Dario Leosco, Guido Iaccarino, Ersilia Cipolletta, Domenico De Santis, Eliana

Pisani, Valentina Trimarco, Nicola Ferrara, Pasquale Abete, Daniela Sorriento,

Franco Rengo and Bruno Trimarco
Am J Physiol Heart Circ Physiol 285:369-374, 2003. First published Mar 13, 2003;
doi:10.1152/ajpheart.00019.2003

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 Am J Physiol Heart Circ Physiol 285: H369–H374, 2003.
First published March 13, 2003; 10.1152/ajpheart.00019.2003.

Exercise restores ␤-adrenergic vasorelaxation

in aged rat carotid arteries
Dario Leosco,1* Guido Iaccarino,2* Ersilia Cipolletta,2 Domenico De Santis,1
Eliana Pisani,1 Valentina Trimarco,2 Nicola Ferrara,3 Pasquale Abete,1
Daniela Sorriento,2 Franco Rengo,1 and Bruno Trimarco2
1
Chair of Geriatrics and 2Chair of Internal Medicine, Department of Clinic Medicine, Cardiovascular,
and Immunological Sciences, University of Naples “Federico II,” 80131 Naples; and 3Department of
Gerontology, Geriatrics, and Metabolic Diseases, II University of Naples, 80131 Naples, Italy
Submitted 14 January 2003; accepted in final form 6 March 2003

Leosco, Dario, Guido Iaccarino, Ersilia Cipolletta,
Domenico De Santis, Eliana Pisani, Valentina Tri-
marco, Nicola Ferrara, Pasquale Abete, Daniela Sorri-
ento, Franco Rengo, and Bruno Trimarco. Exercise re-
stores ␤-adrenergic vasorelaxation in aged rat carotid arter-
nized (7). During the past years, the implications of
impaired ␤-AR signaling in the pathophysiology of sev-
eral cardiovascular disorders were explored in animals
as well as in humans. Data from these studies indicate

Downloaded from ajpheart.physiology.org on February 14, 2009

ies. Am J Physiol Heart Circ Physiol 285: H369–H374, 2003.
First published March 13, 2003; 10.1152/ajpheart.00019.
2003.—Aging is associated with alterations in ␤-adrenergic
receptor (␤-AR) signaling and reduction in cardiovascular re-
sponses to ␤-AR stimulation. Because exercise can attenuate
age-related impairment in myocardial ␤-AR signaling and func-
tion, we tested whether training could also exert favorable
effects on vascular ␤-AR responses. We evaluated common
carotid artery responsiveness in isolated vessel ring prepara-
tions from 8 aged male Wistar-Kyoto (WKY) rats trained for 6
wk in a 5 days/wk swimming protocol, 10 untrained age-
matched rats, and 10 young WKY rats. Vessels were precon-
stricted with phenylephrine (10⫺6 M), and vasodilation was
assessed in response to the ␤-AR agonist isoproterenol (10⫺10-
3 ⫻ 10⫺8 M), the ␣2-AR agonist UK-14304 (10⫺9-10⫺6 M), the
muscarinic receptor agonist ACh (10⫺9-10⫺6 M), and nitroprus-
side (10⫺8-10⫺5 M). ␤-AR density and cytoplasmic ␤-AR kinase
(␤-ARK) activity were tested on pooled carotid arteries. ␤-ARK
expression was assessed in two endothelial cell lines from bo-
vine aorta and aorta isolated from a 12-wk WKY rat. ␤-AR,
␣2-AR, and muscarinic responses, but not that to nitroprusside,
were depressed in untrained aged vs. young animals. Exercise
training restored ␤-AR and muscarinic responses but did not
affect vasodilation induced by UK-14304 and nitroprusside.
Aged carotid arteries showed reduced ␤-AR number and in-
creased ␤-ARK activity. Training counterbalanced these phe-
nomena and restored ␤-AR density and ␤-ARK activity to levels
observed in young rat carotids. Our data indicate that age
impairs ␤-AR vasorelaxation in rat carotid arteries through
␤-AR downregulation and desensitization. Exercise restores
this response and reverts age-related modification in ␤-ARs and
␤-ARK. Our data support an important role for ␤-ARK in
vascular ␤-AR vasorelaxation.
aging; beta-adrenergic receptor; exercise
THE ROLE OF ␤-ADRENERGIC RECEPTOR (␤-AR) in the regu-
lation of the cardiovascular system is widely recog-
that changes in ␤-AR function are associated with
heart failure (6, 38), hypertension (13, 14), and hyper-
tension complicated with ventricular hypertrophy (2).
Upregulation of ␤-AR kinase 1 (␤-ARK, also known
as the G protein-coupled receptor kinase 2) has been
recognized as one of the mechanisms responsible for
␤-AR dysfunction (29). Transgenic mice with cardiac
overexpression of ␤-ARK show a depressed contractile
response to isoproterenol (Iso) (22). In the failing hu-
man heart the uncoupling of cardiac ␤1- and ␤2-ARs
from G proteins has been attributed to increased levels
of myocardial ␤-ARK (38). Abnormalities of ␤-AR sig-
naling due to increase in ␤-ARK activity have been
observed in both human (14) and animal (10, 13) hy-
pertension.
Interestingly, similar alterations in vascular and
cardiac ␤-AR function were found with physiological
aging (8, 24). In the rat myocardium, the age-related
decline in ␤-AR responsiveness was ascribed to ␤-AR
desensitization and uncoupling of ␤-ARs from stimu-
lating G proteins (30). Similarly, vascular reactivity
studies conducted in the aorta of aged rats (4) or in the
dorsal hand vein and saphenous vein of elderly hu-
mans (26) showed a reduced vasorelaxant response to
␤-AR agonists such as Iso. The recently demonstrated
␤-AR desensitization in aged rat aorta due to ␤-ARK
upregulation has been proposed as one of the molecular
mechanisms responsible for age-related ␤-AR dysfunc-
tion and decreased vasorelaxation (31).
Regular physical activity may counteract the decline
of cardiovascular function observed with age (11, 33).
Improvements in left ventricular performance, includ-
ing higher maximal stroke volume, ejection fraction,
and cardiac output and lower resting and exercise
peripheral vascular resistances, are beneficial effects
of exercise in the elderly related to enhanced cardio-
vascular ␤-AR responsiveness (1, 32).

