Vascular Sensitivity to Phenylephrine in Rats Submitted to
Anaerobic Training and Nandrolone Treatment
Tatiana Sousa Cunha, Maria José Costa Sampaio Moura, Celene Fernandes Bernardes,
Ana Paula Tanno, Fernanda Klein Marcondes
Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017
Abstract—The effect of anaerobic physical training and nandrolone treatment on the sensitivity to phenylephrine in
thoracic aorta and lipoprotein plasma levels of rats was studied. Sedentary and trained male Wistar rats were treated with
vehicle or nandrolone (5 mg/kg IM; twice per week) for 6 weeks. Training was performed by jumping into water (4 sets,
10 repetitions, 30-second rest, 50% to 70% body weight load, 5 days/week, 6 weeks). Two days after the last training
session, the animals were killed and blood samples for lipoprotein dosage were obtained. Thoracic aorta was isolated
and concentration– effect curves of phenylephrine were performed in intact endothelium and endothelium-denuded
aortic rings in the absence or presence of NG-L-arginine-methyl ester. No changes were observed in endotheliumdenuded aortic rings. However, in endothelium-intact thoracic aorta, anaerobic physical training induced subsensitivity
to phenylephrine (pD2⫽7.11⫾0.07) compared with sedentary group (7.55⫾1.74), and this effect was canceled by the
inhibition of nitric oxide synthesis. No difference was observed between trained (7.22⫾0.07) and sedentary (7.28⫾0.09)
groups treated with nandrolone. Anaerobic training induced an increase in high-density lipoprotein levels in
vehicle-treated rats, but there were no changes in nandrolone-treated groups. Training associated with nandrolone
induced an increase in low-density lipoprotein levels but no change in the other groups. If altering endotheliumdependent vasodilatation is considered to be a beneficial adaptation to anaerobic physical training, it is concluded that
nandrolone treatment worsens animals’ endothelial function, and this effect may be related to lipoprotein blood levels.
(Hypertension. 2005;46[part 2]:1010-1015.)
Key Words: aorta 䡲 endothelium 䡲 exercise 䡲 lipoproteins 䡲 nitric oxide 䡲 phenylephrine 䡲 rats
A
nabolic androgenic steroids (AAS) are formed from
testosterone or one of its derivatives and present both
anabolic and androgenic effects. Although the therapeutic
indications of AAS are hypogonadism and protein metabolism deficiency, high doses of AAS are frequently used by
persons in good health to improve physical performance and
appearance, and this practice results in serious health risks.1
With regard to the cardiovascular system, it is well known
that AAS can cause stroke,2 ischemic heart disease, myocardial infarction,3 electrocardiographic alterations,4 and sudden
cardiac death.5 However, there are few studies about their
effects on vascular reactivity. Ferrer et al6 observed an
inhibition of endothelium-dependent and endotheliumindependent relaxation in the aortic rings of rabbits treated
with nandrolone. Vasoconstrictor responses to angiotensin
and tyramine, but not to noradrenaline, and vasodepressor
responses to acetylcholine are reduced in testosterone-treated
dogs.7
Although it is well documented that postexercise hypotension results from a decrease in systemic vascular resistance
after aerobic exercise, both in humans and animals,8 there are
no data about the vascular effects of anaerobic training.
Because the use of supraphysiological doses of AAS is
frequently associated with anaerobic exercise, the aim of this
study was to determine its influence, as well as that of
nandrolone treatment, on the sensitivity to phenylephrine in
the thoracic aorta of rats.
Because vascular wall properties are influenced by highdensity lipoprotein (HDL) and low-density lipoprotein (LDL)
levels, and because androgenic steroids have different effects
on blood concentration of HDL and LDL,6,9 the serum levels
of these lipoproteins were also evaluated.
Methods
Animals
Fifty-three male Wistar rats (60 days old) were housed in a
temperature-controlled room with a 12:12-hour light– dark cycle.
Water and rodent chow were provided ad libitum. After approval by
the institutional Committee for Ethics in Animal Research (protocol
number 391-1), the rats were randomized into 4 groups: sedentary
Received April 28, 2005; first decision May 23, 2005; revision accepted June 8, 2005.
From Department of Physiological Sciences (T.S.C., A.P.T., F.K.M.), Faculty of Dentistry of Piracicaba, State University of Campinas, Piracicaba, Sao
Paulo, Brazil; Laboratory of Physiology (M.J.C.S.M.), Life Sciences Center, Pontifical Catholic University of Campinas, Campinas, Sao Paulo, Brazil;
Laboratory of Biochemistry (C.F.B.), Life Sciences Center, Pontifical Catholic University of Campinas, Campinas, Sao Paulo, Brazil.
