0021-972X/90/7104 -0944$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright© 1990 by The Endocrine Society
Vol. 71, No. 4 Printed in U.S.A.
Dysregulation of Atrial Natriuretic Factor in Hypertension-Prone Man* PAOLO FERRARI, PETER WEIDMANN, CLAUDIA FERRIER, ROLAND DIETLER, RALPH HOLLMANN, REIN JAN PISO, JOSEPH WEY, AND SIDNEY SHAW Medizinische Poliklinik, University of Berne, Berne, Switzerland
ABSTRACT. To evaluate the hypothesis of an atrial natriuretic factor (ANF) deficiency in hypertension-prone humans, we investigated plasma ANF and other variables in 116 white offspring of normotensive parents (ONorm) or essential hypertensive parents (OHyp). Ten ONorm and 10 OHyp, all men matched for age and body habitus, were studied after 4 days of low (70 mmol/day) and high (350 mmol/day) dietary sodium intake. After mild sodium restriction, plasma ANF did not differ between ONorm and OHyp (9.7 ± 0.7 vs. 9.0 ± 1.3 fmol/L). On high sodium intake, plasma ANF increased in ONorm, but not in OHyp (to 18.3 ± 1.7 vs. 11.7 ± 1.7 fmol/L; P < 0.001). On the other hand, acute responses of plasma immunoreactive ANF (irANF) to saline loading or a norepinephrine-induced rise in blood pressure did not differ significantly between 8 ONorm and 8 OHyp. Fifty-one additional ONorm and 45 OHyp were evaluated during liberal sodium intake. Groups were further subdivided according to whether 24-h urinary sodium excretion was 91 mmol/m2 or less (modest salt intake) or more than 91 mmol/
T
HE PATHOGENESIS of essential hypertension involves hereditary disturbance(s). Vascular hyperreactivity to norepinephrine occurs commonly in yet normotensive offspring of essential hypertensive parents (1, 2). Moreover, an impaired capacity of the kidneys to excrete sodium (3, 4) could result from a deficiency in and/or a decreased renal response to endogenous natriuretic factor(s). The excessive dietary sodium intake of modern man compared with his ancestors necessitates a powerful compensatory mechanism. In normal humans, circulating atrial natriuretic factor (ANF) increases during sodium loading or acute rises in blood pressure (BP) and is thought, although yet not proven, to be an endogenous modulator of natriuresis, vascular reactivity to pressor agents, and BP (5-7).
m2 (high salt intake). Twenty-four-hour urinary sodium was similar in the 26 ONorm and 21 OHyp on a modest salt intake (121 ± 6 vs. 116 ± 9 mmol) and in the 25 ONorm and the 24 OHyp on a high salt intake (226 ± 10 vs. 221 ± 9 mmol). However, compared with ONorm, plasma irANF in OHyp was slightly lower on modest sodium intake (7.7 ± 0.7 vs. 5.3 ± 0.7 fmol/L; P < 0.05) and markedly reduced on high sodium intake (15.0 ± 1.3 vs. 8.0 ± 1.3 fmol/L; P < 0.001). Moreover, the slope of the relationship between plasma irANF and 24-h urinary sodium was flatter in OHyp than in ONorm (z test = 2.4). We postulate a new endocrine syndrome characterized by a relative plasma ANF deficiency during high sodium intake in some hypertension-prone humans. This functional defect becomes apparent during chronic, rather than acute, stimulation of ANF release. It occurs as a familial disturbance and may potentially predispose to the development of hypertension, (j Clin Endocrinol Metab 7 1 : 944-951, 1990)
normotensive parents compared with those in agematched normotensive offspring of hypertensive parents. One series of studies was performed after 4 days of fixed sodium intakes, including 70,130, and 350 mmol sodium/ day. Some of these data have been presented in preliminary form (8). To further assess the ANF-sodium relationship under the influence of individual dietary habits, an additional, larger group of offspring was studied during liberal sodium intake. Materials and Methods Studies on defined sodium intakes Two age-matched (age ± SEM, 25 ± 1 yr) of healthy young men were studied. One group included 10 offspring of normotensive parents (ONorm); the other group 10 offspring, 1 of whose parents had essential hypertension (OHyp). All subjects were volunteers in excellent physical and mental condition, with a BP consistently below 140/90 mm Hg; none was taking any drugs. Written informed consent was obtained to assess the family history of essential hypertension by the following strict approach: 1) information on BP, the use of antihypertensive drugs, and cardiovascular complications in parents and any siblings was obtained from the family doctors and, in
To test the hypothesis of a familial ANF deficiency, we investigated plasma immunoreactive ANF (irANF) and some other variables in normotensive offspring of Received March 23, 1990. Address all correspondence and requests for reprints to: Peter Weidmann, M.D., Medizinische Universitatspoliklinik, Freiburgstrasse 3, 3010 Bern/Switzerland. * This work was supported in part by the Swiss National Science Foundation. 944
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 13 November 2015. at 07:48 For personal use only. No other uses without permission. . All rights reserved.
