Am J Physiol Heart Circ Physiol 285: H527-H534, 2003;
doi:10.1152/ajpheart.01034.2002
0363-6135/03 $5.00
Gender differences on the effects of aging on cardiac and peripheral adrenergic stimulation in old conscious monkeys
Gen Takagi,1
Kuniya Asai,1
Stephen F. Vatner,1
Raymond K. Kudej,1
Franco Rossi,1
Athanasios Peppas,1
Ikuyo Takagi,1
Ranillo R. G. Resuello,2
Filipinas Natividad,3
You-Tang Shen,1 and
Dorothy E. Vatner1
1Department of Cell Biology and Molecular
Medicine, University of Medicine and Dentistry of New Jersey, New Jersey
Medical School, Newark, New Jersey 07101-1709; 2Simian
Conservation Breeding and Research Center, Incorporated, Manila 1231; and
3St. Luke's Medical Center, Quezon City 1102,
Philippines
Submitted 2 December 2002
; accepted in final form 4 April 2003
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ABSTRACT
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We examined the effects of gender and aging on cardiac and peripheral
hemodynamic responses to
-adrenergic receptor (
-AR) stimulation in
young (male = 5.9 ± 0.4 yr old and female = 6.5 ± 0.7 yr old)
and old (male = 19.8 ± 0.7 yr old and female = 21.2 ± 0.2 yr
old) conscious monkeys (Macaca fascicularis), chronically
instrumented for measurements of left ventricular (LV) and arterial pressures
as well as cardiac output. Baseline LV pressure, the first derivative of LV
pressure (LV dP/dt), cardiac index, mean arterial pressure, total
peripheral resistance (TPR), and heart rate in conscious monkeys were not
different among the four groups. Increases in LV dP/dt in response to
0.1 µg/kg isoproterenol (Iso) were diminished (P < 0.05) in old
males (+99 ± 11%) compared with young males (+194 ± 18%). In
addition, the inotropic responses to norepinephrine (NE) and forskolin (FSK)
were significantly depressed (P < 0.05) in old males. Iso-induced
reductions of TPR were less (P < 0.05) in old males (28
± 2%) than in young males (49 ± 2%). The changes of TPR
in response to NE and FSK were also significantly attenuated (P <
0.05) in old males. However, the LV dP/dt responses to BAY y 5959 (15
µg · kg1 ·
min1), a Ca2+ channel
promotor independent of
-AR signaling, were not significantly different
between old and young males. In contrast to results in male monkeys, LV
dP/dt and TPR responses to Iso, NE, and FSK in old females were
similar to those observed in young females. Thus both cardiac contractile and
peripheral vascular dynamic responses to
-AR stimulation are preserved
in old female but not old male monkeys. This may explain, in part, the reduced
cardiovascular risk in the older female population.
sympathetic nerves; nonhuman primates; cardiac function; catecholamine desensitization; vascular function; adenosine 3',5'-cyclic monophosphate
IT IS GENERALLY RECOGNIZED that female life expectancy is
greater than males and cardiovascular risk is less
(16). It is also well known
that
-adrenergic receptor (
-AR) responsiveness is reduced in old
males, which has been documented in rodents, primates, and humans
(4,
17,
26,
27). However, it remains
unclear whether
-AR signaling is altered in old females, because almost
no data utilizing direct measurements are available. Thus the present study
was specifically designed to determine whether the effects of aging on cardiac
contractile and peripheral vascular dynamic responses to adrenergic
stimulation are regulated differentially by gender in conscious monkeys. A
nonhuman primate model was selected because of its phylogenetic similarity to
humans but lack of associated chronic diseases, e.g., diabetes or
atherosclerosis. Cardiac and systemic hemodynamics were measured directly from
chronically implanted instrumentation. To avoid potential influences from
surgical injury and anesthesia, all experiments were performed after the
monkeys had completely recovered from surgery, i.e., while conscious in their
cages.
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METHODS
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Animals. Young males (YM; n = 14, aged 5.9 ± 0.4
yr), old males (OM; n = 8, aged 19.8 ± 0.7 yr), young females
(YF; n = 7, aged 6.5 ± 0.7 yr), and old females (OF;
n = 8, aged 21.2 ± 0.2 yr) monkeys (Macaca
fascicularis) were studied. The monkeys were fed with a standard primate
diet as previously described
(2,
3). All of the young monkeys
were born in captivity, thus enabling us to know their exact age. All old
monkeys were feral animals captured between the ages of 5 and 7 yr old and had
been kept in captivity for 1215 yr at the Simian Conservation Breeding
and Research Center (Manila, Philippines). The age at the time of capture was
estimated from eruption of dentition, general appearance, sexual development,
and body weight. All monkeys used in the present study had normal fasting
blood sugars and were maintained in accordance with guidelines for the
National Institutes of Health Guide for the Care and Use of Laboratory
Animals (NIH Pub. No. 83-23, Revised 1996).