Correspondence to Fernanda Klein Marcondes, PhD, Departamento de Ciências Fisiológicas, Faculdade de Odontologia de Piracicaba, Universidade
Estadual de Campinas, FOP/UNICAMP, Av. Limeira, 901, 13414-903 Piracicaba, Sao Paulo, Brazil. E-mail [email protected]
© 2005 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
DOI: 10.1161/01.HYP.0000174600.51515.e7
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Cunha et al
Effect of Exercise and Nandrolone in Rat Aorta
1011
vehicle-treated, trained vehicle-treated (vehicle⫽propilenglycol: 0.2
mL body weight twice per week, intramuscularly, for 6 weeks),
sedentary nandrolone-treated, and trained nandrolone-treated (nandrolone decanoate; Organon; 5 mg/kg body weight twice per week,
intramuscularly, for 6 weeks).10 This dose is comparable to the dose
that has been reported as being frequently used by heavy abusers of
AAS.11
Maximum Response (mg/100 mg Tissue) and pD2 Values of
Phenylephrine in Endothelium-Intact and Endothelium-Denuded
Thoracic Aortic Rings, Isolated From Sedentary or Trained Rats,
Treated With Vehicle or Nandrolone Decanoate
Training Protocol
Groups
The anaerobic training protocol has been described previously.
Briefly, after 1 week of water adaptation the rats were exercised by
jumping into the water (30⫾2°C), once per day for 5 days, for 5
weeks, carrying a load of 50% body weight strapped to the chest,
with 30 seconds of rest between each set of jumps. In the third and
fourth training weeks, the animals performed the same exercise
carrying a load of 60% body weight, and in the last week, this load
was adjusted to 70% of body weight. The weights were attached to
the animals’ chests not only to avoid flotation but also to make them
exercise against an overload, simulating the squat exercise in water.
10
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Blood Sampling, Tissue Collection, and
Analytic Methods
Forty-eight hours after the last exercise session, the rats were
anesthetized under halothane, and blood was immediately collected
from left renal vein10 and centrifuged to separate the serum. Seric
total cholesterol, HDL, and LDL were determined using commercially available kits (Laborlab). The animals were killed by pneumothorax and the thoracic aorta was excised and dissected free of
fatty and connective tissue before being cut into 2 3-mm-long to
5-mm-long rings.
Concentration–Effect Curve
Two matched rings, taken from the same animal, were obtained from
the middle portion of each aorta and used for functional assays as
previously described.12 Briefly, cumulative concentration– effect
curves for phenylephrine (PE) were obtained from one ring with
intact endothelium and the other without endothelium. To evaluate
the role of nitric oxide (NO) on the modulation of thoracic aorta
sensitivity to PE, rings with intact endothelium obtained from other
animals were incubated for 40 minutes with the NO synthesis
inhibitor, NG-L-arginine-methyl-ester (L-NAME) (10⫺5 M) before
concentration– effect curves. Changes in thoracic aorta sensitivity to
PE were evaluated by determining the concentration that produced
50% of the maximum response (EC50) and were expressed as the
mean negative logarithm (pD2).
Statistical Analysis
Statistical differences were determined by 2-way analysis of variance
(ANOVA) followed by the Tukey test. Differences were considered
significant at P⬍0.05. The results are presented as means⫾SEM.
Results
Neither physical training nor nandrolone treatment altered the
maximum response of isolated thoracic aorta to PE (Table).
There was subsensitivity to PE in endothelium-intact thoracic
aorta rings isolated from trained rats treated with vehicle
when compared with the respective sedentary group also
treated with vehicle (Table), with 2.8-fold shift to the right in
the concentration– effect curve (Figure 1) (P⬍0.05). However, physical training did not induce any changes in the
sensitivity to PE in endothelium-intact thoracic aorta rings
isolated from AAS treated animals. There was no difference
among the groups in the sensitivity to PE of endotheliumdenuded aortic rings (Table and Figure 1) (P⬎0.05). In the
presence of the NO synthesis inhibitor, L-NAME, no alterations in the sensitivity to PE were observed in endothelium-
Endothelium-Intact Rings
Endothelium-Denuded Rings
Maximum
Response
Maximum
Response
pD2
pD2
Sedentary vehicle
13.7⫾1.7
7.55⫾1.74
12.5⫾1.8
7.82⫾0.07
Trained vehicle
14.1⫾1.2
7.11⫾0.07*
19.9⫾1.6
7.86⫾0.12
Sedentary nandrolone
13.3⫾1.5
7.28⫾0.09
13.0⫾1.6
7.74⫾0.08
Trained nandrolone
16.7⫾1.8
7.22⫾0.07
17.2⫾2.8
7.89⫾0.04
pD2 ⫽ Negative logarithm of the molar concentration of agonist producing
50% of the maximum response.
