Aldosterone and renin in essential hypertension* Jacques Genest,! cc, md, frcp[c]; Wojciech Nowaczynski, d sc; Roger Boucher,
d
sc; J. Manuel
Rojo-Ortega,
md,
Summary: A review of some recent laboratory findings indicates definite
disturbances in aldosterone metabolism and regulation in patients with mild essential hypertension: (a) a significant mean increase in plasma aldosterone concentration in patients with mild and stable essential hypertension, in contrast to the absence of any difference in patients with labile borderline essential hypertension when in a normotensive phase, compared with control subjects; and (b) a significant mean decrease in metabolic clearance rate of aldosterone, associated with a 12% decrease in hepatic blood flow and an increased binding of aldosterone to a transcortin-like plasma globulin. The secretion rate of
measurements are repeated over a long period, one or two low values of plasma renin cannot be considered
permanent marker indicating a special category of patients with essential hypertension. a
Tonin,
a new
enzyme discovered
by Boucher, which forms angiotensin II directly from a plasma protein, from the tetradecapeptide substrate and from angiotensin I, is present in most tissues, but in highest concentration in the submaxillary gland. This enzyme is under the control of /S-adrenergic receptors.
is above the upper range of normal in 60% of patients with mild,
de certains resultats de laboratoire recents indiquent une nette perturbation dans le metabolisme et la regulation de I'aldosterone chez les patients souffrant d'hypertension essentielle legere:
The incidence of low-renin hypertension, when age and race are taken into account, is much lower than previously assumed. Unless
significative de la concentration plasmatique de I'aldosterone chez les patients avec hypertension essentielle legere et stable, tandis
18-hydroxy-11-deoxycorticosterone
uncomplicated essential hypertension.
?Adapted from the International Lecture
presented at the annual meeting of the American Heart Association, Dallas, Texas,
November 1974.
tDirector, multidisciplinary research group on hypertension of the Medical Research Council of Canada; director of the Clinical Research Institute of Montreal; professor of medicine and chief, nephrology-hypertension service, University of Montreal Hdtel-Dieu Hospital Reprint requests to: Dr. Jacques Genest, Scientific director, Clinical Research Institute of Montreal, 110 Pine Ave. W, Montr6al, Que\ H2W 1R7
ph
d; Otto
Kuchel, md,
ph d
Resume: Une
(a)
une
revue
augmentation moyenne
qu'aucune difference n'est obtenue comparaison aux sujets controles chez les patients avec hypertension par
essentielle labile "borderline" durant une periode de normotension; et (b) une diminution moyenne significative de la "clearance" metabolique de I'aldosterone, associee a une diminution de 12% du debit
sanguin hepatique
et une
augmentation
de la liaison de I'aldosterone
a une
proteine plasmatique "transcortin-like". Le taux de secretion de la
18-hydroxy-11-deoxycorticosterone
est au-dessus des limites normales chez plus de 60% des patients souffrant d'une hypertension essentielle legere et sans complication. L'incidence de l'hypertension a renine supprimee, quand on tient compte des facteurs d'age et de race, est beaucoup plus basse que
generalement rapportee.
A moins que
plasmatique
etre
les mesures ne soient repetees a des intervalles frequents sur une longue periode de temps, une ou deux valeurs basses de la renine ne
peuvent
interpretees comme un signe indelebile d'une categorie speciale de patients avec hypertension essentielle.
La tonine, une nouvelle enzyme decouverte par Boucher, qui forme directement de I'angiotensine II a partir d'une proteine plasmatique, du substrat de tetradecapeptide, et de I'angiotensine I, est presente dans presque tous les tissus, mais en concentration la plus elevee au niveau des glandes sousmaxillaires. Cette enzyme est sous le controle de recepteurs /3-adrenergiques.
In this paper we review some recent findings on aldosterone metabolism and regulation, attempt to clarify the prob¬ lem of low-renin essential hyperten¬ sion, and present our recent observa¬ tions on the control of the new enzyme "tonin" by /?-adrenergic receptors.
