1-81
Non-modulating Hypertension
A Subset of Sodium-Sensitive Hypertension
Gordon H. Williams and Norman K. Hollenberg
A
Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017
major difficulty in determining the mechanisms responsible for human hypertension is
- the great variety of systems involved in regulating blood pressure and our tendency to assume
that these mechanisms are similar in all hypertensive
patients. Even when patients are separated into
those whose blood pressure is or is not sensitive to
the level of sodium intake, it is often assumed that all
"salt-sensitive" hypertensive patients have similar
defects. However, an accumulating body of evidence
suggests this is not the case, and at least six different
mechanisms have been proposed to account for a
substantial change in blood pressure when a patient's
salt intake is modified (Table 1). This article will
review one of these subgroups—non-modulators.
Role of Aldosterone and Renal Vasculatnre in
Sodium Homeostasis
Changes in the level of aldosterone and in renal
blood flow have profound effects on renal sodium
handling. The absence of aldosterone, that is, Addison's disease, clearly leads to a state of decreased
renal conservation of sodium, whereas an aldosterone
excess, that is, primary aldosteronism, leads to increased renal sodium conservation, at least acutely.
Evidence has accumulated that the renal vasculature
also participates in modifying renal sodium handling.
For example, when sodium intake is restricted and the
renin-angiotensin system is activated, renal blood flow
is reduced and sodium concentration is enhanced.
Under conditions of a low sodium intake, if a competitive antagonist to angiotensin II or converting enzyme
inhibitors are administered, renal blood flow is increased in a dose-related fashion, with a concomitant
increase in sodium excretion, documenting that angiotensin II contributes to sodium handling by the kidney.1-2 Intriguingly, not only do these two factors play
a critical role in modifying sodium homeostasis, but
also their level of responsiveness to angiotensin II is
modified by the level of sodium intake in a reciprocal
fashion. Sodium restriction enhances the adrenal but
reduces the renal vasculature (and the general vascuFrom the Departments of Medicine and Radiology, Brigham
and Women's Hospital/Harvard Medical School, Boston, Mass.
Address for reprints: Gordon H. Williams, MD, EndocrineHypertension Division, 221 Longwood Avenue, Boston, MA
02115.
lature) response to angiotensin II; sodium loading
produces the opposite effect.
Because administration of converting enzyme inhibitors or angiotensin II antagonists acutely modifies the responsiveness of the vascular system to
infused angiotensin II when the endogenous reninangiotensin system is activated (i.e., sodium restriction), it is likely that a change in the angiotensin
receptor itself is likely to mediate the changing
responsiveness of the vascular system when sodium
intake is modified.1-3 However, the mediator of the
change in aldosterone responsiveness is less clear.
At least two possibilities exist. Either the change in
sensitivity is secondary to a change in a postreceptor
event, or it is receptor mediated. In the rat glomerulosa cell, angiotensin II receptors have been reported
to be increased with sodium restriction or chronic
infusion of angiotensin II.4'S However, binding studies
using primate adrenal tissue have documented a reduction in the number of receptors when the animal is
sodium restricted.6 Further evidence that the angiotensin II receptor is not a major participant in this
event has been the documentation that reducing
plasma angiotensin II with a converting enzyme inhibitor does not modify the adrenal response to angiotensin II in normal subjects although it does change
the renal vascular response to angiotensin II.7"9 Thus,
how the adrenal gland "knows" what the level of
sodium intake is requires further investigation.
Non-modulating Essential Hypertension
With a clearer understanding of the normal relation among the adrenal and renal vasculature,
changes in sodium intake, and responsiveness to
angiotensin II, it became feasible to evaluate potential abnormalities in this relation in patients with
essential hypertension. Two observations in the 1970s
led to the formulation of the concept of the subset of
patients with hypertension, termed "non-modulators." First, in normal subjects renal blood flow
increases when dietary sodium intake is increased.
However, in some patients with essential hypertension, no change was observed.10-11 Second, some
hypertensive patients do not increase their aldosterone output in response to acute volume depletion in
a manner similar to that observed in normotensive
subjects.12 Because the response of both the adrenal
and the renal blood supplies with shifts in total body
1-82
Supplement I
Hypertension
Vol 17, No 1, January 1991
TABLE 1. Frequency of Causes of Sodlnm-Sensitive Hypertension
Cause
1%
Bilateral renal artery stenosis
1%
Acromegaly
Characteristics of the Non-modulating Trait
Frequency
Primary aldosteronism
Bilateral renal parenchymal disease
TABLE 2.