Implantation of instrumentation. The method of surgically
implanting instrumentation has been previously described
(2,
3). Briefly, the animals were
tranquilized with ketamine hydrochloride (23 mg/kg im), anesthetized
with thiamylal sodium (510 mg/kg iv), and maintained with isoflurane
(1.02.0 vol/100 ml in oxygen). With the use of sterile surgical
techniques, a left thoracotomy was performed at the fourth intercostal space.
Tygon catheters were implanted in the descending aorta and left atrium for
pressure measurements and administration of pharmacological agents. A
miniature solid-state pressure gauge (Konigsberg Instruments; Pasadena, CA)
was inserted into the left ventricle (LV) through an apical stab wound for the
measurements of LV pressure and the first derivative of LV pressure (LV
dP/dt) (n = 8 OM, 8 OF, 14 YM, and 7 YF). A Transonic flow
probe (Ithaca, NY) with a diameter of 810 mm was placed around the root
of the ascending aorta to measure the ascending aortic blood flow, i.e.,
cardiac output minus coronary blood flow (n = 8 OM, 8 OF, 11 YM, and
7 YF). The incision was closed in layers, and air in the chest was evacuated.
All animals were allowed to recover for 1014 days before experiments
were initiated.
Hemodynamic measurements. Hemodynamic measurements were made when
the monkeys were fully awake in their individual cages. A special swivel
tether system (2,
27) was used to house both the
wires and fluid-filled catheters, which were connected to the recording
system. There were no signs indicating that the system affected the monkey's
daily activities. Throughout the experiment, all animals remained healthy as
evidenced by demeanor and normal appetite. Hemodynamic measurements were
recorded on a digital multiple-channel recorder (PC216Ax, Sony Precision
Technology; Tokyo, Japan) and then analyzed with a computerbased system
(Notocord; Croissy, France). The catheters were connected to pressure
transducers (Datex Ohmeda; Madison, WI) for measurements of aortic and left
atrial pressures, which were calibrated in vitro against a mercury manometer.
LV pressure measured by a miniature solid-state pressure gauge was
cross-calibrated with aortic and left atrial pressure measurements. LV
dP/dt was obtained by electronically differentiating the LV pressure
signal. Cardiac output was measured using a volume Transonic flowmeter.
Cardiac index (CI) was calculated as cardiac output divided by body surface
area (BSA). BSA was calculated as 71.84 · (body weight)0.425
· (height)0.725
(7). Total peripheral
resistance (TPR) was calculated as the quotient of mean aortic pressure and
CI.
Protocol. The following pharmacological agents were administered
through the left atrial catheter to investigate the effects of
-AR
stimulation on LV contractile function and peripheral vascular dynamics:
isoproterenol (Iso; 0.02, 0.05, and 0.1 µg/kg), which stimulates both
1- and
2-AR; norepinephrine (NE; 0.1, 0.2,
and 0.4 µg/kg), which stimulates
- and
-AR; forskolin (FSK;
25, 50, and 75 nmol/kg), which stimulates the catalytic unit of adenylyl
cyclase; and BAY y 5959 (5, 10, and 15 µg ·
kg1 · min1),
an L-type calcium channel promoter, which acts independently of the
-AR
signaling pathway. Except for BAY y 5959, all the agents were administered by
bolus injection. The responses to Iso, NE, FSK, and BAY y 5959 were allowed to
return to baseline values between doses. It was not possible to complete the
protocol on all animals. Animals were excluded from data analysis if they did
not go through the entire drug dose response. However, the smaller numbers of
animals studied in some protocols were always a subset of the overall groups.
The specific numbers for each protocol are included in RESULTS.
Blood sampling. Arterial blood samples were obtained for measuring
baseline plasma concentrations of NE, epinephrine, and estradiol in the
morning before feeding and administration of any agents. NE and epinephrine
were measured with electrochemical detection using high pressure liquid
chromatography (19). Estradiol
was measured by a radioimmunoassay
(13).
