J. D. Barrett

Clonidine, a centrally acting sympathetic inhibitor, as monotherapy for mild to moderate hypertension

Sixteen patients with uncomplicated essential hypertension were treated with 0.2 mg of clonidine three times daily as the sole antihypertensive drug. Blood pressure decreased from 167 +/- 4/105 +/- 2 to 139 +/- 3/89 +/- 2 mm Hg (mean +/- standard error of the mean) after 1 week (p less than 0.001) and remained at 140 +/- 3/90 +/- 2 mm Hg after 3 months of therapy. There were no significant changes in cardiac output, blood volume, renal blood flow or glomerular filtration rate during clonidine therapy. Clonidine significantly decreased plasma catecholamines and there was a linear correlation between the change in blood pressure and decreases in plasma catecholamine concentration (r = 0.61, p less than 0.001). There was also a significant correlation between the decreases in heart rate and blood pressure (r = 0.78, p less than 0.001). It is concluded that clonidine can be used effectively and safely as the sole agent in the treatment of mild to moderate hypertension.

Purification and partial characterization of human angiotensinogen

Renin substrate was initially extracted from human plasma by (NH4)2SO4 followed by chromatography on Sephadex G-150, DEAE cellulose, calcium phosphate gel, isoelectric focusing and preparative polyacrylamide gel electrophoresis. On the basis of one mol of angiotensin per mol of substrate, the purity of the preparation is in excess of 95%. On analytical polyacrylamide gel electrophoresis in the presence of 1% sodium dodecyl sulfate or 8 M urea, the protein appears homogenous. In addition, the purified protein shows only one preciptin line against anti-normal human serum on either Ouchterlony immunodiffision or immunoelectrophoresis. The biological activity appears similar to native renin substrate since the Km is the same as that reported for the renin reaction in whole plasma. The molecular weight was determined as 110 000 by gel filtration and polyacrylamide gel electrophoresis; amino acid analysis of the human substrate differs from that reported for hog, especially in the Asp, Glu and Gly composition.

Renin regulation in type II diabetes mellitus: influence of dietary sodium

Numerous abnormalities in the renin-angiotensin system have been described in diabetes mellitus. Plasma renin activity (PRA) has been noted to be low, normal, and high in diabetic patients; these variable results may be explained by differences in patient selection and standardization of study conditions. We evaluated PRA and inactive renin responses in Type II normotensive (n = 7) and hypertensive (n = 12) diabetic patients specifically selected for no or minimal evidence (background retinopathy) for microvascular complications. Patients were studied in a metabolic ward after 7 days on a constant low sodium (20 meq/day) and 7 days on a high sodium (250 meq/day) diet. Nondiabetic control subjects (n = 7) were evaluated under similar conditions. On low sodium intake, mean PRA levels were significantly reduced in the hypertensive diabetic group, but were not different between the control and normotensive diabetic groups. Hypertensive diabetic patients on high sodium intake also had greater reductions in PRA responses compared with the other study groups. In general, diabetic subjects on high sodium intake excreted less sodium and had more cumulative sodium retention than control subjects. Levels of inactive renin were not significantly different between the normotensive and hypertensive diabetic patients and were comparable with the levels in control subjects. Inactive renin levels changed in a similar direction and magnitude as PRA in response to sodium intake and posture in the three study groups. Infusion of angiotensin II led to comparable reductions in PRA in both diabetic groups and in the control group, suggesting an intact short feedback loop control.(ABSTRACT TRUNCATED AT 250 WORDS)

Hormonal correlates of weight loss associated with blood pressure reduction.

This study investigated changes in plasma norepinephrine and the renin-angiotensin-aldosterone system during weight loss. Subjects were maintained on a hypocaloric and low sodium diet for 12 weeks. During weight loss statistically significant decreases in blood pressure, aldosterone, plasma renin activity, and norepinephrine were evident. Plasma renin substrate was suppressed from week one to eight and returned to control levels by week twelve. The data indicate that a reduction in the activity of the renin-angiotensin-aldosterone system, modulated by circulating norepinephrine and plasma renin substrate, may significantly contribute to the fall in blood pressure associated with weight loss.

Dopaminergic Modulation of Renin Release

The effect of metoclopramide, a procainamide derivative with dopamine antagonistic properties, and L-dopa on plasma renin activity (PRA) was studied in adult rats. Following an intravenous bolus of metoclopramide (200 microgram/kg) to the American Wistar rat there was a significant (p less than 0.05) elevation in PRA at 10 min and a maximum response at 30 min. There was a significant depression (p less than 0.05) in PRA at 15 through 40 min following an intravenous bolus of L-dopa (30 mg/kg). Pre-administration of L-dopa delayed and blunted the PRA response to metoclopramide. However, the PRA response to this dopamine antagonist was not altered by beta blockade with propranolol and alpha blockade with phentolamine. Administration of metoclopramide resulted in considerably greater (p less than 0.01) PRA responses in spontaneously hypertensive rats than in Wistar Kyoto (WKY) normotensive controls. Administration of L-dopa resulted in similar suppression of PRA in the two groups. These results indicate that there is a dopaminergic inhibitory control mechanism for renin secretion. Dopaminergic control of renin release appears to be altered in the spontaneously hypertensive rat.