ANF DEFICIENCY IN HYPERTENSION-PRONE MAN essential hypertensive parents attending our clinic as regular out-patients, also from the clinic records; 2) the historical information was further validated by direct questioning of all parents; 3) the BP of the parents was determined by one of the authors; and 4) in the hypertensive parents, secondary forms of hypertension were excluded with usual tests. A negative family history for essential hypertension was recorded when neither parent and none of the siblings of the subjects had experienced any previous episodes of high BP or myocardial or cerebral ischemic disease, and the current BP was also normal; the latter averaged in normotensive mothers and fathers 126/ 82 ± 4/2 (±SEM) and 130/85 ± 3/1 mm Hg, respectively. All young men with a positive family history had 1 parent with essential hypertension; the untreated BP in the hypertensive parents averaged 178/111 ± 6/3 mm Hg. Subjects with an uncertain family history were excluded from the study. All participants gave their written informed consent to undergo the following special investigations (parts 1-3 below). Part 1. Plasma immunoreactive ANF (irANF) and other variables were assessed at several time points of a detailed and carefully supervised dietary protocol under ambulatory conditions. Measurements were performed in all subjects after 4 days of mild dietary sodium restriction (70 mmol/day), 4 days of high sodium intake (350 mmol/day), and after furosemide administered on the fifth day of high sodium intake. During the entire study period, the intake of potassium (70 mmol/day) and calories (2200 Cal/day) was kept constant, alcohol was avoided, and the subjects were instructed to maintain their usual physical activity. During the phase of dietary sodium restriction, a 24-h urine for determination of sodium, potassium, and creatinine was collected from 0800 h on day 4 to 0800 h on day 5. On the morning of day 5, after overnight fasting, body weight was recorded, and an indwelling cannula was inserted at 0800 h in an antecubital vein for blood sampling. After an equilibration period of 1 h in the supine position, BP, heart rate (HR), and plasma sodium, potassium, creatinine, irANF, aldosterone, renin activity, and catecholamine levels were determined. Thereafter, the subjects started the high sodium intake. At 0800 h on day 4, an oral dose of 24Na (60 jitCi) was administered for determination of exchangeable body sodium (9). From 0800 h on day 4 to 0800 h on day 5, a 24-h urine was collected for the determination of sodium (23Na and 24Na), potassium, and creatinine excretion rates. On the morning of day 5, after overnight fasting, body weight was recorded, and an indwelling cannula was inserted at 0800 h in an antecubital vein. After an equilibration period of 1 h in the supine position BP, HR, hematocrit, and plasma sodium (23Na and 24Na), potassium, creatinine, irANF, aldosterone, renin activity, and catecholamine levels were determined. Thereafter, 20 mg furosemide were injected iv. BP and HR were recorded every 30 min; 120 min after furosemide administration, blood samples were drawn for determination of plasma catecholamines and irANF, and the corresponding 2-h urine collection for determination of sodium, potassium, and creatinine excretion rates was completed. A separate urine collection was continued during the subsequent 22 h until 0800 h on day 6. At 0800 h on day 5, 40 mg furosemide were
