Download Atrial natriuretic factor: Its role in hypertension

JACC Vol.
September
725
14. No. 3
1989:725-7
Editorial Comment
Atria1 Natriuretic Factor:
Its Role in Hypertension*
EDWARD
D. FROHLICH,
Neus Orlems,
MD, FACC
Louisiana
The story of the atrial natriuretic factor is a fascinating one.
Over an extremely short time. a putative hormone was
suggested. its biochemical characteristics were identified.
the amino acid sequence was determined, the peptide was
cloned and the pure hormone was made available through
recombinant technology. Thus, thanks to modern day high
technology, a new hormone, one originating in the heart.
was identified and commercially synthesized. Yet industry
became frustrated because the commercial potential of atria1
natriuretic factor made available through “high tech” developments outpaced the physiologic knowledge about its role
in health and disease. The latter requires the luxury of time
to permit acquisition of biologic (e.g., physiologic, biochemical) information, scientific interchange at meetings and in
publications and, of course, confirmation of the data. It is
inevitable that this experience will recur in the future.
Pathophysiologyof atrial natriuretic factor. In this issue
of the Journal (1) we are presented with new physiologic
information concerning the role of atrial natriuretic factor in
health and disease. Before commenting on this article, I will
examine briefly the teleology of the pathophysiology of atrial
natriuretic factor. Consider the circumstances of a volumeoverloaded circulation. Here we find a situation of an
increased venous return to the heart and an expanded
cardiopulmonarv volume. Ideally, if the heart could “sense”
this overload in-its low pressure chamber and then initiate a
response to induce natriuresis and diuresis, this would
provide the negative feedback that we expect from finely
tuned circulatory homeostasis. Indeed, we now know that
atrial stretch associated with volume overload serves to
release atrial natriuretic factor from the atrium: this, in
turn, stimulates the renal excretion of sodium (and water),
which restores a normal cardiopulmonary volume and circulation (2).
However, the foregoing events are only partially true and
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certain data are, at present, conflicting. As a result, the
teleology is not totally supported. On the one hand, early
studies demonstrated that, in vitro, atria1 natriuretic factor
reduced vascular smooth muscle tone in vessel strip preparations and produced a potent natriuresis and diuresis with
minimal kaliuresis in vivo (3). On the other hand, in the total
body situation. atrial natriuretic factor has been shown to
reduce arterial and venous pressures associated with a
reduced cardiac output and an increased total peripheral
resistance (4). These findings, of course, suggest a questionable role for atrial natriuretic factor in cardiac failure and a
less than ideal action for a new antihypertensive agent.
Commercial interests were soon diverted to providing the
hormone for investigative and radioimmunoassay purposes
rather than for therapeutic goals. However, more recently,
long-term infusion of atrial natriuretic factor was shown to
decrease total peripheral resistance (5) and to increase
cardiac output in patients with cardiac failure (6). These
responses have been difficult to utilize clinically because of
the short half-life of the native peptide, although current
studies reported in abstracl form (7-9) using endopeptidase
inhibitors that interfere with the degradative metabolism of
atrial natriuretic factor support a potential role for this
peptide in the treatment of hypertension.
Present study. Data are now becoming available on the
role of atrial natriuretic factor in health and disease (1). In
their study, tianau et al. (I) were concerned with the relation
of atrial natriuretic factor to systemic hemodynamics and
cardiac structure in patients with systemic arterial hypertension. Well established essential hypertension is characterized by an elevated arterial pressure secondary to an increased total peripheral resistance that is associated with a
contracted intravascular (plasma) volume and with adaptive
structural changes characterized by left ventricular hypertrophy and vessel wall thickening (IO). Even before these
changes are found in patients with established essential
hypertension, the elevated arterial pressure may be related
to an increased cardiac pulmonary volume. This increased
volume elevates cardiac output in association with an “inappropriately normal” total peripheral resistance that would
actually be reduced in normal subjects with that degree of
elevation in cardiac output (I I). The incremental increase in
cardiopulmonary volume (and cardiac output) results from
peripheral venoconstriction that redistributes the (normal)
circulating intravascular volume centrally. In this regard,
alterations in atrial natriuretic factor levels have been shown
with related physiologic interventions and in disease. Thus,
with cardiopulmonary volume expansion or peripheral venoconstriction (e.g., water immersion), or both, atrial natriuretic factor levels increase. In certain diseases associated
with expanded cardiopulmonary volume, such as congestive
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FROHLICH
EDITORIAL
JACC Vol. 14, No. 3
September 1989:725-7
COMMENT
heart failure or mitral stenosis, and after paroxysmal atrial
tachycardia, atria1 natriuretic factor levels also are increased. Each of these conditions is associated with atrial
distension and a ready stimulus for atria1 natriuretic factor
release (12).
Ganau and associates (I) evaluated the various physiologic and clinical determinants of atrial natriuretic factor in
normal subjects and patients with essential hypertension.
