Hypertension. 1999;34:790-794
(Hypertension. 1999;34:790-794.)
© 1999 American Heart Association, Inc.
Modulation of Coronary Flow and Cardiomyocyte Size by Sensory Fibers
Angelina Zanesco;
Soraia K. P. Costa;
Sonia R. Riado;
Luciana P. Nathan;
Claudia F. de Oliveira;
Iara M. S. De Luca;
Edson Antunes;
Gilberto De Nucci
From the Department of Physical Education, Biosciences Institute (A.Z.),
Paulista State University, Rio Claro (SP) and the Department of Pharmacology,
Faculty of Medical Sciences (S.K.P.C., S.R.R., L.P.N., C.F. de O., E.A., G. De
N.); and Department of Histology and Embryology, Biology Institute, State
University of Campinas, (I.M.S. De L.), Campinas (SP), Brazil.
Correspondence to Angelina Zanesco, PhD, Department of Physical Education, Biosciences Institute, Paulista State University, Av 24A No. 1515, Bela Vista, CEP 13506-900, Rio Claro (SP), Brazil. E-mail azanesco{at}bestway.com.br
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Abstract
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AbstractCardiac tissue is
densely innervated by sensory
neurons that are believed to
play important modulatory roles
in cardiac functions. In this
study, pretreatment of neonate
rats with capsaicin was performed. In
adult rats, cardiomyocyte
size and amount of fibrous tissue
in left ventricles as well
as in vitro coronary flow were
evaluated. The chronotropic and
inotropic responses to ß-adrenoceptor
agonists (norepinephrine
and isoproterenol), muscarinic
agonists (carbachol and pilocarpine),
and calcitonin generelated
peptide (CGRP) were also investigated
with the use of the isolated
right atria preparation. Capsaicin
pretreatment significantly
(
P<0.05) reduced both basal coronary
flow (18%
reduction) and cardiomyocyte size (34% reduction)
without
affecting the amount of fibrous tissues in the left
ventricles. The
positive inotropic and chronotropic effects
in response to
norepinephrine in the isolated rat heart did
not
significantly differ between control and capsaicin-treated
rats.
Similarly, the positive chronotropic effects in response
to
norepinephrine, isoproterenol, and CGRP as well as the
negative
chronotropic responses to carbachol and pilocarpine in the
isolated
right atria were not affected by capsaicin pretreatment. Our
data
are consistent with the suggestion that reductions of both
basal
coronary flow and cardiomyocyte size seen in
hearts from capsaicin-pretreated
rats may be consequences of CGRP
depletion. The cardiomyocyte
size reduction produced by
capsaicin treatment may be related
to a modulatory role of CGRP as a
growth factor.
Key Words: capsaicin receptors, muscarinic receptors, adrenergic, beta neuropeptides peptides
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Introduction
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Sensory fibers have been associated with the control of
smooth
muscle tone, autonomic ganglia transmission, immunologic
processes,
tissue growth,
1 and heart
functions.
2 3 4 5 A number of substances,
including the
peptides substance P and calcitonin generelated
peptide (CGRP), are
released by the sensory nerve endings.
1 6 Capsaicin
(8-methyl-
N-vanillyl-6-nonenamide) is a highly
selective
neurotoxin that, on systemic administration, causes
CGRP and substance
P depletion from sensory neurons
7 8 9 and
thus has
largely been used to study the involvement of sensory
fibers in
different pathophysiological
functions.
10
In the heart, capsaicin increases contractile force and spontaneous
heart rate3 as well as evokes coronary
vasodilation through CGRP release.11 12 Previous studies
reported the presence of CGRP in the heart, predominantly in the right
atria, followed by the left atria and right and left
ventricles,3 13 where it causes concentration-dependent
and long-lasting positive inotropic and chronotropic effects in several
species,9 14 15 16 17 including humans.18 Although
CGRP has also been described as a potent hypertrophic factor for
cardiomyocytes,19 no study has been performed
to investigate the effect of CGRP depletion on
cardiomyocyte size. The existence of interactions of
sympathetic and parasympathetic nerves with sensory fibers in in
vitro20 21 and in vivo22 preparations has
been reported.23 In this study, pretreatment of neonate
rats with capsaicin was performed and the rats were used at adult ages.