945
administered orally. On the morning of day 6, after overnight fast, body weight was registered, and an indwelling cannula was inserted into an antecubital vein. After an equilibration period of 1 h in the supine position, BP, HR, and plasma sodium, potassium, creatinine, irANF, aldosterone, renin activity, and catecholamines were determined. Part 2. Eight ONorm (age, 24 ± 1 yr) and 8 OHyp (age, 24 ± 1 yr) were further evaluated. After 4 days of a fixed diet with a daily intake of 130 mmol sodium, 70 mmol potassium, and 2200 Cal, plasma irANF and some renal function parameters were investigated before, during, and after an acute iv load of 0.9% saline. On day 4, a 24-h urine sample was collected for determination of sodium, potassium, and creatinine excretion rates; at 2000 h the subjects ingested 12.2 mmol lithium (450 mg lithium carbonate). Thereafter, they abstained from all fluids containing methylxanthines. On the morning of day 5, after overnight fasting, body weight was recorded, and indwelling iv cannulas were inserted at 0700 h for sampling and the saline infusion. After a 1-h equilibration period in the supine position, basal values of BP, HR, and plasma irANF and lithium were obtained. Thereafter, the subjects emptied their bladder to complete the 24-h urine collection. To induce diuresis, 1 L tap water was then administered orally, and urine collections were performed for six periods of 60 min each, blood being drawn twice during each clearance period, one halfway and one just before emptying the bladder. After two control periods, 2 L NaCl 0.9% were administered iv into an antecubital vein, contralateral from the arm for peripheral venous sampling, and delivered at a constant infusion rate of 22 mL/min during 90 min. Blood samples were collected for the determination of plasma electrolytes, lithium, and irANF, and urine samples for the determination of volume, electrolytes, and lithium excretion rates. Part 3. All subjects included in part 2 underwent, with an interval of at least 3 days, an iv infusion of norepinephrine. After an overnight fast, 5% dextrose was infused slowly (0.1 mL/min, iv) for 45 min, and BP, HR, hematocrit, plasma sodium, potassium, creatinine, norepinephrine (NE), and epinephrine (E) were measured after this equilibration period. The dextrose infusion then was replaced by an infusion of /-NE bitartrate in 5% dextrose, which was infused in increasing doses of 120, 245, and 590 pmol/kg BWmin and, if the NE-induced increase in mean BP did not reach 20 mm Hg, at rates of 1180 and 2360 pmol/kg-min, each for 20 min. During the last 10 min of each infusion period, HR and BP were recorded every minute. At the end of each infusion period, blood was sampled from the contralateral arm for determination of plasma NE, E, and irANF. Study on liberal sodium intake Ninety-six young healthy subjects, including 51 ONorm (43 males and 8 females) and 45 OHyp (38 males and 7 females), were studied. The groups were matched for age (23 ± 1 and 23 ± 1 yr), height (177 ± 1 and 178 ± 1 cm), and body surface (1.87 ± 0.02 and 1.86 ± 0.03 m2). All were volunteers in excellent physical and mental condition. Inclusion criteria concerning the family history of essential hypertension were similar to
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 13 November 2015. at 07:48 For personal use only. No other uses without permission. . All rights reserved.
FERRARI ET AL.
