Effect of Sodium Depletion on Plasma Renin Concentration Before and During Adrenergic P-Receptor Blockade with Propranolol in Normotensive Man
Plasma renin levels have been used to discriminate between different forms of hypertension, but how to define the normal range of plasma renin levels has not been agreed upon. Sodium depletion stimulates renin release. Evaluation of plasma renin would, therefore, seem possible only in relation to sodium balance. Plasma renin concentration and concurrent daily sodium excretion were determined in 33 healthy normotensive subjects (control group) ingesting high, normal and low sodium diets. A well-defined hyperbolic relationship was found between the two variables indicating that the physiologic level of plasma renin concentration depends on the state of sodium balance. An increase in plasma potassium concentration may reduce plasma renin concentration, but this appeared to be overruled by the stimulating effect of sodium depletion. To examine whether &adrenergic stimulation contributes to the increase in plasma renin concentration during sodium depletion, the relationship between plasma renin concentration and concurrent sodium excretion was studied during P-receptor blockade with propranolol. In 20 healthy normotensive subjects in whom &receptor blockade was verified by a significant reduction in pulse rate, the same hyperbolic relationship was found between plasma renin concentration and sodium excretion as in the control group showing that sodium depletion stimulates renin release independent of sympathetic nervous activity.
PER OMVIK, M.D.’ ERIK ENGER, M.D. WAR EIDE, M.D. Oslo, Norway
From the Medical Department VII, Ullevaal Hospital, Oslo, and Institute for Experimental Medical Research, University of Oslo, Ullevaal Hospital, Oslo, Norway. Requests for reprints should be addressed to Dr. lvar Eide, Medical Department VII, Ullevaal Hospital, Oslo, Norway. Manuscript accepted March 3, 1976. Present address: Medical Department A, Haukeland Hospital, 5000 Bergen, Norway. l
609
November 1976
Plasma renin activity increases during sodium depletion both in experimentai animals [1,2] and in man [3-51, but the mechanisms involved have not been fully elucidated. In man, the relationship between sodium balance and plasma renin has been most extensively studied by Laragh and associates [4,6] _They have repeatedly claimed a hyperbolic correlation between urinary sodium excretion and plasma renin activity. The significance of this correlation has been challenged [ 71, and other measures of sodium balance have been used to define the normal range of plasma renin [3,5,8]. The first aim of this study was, therefore, to re-examine the changes in plasma renin in normotensive man in response to changes in sodium excretion. Various stimuli, including a decrease in sodium excretion [6], activation of the sympathetic nervous system [9, lo] and autoregulated
The American Journal of Medicine
Volume 61
PLASMA
RENIN, SODIUM DEPLETION AND &ADRENERGIC
renal vasodilatation by reducing blood pressure [ ll131, increase plasma renin concentration by increasing the release of renin from the kidney. A negative sodium balance reduces tubular sodium delivery at the macula densa. This might stimulate the release of renin from juxtaglomerular cells [ 141, but since a negative sodium balance also leads to a reduction in plasma volume and thereby to increased sympathetic activity, the inverse relationship between plasma renin concentration and sodium excretion might be caused by stimulation of the sympathetic nervous system [ 15,161. These possibilities were examined by comparing the effect of sodium depletion on plasma renin concentration in nOrKIOtensive man before and during adrenergic P-receptor blockade with propranolol. METHODS Plasma renin concentration was determined in 53 healthy normotensive medical students and members of the medical staff ingesting high, normal and low sodium diets. In 33 subjects adrenergic P-receptor blockade was not given (control group) whereas 20 subjects received P-receptor blockade with propranolol (Inderale, Imperial Chemical Industries). The drug was administered orally at 40 mg/day, divided into two daily doses for two days and then gradually increased to 160 mglday. This dosage was