(Hypertension. 1995;26:213-220.)
© 1995 American Heart Association, Inc.
Articles |
Chromogranin A in Human Hypertension
Influence of Heredity
From the Departments of Medicine and Family and Preventive Medicine, University of California, San Diego; the Department of Veterans Affairs Medical Center, San Diego; and Charles R. Drew University of Medicine and Science, Los Angeles, Calif.
Correspondence to Daniel T. O'Connor, MD, Division of Nephrology-Hypertension (9111H), University of California, San Diego, 3350 La Jolla Village Dr, San Diego, CA 92161. E-mail doconnor@ucsd.edu.
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Abstract Multiple heritable traits are associated with essential (genetic) hypertension in humans. Because chromogranin A is increased in both human and rodent genetic hypertension, we examined the influence of heredity and blood pressure on chromogranin A in humans. In estimates derived from among- and within-pair variance in monozygotic versus dizygotic twins, plasma chromogranin A displayed significant (F15,18=2.93, P=.016) genetic variance (
2g), and its broad-sense
heritability was high (h2B=0.983).
Plasma chromogranin A was increased in essential hypertension
(99.9±6.7 versus 62.8±4.7 ng/mL, P<.001) but was
influenced little by genetic risk for (family history of) hypertension
(in normotensive or hypertensive subjects), by race, or by several
antihypertensive therapies (angiotensin-converting enzyme
inhibitor, diuretic, or ß-adrenergic
antagonist). In normotensive subjects at genetic risk for
essential hypertension, neither basal nor sympathoadrenal stress-evoked
chromogranin A differed from values found in subjects not at risk. In
established essential hypertension, plasma chromogranin A responses to
adrenal medullary (insulin-evoked hypoglycemia) or sympathetic neuronal
(dynamic exercise) activation were exaggerated, whereas responses to
sympathoadrenal suppression (ganglionic blockade) were diminished,
suggesting increased vesicular stores of chromogranin A and an
adrenergic origin of the augmented chromogranin A expression in this
disorder. We conclude that plasma chromogranin A displays substantial
heritability and is increased in established essential hypertension.
Its elevation in established hypertension is associated with evidence
of increased vesicular stores of the protein and with adrenergic
hyperactivity but is influenced little by customary antihypertensive
therapies. However, the chromogranin A elevation is not evident early
in the course of genetic hypertension.
Key Words: chromogranins • hypertension, essential • adrenal medulla • genetics
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Introduction |
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There is substantial evidence for autonomic dysfunction, including excess sympathoadrenal activity, in the pathogenesis of human essential (genetic) hypertension.1 Indeed, elevation of plasma norepinephrine2 and depression of baroreflex sensitivity,3 each of which might play pathogenic roles in blood pressure elevation, have been described even in still-normotensive subjects at genetic risk for essential hypertension.
Chromogranin A, an acidic-soluble protein in adrenal medullary and sympathetic neuronal catecholamine storage vesicles,4 5 is coreleased by exocytosis with catecholamines into the bloodstream during sympathoadrenal activation in humans.6 7 8
In human essential hypertension, plasma chromogranin A is substantially elevated,9 10 and adrenal medullary chromaffin granule storage of chromogranin A is augmented in the spontaneously (genetically) hypertensive rat.11 Because both rodent spontaneous and human essential hypertension are at least in part heritable,12 13 14 15 16 we asked whether increased chromogranin A may represent a heritable "intermediate phenotype"17 associated with genetic risk of hypertension.
To explore this question, we measured plasma chromogranin A concentration in twin pairs and in subjects stratified by blood pressure status and genetic risk (family history) of essential hypertension. We also measured chromogranin A and catecholamine responses to activation and suppression of sympathoadrenal neurosecretion in subjects with normal and elevated blood pressure. Our results suggest that, while plasma chromogranin A is largely heritable and is elevated in established essential hypertension, the elevation is not seen in early association with genetic risk of essential hypertension.
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Methods |
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Subjects
The study group in San Diego, Calif, included 34 healthy normotensive volunteers (17 male, 17 female; 33 white, 1 black) and 55 subjects with essential hypertension (53 male, 2 female; 45 white, 10 black); the 89 subjects (70 male, 19 female; 78 white, 11 black) were 21 to 70 years old. Subjects were on unrestricted dietary sodium intake and were living at home (ie, they were not hospitalized) unless otherwise noted. In the hypertensive subjects, antihypertensive medications were discontinued at least 2 weeks before study unless otherwise noted. The diagnosis of essential hypertension was established by outpatient diastolic blood pressure (DBP) consistently >95 mm Hg in patients in the sitting position and exclusion of secondary forms of hypertension by history, physical examination, and screening laboratories (chemistry panel, hemogram, and urinalysis). Because chromogranin A immunoreactivity is removed in part by the kidneys,18 plasma chromogranin A is markedly elevated in renal insufficiency18 ; accordingly, subjects with serum creatinine (sCr) >1.3 mg/dL were not included in this study. Glomerular filtration rate was estimated from sCr by the Cockroft-Gault19 algorithm.