CMA JOURNAL/SEPTEMBER 6, 1975/VOL. 113 421
assumed,12 for they are based only on input and output. were hor¬ mineralocorticoid the forgotten the points Important Among mones, aldosterone has received the concentration of hormone in plasma most attention. We first reported in available for delivery to receptor sites 19561 an increased excretion of aldo¬ and the regulation of aldosterone in sterone in patients with severe essen¬ response to various physiological sti¬ tial, or malignant, hypertension; this muli. 3. The criteria for selection of pa¬ observation has generally been con¬ firmed, first by Laragh and associates2 tients were loose and the populations in 1960. On the other hand, we found studied were not homogeneous. It was therefore essential to define in 1958-60 a significant mean increase in aldosterone excretion in patients more precisely the type of patients to with mild essential hypertension,3'5 be studied and to concentrate our work measuring aldosterone physicochemic- on patients with mild essential hyper¬ ally after two chromatographic purifica- tension to determine if aldosterone or tions of urinary extracts;6 this increase other mineralocorticoids, or both, are could not be confirmed later by others involved in the sodium disturbances of with more precise methods based on this condition and possibly in their double isotope dilution assays.7"11 On mechanism. Simultaneous measure¬ the basis of the latter findings it has ments would have to be made of the repeatedly been claimed that the daily secretion and excretion, metabolic "metabolism" of aldosterone is normal clearance rate and plasma concentra¬ in mild essential hypertension and that tion of aldosterone.
Aldosterone
measurements of
.
the disturbances in rates of aldosterone secretion and excretion are manifesta¬ tions of the later stages of the disease and are associated with advanced renal arteriolar disease.11 When Conn12 reported in 1967 re¬ sults opposite to ours4,5 in measuring urinary aldosterone in patients with essential hypertension by the double isotope dilution assay, we decided to restudy the whole problem in depth. The sources of confusion and of differences in results of the various groups were the following: 1. There were differences in metho¬
dology.
2. Measurements of secretion and excretion rates of aldosterone are not indicative of its "metabolism", as was PLASMA ALDOSTERONE BEHI6H ESSENTIAL C0HTROL
HYPERTEMSI0M
SUBJECTS (n«42)
STABLE
LOW RENIN
(n*40)
(n-23)
Patients and methods
The criteria for selection of patients (a) minimal or no symptoms; (b) age between 25 and 50 years; (c) no abnormality related to the cardiovascu¬ lar system found by physical examina¬ tion, including absence of retinopathy and of any definite sign of arterioatherosclerosis of the large vessels; (d) normal plasma sodium, potassium and bicarbonate values; (e) normal renal function, as determined from blood urea, serum creatinine and creatinine clearance values, normal rapid-sequence intravenous pyelogram (IVP) and renal arteriogram; (f) normal electrocardio¬ gram and chest radiograph, without were
L/min/m2 1.0
0.8
M
r
£
0.7
HEPATIC RESISTANCE
o o
mm
8 8
P
d
sc; J. Manuel
Rojo-Ortega,
md,
Summary: A review of some recent laboratory findings indicates definite
disturbances in aldosterone metabolism and regulation in patients with mild essential hypertension: (a) a significant mean increase in plasma aldosterone concentration in patients with mild and stable essential hypertension, in contrast to the absence of any difference in patients with labile borderline essential hypertension when in a normotensive phase, compared with control subjects; and (b) a significant mean decrease in metabolic clearance rate of aldosterone, associated with a 12% decrease in hepatic blood flow and an increased binding of aldosterone to a transcortin-like plasma globulin. The secretion rate of
measurements are repeated over a long period, one or two low values of plasma renin cannot be considered
permanent marker indicating a special category of patients with essential hypertension. a
Tonin,
a new
enzyme discovered
by Boucher, which forms angiotensin II directly from a plasma protein, from the tetradecapeptide substrate and from angiotensin I, is present in most tissues, but in highest concentration in the submaxillary gland. This enzyme is under the control of /S-adrenergic receptors.
is above the upper range of normal in 60% of patients with mild,
de certains resultats de laboratoire recents indiquent une nette perturbation dans le metabolisme et la regulation de I'aldosterone chez les patients souffrant d'hypertension essentielle legere:
The incidence of low-renin hypertension, when age and race are taken into account, is much lower than previously assumed. Unless
significative de la concentration plasmatique de I'aldosterone chez les patients avec hypertension essentielle legere et stable, tandis
18-hydroxy-11-deoxycorticosterone
uncomplicated essential hypertension.