5-8%
1%
Low renin essential hypertension
25-35%
Non-modulating essential hypertension
55-65%
Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017
sodium or effective blood volume is primarily determined by angiotensin II, the data suggested that the
underlying difficulty was an abnormality in the interaction of these tissues with angiotensin II. Indeed,
one study13 suggested that these two defects were
occurring in the same patient and that they might be
related to an abnormality in the way the renal
vasculature and adrenal sensitivity to angiotensin II
change with sodium intake. This hypothesis was
directly tested14 in a group of normal and high renin
essential hypertensive patients. The patients were
divided into normal or abnormal responders, based
on their renal vascular response to a 3 ng/kg/min
infusion of angiotensin II on a 200 meq sodium
intake. Normal subjects have a reduction of at least
105 ml/min/1.73 m2. However, nearly half of the
hypertensive subjects had a smaller decrement. The
abnormal responders had three major characteristics
distinguishing them from normal subjects free of a
family history of hypertension and the normal-responding hypertensive patients. First, not only was
their renal vascular response to angiotensin II reduced on a high salt diet, but also the level of sodium
intake did not change the responsiveness at all.
Second, sodium intake also did not change the adrenal response to angiotensin II. Finally, with chronic
sodium loading there was no increase in renal blood
flow, a finding in sharp contrast to what was observed
in normotensive subjects and modulating hypertensive patients. Thus, these data strongly suggest that
there is a subgroup of patients with hypertension in
whom sodium intake no longer modulates target
tissue responsiveness to angiotensin II. It is the
failure of this sodium-mediated modulation that resulted in coinage of the term non-modulators.
There are several additional characteristics that
partially distinguish non-modulators from other
hypertensive patients (Table 2). Importantly, not all
may be present in each non-modulator. First, when
subjects are sodium restricted and placed in the
upright position, the plasma renin activity and angiotensin II levels tend to be higher and the plasma
aldosterone levels tend to be lower in non-modulators; thus, a lower change in aldosterone/change in
plasma renin activity ratio results.16 Second, both
angiotensin II17 and acute sodium chloride infusion18
have a reduced ability to suppress plasma renin
activity in the sodium-restricted non-modulator.
Third, plasma dopamine levels are increased in nonmodulators, particularly on a low sodium intake, and
Characteristics
Corrected by
converting enzyme
inhibitors?
Decreased renal blood flow response to
angiotensin II on high salt diet14
Decreased renal blood flow response to
sodium loading14'15
Yes 15
Decreased aldosterone response to
angiotensin II on low salt diet14
Renin suppression by angiotensin II on low
salt diet 17
Yes 16
Renin suppression by saline on low salt
diet18
Reduced sodium excretion20
Yes 15
Yes 17
No 1 '
Yes 1 '
Decreased increments in aldosterone
divided by increments in renin in
response to posture and sodium
restriction 18
Elevated sodium-lithium countertransport
in red blood cells21
Increased plasma norepinephrine levels in
response to posture and salt restriction
Increased plasma dopamine levels22
References are indicated for the various characteristics.
dopamine excretion isfixedregardless of the level of
sodium intake.22 Fourth, sodium-lithium countertransport in red blood cells is significantly elevated in
non-modulators.21 Fifth, non-modulators have a decreased ability to handle a sodium load.19-20 Finally,
plasma norepinephrine levels are increased in nonmodulators, particularly in response to sodium restriction and upright posture.
Non-modulators, however, do not differ from other
essential hypertensive patients in age, duration of
hypertension, sodium or potassium balance, renal
function, cardiac output, gender, or plasma volume.
There also appear to be no clinical differences in the
severity of the hypertension as judged by electrocardiograms, physical examination, or admission blood
pressures.
Thus, there are 10 different characteristics associated with the non-modulating phenotype (Table 2).