Genetic risk (positive family history) of essential hypertension was defined as documented DBP >90 mm Hg or blood pressure elevation requiring antihypertensive therapy in a first-degree relative (ie, parent, sibling, or child) before the age of 60 years.3 20 All subjects had hypertension family histories documented, if necessary, by contact with first-degree relatives or their treating physicians. If the hypertension family history of a subject could not be definitely established (eg, if the subject was adopted or if a parent had died before the usual age of onset of hypertension, before the fourth, fifth, or sixth decade), the subject was classified as having an "indeterminate" family history.
The studies were approved by the University of California, San Diego, Human Subjects Committee, and all subjects gave written informed consent.
Subjects were studied in the morning after an overnight fast unless otherwise noted. Blood samples were drawn through a heparin-lock catheter placed into a forearm vein 30 minutes before a study. Plasma was separated and stored at -70°C until assayed.
Chromogranin A: Effect of Heredity
Blood samples for chromogranin A determination were collected
from 22 pairs of normotensive adult twins, both monozygotic (MZ; n=11
pairs; 2 female, 9 male; age, 28±2 years) and dizygotic (DZ; n=11
pairs; 2 female, 9 male; age, 33±3.6 years). The twins, all natives of
Barbados,21 were originally of African ancestry.
There are several ways of estimating heritability of a trait from twin
data.22 23 Broad-sense heritability
(h2B) of plasma chromogranin A
concentration was estimated in this study by the method outlined by
Khoury et al22 using one-way analysis of
among-pair and within-pair variance of the trait computed on MZ and DZ
twins separately. To minimize the effects of differences in similarity
of environments of MZ versus DZ twin pairs (ie, unequal environmental
covariances between MZ and DZ twins), we used the
among-components approach22 to test (exclude) the null
hypothesis that the genetic variance was zero
(2g=0) and to estimate broad-sense
heritability.
Chromogranin A: Effects of Antihypertensive Therapies
Blood samples were collected in otherwise untreated essential
hypertensive outpatients before and after antihypertensive monotherapy
by oral administration of captopril (50 to 150 mg/d for 6 weeks; n=7
white men), hydrochlorothiazide (25 to 50 mg/d for 6
weeks; n=9 subjects; 8 white men, 1 black man), propranolol
(80 to 240 mg/d for 6 weeks; n=11 white men), enalapril (10 to 40 mg/d
for 12 weeks; n=8 subjects; 7 white men, 1 black man), or metoprolol
(50 to 150 mg/d for 6 weeks; n=8 subjects; 1 white woman, 7 white men).
Drug doses were increased (within the stated range) until seated DBP
decreased to <90 mm Hg or until unacceptable side effects were
reported. For salt restriction,24 23 (18 white, 5 black)
otherwise unmedicated essential hypertensive inpatients in a
metabolic ward were maintained on a 150-mEq/d sodium diet
for 5 days and then a 30-mEq/d sodium diet for 5 days. Plasma was
assayed for chromogranin A.
Adrenal Medullary Chromogranin A: Release by Insulin-Evoked
Hypoglycemia
During insulin-evoked hypoglycemia, the source of the increment
in plasma chromogranin A is the adrenal medulla.3 4 5 6 7 8 25 To
release adrenal medullary chromogranin A stores,3 4 5
hypoglycemia was induced in supine hypertensive and normotensive
subject groups by intravenous regular human insulin
(Humulin, Eli Lilly; 0.15 U/kg body wt). Blood samples were collected
immediately before and 30, 60, 90, and 120 minutes after insulin
administration. Collected blood was assayed for glucose, chromogranin
A, and catecholamines.
In addition, a subgroup of normotensive subjects, stratified by documented family history of hypertension, was also studied during insulin-evoked hypoglycemia.3 4 5
Sympathetic Neuronal Chromogranin A: Release by Short-term
Dynamic Exercise
During active, dynamic exercise, postganglionic sympathetic
axons are the source of the increment in plasma chromogranin
A.3 4 5 6 8 To provoke release of sympathetic neuronal
chromogranin A stores,3 4 5 6 8 hypertensive and normotensive
subject groups underwent graded dynamic exercise on a calibrated
bicycle ergometer (Monark Industries). The initial energy expenditure
was 50 W for 3 minutes, which was increased by 50 W at each 3-minute
stage until the study goal (200 W) was achieved. Blood pressure and
heart rate were measured and blood was sampled before and at the end of
exercise. Blood was assayed for chromogranin A and
catecholamines.
