Download Pediatric Research:Volume 39(5)May 1996pp 774-778

Pediatric Research:Volume 39(5)May 1996pp 774-778
Sympathetic Activity in Children Undergoing Balloon Valvuloplasty of Pulmonary
Stenosis
[Regular Articles]
GALAL, OMAR; DZIMIRI, NDUNA; MOORJI, AZADALI; BAKR, SOLIMAN; ALMOTREFI, ABDULRAHMAN A.
Department of Cardiovascular Diseases [O.G.], Biological and Medical Research Department [N.D., A.M.,
S.B.], King Faisal Specialist Hospital and Research Centre, and the Department of Pharmacology, King Saudi
University[A.A.M.], Riyadh, Saudi Arabia
Received March 1, 1995; accepted November 9, 1995.
Correspondence and reprint requests: Dr. Omar Galal, Department of Cardiovascular Diseases (MBC-16),
King Faisal Specialist Hospital and Research Centre, P. O.
3353, Riyadh 11211, Saudi Arabia.
Article Outline
ABSTRACT TOP

ABSTRACT
We studied the influence of balloon valvuloplasty on α- andβ
METHODS
adrenoceptor densities, plasma catecholamine, and cAMP

RESULTS
levels in children and infants with pulmonary stenosis before

DISCUSSION
and 10 min after balloon dilatation, employing as controls

REFERENCES
children undergoing transcatheter occlusion of patent ductus
arteriosus (PDA) with Qp/Qs ratio <1.5. In the PDA group, the

α-adrenoceptor density (Bmax) was 3.75 ± 0.72 fmol/107 cells
(n = 15) before occlusion and remained unchanged at 3.35 ±
Figures/Tables
0.47 fmol 10 min thereafter. In the pulmonary stenosis
patients (n = 31), the receptor density was 59% higher (p <
0.05) before, and decreased to PDA levels 10 min after, the

Table 1
procedure. The control β-adrenoceptor density was 64.8± 11.0

Figure
1
fmol/106 cells before, and 71.2 ± 13.2 fmol 10 min after,

Figure 2
occlusion. In the study group, the density was 23% lower (p<

Table 2
0.07) and increased to the PDA levels 10 min after the
dilatation. Compared with the PDA, preand postdilatation
plasma norepinephrine levels were not significantly changed;
epinephrine was slightly elevated before, but increased by
73% after, dilatation; dopamine was 80% (p < 0.05); and cAMP was 37% higher before, and remained
elevated at 70 and 23% above the PDA values after, the procedure. Accordingly, α-adrenoceptor density is
significantly elevated in children with pulmonary stenosis and decreases significantly immediately after balloon
valvuloplasty. On the other hand,β-adrenoceptor density is attenuated and increases toward normal levels
after the procedure. The immediate reversal of the receptor levels after balloon valvuloplasty suggests that
this procedure exerts acute effects on the sympathetic functional level in this disease.
Abbreviations: Bmax, maximal number of receptor binding sites; Kd, ligand dissociation constant; PDA,
patent ductus arteriosus;Qp/Qs, ratio of pulmonary blood flow to systemic blood flow
Balloon dilatation is finding increasing application as a palliative nonsurgical method for therapy of
congenital heart diseases such as coarctation of the aorta (1, 2), pulmonary stenosis(3-5), and tetralogy
of Fallot(6-9) in children, infants, and neonates. In particular, balloon angioplasty appears to reduce the
probability of developing paradoxical hypertensive crisis (10) which is often observed after surgical relief
of aortic coarctation(11, 12). The development of such hypertensive crisis is associated with a sudden
elevation in circulating catecholamines, particularly norepinephrine, as a result of surgical stress (1, 1315). Accordingly, balloon angioplasty of aortic coarctation appears to successfully prevent the events
triggering an increased spillover of this hormone, implying therefore that this procedure may lead to an
immediate restoration of normal sympathetic activity.