However, only three of them have demonstrated
sufficient specificity and sensitivity to be useful in the
identification of these patients. The most precise way
of identifying non-modulators is to determine the
increment in plasma aldosterone in response to a 3
ng/kg/min infusion of angiotensin II when subjects
are in balance on a low (10 meq) sodium intake.
Nearly as precise is the increment in/>-aminohippuric
acid clearance (renal blood flow), when using plasma
rather than urine clearance techniques, in patients
changing from a 10 to a 200 meq sodium intake. The
final technique is the assessment of the decrement in
renal blood flow in response to a 3 ng/kg/min infusion of angiotensin II when the subject is in balance
on a high (200 meq) sodium intake. None of the
other characteristics listed in Table 2 have sufficient
specificity to allow identification of these patients.
Williams and Hollenberg
What is the concordance between the adrenal and
renal blood flow criterion for identifying non-modulators? When the responses in 34 patients who have
received angiotensin II infusions both on a low and
on a high sodium intake were examined, the concordance was extremely high.14-15 Eighty-four percent of
the patients were identified as modulators or nonmodulators by both the adrenal and the renal vascular responses to angiotensin II. Thus, it is reasonable
to assume that using only one of the three procedures
outlined above is necessary to identify a non-modulator. However, of critical importance, as mentioned
earlier, the level of sodium intake markedly influences the responsiveness of both these target tissues
to angiotensin II. Thus, sodium balance needs to be
carefully controlled to prevent misclassification.
Non-modulating Hypertension
1-83
ing phenotype has been observed in normotensive
subjects. In normotensive kidney donors with a positive family history for hypertension, there is a significantly lower plasma aldosterone response to sodium
restriction than in those with a negative family history, despite equivalent plasma renin activity levels—a feature suggestive of non-modulation.24 Furthermore, when normotensive subjects with a positive
family history of hypertension are infused with angiotensin II, their aldosterone responses are less than
in subjects with a negative family history.25 Finally,
when sibling pairs with hypertension are analyzed for
the presence or absence of the non-modulating phenotype, a high degree of concordance is observed
(/XO.0001).26 Thus, the non-modulating phenotype
aggregates in families, providing further evidence
that this is an inherited abnormality.
Heritability of the Non-modulation Trait
Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017
One of the initial questions addressed in the study
of non-modulators was "Are they a discrete group or
are the abnormalities simply part of a continuum of
responsiveness different at the extremes from that
observed in normotensive subjects?" The accumulated evidence strongly suggests that non-modulation
reflects a discrete subgroup.23 One of the first techniques to separate patients into modulators and
non-modulators was to measure their aldosterone
secretory response to acute volume depletion induced by a diuretic after sodium restriction. By use of
this technique in 46 normal and high renin hypertensive patients, the responses could be separated into
two distinct subgroups: in one, comprising 54% of the
subjects, the increment in aldosterone secretion was
similar to that observed in normotensive subjects; in
the other, little, if any, increase in aldosterone secretion occurred. Reanalysis of previously published
data23 using maximum-likelihood analysis established
that the probability was highly significant that this
distribution reflected a bimodal versus a unimodal
distribution (/xO.OOOOl).
Confirmation of this observation has occurred with
the assessment of adrenal responses to infused angiotensin II in 157 sodium-restricted normal and high
renin hypertensive subjects and 46 normotensive
subjects.23 Again, reanalysis of these data indicate
that the responses in the hypertensive but not the
normotensive patients are bimodal, with a significant
likelihood (p< 0.00009) when compared with a unimodal frequency distribution. It is important to point
out that in these studies normotensive patients were
screened to eliminate those with a positive family
history of hypertension.
These data also raise the question of whether
non-modulation is an inherited trait. Several lines of
evidence support this possibility. First, there is a high
degree of correlation between a positive family history of hypertension and non-modulation.1011-20 Indeed, presently available data suggest that 85% of
non-modulators have a positive family history for
hypertension in contrast to 25-30% in the modulating hypertensive subjects. Second, the non-modulat-
Relation Between Non-modulation
and Hypertension
In normal subjects an increase in sodium intake
produces an increase in renal blood flow, thereby
enhancing the ability of the kidney to excrete sodium.