Sympathetic Neuronal Chromogranin A: Suppression of Release by
Ganglionic Blockade
Supine hypertensive and normotensive subject groups were studied
as previously described.25 Baseline blood samples were
drawn twice. A solution of the ganglionic blocker (nicotinic
cholinergic antagonist) trimethaphan (Arfonad, Roche
Laboratories) in 5% dextrose in water was infused over 1 hour.
Trimethaphan infusion was begun at a rate of 50 mg/h (0.83 mg/min) and
adjusted rapidly (over 10 minutes) until a decrease of 20 mm Hg in DBP
was achieved. Blood samples were collected before, during, and after
infusion. Blood was assayed for chromogranin A,
catecholamines, and total protein concentration. Blood
pressure and heart rate were determined before, during, and after the
infusion.
Assays
Human chromogranin A was quantified by a soluble-phase,
double-antibody, homologous-species radioimmunoassay as previously
described.26 27 The assay had intra-assay and interassay
coefficients of variation of 4.2% and 8.2%,
respectively.26 For explicit comparisons (eg, hypertensive
versus normotensive subjects; control versus drug treatment),
contrasted groups were evaluated in the same chromogranin A assay.
Plasma catecholamines (norepinephrine and
epinephrine) were measured radioenzymatically.28
Plasma glucose was measured by the glucose oxidase method in a glucose
analyzer (Beckman Instruments).29 Protein
concentration was measured by the method of Lowry et
al.30
Statistics
Results are expressed as mean±SEM. Heritability
estimations22 are outlined above. One-way ANOVA with
repeated measures was used to analyze intragroup changes over
time. Two-way ANOVA with a Bonferroni post hoc test was used for
intergroup comparisons. Simultaneous model multiple
regression analysis was performed to assess the effect of blood
pressure status and family history of hypertension on plasma
chromogranin A. Statistical analyses were performed with
SYSTAT computing programs (SYSTAT, DOS version) on an
IBM-compatible 386-chip microcomputer. Statistical significance was
construed at a value of P<.05.
Results are converted to Système International units (refer to figure and table legends).
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Results |
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Effects of Heredity, Hypertension, Genetic Risk for High Blood Pressure, and Race on Basal Chromogranin A
Using the ANOVA method22 on the MZ and DZ twins' chromogranin A data, we rejected (F15,18=2.93, P=.016) the null hypothesis that there was no genetic component to the variance of chromogranin A (ie,
2g=0). The broad-sense heritability
estimate was h2B=0.983. Within-twin
pair correlations for chromogranin A were r=.735
(P=8.7x10-5; 95% confidence interval,
r=.355 to .942) for 11 monozygotic twin pairs, and
r=.0531 (P=.81) for 11 dizygotic twin pairs. Normotensive and hypertensive subjects differed significantly (99.9±6.7 versus 62.8±4.7 ng/mL, P<.001) in mean chromogranin A concentration (Table 1). Chromogranin A concentration was not associated with genetic risk for or family history of hypertension in either hypertensive or normotensive subjects (Table 2).
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To explore whether chromogranin A is determined by interactions between blood pressure status and genetic risk of hypertension, multiple linear regression was used (Table 3). Blood pressure status was clearly the more important determinant of chromogranin A (P<.001); indeed, there was a nonsignificant (P=.086) trend toward lower chromogranin A in subjects with family histories of hypertension.
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Because normotensive and hypertensive groups differed (P<.001) in mean age (Table 1) and the normotensive family history subgroups (Table 2) also differed in age (P=.004), we evaluated the effect of age on chromogranin A; there was no correlation between age and chromogranin A in control subjects (n=34; r=.019, P=.915), confirming earlier observations of age independence of chromogranin A.27 31
White (n=45) and black (n=10) hypertensive patients did not differ in chromogranin A concentration (98±8 versus 108±15 ng/mL, P=.557), age (60±1 versus 56±2 years, P=.239), body mass index (29±1 versus 29±2 kg/m2, P=.802), or glomerular filtration rate (89±3 versus 86±5 mL/min, P=.690).
Effect of Antihypertensive Therapies on Chromogranin
A
Chromogranin A concentration was unaltered in essential
hypertension during antihypertensive treatment (monotherapy) with
angiotensin-converting enzyme inhibition (with captopril or
enalapril), ß-adrenergic blockade (with propranolol or
metoprolol), the diuretic hydrochlorothiazide,
or dietary sodium restriction (P>.1 in each case; data not
shown).
Adrenal Medullary Chromogranin A Releasable Pool
Hypertensive Versus Normotensive Subjects
Hypertensive and normotensive subjects did not differ in
basal glucose concentration (P=.258; Fig 1).