We then evaluated the following parameters in the heart:
(1) cardiomyocyte size, (2) basal and stimulated
coronary flow in vitro, and (3) chronotropic and inotropic
responses of ß-adrenoceptors and muscarinic agonists as well as CGRP,
with both whole rat isolated heart and isolated right atria.
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Methods
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Capsaicin Treatment
The experiments were performed in Wistar rats of both sexes
bred
in the department of Animal Care of the Faculty of Medical
Sciences,
State University of Campinas (São Paulo, Brazil).
In
total, 102 neonatal rats were pretreated subcutaneously on
the second
day of life with capsaicin (50 mg/kg; Sigma Chemical
Co) or the
corresponding volume (100 µL) of capsaicin-vehicle
(10% ethanol and
10% Tween 80, in 0.9% [wt/vol] NaCl solution)
under ether
anesthesia.
8 Rats were used 12 to 14 weeks
after
capsaicin pretreatment, at which time they weighed 200 to
300
g. All procedures were designed in accordance with the
guidelines
of the State University of Campinas for animal care.
Langendorff Preparation
Male Wistar rats (weight, 250 to 350 g) were
anesthetized with sodium pentobarbital (Sagatal; 50 mg/kg IP)
and given heparin (500 IU/kg IP) 5 minutes before thoracotomy. The
hearts were rapidly excised and mounted on a Langendorff
apparatus and perfused at constant pressure (65
mm Hg) with oxygenated (95% O2/5%
CO2) Krebs-Henseleit solution containing (in
mmol/L) NaCl 118, KCl 4.7,
KH2PO4 1.2,
MgSO4 1.2, CaCl2 2.5,
NaHCO3 25, and glucose 11, pH 7.4, at 37°C.
Left ventricular developed pressure (LVDP) (mm Hg) and
heart rate (HR) (bpm) were recorded via a latex balloon inserted
into the left ventricle (basal end-diastolic pressure,
5 mm Hg). A polyethylene cannula was then connected to a
pressure transducer (model PRC 21/3, Ugo Basile) and a 2-channel
recorder (Gemini 7070, Ugo Basile). The preparations were allowed
to stabilize for 30 minutes. Coronary flow (mL/min) was
measured manually by 15-second timed collections of the
coronary effluent.
Functional Assays With Isolated Right Atria
Animals were anesthetized with halothane, and the hearts
were rapidly removed. The right atria were isolated and mounted in a
water-jacketed tissue chamber (10-mL volume) containing Krebs-Henseleit
solution, pH 7.3 to 7.5, at 37°C and gassed with 95%
O2/5% CO2. The composition
of the Krebs-Henseleit solution was as follows (mmol/L): NaCl 124, KCl
4.75, MgSO4 1.30, CaCl2
2.25, NaHCO3 25.0,
NaH2PO4 0.6, dextrose 10.0,
sodium ascorbate 0.3, and disodium EDTA 0.03. Ascorbate and EDTA were
added to inhibit the oxidation of
catecholamines.24 To block the neuronal and
extraneuronal uptake of catecholamines, both
phenoxybenzamine (10 µmol/L; Sigma Chemical Co) and
17ß-hydroxyestradiol (5 µmol/L; Sigma Chemical Co) were added
to the tissue bath.25
Construction and Analyses of Concentration-Response
Curves
Concentration-response curves for the positive and negative
chronotropic actions of isoproterenol, norepinephrine, rat
CGRP, carbachol, and pilocarpine (all Sigma Chemical Co) were
constructed by the cumulative variation of agonist concentration at
one-half log unit increments.26
All concentration-response data were evaluated for a fit to a logistic
function in the following form:
where
E is the increase in rate above basal;
E
max is the maximum response
that the agonist can
produce; c is the logarithm of the EC
50,
the
concentration of agonist that produces half-maximal response;
x is the
logarithm of the concentration of agonist; the exponential
term, n, is
a curve-fitting parameter that defines the slope
of the
concentration-response line; and

is the response observed
in the
absence of added agonist. Nonlinear regression analyses
to
determine the parameters E
max, log
EC
50, and n were performed
with GraphPad Prism
(GraphPad Software) with the constraint
that

=zero.