The influence of balloon dilatation on the sympathetic nervous system in pulmonary stenosis is
unknown. Unlike coarctation of the aorta, patients with pulmonary stenosis do not experience clinically
significant increase in arterial pressure after balloon dilatation. The increase in systolic pressure in the
pulmonary artery and in peak pressure in these patients is generally attributed to improved flow through
the valve. It is also well established that balloon dilatation usually leads to the relief of the valvular
gradient and a drop in systolic gradient (4, 5), probably due to the changes in pulmonary blood flow and
the valve area. These changes are usually observed soon after the balloon valvuloplasty. We
hypothesized that such drastic acute alterations in the hemodynamic factors are likely to challenge the
sympathetic system to adapt to the changed conditions in a similarly subtle fashion. In this study, we
therefore compared the α- and β-adrenoceptor density and responsiveness, as well as the plasma
catecholamine and cAMP levels in infants and children before and 10 min after balloon dilatation of
pulmonary stenosis, to evaluate the potential alterations in sympathetic activity associated with this
procedure and their clinical implication for the postprocedural care of such patients.
METHODS TOP
Study population. Thirty-one infants and children ranging in age between 8 mo to 15 y (mean age 58.1
± 17.4 mo) admitted for balloon dilatation of pulmonary stenosis were included in the study. Fourteen
(45%) of the patients were male and 17 (55%) were female. All patients were premedicated with a
mixture of meperidine, promethazine, and chlorpromazine. Ketamine (0.5 mg/kg) was occasionally
administered, if required. The size of the angioplasty balloon catheter was selected to be 1.2-1.4 times
that of the pulmonary artery annulus. Before advancing the catheter across the stenosis, the heart rate
and the systemic pressure were recorded via an 18-inch sheath positioned in the right femoral artery.
After obtaining the pressures and saturation in the right heart, the valvuloplasty catheter was positioned
across the stenosis, and the balloon was inflated several times with diluted contrast medium to 4-5
atmospheres for a few seconds. Several hemodynamic variables including pulmonary artery pressure,
right ventricular pressure, pullback peak to peak systolic gradient across the pulmonary valve, and
systemic pressure were recorded before and 10 min after balloon dilatation. Fifteen consecutive children
and infants ranging in age between 11 mo to 13 y(mean age 60.8 ± 12.3 mo) undergoing transcatheter
occlusion for PDA with a Qp/Qs < 1.5 were elected as controls. These patients were considered to be
functionally normal with regard to their sympathetic activity. The study was performed in accordance
with the rules and regulations laid down by the Hospital's Ethics and Clinical Protocols Committees.
Binding studies. Blood samples were drawn in EDTA tubes between 0800 and 1000 h on the morning
of the balloon dilatation in study patients or occlusion in PDA patients and 10 min after the respective
procedures. The blood was layered over Leucoprep (Becton Dickinson, Heidelberg, Germany) and
centrifuged at 1500 × g for 15 min. The supernatant was collected for catecholamine and cAMP
determination; the fluffy layer was resuspended in Tris/EDTA buffer and centrifuged at 200 × g for 10
min. The resultant lymphocyte pellet was suspended in Tris buffer for the β-adrenoceptor studies. The
supernatant was recentrifuged at 1800 × g to obtain the platelet pellet which was also suspended in
Tris/EDTA buffer forα-adrenoceptor studies.
The α-adrenoceptor density and binding affinity were determined by specific binding of [3H]yohimbine
(83 Ci/mmol, NEN Corp., Stevenage, UK) to platelets. Approximately 10 7-108 cells were suspended in
Tris/EDTA buffer containing 50 mM Tris-HCl (pH 7.4), 5 mM EDTA, 120 mM NaCl, 10 mM MgCl2, and
incubated with 0.5-8.0 nM [3H]yohimbine at room temperature for 30 min in a final volume of 300 μL.