Insulin administration induced greater (P=.014)
absolute decrements in blood glucose in normotensive (66±1.7 mg/dL)
than in hypertensive subjects (54±5 mg/dL). Plasma epinephrine
rose 22±7- versus 15±6-fold (P=.457) in normotensive and
hypertensive subjects, respectively, while plasma
norepinephrine rose 1.8± 0.2- versus 2.1±0.4-fold
(P=.509). Despite similar changes in
catecholamines, normotensive and hypertensive subjects
differed significantly (P=.023) in chromogranin A response
to adrenal medullary activation, with chromogranin A rising 1.2±0.06-
versus 1.5±0.1-fold, respectively.
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; 2 black, 6 white; 4 with positive family history
for hypertension, 4 with indeterminate family history of hypertension;
age, 39±1 years; BMI, 32±1 kg/m2; systolic blood pressure
[SBP], 122±5 mm Hg; diastolic blood pressure [DBP],
77±3 mm Hg) and 10 unmedicated essential hypertensive subjects
(
; 3 black, 7 white; all with positive family history of
hypertension; age, 36±3 years; BMI, 32±2 kg/m2; SBP,
147±5 mm Hg; DBP, 96±3 mm Hg). Data were analyzed by
two-way ANOVA for repeated measures. *P<.05 for
hypertensive patients (vs baseline). 
P<.05 for
normotensive subjects (vs baseline). 
P<.05 for fold rise
in chromogranin A, comparing hypertensive and normotensive subjects. To
convert blood glucose to mmol/L, multiply by 0.05551. To convert plasma
norepinephrine values to nmol/L, multiply by 0.005911. To
convert plasma epinephrine values to pmol/L, multiply by 5.458.
To convert plasma chromogranin A to µg/L, multiply by 1.0.
Normotensive Subjects Stratified by Genetic Risk of
Hypertension
As Table 4 shows, normotensive subjects with
positive family histories of hypertension (FH[+]) had higher baseline
blood glucose than subjects with negative family histories of
hypertension (FH[-]) (89±5 versus 76±3 mg/dL, P=.033).
After insulin administration, the absolute decline in glucose
concentration from baseline was not different between FH[-] and
FH[+] subjects (58±2 versus 59±4 mg/dL, P=.796).
Epinephrine rose 22.2±5.9- versus 12.1±4.2-fold
(P=.375) in FH[-] and FH[+] subjects, respectively,
while norepinephrine rose 1.46±0.22- versus 1.91±1.2-fold
(P=.345). Chromogranin A rose 1.69±0.14- versus
1.31±0.13-fold in FH[-] versus FH[+] subjects; indeed, the trend
(P=.075) was toward greater chromogranin A release in the
FH[-] subgroup.
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Sympathetic Neuronal Stimulation
Hypertensive Versus Normotensive Subjects
All subjects achieved the study goal of energy expenditure (200
W). Active, dynamic exercise (Fig 2) resulted in a
greater rise in heart rate (2.5±0.2- versus 1.95±0.1-fold,
P=.031) and in plasma epinephrine (6.1±1.3- versus
2.4±0.9-fold, P=.053) in normotensive than in hypertensive
subjects, while the rise in plasma norepinephrine was
comparable (6.2±1.4- versus 4.7±1.2-fold, P=.429). By
contrast, chromogranin A rose to a greater degree in hypertensive than
in normotensive subjects (1.5±0.1- versus 1.1±0.03-fold,
P=.01).
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Sympathetic Neuronal Suppression by Ganglionic
Blockade
Hypertensive Versus Normotensive Subjects
The total amount of trimethaphan infused to diminish DBP by 20
mm Hg over a 1-hour time course did not differ between hypertensive
and normotensive subjects (154±35 versus 178±22 mg,
P=.57). In each group, both systolic pressure and DBP
decreased (P<.05), while pulse rate increased
(P<.05) during ganglionic blockade (Fig 3).
In each group, plasma norepinephrine decreased
(P<.05), sustaining its nadir at the end of the 1-hour
infusion period, while plasma epinephrine (Fig 3) and total protein concentrations (data not shown)
were unaltered. Mean percent decline in plasma
norepinephrine from baseline did not differ between
normotensive and hypertensive subjects (64±3% versus 56±5%,
P=.160). Chromogranin A decreased to a lesser degree
(P=.046) in hypertensive than in normotensive subjects, who
showed a 32±4% decline from baseline.
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Discussion |
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Many lines of evidence indicate that human essential hypertension is a complex disorder determined by both genetic and environmental factors.32 For several phenotypic traits associated with essential hypertension, such as decreased urinary kallikrein excretion,33 elevated erythrocyte sodium-lithium countertransport,34 increased intracellular sodium concentration,35 baroreflex dysfunction,3 and nonmodulation of renal and adrenal responses to angiotensin II,36 37 heritability has been established.