946
those previously described. BP in normotensive mothers and fathers averaged 122/76 ± 2/1 and 131/81 ± 3/1 mm Hg, respectively. In the hypertensive parents, the untreated BP averaged 171/105 ± 4/3 mm Hg. The subjects were advised to maintain their usual lifestyle and diet. They gave their oral informed consent to undergo the following. After overnight fasting, body weight was recorded, and subjects emptied their bladder at 0800 h. Thereafter, an indwelling cannula was inserted in an antecubital vein for blood sampling. After an equilibration period of 1 h in the supine position, BP, HR, and plasma sodium, potassium, creatinine, and irANF were determined. Twenty-four-hour urines were collected for determination of urinary sodium and creatinine excretion rates. In 32 ONorm and 32 OHyp, 2 consecutive 24-h urines were collected for evaluation of intraindividual variation in sodium and creatinine excretion. Analytical methods BP was determined with standard cuff and sphygmomanometer; the mean of three recordings was used for analysis. Plasma and urinary sodium and potassium were measured by flame photometer, creatinine by autoanalyzer (Greiner SA, Langenthal, Switzerland), PRA and plasma aldosterone levels by RIA (10, 11), and plasma NE and E by high performance liquid chromatography (Waters, Milford, MA) with electrochemical detection (12, 13). Plasma irANF was determined by RIA, as reported previously from this laboratory (14, 15). During the course of the present study the intraassay variation was 9.9%; the interassay variation for values in the range of 13-55 fmol/ L was 10.5% (n = 30). All plasma values were calculated from an extracted standard curve after correction for nonspecific binding of tracer. An approximate estimate of the reabsorption of sodium from the proximal renal tubule was derived from the difference between clearances of creatinine and lithium, and an estimate of the distal tubular sodium reabsorption was derived from the difference between the clearances of lithium and sodium (16, 17). Statistical analysis was performed with the help of the Statistical Analysis System software package (version OS 5.0, SAS Institute, Inc., Cary, NC). Methods included analysis of variance and covariance complemented by Student-Newman-Keuls t test for comparison between repeated measurements. Values are given as the mean ± SEM. Since natural logarithmic transformation rather than absolute values followed a Gaussian distribution, the transformed values of PRA, aldosterone, NE, E, and irANF levels were used for statistical analysis.
Results Studies on defined sodium intakes Low sodium diet. After 4 days of 70 mmol/day sodium, body surface [1.86 ± 0.04 m2 in ONorm; 1.91 ± 0.03 m2 in OHyp (±SEM)], supine mean BP (95 ± 2 and 94 ± 2 mm Hg), plasma sodium (141 ± 1 and 141 ± 1 mmol/L), and plasma potassium (4.15 ± 0.1 and 4.03 ± 0.1 mmol/ L) did not differ between ONorm and OHyp. Twenty-
JCE & M • 1990 Vol 71 • No 4
four-hour urinary sodium excretion (54 ± 9 and 66 ± 8 mmol), plasma irANF (8.7 ± 0.7 and 9.0 ± 1.3 fmol/L), and aldosterone (416 ± 55 and 360 ± 55 pmol/L) also did not differ (Fig. 1). Plasma NE, E (103 ± 22 and 82 ± 16 pmol/L), and PRA tended to be lower in OHyp (P < 0.05). High sodium diet. After 4 days of high sodium intake (350 mmol/day), body surface (1.88 ± 0.03 and 1.92 ± 0.04 m2), mean BP (95 ± 2 and 96 ± 3 mm Hg), plasma sodium (140 ± 1 and 141 ± 0 mmol/L) and plasma potassium (4.08 ±0.1 and 3.98 ±0.1 mmol/L), exchangeable sodium (3.12 ± 0.04 and 3.04 ± 0.03 mol), and 24-h sodium excretion (276 ± 22 and 334 ± 38 mmol) did not differ significantly between ONorm and OHyp. Plasma irANF increased significantly in ONorm (P < 0.001), but not in OHyp (Fig. 1). Plasma irANF on high sodium intake was lower in OHyp than in ONorm (11.7 ± 1.7 and 18.3 ± 1.7 fmol/L; P < 0.01). Considering individual subjects, plasma irANF responded to the change from a
Sodium Intake Restricted 20n
High
High + Furosemide
Plasma irANF (fmol/l) **r P
Vol. 71, No. 4 Printed in U.S.A.