* D. Leosco and G. Iaccarino contributed equally to this work. The costs of publication of this article were defrayed in part by the
Address for reprint requests and other correspondence: D. Leosco, payment of page charges. The article must therefore be hereby
Cattedra di Geriatria, Università degli Studi di Napoli “Federico II,” marked ‘‘advertisement’’ in accordance with 18 U.S.C. Section 1734
Via Sergio Pansini 5, 80131 Naples, Italy (E-mail: dleosco@unina.it). solely to indicate this fact.

http://www.ajpheart.org 0363-6135/03 $5.00 Copyright © 2003 the American Physiological Society H369
H370 EXERCISE AND AGE-IMPAIRED ␤-ADRENERGIC VASODILATION
The ability of exercise to attenuate the age-related
alterations in ␤-AR function was demonstrated in ex-
perimental studies conducted on aged rat myocardium
(30). Whether physical activity may improve ␤-AR re-
sponsiveness by modulating ␤-ARK levels in aging
vasculature has not yet been explored. To investigate
this issue, we conducted a study exploring the vasore-
laxant responses to ␤-AR stimulation of rat carotids
from aged trained and untrained animals. Vascular
reactivity data were correlated with exercise-induced
changes in vascular ␤-ARK activity. Because ␤-AR
vasorelaxation in the rat carotid is largely endothelium
dependent, we confirmed for the first time that ␤-ARK
is indeed expressed in the endothelium.
METHODS
Endothelial cell culture and ␤-ARK expression. Two endo-
thelial cell lines from bovine aorta (BAEC; American Type
Culture Collection) and aorta isolated from a 12-wk-old
Wistar-Kyoto (WKY) rat as previously described (20) were
assessed for ␤-ARK expression. Cells were cultured to 75%
confluence in DMEM-10% FBS, washed twice in phosphate-
buffered saline, and then Dounce homogenized with an insu-
lin syringe in 25 mM Tris 䡠 HCl (pH 7.5), 5 mM EDTA, 5 mM
EGTA, 10 ␮g/ml leupeptin, 20 ␮g/ml aprotinin, and 1 mM
PMSF. Soluble cytosol fractions were separated from mem-
brane fractions by centrifugation. Alternatively, cells were
solubilized with ice-cold 50 mM Tris 䡠 HCl (pH 8.0), 5 mM
EDTA, 150 mM NaCl, 1% Nonidet P-40, 0.5% sodium deoxy-
cholate, 0.1% SDS, 10 mM NaF, 5 mM EGTA, 10 mM sodium
pyrophosphate, and 1 mM PMSF and ␤-ARK was immuno-
precipitated from 200 ␮g of protein from clarified extracts
with 1:2,000 of a monoclonal anti-␤-ARK1/2 (C5/1) antibody
(19) and 35 ␮l of a 50% slurry of protein A agarose conjugate
agitated for 1 h at 4°C. Cytosol fractions or immune com-
plexes were resolved on 10% polyacrylamide Tris-glycine gels
and transferred to nitrocellulose. The 80-kDa ␤-ARK protein
was visualized with a commercially available polyclonal an-
tibody (SC-562; Santa Cruz) and a standard chemilumines-
cence technique (Renaissance; NEN).
Rat strain and training protocol. The study protocol was
designed in accordance with the American Physiological So-
ciety’s “Guiding Principles for Research Involving Animals
and Human Beings” and approved by the ethics committee of
our institution. Ten aged male WKY rats (age ⫽ 24 mo; wt ⫽
490 ⫾ 40 g) were trained according to Orenstein et al. (25).
The training program lasted 6 wk, starting with a 5 min/day,
5 days/wk swimming exercise that was gradually increased
over the period until the rats were swimming continuously
for 40 min/day. The rats swam in groups of four in a 60-cm-
deep tub with water temperature maintained constant at
35°C and were air-dried after each session. Of 10 trained