Numerous studies documented increased sympathetic activity in established essential hypertension, including increased plasma norepinephrine1 38 39 and increased norepinephrine spillover from synaptic clefts to plasma.1 38 39 40 41 An increase plasma chromogranin A has also been noted.10 31 42 Chromogranin A is a protein costored and coreleased by exocytosis with catecholamines,6 7 8 9 10 25 43 whose basal6 7 25 44 and stimulated6 7 8 24 25 plasma concentrations reflect exocytotic sympathoadrenal activity.6 7 25 44
Indeed, increased sympathetic activity, investigated by plasma norepinephrine concentration,45 46 47 norepinephrine spillover,41 48 or catecholamine responses,49 50 may precede the onset of hypertension in subjects at genetic risk of high blood pressure; augmented sympathetic tone may thus play an early or pathogenic role in essential hypertension.
Genetic variance and broad-sense heritability of chromogranin A were
derived22 from among-pair and within-pair variance in
twins grouped according to zygosity.21 Using the
among-components approach to minimize the effects of unequal
environmental covariances between MZ and DZ twins, we found
that plasma chromogranin A had significant (F15,18=2.93,
P=.016) 2g, with
h2B=0.983. While a variety of
methods are available for computing heritability of a trait based on
twin data22 23 and while environmental perturbations
certainly affect chromogranin A,6 7 8 18 25 26 27 our findings
certainly indicate a substantial genetic contribution to basal
(resting) plasma chromogranin A and suggest that heredity, rather than
environment, may be the major determinant of chromogranin A
concentration, at least in subjects with normal blood pressure studied
in a uniform protocol environment (the twins in this study).
In line with previous findings,51 chromogranin A was significantly higher in essential hypertensive than in normotensive subjects (Table 1). However, increased risk for high blood pressure conferred by positive family history of hypertension did not play a substantial role in chromogranin A expression (Tables 2 and 3). In the comparison of normotensive and hypertensive plasma chromogranin A values (Table 1), 51 hypertensive patients were under antihypertensive treatment, and 4 hypertensive patients were untreated. However, we previously showed elevated chromogranin A in untreated hypertensive patients.31 42 51
Is the increase in chromogranin A specific to human genetic (essential) hypertension? Chromogranin A is also elevated in subjects with pheochromocytoma but not in subjects with secondary hypertension resulting from renal artery stenosis or primary aldosteronism.10 51 Thus, its elevation is unlikely to be simply a response to hypertension, a conclusion also supported by unchanged chromogranin A values after antihypertensive treatment.
Insulin-evoked hypoglycemia stimulated release of adrenal chromogranin A stores,3 4 5 8 and the release of chromogranin A was exaggerated in patients with established hypertension (Fig 1). We previously showed that the increment in plasma chromogranin A during this stimulus is of adrenal medullary origin.7 In this study, insulin induced a greater decrement in blood glucose in normotensive than in hypertensive subjects, suggesting, as noted by others, relative insulin resistance in essential hypertension.47 Despite a lesser hypoglycemic stimulus, greater increments in chromogranin A were found in essential hypertension (Fig 1). Because hypertensive and normotensive subjects did not differ significantly in catecholamine responses, the data suggest an increased ratio of releasable chromogranin A to catecholamines in adrenal medullary storage vesicles. This apparently increased releasable chromaffin cell pool of chromogranin A in human essential hypertension is reminiscent of the report by Schober et al11 of increased stores of chromogranin A in adrenal medullary storage vesicles of the spontaneously hypertensive rat.
The magnitude of chromogranin A release after hypoglycemia in this study (Fig 1) was diminished compared with results in our previous reports6 7 25 ; in the current studies, however, the degree of hypoglycemic stimulus was also reduced (Fig 1).
Short-term, high-intensity dynamic exercise provoked sympathetic neuronal exocytotic secretion accompanied by some adrenomedullary secretion (Fig 2). We previously showed that sympathetic axons are the source of the plasma chromogranin A increment after dynamic exercise.6 8 Although the rise in catecholamines tended to be higher in normotensive subjects, chromogranin A increased to a greater degree in hypertensive subjects (P=.01). This finding also suggests augmented chromogranin A storage in established essential hypertension, but here the results point to augmented sympathetic neuronal (as opposed to adrenal chromaffin) vesicular storage.
During effective ganglionic blockade of efferent autonomic outflow (Fig 3), plasma chromogranin A was suppressed to a lesser (P<.05) degree in hypertensive than in normotensive subjects, despite a comparable decline in plasma norepinephrine. This result is also compatible with augmented sympathetic neuronal stores of chromogranin A in established hypertension (Fig 2). Simon et al52 showed that nicotinic cholinergic stimuli influence not only secretion but also biosynthesis of chromogranin A. However, the 3-day half-life of cellular chromogranin A53 would seem to preclude a meaningful nicotinic effect on chromogranin A biosynthesis in this acute study of 1 hour of nicotinic blockade (Fig 2).