The reaction was terminated, and the cells subsequently washed twice with 5 mL of iced-cold Tris buffer
through Whatman GF/B filters (Whatman Inc., Clifton, NJ) on a Brandel Harvester (Biomed Research
and Development Laboratories, Inc., Gaithersburg, MD). The filters were dried, and the radioactivity was
counted in 10 mL of Optifluor scintillation fluid (Packard, Meridian, CT). The difference between the
platelet binding to [3H]yohimbine in the absence and presence of 50 μM phentolamine was considered
specific binding.
The β-adrenoceptor activity was determined by specific binding of[ 125I]iodocyanopindolol (2200 Ci/mmol,
NEN Corp.) to lymphocytes. Approximately 1 × 106 cells were suspended in Tris buffer (pH 7.4)
containing 50 mM Tris-HCl, 120 mM NaCl, 10 mM MgCl2, and incubated with 10-160 [rho]M
[125I]iodocyanopindolol at 37°C for 60 min in a final volume of 300 μL. The reaction was terminated, and
the cells were washed as described above. The radioactivity was counted on an LKB gamma counter.
The difference between the receptor binding to[125I]iodocyanopindolol in the absence and presence of
5.0 μM propranolol was considered specific binding. Assays were conducted in duplicate.
Plasma catecholamine and cAMP levels. The catecholamines norepinephrine, epinephrine, and
dopamine were extracted from plasma with activated alumina according to the method of Anton and
Sayre(16) and assessed by HPLC with electrochemical detector(Waters System, Miliford, MA). cAMP
was determined by RIA (Amersham Corp., Amersham, UK). Drugs used were
[3H]yohimbine,[125I]iodocyanopindolol (NEN), propranolol (Beck Pharmaceuticals, Macclesfield, UK), and
phentolamine (Sigma Chemical Co., St. Louis, MO). All other reagents were of analytical grade.
Statistical analysis. Receptor density and ligand binding were calculated from Scatchard saturation
binding isotherms using Receptorfit Saturation Two-site Program (Ligand Software, Cleveland, OH).
Analysis of variance followed by Scheffe's test was performed using Statgraphics Software(Statistical
Graphics Corp., Rockville, MD). The pre- and postangioplasty data were compared by the t test using
Sigmaplot (Janel Scientific Software, San Rafael, CA) statistical package, taking the probability levels of
less than 0.05 as indicating significant difference. Data are given as means ± SEM.
RESULTS TOP
After balloon dilatation, the mean right ventricular systolic pressure decreased significantly from 110.1 ±
6.3 to 62.5 ± 6.9 mm Hg(p < 0.0000002), right ventricular diastolic pressure from 13.1± 1.3 to 9.8 ± 0.9
mm Hg (p < 0.05), peak-to-peak systolic gradient from 89.2 ± 7.4 to 13.3 ± 0.7 mm Hg(p < 0.000001),
and the heart rate from 116 ± 6.5 to 107.5± 5.6 beats/min (p < 0.05). On the other hand, the systolic
pulmonary pressure increased also significantly from 21.9 ± 0.9 to 25.8 ± 2.0 mm Hg (p < 0.05). A
summary of these and other determined clinical parameters is given in Table 1.
Table 1. Hemodynamic and clinical data of 31 patients before and 10 min after balloon dilatation of pulmonary stenosis
In the PDA patients, the mean Kd value for theα-adrenoceptor binding to [3H]yohimbine was 2.12 ± 0.32
nmol/L (n = 15) before occlusion, and 1.61 ± 0.15 nmol/L 10 min thereafter. The Bmax value was 3.57 ±
0.38 fmol/107 cells. It remained unchanged at 3.36 ± 0.47 fmol after occlusion. There was no significant
difference in the α-adrenoceptor affinity and density of the PDA group before and immediately after
occlusion. In the pulmonary stenosis population (n = 31), theKd was 3.13 ± 0.56 nmol/L before balloon
dilatation and decreased to 2.18 ± 0.26 nmol/L 10 min after the valvuloplasty. The receptor density
(Bmax) was 5.53 ± 0.64 fmol before, and 3.86 ± 0.24 fmol per 10 7 cells after, the balloon dilatation(Fig. 1).