The non-modulators do not increase renal blood flow
when sodium intake is increased; therefore, one
would predict that they would retain sodium. This
sodium retention could underlie their elevated blood
pressure. The validity of this hypothesis has been
demonstrated in a number of ways. First, the time
necessary to achieve sodium balance is distinctly
increased in non-modulators; this increase strongly
suggests an expanded sodium space. Thus, the halftime of disappearance of sodium from the urine
when subjects are placed on a 10 meq sodium diet is
approximately 50% longer (36 hours) in non-modulators than in normotensive subjects or modulators.20
Second, when non-modulators are given an acute
sodium load they fail to excrete it as rapidly as do
modulating hypertensive patients.19 Finally, when
non-modulators are chronically sodium loaded (for 5
days after achieving balance on a low salt diet), they
take longer to reestablish high salt equilibrium, and
when they do, the net accumulated sodium balance is
nearly twice as great as in modulating hypertensive
patients.20
Thus, several lines of evidence suggest that, when
compared with the rest of the normal and high renin
essential hypertensive population, non-modulators
fail to handle sodium loads appropriately. As has
been described for other clinical states in which an
abnormality in sodium handling has been described,
that is, primary aldosteronism and bilateral renal
artery stenosis, one would anticipate that these patients' blood pressures would be sensitive to the level
of sodium intake. This has been documented acutely
in response to sodium chloride infusion27-28 and with
short-term oral salt loading (5 days on a high salt
diet)15; only in the non-modulator subgroup was a
substantial (6 mm Hg) rise in blood pressure documented. In a preliminary study of 20 patients, sodium
sensitivity was defined as a rise in mean blood
1-84
Supplement I Hypertension Vol 17, No 1, January 1991
Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017
pressure of 10 mm Hg after 2 weeks on a 250 meq salt
diet. Eighty percent of the sodium-sensitive patients
were non-modulators; there were no non-modulators
in the sodium-resistant group.
Thus, the available evidence strongly suggests that
when non-modulators increase their sodium intakes,
they are unable to excrete it appropriately, presumably because of the defect in their renal hemodynamic responses to the sodium load. Because the
frequency of non-modulation is approximately 40%
in the normal and high renin essential hypertensive
group, non-modulators probably account for all of
the sodium-sensitive subjects in this subgroup and
form the largest sodium-sensitive hypertensive subgroup.29
What could account for the absence of an effect of
sodium intake on tissue responsiveness to angiotensin II? Evidence accumulated so far strongly suggests
that it is due to a difference in tissue angiotensin II
levels. This is based primarily on the seminal observation that in non-modulators the defects in both the
adrenal and renal vascular response to angiotensin
II, the renal vascular response to sodium intake, and
the kidney's ability to excrete a salt load are all
corrected after the administration of converting enzyme inhibitors. In contrast, neither normotensive
subjects nor modulating hypertensive patients change
any of these parameters after administration of converting enzyme inhibitors. Because modulators and
non-modulators have similar levels of circulating
renin activity and angiotensin II, particularly on a
high salt diet, abnormalities in locally produced
angiotensin II are likely to underlie these defects.
This provides a particularly appealing hypothesis to
explain the abnormal renal blood flow and sodium
handling in non-modulators. Thus, if there is an
increase in the intrarenal angiotensin II production
or an abnormality in the renal angiotensin II receptors, this could produce an apparent high local
angiotensin II state, which would reduce the renal
vascular response to exogenously administered angiotensin II and prevent an increase in renal blood flow
when sodium intake is increased and thereby reduce
the ability of the kidney to excrete a salt load.
What does this mean to the hypertensive patient?
In part, the answer lies in the non-modulator's blood
pressure response to converting enzyme inhibitors on
a high salt diet. Under these circumstances, the
"sodium-sensitive hypertensive," who should be particularly resistant to converting enzyme inhibitors,
actually is particularly sensitive to them. Indeed, the
fact that converting enzyme inhibitors correct the
underlying defects in the non-modulators provides a
reasonable explanation to what had been a puzzling
observation. Most studies have documented that
nearly 50% of the hypertensive population will show
a substantial reduction in blood pressure when given
a converting enzyme inhibitor on a high salt diet — a
circumstance that would not logically favor a positive
response. Observations noted above would suggest
that responders to converting enzyme inhibitor
monotherapy are non-modulators.