Fig. 1. ␤-Adrenergic receptor (␤-AR) kinase 1 (␤-ARK) expression in endothelial cells. To test the expression of the
kinase we performed Western blot of cytosolic extracts from bovine (lane 1) and rat (lane 2) aorta endothelial cells
and immunoprecipitation of cytosolic ␤-ARK from bovine (lane 4) and rat (lane 5) endothelial cells in culture. As
positive control we used purified bovine ␤-ARK (lanes 3 and 6). Arrow indicates 80-kDa molecular mass marker.
AJP-Heart Circ Physiol • VOL
animals, 2 did not complete the exercise protocol because of
injuries (n ⫽ 1) or death (n ⫽ 1) unrelated to swimming.
Ten aged male WKY rats (age ⫽ 24 mo; wt ⫽ 480 ⫾ 30 g)
maintained under sedentary conditions were dipped in a
10-cm-deep tub containing water at temperature maintained
constant at 35°C for 30 min for 5 days/wk. Ten young male
WKY rats (age ⫽ 4 mo; weight ⫽ 340 ⫾ 40 g), under the same
protocol used for aged sedentary animals, completed the
animal population of this study. Care was taken to avoid
sedentary rats swimming or making any physical effort dur-
ing the bath. Total protocol duration was 6 wk, and all
sedentary animals completed this period in good condition.
Vascular reactivity studies. All animals were anesthetized
with a mixture of ketamine (50 mg/kg) and xylazine (0.5
mg/kg) and killed by decapitation. Right and left common
carotid arteries were rapidly dissected free and cut into
4-mm-long rings. Vascular reactivity studies were conducted
as previously described (20).
␤-AR-mediated vasorelaxation was assayed after phenyl-
ephrine (PE; 10⫺6 M) by the addition of increasing amounts
of Iso (10⫺10-3 ⫻ 10⫺8 M). Dose-response curves to Iso were
Downloaded from ajpheart.physiology.org on February 14, 2009
also evaluated after nitric oxide (NO) synthase inhibition
with N␻-monomethyl-L-arginine (L-NMMA; 10⫺5 M).
Endothelium-dependent vasodilation was assessed with
the muscarinic receptor agonist ACh and the ␣2-AR agonist
UK-14304 (10⫺9-10⫺6 M) (34). Endothelium-independent va-
sodilation was evaluated in response to nitroprusside (10⫺8-
10⫺5 M).
␤-AR density and cytosolic ␤-ARK activity in rat carotids.
Rat carotids were pulverized in a liquid nitrogen-chilled
stainless steel Dounce homogenizer and resuspended in 250
␮l of ice-cold lysis buffer [25 mM Tris 䡠 HCl (pH 7.5), 5 mM
EDTA, 5 mM EGTA, 10 ␮g/ml leupeptin, 20 ␮g/ml aprotinin,
and 1 mM PMSF]. Cytosolic and membrane fractions were
separated by serial centrifugation (19).
Receptor binding on pooled rat carotid membranes was
performed with the nonselective ␤-AR ligand 125I-labeled
cyanopindolol. Nonspecific binding was determined in the
presence of 10 ␮M alprenolol. Reactions were conducted in
100 ␮l of binding buffer at 37°C for 1 h and then terminated
by vacuum filtration through glass fiber filters. All assays
were performed in triplicate, and receptor density (in fmol)
was normalized to milligrams of membrane protein. ␤-ARK
activity was tested by rhodopsin phosphorylation assays on
rat carotid cytosolic extracts as previously described (19).
Statistical analysis. All values are presented as means ⫾
SE. A one-way ANOVA was performed to separately test the
main effects of age and exercise training in adult and seden-
tary and trained aged rats. Dose-response curves to all drugs
used were analyzed by a two-way ANOVA for repeated mea-
sures with Bonferroni’s post hoc analysis. ␤-AR density and
␤-ARK activity values from different groups were compared
285 • JULY 2003 • www.ajpheart.org
 EXERCISE AND AGE-IMPAIRED ␤-ADRENERGIC VASODILATION H371

