Jacques Genest

Angiotensin-Forming Enzyme in Brain Tissue

A renin-like enzyme is present in brain tissue and is independent of kidney and plasma renin. In the presence of homologous substrate it forms angiotensin. Administration of aldosterone significantly decreases this angiotensinforming enzyme activity, while administration of progesterone markedly enhances it.

Endocrine factors in congestive heart failure

HERE IS impressive evidence that patients with congestive heart failure fail to excrete sodium and lack ability to maintain sodium balance. The evidence is both clinical and experimental. First, it is a basic clinical fact that a diet severely restricted in sodium will improve the condition of patients with congestive heart failure and that salt loads will aggravate it. Braunwald et al. l have recently devised a sodium tolerance test that clearly demonstrates the inability of patients with congestive heart failure to excrete a salt load. Similar findings were observed by Barge? in dogs with congestive heart failure induced experimentally by pulmonary stenosis and tricuspid insufficiency. Tricuspid insufficiency alone in dogs produced a rise in right atria1 pressure with definite al.terations in sodium excretion but without signs of congestive heart failure. However, the combination of tricuspid insufficiency and pulmonary artery stenosis in dogs results in a state of congestive heart failure similar to that seen in man with failure to excrete salt loads. In such an animal preparation, an infusion of 3.5 per cent sodium chloride solution directly into one renal artery produces no rise in sodium excretion, in contrast to the findings in similar experiments, performed in a normal dog. This failure of sodium excretion occurs without any change in the rate of glomerular filtration. These findings are convincing evidence of the increased tubular rea.bsorption of sodium in dogs with congestive heart failure. Second, a normal rate of glomerular filtration has been found in a number of patients with frank congestive heart failure.3s4 Bradley and Blake4 emphasized the absence of any significant change in this rate in many patients during or after recovery from congestive heart failure. They pointed out that in some patients the rate of glomerular filtration even fell during recovery without in any way preventing the diuretic response to therapy. It should also be recalled that in many cases of parenchymatous renal diseases, such as nephrosclerosis, pyelonephritis or glomerulonephritis, the rate of glomerular filtration may be extremely low without any evidence of edema formation. These observations again indicate the importance of increased tubular reabsorption of sodium in the pathogenesis of edema in congestive heart failure. Third, many investigators have emphasized the low concentration of sodium in the urine, sweat and saliva of patients with congestive heart failure, thereby indicating the presence of increased mineralocorticoid activity in the blood. Fourth, detailed studies of renal hemodynamics

Radioimmuoassay for aldosterone and normal values under various physiological conditions

Abstract A rapid, specific, precise and reproducible radioimmunoassay for plasma and urinary aldosterone has been developed using sheep antibody preparation. Two millilitres of plasma were usually extracted with dichloromethane and the dry residue chromatographed on a blank-free sephadex LH-20: water column. Separation of free from bound hormone was achieved by dextran-coated charcoal suspension. The recovery of [ 3 H]-aldosterone ranged from 69 to 80%. The sensitivity in measuring the unknown samples was 15 pg. The plasma levels of aldosterone were measured in men and women under various physiological conditions. In 45 male and female controls on a diet containing 135 m-equiv of Na and 90m-equiv of K, the mean recumbent plasma aldosterone, at 0800 h, was 8.0 ± 4.2 S.D. ng/100ml and at noon after 4 h upright, ( n = 11) 18.3 ± 9.5 ng/100 ml, as compared to 7.9 ± 4.1 S.D. ng/100 ml recumbent; the recumbent mean was 7.7 ± 4.1 in 25 males and 8.4 ± 4.4 in 20 females (blood sampling, always within 6 days of the onset of the menstruation). The mean recumbent (0800 h) plasma aldosterone in 22 similar controls on random diet was 6.6 ± 3.5 ng/100 ml. Plasma aldosterone in 15 female controls on random diet after the 6th day of the menstrual cycle gave a higher mean of 9.9 ± 5.4 ng/100 ml. Plasma aldosterone (0800 h in recumbent posture) showed two peaks in two experiments involving two ovulatory menstrual cycles—one in midfollicular and one in mid-luteal phase (11.1 and 8.5 ng/100 ml). The second peak was present in a third anovulatory cycle (12.7 ng/100 ml) as well. Plasma aldosterone in all three experiments ranged from 2 to 12.7 ng/100 ml. Excretion of the 18-hydroxyhemiacetal glucuronoside of aldosterone in 11 controls gave a mean of 9.1 βg/24h ± 4.8 S.D.