Analysis of variance showed that theα-adrenoceptor density before dilatation was significantly higher
than that of the PDA as well as the postdilatation value. On the other hand, the postprocedure density
was similar to that of the PDA group.
Figure 1. The α-adrenoceptor density(Bmax) in 31 children with pulmonary stenosis before(PSA) and 10 min after (PSP) balloon
valvuloplasty, compared with children undergoing transcatheter occlusion of PDA before(n = 15) and after (PDP, n = 7) the
procedure.*p < 0.05 precompared with postdilatation.
The Kd for the β-adrenoceptor binding to[125I]iodocyanopindolol in PDA patients was 8.09 ± 1.32 pmol/L
before and 7.77 ± 1.76 pmol/L after occlusion. TheBmax also hardly changed from 64.8 ± 11.0 fmol to
71.2± 13.2 fmol/106 cells. In the pulmonary stenosis patients, theKd increased from 6.28 ± 0.62 pmol/L
to 11.5 ± 2.7 pmol/L, and the density from 50.0 ± 5.5 fmol to 73.7 ± 13.4 fmol/106 cells 10 min after the
dilatation (Fig. 2). Thus, in contrast to α-adrenoceptors, the β-adrenoceptor density of the study patients
was lower than that of the control group prior to valvuloplasty, and increased to the level of the latter
thereafter. The analysis of variance showed no significant difference among the densities of the study
patients and the controls. However, the receptor density after dilatation was 47% (p < 0.07) higher than
before the procedure, showing that the increase was nevertheless quite large.
Figure 2. The β-adrenoceptor density (Bmax) in 31 children with pulmonary stenosis before (PSA) and 10 min after(PSP) balloon
valvuloplasty, compared with children undergoing transcatheter occlusion of PDA before (n = 15) and after(PDP, n = 7) the
procedure. *p < 0.07 pre- compared with postdilatation.
Plasma norepinephrine level of the controls was 558.5 ± 104.5 pg/mL, epinephrine was 266.3 ± 63.1
pg/mL, dopamine was 103.6 ± 14.4 pg/mL, and cAMP was 15.5 ± 1.6 pg/mL. The plasma levels of these
catecholamines and cAMP in the study patients are depicted in Table 2. The table shows that there was
no significant difference between the pre- and post-dilatation plasma norepinephrine levels of the study
group and those of the PDA group. On the other hand, epinephrine was only slightly elevated against
the PDA levels before dilatation, but increased significantly (p < 0.05) by 73% after the procedure.
Dopamine was 80% (p < 0.05) and cAMP 37% higher before dilatation, and remained significantly
elevated at 70% (p < 0.05) and 23% above the PDA values thereafter.
Table 2. Plasma catecholamines and cAMP in 31 pulmonary stenosis patients before and 10 min after balloon angioplasty of pulmonary stenosis, compared
with those of 15 PDA controls
DISCUSSION TOP
The present study investigated the influence of balloon valvuloplasty on the sympathetic function in
children with pulmonary stenosis. As controls, we determined the α- and β-adrenoceptor density and
their ligand binding affinity in children undergoing occlusion of PDA under the same conditions as the
study population. The results show that neither the plateletα-adrenoceptor nor the lymphocyte βadrenoceptor density and their ligand binding affinity were altered as a result of the occlusion in this
group of patients. This finding supports the argument in favor of employing PDA patients with an
insignificant left-to-right shunt as controls to evaluate alterations in the sympathetic function in children
undergoing surgical or therapeutic manipulations for congenital disorders.