No. of experiments indicated in Figure 1.
The values are expressed as means⫾SEM.
*P⬍0.05 compared to the respective sedentary group.
intact thoracic aorta (Figure 2) (P⬎0.05). No changes were
observed in the serum concentration of total cholesterol
among the groups (Figure 3) (P⬎0.05). Rats treated with
vehicle and submitted to anaerobic physical training presented higher levels of HDL compared with the respective vehicle
sedentary group and trained AAS-treated group (Figure 3)
(P⬍0.05), with no changes between AAS-treated sedentary
and trained rats (Figure 3) (P⬎0.05). Although anaerobic
training did not change LDL seric levels in vehicle-treated
animals, trained rats treated with nandrolone presented higher
levels of LDL compared with the respective sedentary group
(Figure 3) (P⬍0.05).
Discussion
According to clinical, epidemiological, and pathological studies, aerobic physical activity appears to play an important role
in the treatment and prevention of several cardiovascular
diseases. Previous studies demonstrated that regular exercise
could reduce sympathetic tone,13 depress the pressor response
to norepinephrine,14 attenuate baroreflex,15 and improve the
bioavailability of endogenous NO in rodents and humans.16,17
Despite some well-documented adaptations with regard to
vascular responsiveness after aerobic training, there are no
data about the effect of anaerobic training on vascular
reactivity.
The anaerobic nature of the high-resistance exercise protocol used in this study was confirmed by a previous study,18
because blood lactate concentration after the second set of
jumps was ⬎5.5 mmol/L, the maximal lactate steady-state for
rats.19 Moreover, it was demonstrated that this protocol was
also efficient for inducing skeletal muscle hypertrophy in
rats.19
Because supra-physiological AAS dose users are frequently anaerobic exercise practitioners, it was of interest to
evaluate the effects of weight-lifting and AAS treatment on
vascular responsiveness. Therefore, the aorta sensitivity to PE
was analyzed in rats. Anaerobic training induced subsensitivity to PE in thoracic aorta isolated from vehicle - treated rats
compared with the respective sedentary group, with no
changes between the 2 groups (trained and sedentary) treated
with AAS.
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October 2005 Part II
Figure 1. Concentration– effect curves for
phenylephrine obtained in endotheliumintact and endothelium-denuded thoracic
aorta rings, isolated from sedentary and
trained rats, treated with vehicle or nandrolone. *P⬍0.05 compared with the
respective sedentary group (2-way
ANOVA⫹Tukey).
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It has been hypothesized that the decrease in arterial
pressure, induced by physical exercise, is related to an
increase in the vasodilator20 –23 and a decrease in the vasoconstrictor responsiveness of blood vessels.24 Support for this
hypothesis has been shown in response to different physical
exercise programs. Abdominal aorta obtained from treadmilltrained rabbits presented higher endothelium-dependent vasorelaxation induced by acetylcholine (ACh). Thoracic aorta
from rats submitted to swimming during 6 weeks showed a
decrease in response to PE, but not to potassium chloride,25 as
also reported in porcine coronary arteries.26 The aortic subsensitivity to PE observed after anaerobic training in the
present study suggests that even in response to the metabolic
demands of different physical exercises (aerobic versus anaerobic), vascular adaptations are established to promote a
decrease in arterial blood pressure. Moreover, this response
can be related to endothelial adaptations to the higher blood
flow induced by aerobic and anaerobic exercise training.27
This subsensitivity to PE was only observed in endothelium-intact aortic rings, with no changes in endotheliumdenuded aorta, indicating that this effect is endotheliumdependent. Moreover, this effect was canceled by aorta
pre-incubation with the nitric oxide synthase (NOS) inhibitor
L-NAME.