reached within two days prior to the study and was maintained for one week. The volunteers were of both sexes (nine female and 44 male), ranging in age between 20 and 36 years with an average of 25 f 3 years (mean f SD). Only volunteers with blood pressure levels less than 140/90 mm Hg were accepted. Blood pressure levels and pulse rate were measured after the subject had had 5 minutes of rest in a chair. Systolic and diastolic (fifth phase) blood pressure levels were determined with a conventional mercury sphygmomanometer. The relationship between plasma renin activity and daily sodium excretion has previously been shown to be similar in outpatients and in subjects examined in metabolic wards [6]. Therefore, in this study, the subjects were treated as outpatients, but the meals were prepared at the hospital by the dietitian. Three different diets were used, calculated to contain approximately 15, 150 and 250 meq sodium/day, respectively. Potassium intake was approximately 80 meq/ day under all three dietary regimens. The control group was studied during the ingestion of all three diets, whereas the subjects blocked with propranolol were examined during the ingestion of low and normal sodium diets only. Each diet was administered for five days except to four students who, during the last two days of the low salt diet period, received an almost sodium-free rice and fruit diet. Plasma concentrations of renin, electrolytes and creatinine were determined in venous blood samples drawn at 12 noon on the fifth day (experimental day) of the respective sodium diet. The students were ambulatory from 7 A.M. and were seated during blood samplings. They received their meals as usuill. A 24 hour urine sample was collected from 7 A.M. to determine creatinine clearance and daily excretion rates of sodium and potassium. Concentrations of electrolytes and
BLOCKADE-OMVIK
ET AL.
creatinine in plasma and urine were measured with a Technicon@ autoanalyzer (Ardsley, New York). Peripheral venous plasma renin concentrations were determined by radioimmunoassay according to the method of Haber et al. [ 171 following incubation of the buffered plasma samples with an excess of exogenous renin substrate. Angiotensinases were inhibited by ethylenediaminetetraacetic acid (EDTA), dimercaprol (BAL), and &hydroxyquinoline as previously described [ 111. Internal standards of human renin (Dr. Erwin Haas, Mt. Sinai Hospital, Cleveland, Ohio) were used according to Haas and co-workers [la]. Analysis of urinary sodium concentrations and plasma renin concentration were performed at different laboratories. Data are presented as means & 1 standard error (SE) of the mean. The statistical probability (P) of differences was calculated with Wilcoxon’s tests for two samples and for paired comparison [ 191. The differences were regarded as significant at P
Plasma renin levels have been used to discriminate between different forms of hypertension, but how to define the normal range of plasma renin levels has not been agreed upon. Sodium depletion stimulates renin release. Evaluation of plasma renin would, therefore, seem possible only in relation to sodium balance. Plasma renin concentration and concurrent daily sodium excretion were determined in 33 healthy normotensive subjects (control group) ingesting high, normal and low sodium diets. A well-defined hyperbolic relationship was found between the two variables indicating that the physiologic level of plasma renin concentration depends on the state of sodium balance. An increase in plasma potassium concentration may reduce plasma renin concentration, but this appeared to be overruled by the stimulating effect of sodium depletion. To examine whether &adrenergic stimulation contributes to the increase in plasma renin concentration during sodium depletion, the relationship between plasma renin concentration and concurrent sodium excretion was studied during P-receptor blockade with propranolol. In 20 healthy normotensive subjects in whom &receptor blockade was verified by a significant reduction in pulse rate, the same hyperbolic relationship was found between plasma renin concentration and sodium excretion as in the control group showing that sodium depletion stimulates renin release independent of sympathetic nervous activity.