In conclusion, from the data cited in this review,
the accumulated evidence suggests that essential
hypertension is not a single disease entity, despite the
fact that a number of features in these patients,
including blood pressure itself, appear to form a
continuum. Even patients whose blood pressures are
sensitive to the level of sodium intake do not form a
discrete group. However, in one of the sodiumsensitive hypertensive subsets, non-modulators, the
intermediate phenotype that characterizes these patients is clearly bimodal. These patients have an
abnormality related to locahy produced angiotensin
II or the angiotensin II receptor, which prevents
them from changing their target tissue responsiveness to exogenous angiotensin II when sodium intake
is modified and thus reduces their ability to excrete a
sodium load. Paradoxically, converting enzyme inhibitors, which theoretically should be ineffective in
these patients, are more effective than they are in the
non-sodium-sensitive subgroups. Finally, preliminary
data strongly suggest that the non-modulating trait is
inherited.
Does this evolving theory account for all abnormalities in patients with essential hypertension? The
answer is clearly no. It can be seen from the discussion cited above that there are a variety of underlying
mechanisms resulting in an increase in blood pressure even in the sodium-sensitive subgroup. Detailed
investigations of the fundamental mechanisms producing sodium-sensitivity in them and in those nonsodium-sensitive subjects with increased vasoconstrictor activity are still required.
References
1. Kibrough HM, Vaughn ED, Carey RM, Ayers CR: Effect of
intrarenal angiotensin n blockade on renal function in conscious dogs. Ore Res 1977;40:174-178
2. Hollenberg NK, Swartz SL, Passan DR, Williams GH:
Increased glomerular filtration rate following converting
enzyme inhibition in essential hypertension. N Engi J Med
1979;301:9-12
3. Williams GH, Hollenberg NK, Brown C, Mersey JH: Adrenal
responses to pharmacological interruption of the reninangiotensin system in sodium restricted man. / Ciin Endocrinol
Metab 1978;47:725-731
4. Douglas J, Catt KJ: Regulation of angiotensin II receptors in
the rat adrenal cortex by dietary electrolytes. / Ciin Invest
1976^8:834-843
5. Aguilera G, Catt K: Regulation of aldosterone secretion by the
renin-angiotensin system during sodium restriction in rats.
Proc NatlAcad Sd USA 1978;75:4057-4061
6. Platia MP, Catt KJ, Hodgen GD, Aguilera G: Regulation of
primate angiotensin II receptors during altered sodium intake.
Hypertension 1986;8:1121-1126
7. Williams GH, Hollenberg NK, Braley LM: Influence of
sodium intake on vascular and adrenal angiotensin II receptors. Endocrinology 1976;98:1343-1350
8. Dawson-Hughes BF, Moore TJ, Dluhy RG, Hollenberg NK,
Williams GH: Plasma angiotensin concentration regulates
vascular but not adrenal responsiveness to restriction of
sodium intake in normal man. Ciin Sd 1981;61:527-534
9. Shoback DM, Williams GH, HoUenberg NK, Davies RO,
Moore TJ, Dluhy RG: Endogenous angiotensin II as determinant of sodium modulated changes in tissue responsiveness to
Williams and Hollenberg
10.
11.
12.
13.
14.
15.
Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017
16.
17.
18.
19.
20.