In the presence of NOS inhibitors, the exercise-induced
enhancement of endothelium-dependent vasorelaxation is
abolished.20,23 Thoracic aortas isolated from swimming
trained rats were also subsensitive to PE, and this effect was
caused by an increase in NO production by endothelial
cells.25 Delp and Laughin21 reported an upregulation of the
expression of endothelial cell NOS mRNA in thoracic aorta
from rats submitted to 4 to 10 weeks of training. These results
are consistent with others who have reported an increase in
NOS mRNA levels in aorta of exercise-trained dogs,28 and in
coronary resistance vessels of exercise-trained pigs.29 The
expression of inducible NOS and endothelial NOS mRNA
were increased in endothelial cells by chronic treadmill
training, and chronic exercise blunted PE-induced vascular
responses, probably by increasing NO release via inducible
NOS, in rat thoracic aorta.30
In this context, the high-intensity training protocol used
here may also cause greater release of NO, which diminishes
or antagonizes the vasoconstrictor effects of PE. This could
explain the subsensitivity observed in thoracic aorta isolated
from trained rats compared with the sedentary group. In
support of this hypothesis, the lower sensitivity to the
vasoconstrictor effect of PE in the trained group was canceled
by the inhibition of NO production by L-NAME.
Figure 2. Concentration– effect curves for
phenylephrine, obtained in the presence
of L-NAME, in endothelium-intact thoracic aorta rings, isolated from sedentary
or trained rats, treated with vehicle or
nandrolone.
Cunha et al
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Figure 3. Seric levels of lipoproteins from sedentary (S) or
trained (T) rats, treated with vehicle (V) or nandrolone (N).
*P⬍0.05 compared with SV and TN groups. **P⬍0.05 compared
with SN group (2-way ANOVA⫹Tukey; P⬍0.05). N⫽9 to 10.
However, when anaerobic training was associated with
AAS treatment, no changes in aorta responsiveness to PE
were observed, suggesting that this hormone interferes in NO
production or in some other mechanisms involved in the
vascular effects of PE.
Different results have been reported concerning the effects
of AAS in vascular reactivity. Perfused canine hind limb
vasoconstrictor responses to angiotensin and tyramine and
vasodepressor response to ACh were reduced in testosteronetreated animals, whereas the vasoconstrictor effect of noradrenaline was not altered.7 However, the pressor response
elicited by noradrenaline was reduced by testosterone in
spinal cats.31
Effect of Exercise and Nandrolone in Rat Aorta
1013
Moreover, the testosterone vascular effect mechanisms
have not also been clearly identified. It has been demonstrated that in rat aorta, testosterone causes endotheliumdependent vasorelaxation, which is likely to be mediated by
activation of NO activity.32 However, NOS inhibition had no
effect on vasorelaxation by testosterone in rabbit aorta.33
Other studies reported that endothelium- and NOindependent vasorelaxation induced by testosterone may
involve activation of potassium channels in vascular smooth
muscle cells.32,33
There appears to be no studies analyzing the combined
effects of anaerobic training and AAS treatment on vascular
reactivity. There is one report about the effect of nandrolone
decanoate on the vascular reactivity of sedentary male rabbits.6 Nandrolone reduced endothelium-dependent relaxation
induced by ACh and endothelium-independent relaxation
induced by NO, sodium nitroprusside, and 8-bromo-cGMP in
thoracic aortas from these animals. The authors also demonstrated that this effect was mediated by diminished production of ACh and NO vasorelaxation mediator, cGMP. It was
concluded that nandrolone decanoate seems to decrease
NO-induced vasodilatation by decreasing guanylate cyclase
activity in the vascular smooth cells.6
This effect could also explain the data presented here
concerning the association of AAS treatment and anaerobic
training. In the present study, nandrolone decanoate canceled
the subsensitivity to PE observed in thoracic aorta isolated
from trained rats and this subsensitivity seems to be related to
major NO synthesis induced by chronic exercise. According
to Ferrer et al,6 nandrolone decanoate decreased the smooth
muscle cell response when anaerobic training was associated
with AAS treatment in the present study, and it is suggested
that nandrolone seems to block the vasodilatory response to
the higher NO synthesis induced by physical training in the
thoracic aorta isolated from rats.
However, in contrast to observations by Ferrer et al,6 in the
present study nandrolone had no effect on vascular response
to PE in sedentary rats. Animal species, AAS treatment
duration, and dose administration regimens may explain this
difference; in the present study, rats were treated with 5
mg/kg of nandrolone decanoate, twice per week for 6 weeks,
whereas in the Ferrer et al6 study, rabbits were treated with
one administration of the same AAS, 10 mg/kg once per week
for 4, 8, or 12 weeks.