They demonstrated that immunoreactive plasma atrial natriuretic factor levels were directly related to age. systolic
pressure and echocardiographically mensurated left atrial
and ventricular chamber sizes in normal subjects, but that
only age and ventricular size were independent predictors of
the hormonal levels. In patients with essential hypertension.
the atrial natriuretic factor levels were directly related to
age, systolic pressure, atria1 size. total peripheral resistance
and ventricular systolic performance, although age, atrial
size and vascular resistance were independent predictors.
Ganau et al. therefore suggest that. in normal subjects,
impaired ventricular relaxation with age may contribute to
atrial natriuretic factor secretion. They state that correlation
with left ventricular size may relate to fluctuations in plasma
volume; the latter was not measured. and plasma and
cardiopulmonary volumes do not expand with aging. Ganau
et al. suggest that in the patients with uncomplicated hypertension, left atria1 enlargement contributes to atrial natriuretic factor release, and they show that there was no
relation with left ventricular hypertrophy or systolic function. Furthermore, it is of particular interest that the atrial
natriuretic factor levels and plasma renin activity were
inversely related in patients with essential hypertension, and
Ganau et al. suggest an inhibitory effect of atrial natriuretic
factor hormone on renin release from the kidney.
Role of intravascular (plasma) volume expansion. In this
respect these speculations relating changes with intravascular (plasma) volume with atrial natriuretic factor levels
would appear to merit further consideration. It is unfortunate that plasma volume was not determined because this
variable is a major determinant of both atrial natriuretic
factor secretion and plasma renin activity. Thus. with volume expansion and increased venous return and cardiopulmonary volume, atria1 natriuretic factor should increase
(3,12). Similarly, with volume expansion, the release of renin
from the kidney should be suppressed in normal individuals
as well as in patients with essential hypertension (13). The
findings of Ganau et al. (I) are perfectly compatible physiologically with previous reports. In normal individuals, vascular and ventricular stiffening, as suggested by these authors, should favor a less distensible vasculature and heart
for the circulating volume. Moreover, in their patients with
mild hypertension, the elevated atrial natriuretic factor levels might reflect the previously reported increase in cardiopulmonary volume of such patients with mild hypertension,
hence the higher cardiac output in these patients (14,15).
Furthermore, patients with milder hypertension may also
have a higher total peripheral resistance, which would
suggest some degree not only of precapillary constriction but
also of postcapillary constriction that increases the vascular
resistance. These changes serve to reduce plasma volume
(16) and are also probable in the patients of Ganau et al. (1)
because of their higher hematocrit levels. The changes arc
consistent with the plasma renin activity levels the investigators found: they should be reduced, particularly in normotensive subjects.
Conclusions. Thus, the findings of this study (1) demonstrate several important concepts. First. immunoreactive
atrial natriuretic factor is elevated in patients with mild to
moderately severe essential hypertension. This elevation
may relate to an increased central distribution of circulating
volume that reflects peripheral arteriolar and venular constriction. Supporting this thesis are the findings of higher
cardiac output, total peripheral resistance and hematocrit in
these patients that were associated with the increased levels
of atria1 natriuretic factor. The findings of a direct relation
with age and systolic pressure are also consistent with stiffer
cardiac chambers and peripheral vessels in patients with
hypertension and in normal subjects with aging. With more
severe degrees of hypertension, arterial pressure increases
in proportion to the increase in total peripheral resistance; in
association with these changes. the left ventricle undergoes
hypertrophy. Because cardiac output was maintained in
these patients,
venous return was normal. However, because of the less compliant cardiac chamber, atrial natriuretic factor remained stimulated.
In the final analysis, we are now learning more of the role
of atrial natriuretic factor in health and disease and can relate
changes in its circulating levels and release mechanisms to
pathophysiologic alterations. As we learn of its relation to
hemodynamic and cardiac functions, we shall know more of
its therapeutic potential. Until then, new data such as these
from Ganau et al. (I) are welcome.
References
I. Cianau
A. Devereux
RB, Atlas SA. et al. Plasma atrial natriuretic factor in
essential hypertension: relation to cardiac size, function and systemic
hemodynamics. J Am Coil Cardiol 1989;14:715-24.
2. Frohhch ED. The first lrvme H. Page lecture: the mosaic of hypertension:
past. present, and future. J Hypertens 1988;6(suppl 4):S2-Il.
3. Trippodo NC. Cole FE. MacPhee AA. Pegram BL. Biologic mechanisms
of atria1 natriuretic factor. J Lab Clin Med 1987:109:112-9.
4. Pegram BL. Trippodo NC. Natsume T. et al Hemodynamic
atrial natriuretic hormone. Fed Proc 1986:4S:2382-6.
effects of
5. Parkes DG. Coghlan JP. McDougall JG. Scoggins BA. Long-term hemodynamic actions of atrial natriuretic factor (99-126) m conscious sheep.
Am J Physiol 1988:254:H81 l-5.
6. Saito Y. Nakao K. Nishimura K, et al. Climcal application of atrial
natriuretic polypeptide in patients wth congestwe heart failure: beneficial
effects on left ventricular function. Circulation 1987;76: 115-24.
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1989:725-Y
7. Samuels GMR, Barclay PL. Peters CJ. Ellis P. Atriopeptidase inhibitors.
a novel class of drug that raises levels of endogenous atrial natriuretic
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COMMENT
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