Dysregulation of Atrial Natriuretic Factor in Hypertension-Prone Man* PAOLO FERRARI, PETER WEIDMANN, CLAUDIA FERRIER, ROLAND DIETLER, RALPH HOLLMANN, REIN JAN PISO, JOSEPH WEY, AND SIDNEY SHAW Medizinische Poliklinik, University of Berne, Berne, Switzerland
ABSTRACT. To evaluate the hypothesis of an atrial natriuretic factor (ANF) deficiency in hypertension-prone humans, we investigated plasma ANF and other variables in 116 white offspring of normotensive parents (ONorm) or essential hypertensive parents (OHyp). Ten ONorm and 10 OHyp, all men matched for age and body habitus, were studied after 4 days of low (70 mmol/day) and high (350 mmol/day) dietary sodium intake. After mild sodium restriction, plasma ANF did not differ between ONorm and OHyp (9.7 ± 0.7 vs. 9.0 ± 1.3 fmol/L). On high sodium intake, plasma ANF increased in ONorm, but not in OHyp (to 18.3 ± 1.7 vs. 11.7 ± 1.7 fmol/L; P < 0.001). On the other hand, acute responses of plasma immunoreactive ANF (irANF) to saline loading or a norepinephrine-induced rise in blood pressure did not differ significantly between 8 ONorm and 8 OHyp. Fifty-one additional ONorm and 45 OHyp were evaluated during liberal sodium intake. Groups were further subdivided according to whether 24-h urinary sodium excretion was 91 mmol/m2 or less (modest salt intake) or more than 91 mmol/
T
HE PATHOGENESIS of essential hypertension involves hereditary disturbance(s). Vascular hyperreactivity to norepinephrine occurs commonly in yet normotensive offspring of essential hypertensive parents (1, 2). Moreover, an impaired capacity of the kidneys to excrete sodium (3, 4) could result from a deficiency in and/or a decreased renal response to endogenous natriuretic factor(s). The excessive dietary sodium intake of modern man compared with his ancestors necessitates a powerful compensatory mechanism. In normal humans, circulating atrial natriuretic factor (ANF) increases during sodium loading or acute rises in blood pressure (BP) and is thought, although yet not proven, to be an endogenous modulator of natriuresis, vascular reactivity to pressor agents, and BP (5-7).
m2 (high salt intake). Twenty-four-hour urinary sodium was similar in the 26 ONorm and 21 OHyp on a modest salt intake (121 ± 6 vs. 116 ± 9 mmol) and in the 25 ONorm and the 24 OHyp on a high salt intake (226 ± 10 vs. 221 ± 9 mmol). However, compared with ONorm, plasma irANF in OHyp was slightly lower on modest sodium intake (7.7 ± 0.7 vs. 5.3 ± 0.7 fmol/L; P < 0.05) and markedly reduced on high sodium intake (15.0 ± 1.3 vs. 8.0 ± 1.3 fmol/L; P < 0.001). Moreover, the slope of the relationship between plasma irANF and 24-h urinary sodium was flatter in OHyp than in ONorm (z test = 2.4). We postulate a new endocrine syndrome characterized by a relative plasma ANF deficiency during high sodium intake in some hypertension-prone humans. This functional defect becomes apparent during chronic, rather than acute, stimulation of ANF release. It occurs as a familial disturbance and may potentially predispose to the development of hypertension, (j Clin Endocrinol Metab 7 1 : 944-951, 1990)
normotensive parents compared with those in agematched normotensive offspring of hypertensive parents. One series of studies was performed after 4 days of fixed sodium intakes, including 70,130, and 350 mmol sodium/ day. Some of these data have been presented in preliminary form (8). To further assess the ANF-sodium relationship under the influence of individual dietary habits, an additional, larger group of offspring was studied during liberal sodium intake. Materials and Methods Studies on defined sodium intakes Two age-matched (age ± SEM, 25 ± 1 yr) of healthy young men were studied. One group included 10 offspring of normotensive parents (ONorm); the other group 10 offspring, 1 of whose parents had essential hypertension (OHyp). All subjects were volunteers in excellent physical and mental condition, with a BP consistently below 140/90 mm Hg; none was taking any drugs. Written informed consent was obtained to assess the family history of essential hypertension by the following strict approach: 1) information on BP, the use of antihypertensive drugs, and cardiovascular complications in parents and any siblings was obtained from the family doctors and, in
To test the hypothesis of a familial ANF deficiency, we investigated plasma immunoreactive ANF (irANF) and some other variables in normotensive offspring of Received March 23, 1990. Address all correspondence and requests for reprints to: Peter Weidmann, M.D., Medizinische Universitatspoliklinik, Freiburgstrasse 3, 3010 Bern/Switzerland. * This work was supported in part by the Swiss National Science Foundation. 944
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 13 November 2015. at 07:48 For personal use only. No other uses without permission. . All rights reserved.