Table 1. Body and left ventricular weights in young demonstrated before. In rat and bovine vascular endo-
and untrained and trained aged rats thelium we showed ␤-ARK expression by Western blot
on whole cell lysate or cytosol immunoprecipitation
Aged
(Fig. 1).
Young Untrained Trained Effect of age and training on whole body and left
BW, g 385 ⫾ 6 601 ⫾ 6* 572 ⫾ 8†‡ ventricle weight. Whole body and left ventricle weight
LW, mg 1.11 ⫾ 0.02 1.56 ⫾ 0.03* 1.61 ⫾ 0.02† and left ventricle-to-body weight ratio of study groups
LW/BW, mg/g 2.88 ⫾ 0.05 2.60 ⫾ 0.47* 2.83 ⫾ 0.07§ are shown in Table 1. Both trained and untrained aged
Values are means ⫾ SE. BW, body weight; LW, left ventricular wet animals had significantly greater body and left ventric-
weight. * Age effect significant at P ⬍ 0.001 between young and ular weights than young rats. A significant training
untrained aged rats. † Age effect significant at P ⬍ 0.01 between effect was observed between untrained and trained
young and trained aged rats. ‡ Training effect significant at P ⬍ 0.01 aged rats, trained being leaner than untrained aged
between untrained and trained aged rats. § Training effect signifi-
cant at P ⬍ 0.05 between untrained and trained aged rats. rats. Accordingly, the left ventricle-to-body weight ra-
tio was smaller in aged trained than young and aged
untrained animals.
by a one-way ANOVA analysis. A P value ⬍0.05 was consid- Vasoreactivity studies. Maximal vasoconstriction in-
ered statistically significant. duced by PE (10⫺6 M) was 572.5 ⫾ 49.9 mg in young,
RESULTS
537.5 ⫾ 44.3 mg in untrained aged, and 577.5 ⫾ 54.7
mg in trained aged animals (P ⫽ not significant be-

Downloaded from ajpheart.physiology.org on February 14, 2009

␤-ARK is expressed in endothelium. Although ␤-ARK tween groups, ANOVA).
expression has been postulated to be ubiquitous, the ISO-induced vasorelaxation was lower in untrained
presence of ␤-ARK in the endothelium has never been aged than in young and trained aged animals (Fig. 2A);

Fig. 2. Effects of aging and training on

vasorelaxant responses of common ca-
rotid arteries from Wistar-Kyoto
(WKY) rats. Vasorelaxation was tested
in response to the ␤-AR agonist isopro-
terenol (A), isoproterenol ⫹ N␻-mono-
methyl-L-arginine (L-NMMA) (B), the
muscarinic agonist ACh (C), the ␣2-AR
agonist UK-14304 (D), and the endo-
thelium-independent vasodilator nitro-
prusside (E). Open circles, young ca-
rotids; black circles, untrained aged ca-
rotids; gray circles, trained aged
carotids. *F ⫽ 4.598, P ⬍ 0.0001; †F ⫽
2.409, P ⬍ 0.05; §F ⫽ 5.593, P ⬍ 0.01
(2-way ANOVA).