Histopathology. After completion of the in vivo experiments, the
animals were euthanized by an overdose of pentobarbital sodium; the uterus and
ovaries were removed from females for histopathological analyses. All samples
were fixed with 10% formalin and paraffin. Sections were cut at 6 µm
thickness and then stained with hematoxylin and eosin. Histopathology of the
aorta was negative for atherosclerosis, as reported previously
(2).
Statistics. All data are expressed as means ± SE. A
repeated one-way ANOVA (SAS Institute; Cary, NC) was used to determine
statistically significant differences among groups, followed by
Student-Newman-Keuls test for post hoc comparison of means. The relation
between the doses of Iso, NE, FSK, and BAY y 5959 was examined by regression
analysis. Comparison of regression lines was performed by determining the
significance of differences in the slope of the lines by the F-test.
A value of P < 0.05 was taken as the minimal level of statistical
significance. The hemodynamic values in
Table 1 were averaged for each
animal from multiple experiments and then averaged for the group. Therefore,
the baseline values in the figures vary slightly, but insignificantly, from
the pooled values in Table
1.
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RESULTS
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Baseline values in conscious monkeys. Baseline data including
hemodynamic parameters and plasma levels of catecholamines in the YM, OM, YF,
and OF groups of conscious monkeys are shown in
Table 1. The body weights were
lower in the female monkeys than in the male monkeys. Because of gender
differences in body weight, cardiac output was indexed to BSA. There were no
differences in LV dP/dt, mean arterial pressure, CI, TPR, and heart
rate among the four groups. Plasma levels of both NE and epinephrine at rest
were significantly elevated (P < 0.05) in the old monkeys compared
with the young monkeys. In the OM group, plasma levels of NE were also higher
(P < 0.05) than those in the OF group. The plasma estradiol levels
were significantly higher (P < 0.05) in the YF group compared with
the YM and OF groups.
Cardiac effects of sympathomimetic amines. Administration of Iso,
NE, and FSK induced dose-dependent increases in LV dP/dt in all
groups (Figs. 1 and
2). However, the increased LV
dP/dt induced by Iso, NE, and FSK were attenuated (P <
0.05) in the OM group compared with the YM group. For example, Iso at a dose
of 0.1 µg/kg increased LV dP/dt less (P < 0.05) in the
OM (+99 ± 11%, n = 8) group than in the YM group (+194
± 18%, n = 14) group (Fig.
3).

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Fig. 1. Representative responses of left ventricular (LV) pressure and the first
derivative of LV pressure (LV dP/dt) to isoproterenol at a dose of
0.1 µg/kg in a conscious young male monkey (A) and an old male
monkey (B). The increase in LV dP/dt was markedly attenuated
in the old monkey compared with the young monkey.
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Fig. 2. Dose-response curves for absolute values of LV dP/dt are shown at
baseline (0 dose) and with graded injections of isoproterenol (Iso;
A), norepinephrine (NE; B), forskolin (FSK; C), and
BAY y 5959 (D) in conscious young male, old male, young female, and
old female monkeys. Values are means ± SE. Regression lines were fitted
to the data. *P < 0.05 vs. the young group.
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Fig. 3. Comparison of the percent change in LV dP/dt, mean arterial
pressure, and heart rate for young and old male and female monkeys in response
to Iso (0.1 µg/kg; A) and NE (0.4 µg/kg; B). The
significant differences (*P < 0.05) are for increases in LV
dP/dt, which were less in old male monkeys, and increases in heart
rate in response to Iso and decreases in heart rate in response to NE, which
were diminished in old male monkeys.
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The response of LV dP/dt to NE at a dose of 0.4 µg/kg was less
(P < 0.05) in the OM (+87 ± 10%, n = 8) group than
in the YM (+150 ± 17%, n = 14) group
(Fig. 3). The response of LV
dP/dt to FSK at a dose of 75 nmol/kg was diminished (P <
0.05) in the OM (+71 ± 16%, n = 8) group compared with the YM
(+144 ± 23%, n = 13) group. In contrast to male monkeys, LV
dP/dt responses were similar in the OF and YF groups. For example,
Iso (0.1 µg/kg), NE (0.4 µg/kg), and FSK (75 nmol/kg) increased LV
dP/dt by 129 ± 15% (n = 7), 129 ± 24%
(n = 6), and 134 ± 21% (n = 7) in the YF group and
125 ± 16% (n = 8), 114 ± 15% (n = 8), and 101
± 12% (n = 7) in the OF group, respectively.