ANF DEFICIENCY IN HYPERTENSION-PRONE MAN essential hypertensive parents attending our clinic as regular out-patients, also from the clinic records; 2) the historical information was further validated by direct questioning of all parents; 3) the BP of the parents was determined by one of the authors; and 4) in the hypertensive parents, secondary forms of hypertension were excluded with usual tests. A negative family history for essential hypertension was recorded when neither parent and none of the siblings of the subjects had experienced any previous episodes of high BP or myocardial or cerebral ischemic disease, and the current BP was also normal; the latter averaged in normotensive mothers and fathers 126/ 82 ± 4/2 (±SEM) and 130/85 ± 3/1 mm Hg, respectively. All young men with a positive family history had 1 parent with essential hypertension; the untreated BP in the hypertensive parents averaged 178/111 ± 6/3 mm Hg. Subjects with an uncertain family history were excluded from the study. All participants gave their written informed consent to undergo the following special investigations (parts 1-3 below). Part 1. Plasma immunoreactive ANF (irANF) and other variables were assessed at several time points of a detailed and carefully supervised dietary protocol under ambulatory conditions. Measurements were performed in all subjects after 4 days of mild dietary sodium restriction (70 mmol/day), 4 days of high sodium intake (350 mmol/day), and after furosemide administered on the fifth day of high sodium intake. During the entire study period, the intake of potassium (70 mmol/day) and calories (2200 Cal/day) was kept constant, alcohol was avoided, and the subjects were instructed to maintain their usual physical activity. During the phase of dietary sodium restriction, a 24-h urine for determination of sodium, potassium, and creatinine was collected from 0800 h on day 4 to 0800 h on day 5. On the morning of day 5, after overnight fasting, body weight was recorded, and an indwelling cannula was inserted at 0800 h in an antecubital vein for blood sampling. After an equilibration period of 1 h in the supine position, BP, heart rate (HR), and plasma sodium, potassium, creatinine, irANF, aldosterone, renin activity, and catecholamine levels were determined. Thereafter, the subjects started the high sodium intake. At 0800 h on day 4, an oral dose of 24Na (60 jitCi) was administered for determination of exchangeable body sodium (9). From 0800 h on day 4 to 0800 h on day 5, a 24-h urine was collected for the determination of sodium (23Na and 24Na), potassium, and creatinine excretion rates. On the morning of day 5, after overnight fasting, body weight was recorded, and an indwelling cannula was inserted at 0800 h in an antecubital vein. After an equilibration period of 1 h in the supine position BP, HR, hematocrit, and plasma sodium (23Na and 24Na), potassium, creatinine, irANF, aldosterone, renin activity, and catecholamine levels were determined. Thereafter, 20 mg furosemide were injected iv. BP and HR were recorded every 30 min; 120 min after furosemide administration, blood samples were drawn for determination of plasma catecholamines and irANF, and the corresponding 2-h urine collection for determination of sodium, potassium, and creatinine excretion rates was completed. A separate urine collection was continued during the subsequent 22 h until 0800 h on day 6. At 0800 h on day 5, 40 mg furosemide were