Stereological Procedures
Stereological analysis was performed according to the
method described by Aherne.27 Formalin-fixed left
ventricle and septum were cut into 5 equidistant rings perpendicular to
the long axis of the ventricle. The rings were then embedded in
paraffin, and 5-µm sections were stained with Masson's trichrome.
Analysis of the slides was performed in blinded fashion on a
light microscope (Zeiss), and the relative volume occupied by each
element of the ventricle (myocardial fibers and fibrous tissue) was
measured with a special ocular apparatus containing a
25-point reticulum (5 parallel lines with 5 points each, kpl x8,
Zeiss). To determine cardiomyocyte size, 15 cells
randomly selected from the subepicardial, midmyocardial, and
subendocardial regions were measured for each animal from the different
experimental groups. For counting, 50 microscopic fields were
evaluated, and the relative volume (Ppi) occupied by each component was
calculated as follows: Ppi=p/P-R, where p is the number of
reticular points hitting each cardiac element, P is the total number of
reticular points, and R is the number of points hitting artifactual
retraction areas.
Blood Pressure Measurement
The systolic blood pressure was measured by a modified
tail-cuff method in awake animals.28 The measurements were
performed 24 hours before the animals were killed.
Statistical Analysis
All values are expressed as mean±SEM. The program InStat
(GraphPad Software) was used for statistical analyses. When
appropriate, 1-way ANOVA followed by a Bonferroni multiple comparisons
post hoc test was performed to determine whether the treatments had an
effect. In some cases, a paired or unpaired Student's t
test was used. P<0.05 was accepted as significant.
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Results
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Body Weight, Stereological Analysis, and Systolic
Blood Pressure
Body weight and systolic blood pressure were not
significantly
affected by the capsaicin pretreatment (n=12) compared
with
the control group (n=5; Table 1
).
Additionally, stereological
analysis of the left ventricle
revealed a 34% reduction (
P<0.05)
of
cardiomyocyte size in the capsaicin-pretreated rats without
change
in the amount of fibrous tissues (Table 1
).
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Table 1. Effect of Capsaicin Pretreatment on Systolic
Blood Pressure, Body Weight, Cardiomyocyte Size, and Fibrous Tissue in
the Rat
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Whole Heart Preparations
Bolus injection of norepinephrine (0.6 nmol) caused
similar increases in LVDP and HR in both control and capsaicin-treated
animals (Table 2).
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Table 2. Effect of Norepinephrine Bolus Injection
(0.6 nmol) on LVDP, HR, and Coronary Flow in Whole Heart From
Control and Capsaicin-Pretreated Rats
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Capsaicin pretreatment significantly reduced basal coronary
flow by
18% (P<0.05; Table 2). Bolus
injection of norepinephrine (1.0 nmol) caused a significant
decrease in coronary flow in the control group at 0.25 minutes
after injection (35% reduction), whereas in capsaicin-treated rats the
reduction in coronary flow by norepinephrine was
attenuated (18.7% reduction; Table 2).
Isolated Right Atria
Addition of capsaicin (1 µmol/L) to the organ bath caused a
positive chronotropic response in isolated right atria of the control
group (44±4 bpm) that was attenuated by
45% (P<0.05)
in capsaicin-treated rats (20±2 bpm).
Chronotropic responses to both ß-adrenoceptor (isoproterenol and
norepinephrine) and muscarinic (carbachol and pilocarpine)
agonists are illustrated in the Figure.
There was no significant shift of the concentration-response curves for
norepinephrine between control and capsaicin groups
(Figure, panel A). With respect to isoproterenol, although there
was a tendency for a rightward shift in the concentration-response
curves, the differences between both groups were not significant
(Figure, panel B). The potency of muscarinic agonists was also
unaffected by capsaicin pretreatment in isolated right atria (Figure,
panels C and D).

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Figure 1. Concentration-response curves to norepinephrine
(A), isoproterenol (B), carbachol (C), pilocarpine (D), and rat CGRP
(E) in isolated right atria from control ( ) and capsaicin-treated
() rats. Values are mean±SEM of 5 to 8 experiments.
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Rat CGRP induced concentration-dependent positive chronotropic effects
of rat right atria that were
30% of maximum response for
isoproterenol and norepinephrine, as observed in either
control or capsaicin groups (Table 3).