BAY y 5959 induced a dose-dependent increase in LV dP/dt in all
groups. There were no differences between any of the groups
(Fig. 2). For example, BAY y
5959 at an infusion dose of 15 µg · kg1
· min1 increased LV dP/dt by 86
± 10%, 63 ± 6%, 70 ± 12%, and 77 ± 9% in the YM
(n = 8), OM (n = 6), YF (n = 5), and OF (n
= 7) groups, respectively.
The responses of mean arterial pressure and heart rate are compared along
with LV dP/dt for Iso (0.1 µg/kg) and NE (0.4 µg/kg) in OM, YM,
OF, and YF monkeys in Fig. 3.
Mean arterial pressure changes were similar among the groups, but heart rate
increased more in YM than in OM monkeys with Iso and decreased more in YM than
in OM monkeys with NE.
Peripheral vascular effects of sympathomimetic amines.
Administration of Iso and FSK decreased, whereas NE increased, TPR dose
dependently in the YM group. However, the responses of TPR to these three
agents were significantly attenuated (P < 0.05) in the OM group
compared with the YM group. For example, Iso (0.1 µg/kg) decreased TPR
significantly less (P < 0.05) in the OM (28 ± 2%,
n = 8) group than in the YM (49 ± 2%, n = 11)
group (Fig. 4). A
representative example is shown in Fig.
5. Also, FSK (75 nmol/kg) induced a significantly less (P
< 0.05) decrease in TPR in the OM (10 ± 3%, n = 7)
group than in the YM (45 ± 2%, n = 8) group. NE (0.4
µg/kg)-induced TPR increases were also significantly less (P <
0.05) in the OM (+20 ± 9%, n = 7) group compared with the YM
(+67 ± 8%, n = 10) group.

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Fig. 4. Dose-response curves for absolute values of total peripheral resistance
(TPR) are shown at baseline (0 dose) and with graded injections of Iso
(A), NE (B), and FSK (C) in conscious young male,
old male, young female, and old female monkeys. Values are means ± SE.
Regression lines were fitted to the data. *P < 0.05 vs. the young
group.
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Fig. 5. Representative responses of aortic blood flow, mean flow, mean aortic
pressure, and TPR to Iso at a dose of 0.1 µg/kg are shown in a conscious
young male monkey (A) and an old male monkey (B).
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In female monkeys, the responses of TPR to these three agents were similar
among all groups. For example, Iso (0.1 µg/kg) and FSK (75 nmol/kg) reduced
TPR by 37 ± 3% (n = 7) and 26 ± 4%
(n = 7) in the YF group and 36 ± 2% (n = 8)
and 34 ± 5% (n = 6) in the OF group, respectively. NE
(0.4 µg/kg) increased TPR similarly in the YF (38 ± 10%, n
= 7) and OF (25 ± 11%, n = 8) groups.
Histopathology. The YF ovaries were well developed, and multiple
large follicles were observed. In addition, the uterus had a well-developed
endometrial lining. OF monkeys had an atrophic uterus, a poorly developed
endometrium, an increased stroma, and indurated ovaries. Finally, a few
atretic secondary follicles and a small number of primary follicles were found
in OF monkeys. There was no evidence for atherosclerosis in aortic samples
examined histologically.