?Adapted from the International Lecture
presented at the annual meeting of the American Heart Association, Dallas, Texas,
November 1974.
tDirector, multidisciplinary research group on hypertension of the Medical Research Council of Canada; director of the Clinical Research Institute of Montreal; professor of medicine and chief, nephrology-hypertension service, University of Montreal Hdtel-Dieu Hospital Reprint requests to: Dr. Jacques Genest, Scientific director, Clinical Research Institute of Montreal, 110 Pine Ave. W, Montr6al, Que\ H2W 1R7
ph
d; Otto
Kuchel, md,
ph d
Resume: Une
(a)
une
revue
augmentation moyenne
qu'aucune difference n'est obtenue comparaison aux sujets controles chez les patients avec hypertension par
essentielle labile "borderline" durant une periode de normotension; et (b) une diminution moyenne significative de la "clearance" metabolique de I'aldosterone, associee a une diminution de 12% du debit
sanguin hepatique
et une
augmentation
de la liaison de I'aldosterone
a une
proteine plasmatique "transcortin-like". Le taux de secretion de la
18-hydroxy-11-deoxycorticosterone
est au-dessus des limites normales chez plus de 60% des patients souffrant d'une hypertension essentielle legere et sans complication. L'incidence de l'hypertension a renine supprimee, quand on tient compte des facteurs d'age et de race, est beaucoup plus basse que
generalement rapportee.
A moins que
plasmatique
etre
les mesures ne soient repetees a des intervalles frequents sur une longue periode de temps, une ou deux valeurs basses de la renine ne
peuvent
interpretees comme un signe indelebile d'une categorie speciale de patients avec hypertension essentielle.
La tonine, une nouvelle enzyme decouverte par Boucher, qui forme directement de I'angiotensine II a partir d'une proteine plasmatique, du substrat de tetradecapeptide, et de I'angiotensine I, est presente dans presque tous les tissus, mais en concentration la plus elevee au niveau des glandes sousmaxillaires. Cette enzyme est sous le controle de recepteurs /3-adrenergiques.
In this paper we review some recent findings on aldosterone metabolism and regulation, attempt to clarify the prob¬ lem of low-renin essential hyperten¬ sion, and present our recent observa¬ tions on the control of the new enzyme "tonin" by /?-adrenergic receptors.
CMA JOURNAL/SEPTEMBER 6, 1975/VOL. 113 421
assumed,12 for they are based only on input and output. were hor¬ mineralocorticoid the forgotten the points Important Among mones, aldosterone has received the concentration of hormone in plasma most attention. We first reported in available for delivery to receptor sites 19561 an increased excretion of aldo¬ and the regulation of aldosterone in sterone in patients with severe essen¬ response to various physiological sti¬ tial, or malignant, hypertension; this muli. 3. The criteria for selection of pa¬ observation has generally been con¬ firmed, first by Laragh and associates2 tients were loose and the populations in 1960. On the other hand, we found studied were not homogeneous. It was therefore essential to define in 1958-60 a significant mean increase in aldosterone excretion in patients more precisely the type of patients to with mild essential hypertension,3'5 be studied and to concentrate our work measuring aldosterone physicochemic- on patients with mild essential hyper¬ ally after two chromatographic purifica- tension to determine if aldosterone or tions of urinary extracts;6 this increase other mineralocorticoids, or both, are could not be confirmed later by others involved in the sodium disturbances of with more precise methods based on this condition and possibly in their double isotope dilution assays.7"11 On mechanism. Simultaneous measure¬ the basis of the latter findings it has ments would have to be made of the repeatedly been claimed that the daily secretion and excretion, metabolic "metabolism" of aldosterone is normal clearance rate and plasma concentra¬ in mild essential hypertension and that tion of aldosterone.
Aldosterone
measurements of
.
the disturbances in rates of aldosterone secretion and excretion are manifesta¬ tions of the later stages of the disease and are associated with advanced renal arteriolar disease.11 When Conn12 reported in 1967 re¬ sults opposite to ours4,5 in measuring urinary aldosterone in patients with essential hypertension by the double isotope dilution assay, we decided to restudy the whole problem in depth. The sources of confusion and of differences in results of the various groups were the following: 1. There were differences in metho¬
dology.
2. Measurements of secretion and excretion rates of aldosterone are not indicative of its "metabolism", as was PLASMA ALDOSTERONE BEHI6H ESSENTIAL C0HTROL
HYPERTEMSI0M
SUBJECTS (n«42)
STABLE
LOW RENIN
(n*40)
(n-23)
Patients and methods
The criteria for selection of patients (a) minimal or no symptoms; (b) age between 25 and 50 years; (c) no abnormality related to the cardiovascu¬ lar system found by physical examina¬ tion, including absence of retinopathy and of any definite sign of arterioatherosclerosis of the large vessels; (d) normal plasma sodium, potassium and bicarbonate values; (e) normal renal function, as determined from blood urea, serum creatinine and creatinine clearance values, normal rapid-sequence intravenous pyelogram (IVP) and renal arteriogram; (f) normal electrocardio¬ gram and chest radiograph, without were
L/min/m2 1.0
0.8
M
r
£
0.7
HEPATIC RESISTANCE
o o
mm
8 8
P