angiotensin II in normal man. / Clin EndocriruA Metab 1983;
51:764-770
Hollenberg NK, Merrill JP: Intrarenal perfusion in the young
"essential" hypertensive: A subpopulation resistent to sodium
restriction. Trans Assoc Am Physicians 1970;133:93-101
Hollenberg NK, Borucki LJ, Adams DF: The renal vasculature in early essential hypertension: Evidence for pathogenic
role. Medicine 1978^7:167-178
Williams GH, Rose LI, Dluhy RG, McCaughn D, Jagger PI,
Hickler RB, Lauler DP: Abnormal responsiveness of the
renin-aldosterone system to acute stimulation in patients with
essential hypertension. Ann Intern Med 1970;72:317-326
Williams GH, Tuck ML, Sullivan JM, Dluhy RG, Hollenberg
NK: Parallel adrenal and renal abnormalities in the young
patient with essential hypertension. Am J Med 1982;72:
907-914
Shoback DM, Williams GH, Moore TJ, Dluhy RG, Podolsky
S, Hollenberg NK: Defect in the sodium-modulated tissue
responsiveness to angiotensin II in essential hypertension. /
Clin Invest 1983;72:2115-2124
Redgrave JE, Rabinowe SL, Hollenberg NK, Williams GH:
Correction of abnormal renal blood flow response to angiotensin II by converting enzyme inhibition in essential hypertensives. J Clin Invest 1985;75:1285-1290
Taylor TT, Moore TJ, Hollenberg NK, Williams GH: Converting enzyme inhibition corrects the altered adrenal response to
angiotensin II in essential hypertension. Hypertension 1984;6:
92-99
Seely EW, Moore TJ, Rogacz S, Gordon MS, Gleason R,
Hollenberg NK, Williams GH: Angiotensin-mediated renin
suppression is altered in non-modulating hypertension. Hypertension 1989;13:31-37
Rabinowe SL, Redgrave JE, Shoback DM, Podolsky S, Hollenberg NK, Williams GH: Renin suppression by saline is
blunted in non-modulating essential hypertension. Hypertension 1987;10:404-408
Rystedt L, Williams GH, Hollenberg NK: The renal and
endocrine response to saline infusion in essential hypertension. Hypertension 1986;8:217-222
Hollenberg NK, Williams GH: Abnormal renal sodium handling in essential hypertension: Relationship to failure of renal
21.
22.
23.
24.
25.
26.
27.
28.
29.
Non-modulating Hypertension
1-85
and adrenal modulation of responses to angiotensin II. Am J
Med 1986;81:412-418
Redgrave J, Canessa M, Gleason R, Hollenberg NK, Williams
GH: Red blood cell lithium-sodium countertransport in nonmodulating essential hypertension. Hypertension 1989;13:
721-726
Gordon MS, Steunkel CA, Conlin PR, Hollenberg NK, Williams GH: The role of dopamine in non-modulating hypertension. J Clin Endocrinol Metab 1989;69:426-432
Williams GH, Hollenberg NK: Are non-modulating patients
with essential hypertension a distinct subgroup? Implications
for therapy. Am J Med 1985;79:3-9
Blackshear JL, Garnic D, Williams GH, Harrington DP,
Hollenberg NK: Exaggerated renal vasodilator response to
calcium entry blockade in first-degree relatives of essential
hypertensive subjects. Hypertension 1987;9:384-389
Beretta-Piccoli C, Pusterla C, Stadler P, Weidmann P:
Blunted aldosterone responsiveness to angiotensin II in normotensive subjects with familial predisposition to essential
hypertension. J Hypertens 1988;6:57-61
Lifton RP, Hopkins PN, Williams RR, Hollenberg NK, Williams GH, Dluhy RG: Evidence for heritability of nonmodulating essential hypertension. Hypertension 1989;13:
884-889
Tuck ML, Williams GH, Dluhy RG, Greenfield M, Moore TJ:
A delayed suppression of the renin-aldosterone axis following
saline infusion in human hypertension. Ore Res 1976;39:
711-717
Rabinowe SL, Redgrave JE, Shoback DM, Podolsky S, Hollenberg NK, Willich SN, Gleason RE, Williams GH: Renin
suppression by saline is blunted in non-modulating essential
hypertension. Hypertension 1987;10:404-408
Williams GH, Hollenberg NK: Abnormal adrenal and renal
responsiveness to angiotensin II in essential hypertension, in
Edwards CRW, Carey RM (eds): Essential Hypertension as an
Endocrine Disease. London, Butterworth and Company, 1985,
pp 184-211
KEY WORDS • sodium-dependent hypertension
modulating hypertension • sodium
Non-modulating hypertension. A subset of sodium-sensitive hypertension.
G H Williams and N K Hollenberg
Hypertension. 1991;17:I81
doi: 10.1161/01.HYP.17.1_Suppl.I81
Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1991 American Heart Association, Inc. All rights reserved.
Print ISSN: 0194-911X. Online ISSN: 1524-4563
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://hyper.ahajournals.org/content/17/1_Suppl/I81.citation
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in
Hypertension can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located, click
Request Permissions in the middle column of the Web page under Services. Further information about this
process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Hypertension is online at:
http://hyper.ahajournals.org//subscriptions/