In the present study, it was also observed that anaerobic
training induced an increase in HDL seric concentration in
rats. Its association with nandrolone treatment canceled this
effect and resulted in higher LDL levels compared with the
respective AAS sedentary group. According to previous
studies, these changes in lipoprotein profile may be related to
AAS treatment, and these alterations are able to modify
vascular reactivity. It has been reported that the incubation of
isolated rabbit aorta with LDL reduced endotheliumdependent relaxation34,35 and guanylate cyclase activation
induced by vasodilators.36 This effect is an early marker of
atherosclerosis and is antagonized by HDL.36 According to
these reports, it may be suggested that the increase in LDL
levels observed in trained rats treated with nandrolone in the
present study may explain why thoracic aorta isolated from
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October 2005 Part II
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these animals did not present subsensitivity to PE. Higher
LDL levels induced by nandrolone could decrease endothelium-dependent relaxation and guanylate cyclase activation,
and thus show opposite effects to those induced by training.
Moreover, the higher HDL levels observed in trained rats
could prevent the effects of LDL in the thoracic aorta.
However, in opposition to some reported effects of AAS on
lipoprotein profiles, no changes were observed in sedentary
rats treated with nandrolone decanoate. In rabbits, decreased
HDL was observed after intramuscular administration of
nandrolone decanoate at 4, 8, and 12 weeks, whereas LDL
was reduced, unaltered, or increased at 4, 8, and 12 weeks,
respectively.6 Differences between rat and rabbit hepatic
AAS metabolizing enzymes could account for the diverse
effects observed in lipoprotein blood levels in these species.
In humans, the effects of androgenic steroids on lipoprotein
levels are not clear. Some studies have shown that AAS
causes a reduction37 in the plasmatic concentration of vascular protective HDL38 and an increase in vascular aggressive
LDL.37 However, the effects of physiological levels of
testosterone were not consistent: testosterone replacement in
men is reported to be associated with decreased HDL,39 no
change in HDL levels,40 and a favorable effect on HDL
levels.41 In addition, the administration of nandrolone decanoate (100 mg/kg, intramuscularly), once per week for 6
weeks did not change HDL or LDL levels of 24 volunteers.9
These discrepancies can be related to the chemical structure
of AAS and administration route. Oral administration of
17-alkylated AAS seems to be related to increased HDL and
decreased LDL levels, but not to oral or parenteral administration of 17-beta sterified AAS, like nandrolone decanoate,9
for example. Some reports showed that there is a greater
induction of HDL catabolic enzyme hepatic triglyceride
lipase by oral versus parenteral AAS administration.42,43
In reports on subjects who self-administered AAS, it is
difficult to determine the steroid doses that have in fact been
used, considering that there is no consistency among such
users. Those who consume AAS without any therapeutic
indications generally combine at least one oral and several
parenteral AAS simultaneously.1,11 Therefore, when evaluating AAS effects on lipoprotein levels, these factors should be
taken into account and may explain the disparate results.
In summary, for the first time to our knowledge, it was
demonstrated that chronic anaerobic physical training causes
a decrease in aorta vascular sensitivity to PE, a beneficial
adaptation that seems to be related to the enhancement of NO
production and to higher blood concentration of HDL. However, nandrolone treatment blocks this subsensitivity to PE
promoted by physical training, probably because this hormone decreases NO vasodilating effect and enhances blood
concentration of LDL, damaging the endothelial function of
trained animals.
Perspectives
The present study provides evidence that supra-physiological
doses of AAS not only induce side effects but also avoid the
development of adaptations promoted by physical training.
Although the underlying physiological mechanisms of these
findings warrant further investigations, it is possible to say
that the findings presented here could be helpful in prevention
programs for AAS abuse.
Acknowledgments
This work was supported by grants from the Fundação de Amparo à
Pesquisa do Estado de São Paulo-FAPESP (02/05427-8) and FAEP/
UNICAMP (398/03 and 680/03). T.S.C. was recipient of CAPES
scholarship grant and A.P.T. was recipient of FAPESP scholarship
grant, Brazil. The authors thank Margery Galbraith for editing the
English of the manuscript.
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Vascular Sensitivity to Phenylephrine in Rats Submitted to Anaerobic Training and
Nandrolone Treatment
Tatiana Sousa Cunha, Maria José, Costa Sampaio Moura, Celene Fernandes Bernardes, Ana
Paula Tanno and Fernanda Klein Marcondes
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Hypertension. 2005;46:1010-1015; originally published online August 15, 2005;
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