Further Studies on Urinary Aldosterone in Human Arterial Hypertension.

Conclusion Our results indicate 1) increased aldosterone excretion in about 55% of patients, 2) a very significant difference between mean aldosterone excretion of patients with essential, renal or malignant hypertension as compared with normal subjects, 3) a much greater degree of fluctuation in serial daily aldosterone determinations in 2 early asymptomatic hypertensive patients as compared to a normal subject. These observations bring additional and direct evidence for an adrenal cortical disturbance in hypertensive cardio-vascular disease. Although the evidence is suggestive, it cannot be established at the present time if these findings play an etiological role in pathogenesis of arterial hypertension. They may provide the explanation for the successful use of salt depletion by chlorothiazide and mercurials as essential adjunct to the “effectiveness” of the present anti-hypertensive therapy.

Adrenocortical Hormones in Human Hypertension and Their Relation to Angiotensin

In summary, we have demonstrated that: (a) Infusions of epinephrine, norepinephrine, and phenylephrine in 5 per cent glucose for 7 to 10 hours have little effect on, or decrease, urinary aldosterone excretion. (b) Angiotensin II infusions markedly decrease sodium excretion and the Na/K ratio and increase the excretion of aldosterone; of its ring-A reduced metabolite, pregnane-3-α,18,21-triol,11,20-dione; and, to a much lesser degree, of cortisol and tetrahydrocortisone in all normal subjects studied. (c) In patients with benign essential hypertension, infusions of angiotensin also stimulate urinary aldosterone excretion hut have a completely opposite effect on electrolytes-that of increasing sodium output and the Na/K ratio. This basic difference in response to angiotensin points to a fundamental problem to be solved for a better understanding of the disease. It is felt that the relative or absolute excess of aldosterone over progesterone secretion may be the important adrenal disturbance among the basic factors involved in the pathogenesis of arterial hypertension. This disturbance is definitely linked with angiotensin and sodium regulation.

Renin Activity Content in Various Tissues of Dogs Under Different Physiopathological States

Summary Plasma renin activity and renin activity content in several tissues of dogs under conditions of severe sodium restriction, congestive heart failure, clipping of one renal artery, and nephrectomy were studied and compared to the values obtained in control dogs. The highest extrarenal RAC was found in adrenal glands followed by liver, spleen, heart, lung, skeletal muscle, and arterial tissue. Severe chronic sodium restriction increased RAC in all tissues, with the exception of the adrenal glands and aorta; whereas, the RAC following nephrectomy did not decrease significantly. In renovascular hypertension secondary to unilateral renal clipping, there is a slight, but not significant, increase in RAC in adrenal glands.

Hypertension with renal arterial stenosis: Humoral, hemodynamic and histopathologic factors☆

In 46 hypertensive patients with unilateral renal arterial stenosis, peripheral and renal venous plasma renin activity, juxtaglomerular cell count and granularity and systolic pressure gradient across the stenosis were determined. After corrective surgery and a mean postoperative observation period of 4.3 years, 18 patients were completely relieved of hypertension (good responders), 14 had a substantial reduction in arterial pressure (fair responders) and 14 remained hypertensive (poor responders). Analysis of plasma renin activity in both renal veins indicated that a ratio (stenotic/nonstenotic side) greater than 2.0 correctly predicted a favorable surgical result in all cases. Peripheral plasma renin activity was greater than normal in 65 percent of good responders, in 50 percent of fair responders and in one nonresponder. The prognostic accuracy of a pressure gradient greater than 40 mm Hg was 78 percent; no patient with a gradient of less than 40 mm Hg benefited from surgery. An increased juxtaglomerular cell count on the affected side predicted a successful operative result in 88 percent, as did increased granularity in 85 percent of cases. Renal venous renin ratio correlated positively (r =0.738, P less than 0.001) with the pressure gradient across the stenosis. The renal venous plasma renin activity of the affected side also correlated positively (r = 0.771, P less than 0.001) with the absolute count of granular cells in the juxtaglomerular apparatus. Plasma renin activity in both renal veins is the most reliable predictor of operative outcome. The addition of juxtaglomerular cell count or pressure gradient across the stenosis increases prognostic accuracy only slightly. The close mutual correlations between renal venous renin ratio, pressure gradient and juxtaglomerular cell count support the experimental evidence of a causal relation between the hemodynamic effects of the arterial lesion and the humoral and histologic changes observed in hypertension with renal arterial stenosis.