In children with pulmonary stenosis, the lymphocyte β-adrenoceptor density was reduced, and the αadrenoceptor density significantly elevated. A decrease in β-adrenoceptor density is a well established
phenomenon in heart failure associated with various forms of cardiomyopathies(17-20). It has also been
previously suggested that, in heart failure, α-adrenoceptors may be mobilized to provide inotropic
support to the failing heart(21-23). Heart failure is, however, not a common feature of pulmonary
stenosis. Our findings suggest that the combination of an elevation in α-adrenoceptors and attenuation
of theβ-adrenoceptors may explain the mode by which the sympathetic nervous system adapts itself to
hemodynamic changes in pulmonary stenosis, with or without the manifestation of heart failure.
Furthermore, we recently observed a similar increase in α-drenoceptors in patients with other congenital
diseases (24) and in stenotic heart valvular disorders(25). A study by McGrath et al.(26) using neuronal
markers also indicated that, in the infundibular tissue of patients with tetralogy of Fallot, α-adrenoceptor
content was increased. Accordingly, the elevation in α-adrenoceptors may indeed constitute a
compensatory mechanism for the decrease inβ-adrenoceptors, not only in pulmonary stenosis, but in
congenital heart disorders in general.
The most important finding of the present study is the observation that both the elevation in the αadrenoceptor density and the attenuation of the β-adrenoceptors were reversed immediately after
balloon angioplasty. One possible mechanism for the decrease in the α-adrenoceptor density is receptor
internalization. This phenomenon has been described forβ-adrenoceptors (27, 28), but there is hardly any
documentation of a similar behavior by α-adrenoceptors in cardiovascular diseases. Conversely, the
increase in β-adrenoceptor density after balloon valvuloplasty may be due to mobilization of spare
receptors (29). The observation that both α- andβ-adrenoceptor levels tend to return to normal indicates
that the underlying mechanism(s) controlling the two processes are probably interrelated. Furthermore,
the time within which these alterations occurred suggests that they were acute responses of the
sympathetic system to the effects of balloon valvuloplasty itself. This may occur as an adaptive
mechanism by the sympathetic system to meet the requirements of the altered conditions triggered by
the abrupt hemodynamic changes. It is noteworthy that the modifications in receptor activity were
accompanied by significant alterations in some important hemodynamic variables, such as the systolic
pulmonary pressure, right ventricular systolic and diastolic pressures, and the systolic gradient. These
changes, which are essentially the product of improved blood flow through the pulmonary valve, are not
likely to be directly responsible for the alterations in the receptor activity per se. Nonetheless, it appears
plausible to suggest that several complex mechanism(s) may be responsible for the changes in the
adrenoceptors, probably involving vagal responses to the sudden changes in the hemodynamic
variables, at least indirectly, as a product of the balloon valvuloplasty. Thus, assuming that the
sympathetic system may be chronically hyperstimulated in pulmonary stenosis to counteract the
pressure resulting from the pulmonary obstruction, sudden relief from this pressure is likely to trigger the
vagus to function in conformation with the new hemodynamic conditions. This may occur by transiently
stimulating an increase in catecholamine turnover, as indicated by the rise in epinephrine in our patients.
This, in turn, would lead to mobilization of spare β-adrenoceptors before a long-lasting adaptation is
attained.
Similarly acute changes have been associated with a significant rise especially in plasma
norepinephrine levels, possibly as a reflection of its spillover from sympathetic nerve terminals after
surgical correction of aortic coarctation (13, 15). However, norepinephrine is less likely to be influenced in
an abrupt fashion by a nonsurgical procedure such as balloon dilatation. Indeed, as observed in our
patients, plasma norepinephrine levels were not influenced by either pulmonary stenosis or balloon
valvuloplasty. On the other hand, epinephrine was only slightly elevated before valvuloplasty, but
increased significantly thereafter. The trends established for norepinephrine and epinephrine in the
present study are in general agreement with the observations of Lewis and Takahashi(30), showing no
change in norepinephrine, but a significant elevation of epinephrine, although not significantly increased
further by balloon angioplasty. They therefore provide additional evidence that norepinephrine is not
influenced, whereas epinephrine may be increased in pulmonary stenosis and elevated further by
balloon valvuloplasty. This rapid increase in circulating epinephrine soon after balloon dilatation is
probably triggered by stress resulting from the angioplasty or valvuloplasty. This may explain, in part at
least, the time course of the increase inβ-adrenoceptor activity. It is not likely, however, that stress alone
can adequately explain all of the observed changes in both adrenoceptor subtypes.
