the acute effects on the renin-angiotensin-aldosterone system and blood pressure.

Twelve hypertensive patients (mean age 46.6 years, range 37-55 years) with fibromuscular dysplasia of the renal artery were treated with percutaneous transluminal renal angioplasty (PTRA) and the effects on the renin-angiotensin-aldosterone system and blood pressure were studied in the acute phase. The technical result of PTRA measured by angiography and reduction of PRA and aldosterone excretion was satisfactory in 11 patients. In spite of this only three patients were cured of their hypertension and two patients were improved at six months follow-up. During PTRA an immediate rise in plasma renin activity was noted in patients without beta-receptor blockade but not in patients treated with beta-receptor blocking agents suggesting a beta-receptor mediated release. This peak in renin release was not accompanied by any rise in systemic blood pressure. The blood pressure response in the acute phase did not show any regular pattern. We conclude that PTRA can serve as a model for studying effects of 'clamping' and 'declamping' of the renal artery in man.

Effect of the angiotensin converting enzyme inhibitor, captopril (SQ14,225), on orthostatic sodium and water retention in patients with idiopathic edema.

Captopril (SQ14,225), an orally administered angiotensin converting enzyme inhibitor, was given to 8 patients with idiopathic edema, in order to study the role of the renin-angiotensin-aldosterone system in orthostatic sodium and water retention. Compared to 5 normal subjects, patients with idiopathic edema showed significantly greater reduction in water and sodium excretion, and greater increment in plasma aldosterone and plasma renin activity, in the upright posture. Captopril significantly restored water and sodium excretion, attenuated the increment in plasma aldosterone, and enhanced the rise in plasma renin activity in patients with idiopathic edema. The effects of captopril on these variables were not remarkable in normal subjects. These results suggest that an enhanced response of the renin-angiotensin-aldosterone system to standing plays an important role in the pathophysiology of idiopathic edema.

Effects of NaHCO3, alpha-, and beta-adrenergic blockade on albuminuria after swimming in splenectomized dogs.

The albuminuria occurring after swimming in splenectomized dogs was investigated. Swimming in splenectomized dogs induces metabolic acidosis, a decrease in renal vascular conductance, and an increase in plasma renin activity, all three factors possibly implicated in the occurrence of albuminuria. The administration of sodium bicarbonate prior to swimming reduced the magnitude of the acidosis and eliminated the increase in albuminuria after swimming. Phenoxybenzamine, an alpha-adrenergic blocking agent that maintains the renal blood flow during exercise also blocked the increase in albuminuria despite a decrease of blood pH during swimming. However, after metoprolol, a beta 1-adrenergic blocking agent that blocks the rise in plasma renin activity during exercise, swimming causes a threefold increase in albuminuria (P less than 0.01). The albuminuric response to swimming preceded by saline was also significant (P less than 0.05). It is likely that post-swimming albuminuria in splenectomized dogs is linked to the decrease of renal vascular conductance or to the decrease in blood pH rather than to the rise in plasma renin activity.

The renin-angiotensin-aldosterone system in infancy and childhood in basal conditions and after stimulation.

Plasma renin activity (PRA), aldosterone (PA), sodium and potassium concentration were measured in 107 healthy infants and children under basal conditions of normal diet and recumbency. Urinary aldosterone (UAldo), sodium and potassium were also measured (n = 51). A significant (P less than 0.001) age-related decrease in PRA (r = -0.67), PA (r = -0.67), UAldo (r = -0.56) was observed, with a striking scatter of values especially in infancy. The reninangiotensin-aldosterone system (RAAS) was also studied after stimulation by standardised sodium restriction during 4 days, followed by acute postural change (n = 40). After salt restriction a rise of PRA and UAldo was noted, but a rise in PA could not be demonstrated in children aged 0-6 months. The influence of postural change on the RAAS seems more important in older children. The reported values not only in basal but also in stimulated conditions allow study of the RAAS in diseases such as salt loss and hypertension.

Plasma renin activity in insulin-dependent diabetics with raised glomerular filtration rate.

Basal and ambulant plasma renin activity (PRA) were measured in 12 insulin-dependent diabetics (IDDS) with elevated glomerular filtration rate (GFR), 12 IDDs with normal GFR matched for age, sex and duration of diabetes and 12 age and sex matched non-diabetic control subjects. The two diabetic groups did not differ with respect to extracellular fluid volume, urinary sodium excretion, arterial blood pressure, mean plasma glucose concentration or urinary glucose excretion. Basal PRA did not differ significantly between the three groups. Ambulant PRA was significantly higher (P less than 0.02) in the group of IDDs with elevated GFR than in the control group. Our data suggest that, in IDDs with high GFR, haemodynamic alterations may stimulate a rise in PRA and thus angiotensin, a potent vasoconstrictor. Whether this represents an attempt of the renin-angiotensin system to normalise GFR or is the result of insensitivity of the renal vasculature to circulating angiotensin remains to be established.

Mechanism of furosemide-induced natriuresis by direct stimulation of renal prostaglandin E2.

Studies were conducted to investigate the interaction of renal prostaglandin E2 (PGE2) production and the renin-angiotensin system in the mechanism of furosemide-induced natriuresis. In conscious rabbits with permanent urinary bladder cannulation, furosemide in vivo (10 mg/kg) increased urinary water, sodium, and PGE2 excretion and plasma renin activity (PRA) over 50 min. Furosemide administered in vivo enhanced renal papillary but not cortical in vitro PGE2 biosynthesis. Prior administration of indomethacin at 2 mg/kg augmented the saluretic effect of furosemide, decreased its effect on UPGE2 V, abolished the rise in PRA, and reduced cortical but not papillary PGE2 biosynthesis. However, at 10 mg/kg, indomethacin reduced the saluretic effect of furosemide and eliminated the increase in UPGE2 V with continued suppression of PRA. Direct addition of furosemide in vitro to the incubation medium (10(-5) and 10(-3) M) markedly augmented papillary PGE2 synthesis. It is concluded that furosemide stimulates renal papillary PGE2 biosynthesis directly without mediation by angiotensin II, resulting in an increase in UPGE2 V, and the enhanced or inhibitory effect of indomethacin on furosemide-induced natriuresis is dose related and dependent on the degree of PGE2 synthesis inhibition in the presence of suppressed PRA, which occurred at all doses studied.