Taken together, the results of adrenal medullary provocation (Fig 1), sympathetic axonal provocation (Fig 2), and sympathetic neuronal suppression (Fig 3) studies suggest increased vesicular stores of chromogranin A in established essential hypertension and an adrenergic origin of the augmented chromogranin A release in this disorder.
Normotensive subjects stratified by family history of hypertension did not differ significantly (Table 4) in adrenal catecholamine and chromogranin A responses to hypoglycemia; indeed, FH[-] subjects showed marginally (P=.075) greater chromogranin A release after a comparable (decrement of 59±2 versus 59±4 mg/dL) hypoglycemic stimulus. This result suggests that, unlike patients with established essential hypertension, still-normotensive subjects at genetic risk26 27 of developing high blood pressure do not already have an augmented adrenomedullary storage pool of releasable chromogranin A.
Thus, despite the significant (F15,18=2.93, P=.016) genetic variance and substantial heritability (h2B=0.983) of plasma chromogranin A, its increased storage and release in established essential hypertension, and the adrenergic origin of this increase, chromogranin A is not closely coupled to genetic risk of hypertension, because its increased plasma concentration is not seen in the earliest or pathogenic phase of essential hypertension. Thus, chromogranin A is unlikely to be an informative early "intermediate phenotype" in human hereditary hypertension.
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Acknowledgments |
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This work was supported by the Department of Veterans Affairs, the National Institutes of Health (HL-43275 [Dr Takiyyuddin], HL-50174 [Dr Parmer], and HL-46366 and HL-35018 [Dr O'Connor]), the American Heart Association (Dr Parmer), and the National Kidney Foundation (Dr Takiyyuddin). We appreciate the technical assistance of Annie Chen, Larry Petz, and Xiao-Ping Xi.
Received October 21, 1994; first decision December 21, 1994; accepted April 10, 1995.
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References |
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1. Goldstein DS, Kopin IJ. The autonomic nervous system and catecholamines in normal blood pressure control and in hypertension. In: Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis and Management. New York, NY: Raven Press Publishers; 1990:chap 7.
2. Ferrier C, Cox H, Esler M. Elevated total norepinephrine spillover in normotensive members of hypertensive families. Clin Sci. 1993;84:225-230. [Medline] [Order article via Infotrieve]
3.
Parmer RJ, Cervenka JH, Stone RA. Baroreflex
sensitivity and heredity in essential hypertension.
Circulation. 1992;85:497-503.
4.
Smith WJ, Kirshner N. A specific soluble
protein from the catecholamine storage vesicles of bovine
adrenal medulla. Mol Pharmacol. 1967;3:52-67.
5.
O'Connor DT, Frigon RP. Chromogranin A, the
major catecholamine storage vesicle soluble
protein. J Biol Chem. 1984;259:3237-3247.
6.
Takiyyuddin MA, Cervenka JH, Sullivan PA, Pandian MR,
Parmer RJ, Barbosa JA, O'Connor DT. Is physiologic
sympathoadrenal catecholamine release exocytotic in
humans? Circulation. 1990;81:185-195.
7.
Takiyyuddin MA, Cervenka JH, Pandian MR, Steunkel CA,
Neumann HPH, O'Connor DT. Neuroendocrine sources of
chromogranin A in man: clues from selective stimulation of endocrine
glands. J Clin Endocrinol Metab. 1990;71:360-369.
8. Takiyyuddin MA, Brown MR, Dinh TQ, Cervenka JH, Braun SD, Parmer RJ, Kennedy B, O'Connor DT. Sympatho-adrenal secretion in humans: factors governing catecholamine and storage vesicle peptide co-release. J Auton Pharmacol. 1994;14:177-190. [Medline] [Order article via Infotrieve]
9. O'Connor DT. Chromogranin A: implications for hypertension. J Hypertens. 1984;2(suppl 3):147-150.
10.
Takiyyuddin MA, Cervenka JH, Hsiao RJ, Barbosa JA,
Parmer RJ, O'Connor DT. Chromogranin A: storage and release in
hypertension. Hypertension. 1990;15:237-246.
11.
Schober M, Howe PRC, Sperk G, Fischer-Colbrie R,
Winkler H. An increased pool of secretory hormones and peptides
in adrenal medulla of stroke-prone spontaneously hypertensive
rats. Hypertension. 1989;13:469-474.
12. Frohlich ED. Is the spontaneously hypertensive rat a model for human hypertension? Hypertension. 1986;4(suppl):S-15-S-19.
13. Williams RR, Hunt SC, Hasstedt SJ, Hopkins PN, Wu LL, Berry TD, Stults BM, Barlow GK, Schumacher MC, Lifton RP, Lalouel JM. Are there interactions and relations between genetic and environmental factors predisposing to high blood pressure? Hypertension. 1991;18(suppl I):I-29-I-37.