AJP-Heart Circ Physiol • VOL 285 • JULY 2003 • www.ajpheart.org

H372 EXERCISE AND AGE-IMPAIRED ␤-ADRENERGIC VASODILATION
differences between groups were abolished by
L-NMMA to demonstrate that the age-impaired vasore-
laxation in untrained aged animals was mainly related
to a defect in the endothelium-mediated component of
vasodilation induced by Iso (Fig. 2B).
ACh-induced vasodilation was lower in untrained
aged than in trained aged and young animals (Fig. 2C).
These data indicate that exercise induces a favorable
effect on muscarinic response.
In contrast, exercise was not able to restore the
␣2-AR-mediated vasorelaxation to UK-14304, which
was depressed in untrained and trained aged animals
compared with young animals (Fig. 2D). Responses to
nitroprusside were not different between groups (Fig.
2E). This demonstrates that the endothelium-indepen-
dent component of vasodilation was unaffected by age
and physical conditioning.
␤-AR density and ␤-ARK activity. Carotid ␤-AR den-
sity was significantly affected by age as demonstrated
by its reduction in untrained aged compared with
young animals. Exercise increased ␤-AR density to
values not statistically different from those measured
in young rats (Fig. 3A).
Fig. 3. Effects of aging and training on vascular ␤-AR signaling
components [␤-AR density (A) and ␤-ARK activity (B and C)] by
rhodopsin phosphorylation in common carotid arteries from WKY
rats. *P ⬍ 0.01; one-way ANOVA.
AJP-Heart Circ Physiol • VOL
␤-ARK activity in cytosol carotid extracts from
young, untrained aged, and trained aged animals was
assessed by rhodopsin phosphorylation. In untrained
aged animals total carotid ␤-ARK activity was in-
creased nearly twofold over that recorded in young
animals. Physical exercise significantly reduced the
kinase activity to levels similar to those observed in
young animals (Fig. 3B).
DISCUSSION
This study shows that aging is associated with a
significant reduction of vascular ␤-AR response caused
by receptor downregulation and desensitization with
functional consequences of the senescent vasculature.
Physical training shows a favorable effect on vascular
reactivity of aged rat carotids and corrects age-im-
paired vascular ␤-AR vasodilation by increasing ␤-AR
density and reducing cytoplasmic ␤-ARK activity.
Downloaded from ajpheart.physiology.org on February 14, 2009
To our knowledge, this is the first study to investi-
gate the relationship between abnormalities of the
␤-AR pathway and impaired vasorelaxation in aged rat
carotid artery. Our data clearly indicate that carotid
responsiveness to ␤-AR stimulation is blunted in aged
sedentary rats compared with young rats and that the
reduced vasorelaxation is associated with a decrease of
␤-AR density in whole artery preparation. The pres-
ence of ␤-AR downregulation in the senescent vascula-
ture is controversial because different studies explor-
ing the age-related changes in vascular ␤-AR pathway
provide opposite results (15, 37). Our study confirms
that the vascular ␤-AR number is reduced in aged
sedentary rats and extends previous evidences by
showing that exercise training corrects this abnormal-
ity.
Our data also point to ␤-ARK upregulation as a
possible mechanism of ␤-AR dysfunction in aged rat
carotids. The important role of increased cardiac
␤-ARK in the pathophysiology of ␤-AR signaling has
been consolidated in animal and human models of
heart failure (29). At the vascular level, increased
␤-ARK protein expression was demonstrated in spon-
taneously hypertensive rats, suggesting that increased
␤-ARK activity might account for the impairment of
␤-AR-mediated vasodilation observed in hypertension
(13, 14). Consistent with this, a recent report showed
impaired ␤-AR vasorelaxation and hypertension in
transgenic mice with selective overexpression of
␤-ARK in vascular smooth muscle cells (10). Our re-
sults indicate that vascular ␤-ARK is increased and
participates in the deterioration of vasodilation to
␤-AR stimulation also in aging. The present study
extends a previous report showing the relationship
between the increase in ␤-ARK activity and the decline
in ␤-AR-mediated signaling occurring with age (31)
and for the first time demonstrates that exercise re-
duces vascular ␤-ARK activity and exerts a beneficial
effect on ␤-AR vasorelaxation.
We also provide a demonstration that ␤-ARK is ex-
pressed in the endothelium and suggest that endothe-
lial ␤-ARK has physiological implications in the control
285 • JULY 2003 • www.ajpheart.org
 EXERCISE AND AGE-IMPAIRED ␤-ADRENERGIC VASODILATION
of the vascular tone. Indeed, in rat carotids ␤-AR va-
sorelaxation is largely endothelium dependent (20).
The physiological relevance of endothelial ␤-ARs is
supported by their distribution in the vasculature. Ev-