945
administered orally. On the morning of day 6, after overnight fast, body weight was registered, and an indwelling cannula was inserted into an antecubital vein. After an equilibration period of 1 h in the supine position, BP, HR, and plasma sodium, potassium, creatinine, irANF, aldosterone, renin activity, and catecholamines were determined. Part 2. Eight ONorm (age, 24 ± 1 yr) and 8 OHyp (age, 24 ± 1 yr) were further evaluated. After 4 days of a fixed diet with a daily intake of 130 mmol sodium, 70 mmol potassium, and 2200 Cal, plasma irANF and some renal function parameters were investigated before, during, and after an acute iv load of 0.9% saline. On day 4, a 24-h urine sample was collected for determination of sodium, potassium, and creatinine excretion rates; at 2000 h the subjects ingested 12.2 mmol lithium (450 mg lithium carbonate). Thereafter, they abstained from all fluids containing methylxanthines. On the morning of day 5, after overnight fasting, body weight was recorded, and indwelling iv cannulas were inserted at 0700 h for sampling and the saline infusion. After a 1-h equilibration period in the supine position, basal values of BP, HR, and plasma irANF and lithium were obtained. Thereafter, the subjects emptied their bladder to complete the 24-h urine collection. To induce diuresis, 1 L tap water was then administered orally, and urine collections were performed for six periods of 60 min each, blood being drawn twice during each clearance period, one halfway and one just before emptying the bladder. After two control periods, 2 L NaCl 0.9% were administered iv into an antecubital vein, contralateral from the arm for peripheral venous sampling, and delivered at a constant infusion rate of 22 mL/min during 90 min. Blood samples were collected for the determination of plasma electrolytes, lithium, and irANF, and urine samples for the determination of volume, electrolytes, and lithium excretion rates. Part 3. All subjects included in part 2 underwent, with an interval of at least 3 days, an iv infusion of norepinephrine. After an overnight fast, 5% dextrose was infused slowly (0.1 mL/min, iv) for 45 min, and BP, HR, hematocrit, plasma sodium, potassium, creatinine, norepinephrine (NE), and epinephrine (E) were measured after this equilibration period. The dextrose infusion then was replaced by an infusion of /-NE bitartrate in 5% dextrose, which was infused in increasing doses of 120, 245, and 590 pmol/kg BWmin and, if the NE-induced increase in mean BP did not reach 20 mm Hg, at rates of 1180 and 2360 pmol/kg-min, each for 20 min. During the last 10 min of each infusion period, HR and BP were recorded every minute. At the end of each infusion period, blood was sampled from the contralateral arm for determination of plasma NE, E, and irANF. Study on liberal sodium intake Ninety-six young healthy subjects, including 51 ONorm (43 males and 8 females) and 45 OHyp (38 males and 7 females), were studied. The groups were matched for age (23 ± 1 and 23 ± 1 yr), height (177 ± 1 and 178 ± 1 cm), and body surface (1.87 ± 0.02 and 1.86 ± 0.03 m2). All were volunteers in excellent physical and mental condition. Inclusion criteria concerning the family history of essential hypertension were similar to
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 13 November 2015. at 07:48 For personal use only. No other uses without permission. . All rights reserved.
FERRARI ET AL.