14. Williams RR. Genes, hypertension, and early familial coronary heart disease. In: Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis and Management. New York, NY: Raven Press Publishers; 1990:chap 9.
15. Morton NE, Gulbrandsen CL, Rao DC, Rhoads GG, Kagan A. Determinants of blood pressure in Japanese-American families. Hum Genet. 1980;53:261-266. [Medline] [Order article via Infotrieve]
16.
Feinleib M, Garrison RJ, Christian JC, Hrubek Z,
Borhani NO, Kannel WB, Rosenman R, Schwartz JT, Wagner JO. The
NHLBI twin study of cardiovascular disease risk
factors: methodology and summary of results. Am J
Epidemiol. 1977;106:284-295.
17.
Williams GH, Dluhy RG, Lifton RP, Moore TJ, Gleason R,
Williams R, Hunt SC, Hopkins PN, Hollenberg NK. Nonmodulation as
an intermediate phenotype in essential hypertension.
Hypertension. 1992;20:788-796.
18. Hsiao RJ, Mezger MS, O'Connor DT. Chromogranin A in uremia: progressive retention of immunoreactive fragments. Kidney Int. 1990;37:955-964. [Medline] [Order article via Infotrieve]
19. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31-41. [Medline] [Order article via Infotrieve]
20.
Lifton RP, Hopkins PN, Williams RR, Hollenberg NK,
Williams GH, Dluhy RG. Evidence for heritability of
nonmodulating essential hypertension.
Hypertension. 1989;13:884-889.
21. Grim CE, Wilson TW, Nicholson GD, Hassell TA, Frase HS, Grim CM, Wilson DW. Blood pressure in blacks: twin studies in Barbados. Hypertension. 1990;15(part 2):803-809.
22. Khoury MJ, Beaty TH, Cohen BH. Fundamentals of Genetic Epidemiology. New York, NY: Oxford University Press; 1993:213-214.
23. Neale MC, Cardon LR. Methodology for Genetic Studies of Twins and Families. Norwell, Mass: Kluwer Academic Publishers; 1992.
24. Warren SE, O'Connor DT. The antihypertensive mechanism of sodium restriction. J Cardiovasc Pharmacol. 1981;3:781-790. [Medline] [Order article via Infotrieve]
25.
Takiyyuddin MA, Baron AD, Cervenka JH, Barbosa JA,
Neumann HPH, Parmer RJ, Sullivan PA, O'Connor DT. Suppression
of chromogranin-A release from neuroendocrine sources in man:
pharmacological studies. J Clin Endocrinol
Metab. 1991;72:616-622.
26.
O'Connor DT, Pandian MR, Carlton E, Cervenka JH, Hsiao
RJ. Rapid radioimmunoassay of circulating chromogranin A: in
vitro stability, exploration of the neuroendocrine character of
neoplasia, and assessment of the effects of organ failure.
Clin Chem. 1989;35:1631-1637.
27. O'Connor DT, Bernstein KN. Radioimmunoassay of chromogranin A in plasma as a measure of exocytotic sympathoadrenal activity in normal subjects and in patients with pheochromocytoma. N Engl J Med. 1984;311:764-770. [Abstract]
28. Peuler JD, Johnson GA. Simultaneous single isotope radioenzymatic assay of plasma norepinephrine, epinephrine, and dopamine. Life Sci. 1977;21:625-636. [Medline] [Order article via Infotrieve]
29. Gochman N, Schmitz JM. Application of a new peroxidase indicator reaction to specific automated determination of glucose with glucose oxidase. Clin Chem. 1972;18:943-950. [Abstract]
30.
Lowry OH, Rosebrough NH, Farr AL, Randall RJ.
Protein measurement with the Folin phenol reagent.
J Biol Chem. 1951;193:265-275.
31. O'Connor DT. Plasma chromogranin A: initial studies in human hypertension. Hypertension. 1985;7:176-179.
32. Ward R. Familial aggregation and genetic epidemiology of blood pressure. In: Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis and Management. New York, NY: Raven Press Publishers; 1990:chap 6.
33. Berry TD, Hasstedt SJ, Hunt SC, Wu LL, Smith JB, Ash KO, Kuida H, Williams RR. A gene for high kallikrein may protect against hypertension in Utah kindreds. Hypertension. 1989;13:3-8. [Abstract]
34.
Rebbeck TR, Turner ST, Sing CF. Sodium-lithium
countertransport genotype and the probability of hypertension
in adults. Hypertension. 1993;22:560-568.
35. Williams RR, Hasstedt SJ, Hunt SC, Wu LL, Hopkins PN, Berry TD, Stults BM, Barlow GK, Kuida H. Genetic traits related to hypertension and electrolyte metabolism. Hypertension. 1991;17(suppl I):I-69-I-73.