Furthermore, there were no significant changes in the potency of rat
CGRP in isolated right atria after capsaicin pretreatment compared with
the control group (Figure, panel E). The maximum responses for
all studied agonists were similar in capsaicin-treated rats and the
control group (Table 3). Table 4
summarizes all studied agonists in isolated right atria from control
and capsaicin-treated rats.
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Table 3. Maximum Responses to Isoproterenol,
Norepinephrine, and Rat CGRP in Isolated Right Atria From
Control Animals and Capsaicin-Treated Rats
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Table 4. Potency of Isoproterenol,
Norepinephrine, Pilocarpine, Carbachol, and Rat CGRP in
Isolated Right Atria From Control Animals and Capsaicin-Pretreated Rats
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Discussion
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In this study we clearly demonstrate that capsaicin pretreatment
caused
a significant reduction in both basal coronary flow and
cardiomyocyte
size. However, other cardiac
parameters, such as the increase
in LVDP in response to
norepinephrine and chronotropic actions
in response to
norepinephrine, isoproterenol, carbachol, pilocarpine,
and
rat CGRP, were not affected by capsaicin pretreatment.
Many vascular tissues, including coronary vessels, are richly
innervated by sensory fibers that, on stimulation, release
substance P and CGRP.16 29 In the rat heart, substance P
has no effect on vascular tone30 whereas CGRP exerts a
potent vasodilatation.31 Capsaicin releases CGRP, leading
to an enhancement of coronary flow.32
Maintenance of coronary vascular tone seems to be
determined by endothelium-dependent and
endothelium-independent mechanisms.33 Our
findings showing a significant reduction of basal coronary flow
in capsaicin-pretreated rats suggest that it is a consequence of CGRP
depletion. In adult rats, systemic capsaicin treatment also reduces
basal coronary flow.12
CGRP causes vasodilatation by a mechanism involving intracellular
accumulation of cAMP34 that counteracts the
norepinephrine-induced increase in inositol
1,4,5-trisphosphate levels.35 Thus, control of vascular
tone in coronary vessels by CGRP may reflect a
counterregulatory mechanism between these second messengers. Our
results showing a decrease of basal coronary flow in the
capsaicin-treated rats could be explained by a sustained decrease of
cAMP levels. However, the lower responsiveness of coronary
vessels to norepinephrine remains unclear.
CGRP has been described as a growth factor in the rat heart, where it
exerts beneficial trophic actions on
cardiomyocytes.1 Accordingly, our
stereological studies have evidenced a decrease in cardiac muscle fiber
size in capsaicin-treated rats. These results are therefore
consistent with the suggestion that CGRP plays an important
role in the maintenance of cardiomyocyte size under
normal conditions by acting as a growth factor. Additionally, constant
coronary flow as a consequence of continuous release of CGRP
may also contribute to regulation of cardiac muscle fiber size.
Reduction in coronary flow leads to an increase in the fibrous
tissue in the heart as a result of ischemic
processes.36 However, capsaicin-treated rats showed no
alterations in the amount of fibrous tissues in the left ventricles,
suggesting that the magnitude of the coronary flow reduction
was insufficient to determine ischemic processes.
The positive chronotropic responses for isoproterenol,
norepinephrine, and rat CGRP and the negative chronotropic
responses for carbachol and pilocarpine were not affected in isolated
right atria by capsaicin treatment. These results may be explained by
the partial depletion (45%) of neuropeptides in our study. However,
this is unlikely since previous work also found no alterations in the
potency of both agonists, isoproterenol and rat CGRP, in right atria
from guinea pigs and rats treated with capsaicin, where complete
depletion of CGRP was detected.37 In a manner similar to
that of chronotropism, capsaicin pretreatment had no effect on the
inotropic responses to norepinephrine in isolated whole
heart, indicating that cardiomyocytes may be able to retain
their physiological responses, including
contraction force, despite their size reduction. Taken together, these
observations presumably indicate that sensory fibers do not play a role
in the primary modulation of cardiac actions (chronotropism and
inotropism) compared with the sympathetic nervous system, in which
norepinephrine is the main neurotransmitter.
In summary, capsaicin treatment in neonatal rats causes a significant
decrease of basal coronary flow, associated with diminishing
cardiomyocyte size, as a consequence of CGRP depletion.
Received May 8, 1999;
first decision June 22, 1999;
accepted July 10, 1999.
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