The observation that plasma dopamine and cAMP may be elevated in congenital heart disorders is quite
intriguing. Brodde (31) has suggested that dopamine may be influenced in cardiac disorders. However,
there is hardly any further documentation in the literature to verify this notion. Further studies should
enrich our understanding of its potential role in these diseases. The elevation in cAMP may, on the other
hand, be a product of several complex events involved in the signaling pathways of either theα- or the βadrenoceptor subfamilies. Thus, such an increase might be expected under conditions that will stimulate
adenylate cyclase activity, or some other indirect mechanism(s) not associated with β-adrenoceptor
signaling pathways. One such possibility is the stimulation of Gs-coupled synthesis of cAMP, either by
increasing the signaling levels of the Gsα-protein at the expense of Giα protein(32-34), or presence of
activating mutational changes in the Gsα proteins(35-37). Inasmuch as we actually observed a decrease
in β-adrenoceptor activity in our patients, it is highly unlikely that the increase in cAMP in our study
population is a result of the stimulation of the Gs via the β-adrenoceptor signaling pathway. Other
possibilities include pathways that are not dependent on adenylate cyclase activity, such as the
inhibition of membrane-associated cGMP-inhibited cAMP-phosphodiesterase activity (38), which should
attract further attention.
Further studies may greatly enhance our understanding of the possible clinical implications of the rapid
changes in both the sympathetic activity and circulating epinephrine, particularly with regard to
postvalvuloplasty patient care. One interesting point in this regard is the observation that the patients
who develop infundibular stenosis after balloon dilatation do respond well to β-adrenoceptor blockers
(39, 40). There appears to be at least a causal relationship between the increase inβ-adrenoceptors and
the events leading to the development of infundibular stenosis after balloon dilatation in such patients.
These patients might be experiencing hyperactivity of these receptors as a result of the valvuloplasty,
which would explain their response to β-adrenoceptor blockers. There are also a small number of
patients who develop infundibular reaction in conjunction with other complications, such as low blood
pressure. Recently, we found that the administration of an α-adrenoceptor blocker to be the ultimate
remedy in a young patient who developed such complications, after all other attempts including βblocker therapy had failed. Although the exact mechanism(s) remains to be clarified, it seems plausible
to suggest that such a patient might have had very high levels of α-adrenoceptors which remained
elevated even after the valvuloplasty. Put together, the present findings indicate that the changes in the
adrenoceptors may be of clinical relevance, particularly with regard to the use of sympathetic agents in
patients who develop complications after balloon valvuloplasty. Further studies should be directed at
delineating the precise mechanism(s) involved in the changes in the receptor function.
In conclusion, the present study demonstrates that α-adrenoceptor density is significantly elevated in
children with pulmonary stenosis and decreases significantly immediately after balloon valvuloplasty.
Conversely,β-adrenoceptor density is attenuated in these patients and returns to normal levels after the
procedure. These changes are associated with a significant drop in the systolic gradient across the
pulmonary valve and a significant increase in plasma epinephrine levels. These observations suggest
that balloon dilatation exerts acute effects on the level of sympathetic activity in patients with pulmonary
stenosis.
Acknowledgments. The authors thank Beck Pharmaceuticals (UK) for their kind gift of propranolol. We
are also grateful to the Cardiac Catheterization staff at King Faisal Specialist Hospital and Research
Centre for their assistance in collecting the blood samples.
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