36. Lifton RP, Hopkins PN, Williams RR, Hollenberg NK, Williams GH, Dluhy RG. Evidence for heritability of non-modulation essential hypertension. Hypertension. 1989;13:884-889.
37. Williams GH, Dluhy RG, Lifton RP, Moore TJ, Gleason R, Williams R, Hunt SC, Hopkins PN, Hollenberg NK. Nonmodulation as an intermediate phenotype in essential hypertension. Hypertension. 1992;20:788-796.
38. Goldstein DS, Eisenhofer G, Garty M, Sax FL, Keiser HR, Kopin IJ. Pharmacologic and tracer methods to study sympathetic function in primary hypertension. Clin Exp Hypertens. 1989;A11(suppl 1):173-189.
39.
Goldstein DS, Lake CR, Chernow B, Ziegler MG, Coleman
MD, Taylor AA, Mitchell JR, Kopin IJ, Keiser HR. Age-dependence
of hypertensive-normotensive differences in plasma
norepinephrine. Hypertension. 1983;5:100-104.
40. Esler MD. Catecholamines and essential hypertension. Ballieres Clin Endocrinol Metab. 1993;7:415-438. [Medline] [Order article via Infotrieve]
41.
Ferrier C, Esler MD, Eisenhofer G, Wallin BG, Horne M,
Cox HS, Lambert G, Jennings GL. Increased
norepinephrine spillover into the jugular veins in
essential hypertension. Hypertension. 1992;19:62-69.
42. O'Connor DT, Cervenka JH, Stone RA, Parmer RJ, Franco-Bourland R, Madrazo I, Langlais PJ. Chromogranin A immunoreactivity in human cerebrospinal fluid: properties, relationship to noradrenergic neuronal activity, and variation in neurologic disease. Neuroscience. 1993;56:999-1007. [Medline] [Order article via Infotrieve]
43.
Takiyyuddin MA, DeNicola L, Gabbai FB, Dinh TQ, Kennedy
BP, Ziegler MG, Sabban EL, Parmer RJ, O'Connor DT.
Catecholamine secretory vesicles: augmented
chromogranins and amines in secondary hypertension.
Hypertension. 1993;21:674-679.
44. Dimsdale JE, O'Connor DT, Ziegler MG, Mills P. Chromogranin A correlates with norepinephrine release rate. Life Sci. 1992;51:519-525. [Medline] [Order article via Infotrieve]
45. Wocial B, Januszewicz W, Bar-Andziak E, Grzesiuk W, Kuczynska K, Berent H, Ignatowska-Switalska H, Kapinski M, Mlynski J. Platelet activity, prostacycline metabolite, plasma lipids and sympathoadrenal activity in patients with borderline hypertension and positive family history of hypertension. Cor et Vasa. 1990;32:265-273. [Medline] [Order article via Infotrieve]
46.
Perini C, Muller FB, Rauchfleisch U, Battegay R, Hobi
V, Buhler FR. Psychosomatic factors in borderline hypertensive
subjects and offspring of hypertensive parents.
Hypertension. 1990;16:627-634.
47. Neutel JM, Smith DH, Graettinger WF, Winer RL, Weber MA. Metabolic characteristics of hypertension: importance of family history. Am Heart J. 1993;126:924-929. [Medline] [Order article via Infotrieve]
48. Soni D, Dhawan S, Gupta L, Chandra N, Agarwal A, Khanna V, Dwivedi SK. The efflux of nor-epinephrine from platelets in genetic hypertension. Indian Heart J. 1992;44:173-176. [Medline] [Order article via Infotrieve]
49. Bachmann AW, Ballantine DW, Gordon RD. Effect of positive family history of hypertension on the blood pressure and catecholamine responses to a 6 hour adrenaline infusion. Clin Exp Pharmacol Physiol. 1993;20:395-398. [Medline] [Order article via Infotrieve]
50. De Lima JJ, Dias MM, Bernardes-Silva H, Bellotti G. Pressor response to norepinephrine in essential hypertension: a study in families. Hypertension. 1990;15(suppl I):I-137-I-139.
51. Hsiao RJ, Parmer RJ, Takiyyuddin MA, O'Connor DT. Chromogranin A storage and secretion: sensitivity and specificity for the diagnosis of pheochromocytoma. Medicine. 1991;70:33-45. [Medline] [Order article via Infotrieve]
52. Simon JP, Bader MF, Aunis D. Effect of secretagogues on chromogranin A secretion in bovine cultured chromaffin cells. Possible regulation by protein kinase C. Biochem J. 1989;260:915-922. [Medline] [Order article via Infotrieve]
53.
Barbosa JA, Gill BM, Takiyyuddin MA, O'Connor
DT. Chromogranin A: posttranslational modifications in secretory
granules. Endocrinology. 1991;128:174-190.
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