Studies on renin activation in normal human plasma.

SUMMARY The phenomenon of plasma renin activation by add dialysis and prelncubation with trypsin was studied in normal human plasma. Activation of plasma renin by exposure to pH 3 3 was shown to require at least one dialysis step and could be inhibited by the presence of Trasylol, indicating the involvement of a protease in add actiration. Amniotic fluid exposed to pH 1.5 to destroy renin and renin substrate was also found to contain an enzyme capable of activating plasma renin. The Michaelis-Menten constant Km and the molecular weight of activated “renin” were found to be similar to those of normal plasma renin. Inactive renins or renin-like enzymes were partially purified from plasma by affinity chromatography on concanavalin A, precipitation with (NH4)tSO4 and isoelectric focusing. Trypsin and acid exposure gave similar results with regard to the activation of this zymogen, suggesting that trypsin and acid dialysis may increase plasma renin activity by the same mechanism.

The effect of erythropoietin on the cardiovascular system

Summary: Partial correction of uraemic anaemia restores the baseline hyperkinetic haemodynamics toward normal, reduces left ventricular size and mass and improves exercise tolerance in dialysis patients. These effects may, in large part, be attributed to increases in haematocrit. Information on whether erythropoietin also acts directly on the heart, as it does on the peripheral vasculature, is not available. Also remaining unanswered is the question as to whether the effects of erythropoietin on the heart reduce cardiovascular mortality in end‐stage renal disease (ESRD) patients. In addition, we do not know whether complete (vs partial) correction of uraemic anaemia will further enhance the beneficial effect of erythropoietin, or whether such gains could be counterbalanced by side effects of erythropoietin, such as the development or exacerbation of hypertension. Studies in the peripheral vasculature suggest erythropoietin also acts directly on the vascular smooth muscle cells, exerting both vasopressive and growth effects. Better understanding of the mechanism and control of such non‐erythropoietic actions of erythropoietin can optimize the beneficial effect and minimize the side effect of this hormone on the cardiovascular system.

Enhanced Renin Levels After Discontinuation of Furosemide: Additional Effects of Loop Diuretics on Renin Release

The rate of recovery of the renin-angiotensin-aldosterone axis after stopping diuretic administration was examined in 18 male patients with essential hypertension. Upright plasma renin activity (PRA) and plasma aldosterone (PA) were measured during sodium restriction (10 mEq sodium intake), after three days of furosemide administration (40 mg BID po) and for five days following cessation of the diuretic. After diuretic administration, the mean PRA level (8.2 +/- 1.7 ng/ml/hr) was significantly elevated compared to the level on low sodium diet (4.2 +/- 0.5 ng/ml/hr). However, the major finding was that PRA levels continued to increase significantly compared to levels during diuresis on days 1 (11.3 +/- 1.7 ng/ml/hr) and 2 (10.8 +/- 1.5 ng/ml/hr) of the postdiuretic period. Mean PA values paralleled PRA responses in the study. Infusion of normal saline on postdiuretic day 1 failed to suppress PRA to levels seen in subjects not receiving diuretics. The postdiuretic period was accompanied by increased urinary sodium reabsorption and decreased urinary potassium excretion and by significant decreases in creatinine, PAH and free water clearance. The mechanism of this sustained renin response several days after cessation of diuretic therapy may be best explained by a prolonged action of furosemide or by partial ongoing volume depletion with reduced sodium load to the distal nephron. Since all patients demonstrated a marked and consistent PRA response after diuretic withdrawal, this time period represents a potent stimulatory challenge for monitering renin responses.

Trypsin Activable Renin in Rat Plasma. Effects of Acute and Chronic Perturbation of the Renin System

Plasma levels of active and inactive renin were measured in the rat following manipulation of renin release. In the anesthetized rat intravenous captopril or sodium nitroprusside resulted in elevation of active renin only. Neither active nor inactive renin were altered following ether anesthesia of 2 hour bilaterally nephrectomized animals. Elevated levels of active and total renin were observed in anesthetized Wistar rats that had received oral captopril for a 6 week period. Renin substrate was decreased suggesting that blood angiotensin II exerts a tonic influence on renin substrate. In sodium deplete SHR, sacrificed by decapitation, chronic captopril resulted in a significant increase of both the active and inactive form of the enzyme concomitant with blood pressure reduction. The present data further confirm the independent control of active and inactive renin in the rat.

In Vitro Generation of Inactive Renin in Hypertensive Human Plasma

When plasma from normal and hypertensive human subjects is incubated at pH 7.4 in the absence of angiotensinase inhibitors, a significant decline of active plasma renin occurs. The fall of active renin was more pronounced in the plasma from normotensive controls and was accompanied by a fall of total renin without change of inactive renin. In hypertensive subjects total renin levels (trypsin treatment) did not change. The fall of active renin in plasma from hypertensive subjects was due therefore to its in vitro conversion to an inactive form of renin which could be reactivated by trypsin. If reversible inactivation of active plasma renin occurs in vivo, inactivated active renin may contribute to a portion of the plasma pool of inactive renin. This form of inactive renin which may be activable in vivo would not therefore represent a renin precursor or prorenin of renal origin.