946
those previously described. BP in normotensive mothers and fathers averaged 122/76 ± 2/1 and 131/81 ± 3/1 mm Hg, respectively. In the hypertensive parents, the untreated BP averaged 171/105 ± 4/3 mm Hg. The subjects were advised to maintain their usual lifestyle and diet. They gave their oral informed consent to undergo the following. After overnight fasting, body weight was recorded, and subjects emptied their bladder at 0800 h. Thereafter, an indwelling cannula was inserted in an antecubital vein for blood sampling. After an equilibration period of 1 h in the supine position, BP, HR, and plasma sodium, potassium, creatinine, and irANF were determined. Twenty-four-hour urines were collected for determination of urinary sodium and creatinine excretion rates. In 32 ONorm and 32 OHyp, 2 consecutive 24-h urines were collected for evaluation of intraindividual variation in sodium and creatinine excretion. Analytical methods BP was determined with standard cuff and sphygmomanometer; the mean of three recordings was used for analysis. Plasma and urinary sodium and potassium were measured by flame photometer, creatinine by autoanalyzer (Greiner SA, Langenthal, Switzerland), PRA and plasma aldosterone levels by RIA (10, 11), and plasma NE and E by high performance liquid chromatography (Waters, Milford, MA) with electrochemical detection (12, 13). Plasma irANF was determined by RIA, as reported previously from this laboratory (14, 15). During the course of the present study the intraassay variation was 9.9%; the interassay variation for values in the range of 13-55 fmol/ L was 10.5% (n = 30). All plasma values were calculated from an extracted standard curve after correction for nonspecific binding of tracer. An approximate estimate of the reabsorption of sodium from the proximal renal tubule was derived from the difference between clearances of creatinine and lithium, and an estimate of the distal tubular sodium reabsorption was derived from the difference between the clearances of lithium and sodium (16, 17). Statistical analysis was performed with the help of the Statistical Analysis System software package (version OS 5.0, SAS Institute, Inc., Cary, NC). Methods included analysis of variance and covariance complemented by Student-Newman-Keuls t test for comparison between repeated measurements. Values are given as the mean ± SEM. Since natural logarithmic transformation rather than absolute values followed a Gaussian distribution, the transformed values of PRA, aldosterone, NE, E, and irANF levels were used for statistical analysis.
Results Studies on defined sodium intakes Low sodium diet. After 4 days of 70 mmol/day sodium, body surface [1.86 ± 0.04 m2 in ONorm; 1.91 ± 0.03 m2 in OHyp (±SEM)], supine mean BP (95 ± 2 and 94 ± 2 mm Hg), plasma sodium (141 ± 1 and 141 ± 1 mmol/L), and plasma potassium (4.15 ± 0.1 and 4.03 ± 0.1 mmol/ L) did not differ between ONorm and OHyp. Twenty-
JCE & M • 1990 Vol 71 • No 4
four-hour urinary sodium excretion (54 ± 9 and 66 ± 8 mmol), plasma irANF (8.7 ± 0.7 and 9.0 ± 1.3 fmol/L), and aldosterone (416 ± 55 and 360 ± 55 pmol/L) also did not differ (Fig. 1). Plasma NE, E (103 ± 22 and 82 ± 16 pmol/L), and PRA tended to be lower in OHyp (P < 0.05). High sodium diet. After 4 days of high sodium intake (350 mmol/day), body surface (1.88 ± 0.03 and 1.92 ± 0.04 m2), mean BP (95 ± 2 and 96 ± 3 mm Hg), plasma sodium (140 ± 1 and 141 ± 0 mmol/L) and plasma potassium (4.08 ±0.1 and 3.98 ±0.1 mmol/L), exchangeable sodium (3.12 ± 0.04 and 3.04 ± 0.03 mol), and 24-h sodium excretion (276 ± 22 and 334 ± 38 mmol) did not differ significantly between ONorm and OHyp. Plasma irANF increased significantly in ONorm (P < 0.001), but not in OHyp (Fig. 1). Plasma irANF on high sodium intake was lower in OHyp than in ONorm (11.7 ± 1.7 and 18.3 ± 1.7 fmol/L; P < 0.01). Considering individual subjects, plasma irANF responded to the change from a
Sodium Intake Restricted 20n
High
High + Furosemide
Plasma irANF (fmol/l) **r P