PER OMVIK, M.D.’ ERIK ENGER, M.D. WAR EIDE, M.D. Oslo, Norway
From the Medical Department VII, Ullevaal Hospital, Oslo, and Institute for Experimental Medical Research, University of Oslo, Ullevaal Hospital, Oslo, Norway. Requests for reprints should be addressed to Dr. lvar Eide, Medical Department VII, Ullevaal Hospital, Oslo, Norway. Manuscript accepted March 3, 1976. Present address: Medical Department A, Haukeland Hospital, 5000 Bergen, Norway. l
609
November 1976
Plasma renin activity increases during sodium depletion both in experimentai animals [1,2] and in man [3-51, but the mechanisms involved have not been fully elucidated. In man, the relationship between sodium balance and plasma renin has been most extensively studied by Laragh and associates [4,6] _They have repeatedly claimed a hyperbolic correlation between urinary sodium excretion and plasma renin activity. The significance of this correlation has been challenged [ 71, and other measures of sodium balance have been used to define the normal range of plasma renin [3,5,8]. The first aim of this study was, therefore, to re-examine the changes in plasma renin in normotensive man in response to changes in sodium excretion. Various stimuli, including a decrease in sodium excretion [6], activation of the sympathetic nervous system [9, lo] and autoregulated
The American Journal of Medicine
Volume 61
PLASMA
RENIN, SODIUM DEPLETION AND &ADRENERGIC
renal vasodilatation by reducing blood pressure [ ll131, increase plasma renin concentration by increasing the release of renin from the kidney. A negative sodium balance reduces tubular sodium delivery at the macula densa. This might stimulate the release of renin from juxtaglomerular cells [ 141, but since a negative sodium balance also leads to a reduction in plasma volume and thereby to increased sympathetic activity, the inverse relationship between plasma renin concentration and sodium excretion might be caused by stimulation of the sympathetic nervous system [ 15,161. These possibilities were examined by comparing the effect of sodium depletion on plasma renin concentration in nOrKIOtensive man before and during adrenergic P-receptor blockade with propranolol. METHODS Plasma renin concentration was determined in 53 healthy normotensive medical students and members of the medical staff ingesting high, normal and low sodium diets. In 33 subjects adrenergic P-receptor blockade was not given (control group) whereas 20 subjects received P-receptor blockade with propranolol (Inderale, Imperial Chemical Industries). The drug was administered orally at 40 mg/day, divided into two daily doses for two days and then gradually increased to 160 mglday. This dosage was reached within two days prior to the study and was maintained for one week. The volunteers were of both sexes (nine female and 44 male), ranging in age between 20 and 36 years with an average of 25 f 3 years (mean f SD). Only volunteers with blood pressure levels less than 140/90 mm Hg were accepted. Blood pressure levels and pulse rate were measured after the subject had had 5 minutes of rest in a chair. Systolic and diastolic (fifth phase) blood pressure levels were determined with a conventional mercury sphygmomanometer. The relationship between plasma renin activity and daily sodium excretion has previously been shown to be similar in outpatients and in subjects examined in metabolic wards [6]. Therefore, in this study, the subjects were treated as outpatients, but the meals were prepared at the hospital by the dietitian. Three different diets were used, calculated to contain approximately 15, 150 and 250 meq sodium/day, respectively. Potassium intake was approximately 80 meq/ day under all three dietary regimens. The control group was studied during the ingestion of all three diets, whereas the subjects blocked with propranolol were examined during the ingestion of low and normal sodium diets only. Each diet was administered for five days except to four students who, during the last two days of the low salt diet period, received an almost sodium-free rice and fruit diet. Plasma concentrations of renin, electrolytes and creatinine were determined in venous blood samples drawn at 12 noon on the fifth day (experimental day) of the respective sodium diet. The students were ambulatory from 7 A.M. and were seated during blood samplings. They received their meals as usuill. A 24 hour urine sample was collected from 7 A.M. to determine creatinine clearance and daily excretion rates of sodium and potassium. Concentrations of electrolytes and
BLOCKADE-OMVIK
ET AL.
creatinine in plasma and urine were measured with a Technicon@ autoanalyzer (Ardsley, New York). Peripheral venous plasma renin concentrations were determined by radioimmunoassay according to the method of Haber et al. [ 171 following incubation of the buffered plasma samples with an excess of exogenous renin substrate. Angiotensinases were inhibited by ethylenediaminetetraacetic acid (EDTA), dimercaprol (BAL), and &hydroxyquinoline as previously described [ 111. Internal standards of human renin (Dr. Erwin Haas, Mt. Sinai Hospital, Cleveland, Ohio) were used according to Haas and co-workers [la]. Analysis of urinary sodium concentrations and plasma renin concentration were performed at different laboratories. Data are presented as means & 1 standard error (SE) of the mean. The statistical probability (P) of differences was calculated with Wilcoxon’s tests for two samples and for paired comparison [ 191. The differences were regarded as significant at P