idence is mounting that ␤-AR vasorelaxation is largely
endothelium dependent in a wide range of vascular
regions that actively participate in the determination
of total peripheral resistances (9, 16, 23). Furthermore,
in vivo studies in cat hindlimb (12), canine coronary
artery (27), and newborn pial arteries (28) suggest that
the endothelium dependence of ␤-AR vasorelaxant re-
sponses is generalized.
Although the role of ␤-ARK in ␤-AR phosphorylation
and desensitization is well recognized, several studies
show a possible implication in the regulation of other
receptor signaling. To this regard, the recent observa-
tion of cross talk between M3 muscarinic receptors and
␤-AR in terms of receptor phosphorylation and desen-
sitization (3, 36) and the demonstration that ␤-ARK
may phosphorylate M3 and M2 muscarinic receptors
(18) provide a possible explanation for our results on
the reduced ACh-mediated vasorelaxation in carotids
of untrained aged animals. The reduction in vascular
␤-ARK activity obtained in trained aged rats could also
contribute to improve muscarinic receptor responsive-
ness and explain our and previous results on the en-
hanced ACh-mediated vasodilation after training
(5, 21).
Several studies suggest that the main mechanism by
which exercise improves impaired vasodilation is in-
creased endothelial NO bioavailability (17, 35). Our
data are only in apparent contrast with these previous
observations. In fact, we agree on the crucial role
played by increased endothelial NO release in the
enhanced endothelium-dependent vasorelaxation in-
duced by exercise.
Nevertheless, we also affirm that activation of the
NO pathway is related to the specific improvement in
␤-AR signaling observed in trained animals. If the only
mechanism by which exercise exerted its favorable
effects on endothelium-dependent vasorelaxation was
the enhancement of NO availability, all the vascular
responses implying NO as final mediator would have
been enhanced after training. This is not the case,
because our data indicate that vasorelaxant response
to ␣2-AR stimulation was still impaired in trained aged
animals. Therefore, we propose that exercise may im-
prove age-impaired endothelium-dependent vasorelax-
ation by interfering with specific receptor signal trans-
duction pathways. Our data suggest the importance of
the integrity of vascular ␤-AR signaling for maintain-
ing adequate levels of endothelial NO production and
preserving the endothelial control of vascular tone.
This observation is supported by the recent demonstra-
tion that the overexpression of ␤2-ARs, via adenovirus-
mediated gene transfer to the vascular endothelium of
the carotid artery, is able to correct impaired ␤-AR
vasorelaxation in hypertensive rats (20).
The favorable effects of exercise on vascular age-
related changes in ␤-AR responsiveness and in the
postreceptor adrenergic pathway reported in this study
AJP-Heart Circ Physiol • VOL
H373
are similar to those previously observed in aged rat
myocardium (33). In fact, chronic dynamic exercise
attenuates the age-determined alterations in postre-
ceptor elements of cardiac signal transduction. This
suggests the potential role of physical activity in a
global cardiovascular improvement in ␤-AR function.
Our study may contribute to a better understanding
of the mechanisms underlying the physiological aging
of the cardiovascular system, providing important in-
sights about the clinical manifestation of cardiovascu-
lar disease in the elderly population. ␤-AR downregu-
lation and desensitization phenomena in senescent
vasculature may partly explain the reduced cardiovas-
cular adaptations to different stressors occurring with
age and may contribute to the vulnerability of the
cardiovascular system typical of the aging process.
Changes in ␤-AR signaling could explain the progres-
sion with age of endothelial dysfunction, which is a
common finding in pathological conditions such as cor-
Downloaded from ajpheart.physiology.org on February 14, 2009
onary and peripheral artery disease, hypertensive sta-
tus, and heart failure.
It seems reasonable to affirm that physiological ag-
ing is characterized by an altered vascular ␤-AR reac-
tivity, which may be one of the molecular backgrounds
for the development of cardiac and vascular diseases.
The ability of physical activity to counteract the bio-
chemical abnormalities related to endothelial dysfunc-
tion and impaired vascular reactivity suggests its po-
tentially useful role in the prevention, treatment, and
prognosis of cardiovascular diseases in the elderly.
This work was funded in part by a grant of the Ministry of
Education, University, and Scientific Research, 2001, Rome, Italy.
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