Dynamic aldosterone and 18-hydroxydeoxycorticosterone studies in labile and stable benign essential hypertension.

Abstract Under baseline conditions of recumbency and normal sodium intake there was a small significant hyperaldosteronism evident from elevated plasma concentration and aldosterone excretion in presence of suppressed metabolic clearance rate (MCR) in benign essential hypertension (BEH). BEH patients, particularly those with hyperkinetic circulation often excreted more oxo-conjugate and present greater than normal response in plasma aldosterone to upright posture. Upright posture decreased aldosterone MCR in controls, but effect was negligible in BEH. In BEH, decreased MCR and excretion of hepatic metabolite (tetrahydroaldosterone) may be due to impaired hepatic extraction related to increased aldosterone binding to a transcortin-like plasma fraction (TLPF). Concomitant fluctuations of TLPF and plasma concentration during circadian rhythm, the menstrual cycle and pregnancy suggest a possible role of TLPF in aldosterone distribution and dynamics. Recumbent BEH patients had increased plasma aldosterone around midnight. BEH patients showed hyperresponsiveness to ACTH infusion in plasma aldosterone with simultaneous sharp decrease of TLPF binding, while aldosterone MCR increased significantly and the ratio of the urinary and hepatic metabolites of aldosterone changed. Changes in binding degree probably contribute to perturbated aldosterone metabolism in BEH. In the majority of BEH patients with normal or low plasma renin activity 18-hydroxydeoxycorticosterone secretion is increased. ACTH stimulation or dexamethasone suppression of 18-hydroxydeoxycorticosterone is comparable in controls and patients. This hormone circulates in unbound form.

ARTERIAL ANGIOTENSIN LEVELS IN EDEMATOUS PATIENTS.

Summary and conclusion Fifteen patients with generalized edema were studied for circulating angiotensin levels in arterial blood. Out of 10 patients with congestive heart failure, 9 had very high levels and 7 of the latter presented, after total or partial relief of edema, a very marked decrease in their angiotensin levels. One presented a rise and one showed no significant change. One of 2 patients with the nephrotic syndrome and one of 3 with cirrhosis of the liver had high arterial angiotensin levels.

The adrenal cortex and essential hypertension.

Publisher Summary This chapter presents views and findings concerning various aspects of the relationship of the adrenal cortex to hypertension. It reviews some aspects of the relationship of the adrenal cortex to hypertension: (1) disturbances in aldosterone regulation [plasma concentration, metabolic clearance rate (MCR), binding to a transcortin-like plasma protein fraction, hepatic blood flow, effects of adrenocorticotropin (ACTH) and angiotensin II on metabolic clearance rate and protein binding of aldosterone), (2) some aspects of low renin essential hypertension, (3) 18-hydroxy-11-deoxycorticosterone secretion rate in patients with mild, uncomplicated essential hypertension and its biological activity in dogs, (4) dehydroepiandrosterone, (5) adrenal isorenin, and (6) tonin. The chapter also outlines a few studies that have been done to understand these aspects, along with the methods applied and the patients taken as models for these studies. The chapter presents the overall results of plasma aldosterone concentration, measured in these studies by radioimmunoassay in 69 control subjects, 42 patients with mild, uncomplicated essential hypertension when in a normotensive phase, and 57 patients with stable mild essential hypertension.