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DISCUSSION
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Even though there is an important inverse correlation between aging and
-adrenergic responsiveness, almost no data are available in determining
whether this also occurs in older female subjects or experimental animals. The
major finding of the present study was that cardiac contractile and peripheral
vascular dynamic responses to Iso, NE, and FSK were not diminished in
conscious OF compared with YF monkeys, in contrast to the well-documented
-AR desensitization with aging in older male subjects and animals
(9,
30), including the data in OM
monkeys in the present investigation. On the basis of these findings, we
conclude that gender is a key factor involved in
-AR desensitization
with increased age. In view of NE's peripheral vascular action mediated
through
-adrenergic receptors, it is likely that
-adrenergic
responses are also desensitized in OM monkeys, consistent with our prior
findings (3). In the present
investigation, we also utilized a calcium channel promotor, BAY y 5959, to
induce an inotropic effect that is independent of
-adrenergic signaling
by either the
-AR or the catalytic unit of adenylyl cyclase. Clearly,
there were no differences in LV dP/dt responses to any doses of the
calcium channel promoter among the OM, YM, OF, and YF monkeys, suggesting that
the
-adrenergic signal transduction pathway is affected primarily. In
addition, we also found that NE levels were increased less in the OF monkeys
compared with those in the OM monkeys. The increased level of circulating
catecholamines, more prominent in OM than OF monkeys, is consistent with
chronically enhanced sympathetic tone. Because chronically enhanced
-AR
stimulation induces desensitization of the
-AR
(8,
12,
17), these differences in
levels of circulating catecholamines can explain, in part, the desensitization
in old monkeys and, conversely, the preservation of
-AR responsiveness
in OF monkeys. However, the cellular mechanisms underlying these differences
are not established. Indeed, simple
-AR downregulation may not be the
answer in view of the divergent results already in the literature with several
studies finding no decrease in
-AR density, examples of which are cited
here (6,
15,
20,
25). More likely, there are
several genomic and protein mechanisms involved. In addition, it is possible
that the mechanism of desensitization may reside, in part, at the level of the
catalytic unit of adenylyl cyclase, based on almost identical degrees of
desensitization in response to FSK versus Iso. This concept is further
supported by a previous study by O'Connor et al.
(23), which suggested that the
defect may reside at the level of the adenylyl cyclase catalytic unit.
Relatively little has been done on gender differences in
-adrenergic
signaling with age. Consistent with our results, a human study
(21) has shown that muscle
sympathetic nerve activity at rest, both in terms of burst incidence and burst
frequency, was lower in older women compared with older men. Furthermore,
lower muscle sympathetic nerve activity in younger women compared with younger
men was also observed in that study
(21). In the present study,
although it was not statistically different, the responsiveness to
sympathomimetic amines at the highest levels tended to be reduced in YF
compared with YM monkeys. A recent study by Turner et al.
(29) indicated that responses
to Iso were diminished in older female subjects but less than in elderly males
and that the responses in younger females were suppressed compared with
younger males. A companion study by Spina et al.
(28) found that there are
gender differences in response to sympathomimetic amines with exercise
training.
Parasympathetic regulation is also altered with aging
(10,
14,
22). We did not determine
whether parasympathetic responses were affected by aging in this study, which
could have modulated the sympathetic effects, particularly for heart rate
responses. We did observe previously that vascular responses to acetylcholine
were blunted in old monkeys, but this was due primarily to depressed vascular
endothelial function (2).
Although the mechanism that is responsible for the difference between the
OM and OF groups was not determined, it is well known that menopause
constitutes a significant cardiovascular landmark in terms of physiology as
well as pathology. In the present study, the histopathological findings
indicate that the uterus of OF monkeys is in a state of atrophy and the
ovaries are indurated. Moreover, only a few atretic secondary and primary
follicles were found. Additionally, the blood estradiol level was
significantly decreased (Table
1). It is also known that the OF monkeys were infertile for
several years. These data, taken together, indicate that these OF monkeys were
postmenopausal, consistent with previous reports
(18,
24), and despite this
-adrenergic desensitization was not observed.
Increased sympathetic tone and circulating catecholamines are inversely
related to cardiac function and survival in patients with heart failure
(5,
11). Therefore, it is
conceivable that in even older animals and in very aged humans, when
deterioration in cardiac function occurs independently of primary heart
disease, this may occur, in part, as a consequence of chronically enhanced
-adrenergic signaling, as it does in transgenic animals with
overexpression of
-AR, Gs
, or protein kinase A
(1,
8,
12,
17). However, in older but not
senescent humans, myocardial systolic function is not depressed, suggesting
the possibility that chronically enhanced sympathetic tone is a compensatory
mechanism that plays a role in maintaining cardiac function with aging.
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DISCLOSURES
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This study was supported in part by National Institutes of Health Grants
HL-59139, HL-33107, HL-33065, HL-69020, HL-62442, HL-65182, HL-65183, and
AG-14121 and by American Heart Association Grant 0030125N.
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FOOTNOTES
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Address for reprint requests and other correspondence: S. F. Vatner, Chair,
Dept. of Cell Biology and Molecular Medicine, Univ. of Medicine and Dentistry
of New Jersey, New Jersey Medical School, PO Box 1709, 185 S. Orange Ave.,
Medical Science Bldg., G609, Newark, NJ 07101-1709 (E-mail:
vatnersf{at}umdnj.edu).
The costs of publication of this article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
``advertisement'' in accordance with 18 U.S.C. Section 1734 solely to
indicate this fact.
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