© 1999 American Heart Association, Inc.
Integrative Physiology |
G Protein ß3 Subunit 825T Allele and Enhanced Coronary Vasoconstriction on 
2-Adrenoceptor Activation
From Abteilung für Kardiologie (D.B., M.H., O.O., R.E.), Institut für Pharmakologie (C.N., W.S.), and Abteilung für Pathophysiologie (G.H.), Universitätsklinikum Essen, Essen, Germany.
Correspondence to Gerd Heusch, MD, Abteilung für Pathophysiologie, Hufelandstr 55, 45122 Essen, Germany. E-mail gerd.heusch{at}uni-essen.de
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Abstract |
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Abstract—Recently,
2-adrenoceptor activation was shown to play an important
role in the vasoconstriction of normal coronary arteries,
whereas in the presence of atherosclerosis, the
activation of both 1- and 2-adrenoceptors
reduces coronary blood flow in humans.
2-Adrenoceptors activate pertussis toxin
(PTX)-sensitive G proteins, whereas 1-adrenoceptors
couple to PTX-insensitive G proteins. Thus, the 825T allele of the
ß3 subunit of heterotrimeric G proteins, associated with enhanced
PTX-sensitive G protein signaling, was expected to determine the
2-adrenoceptor–, but not the
1-adrenoceptor–, mediated reduction in coronary
blood flow (CBF). Genotyping was performed on 48 individuals. Twelve of
the 48 received the 1-adrenoceptor agonist
methoxamine (MTX; 5 mg IC), and 12 received the
2-adrenoceptor agonist BHT 933 (BHT; 5 mg IC).
Twenty-four additional individuals received both MTX and BHT during the
same investigational procedure. CBF was calculated on the basis of
coronary angiography and intracoronary Doppler flow
velocity measurement. Drug-related ischemia was assessed on the
basis of ST-segment changes and angina pectoris. In response to BHT,
but not to MTX, CBF was reduced to a significantly greater extent in
825T allele carriers (58±4%, n=16) than in individuals homozygous
for the C825 allele (28±4%, n=19, P=0.001). This
finding was independent of cholesterol levels, mean
arterial blood pressure, and the presence or absence of
coronary artery disease. Ischemic events in response to
BHT occurred more frequently in 825T allele carriers than in
homozygous 825C allele carriers (P=0.01).
2-Adrenoceptor coronary vasoconstriction is
genetically determined and significantly enhanced in
GNB3 825T allele carriers.
Key Words: proteins • receptor, adrenergic • blood flow • genes • arteries
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Heterotrimeric G proteins composed of
, ß,
and 
subunits are important components of intracellular signal
transduction and ultimately responsible for the transduction of
hormonal activation of heptahelical receptors into complex
physiological responses, including cell
proliferation, chemotaxis, and vasoconstriction.
With the use of immortalized lymphoblasts and skin fibroblasts from
patients with essential hypertension who display enhanced activation of
pertussis toxin (PTX)-sensitive G proteins, we recently described a
polymorphism (C825T) in the human gene GNB3 encoding for
the ß3 subunit of heterotrimeric G proteins
(Gß3).1 The 825T allele appears to cause
alternative splicing of the gene encoding for Gß3, thereby
contributing to the generation of a functionally active splice variant,
referred to as Gß3s. Because enhanced PTX-sensitive G protein
activation seemed to be the common phenotype in 825T allele
carriers,1 we hypothesized that genotyping at the
GNB3 825 locus allows, for the first time, the prediction of
the efficacy by which hormones activate PTX-sensitive G
proteins and the strength of subsequent cellular responses in humans.
After this hypothesis, we recently reported that chemotaxis of
neutrophils, which is mediated via ß subunits released from
PTX-sensitive G protein subunits, is significantly enhanced in 825T
allele carriers expressing Gß3s.2 Stimulated by
these findings, we became interested in whether these in vitro
observations can be generalized and extended to more complex
physiological in vivo responses. In this context,
-adrenergic coronary vasoconstriction is an interesting
candidate, because the involved -adrenoceptors represent
typical heptahelical G protein–coupled receptors.3
Because the 825T allele seems to exclusively enhance PTX-sensitive
G protein signaling, we hypothesized that
2-adrenergic activation, which was recently
shown to occur via PTX-sensitive G proteins containing the Gß3
subunit,4 but not 1-adrenergic
activation, which occurs via PTX-insensitive G proteins, causes
enhanced coronary constriction in 825T allele carriers.
We recently demonstrated in humans that in normal
coronary vessels, predominantly
2-adrenoceptor activation reduces
coronary blood flow (CBF), mainly through microvascular
constriction.5 In the presence of
atherosclerosis, both 1- and
2-adrenergic epicardial and microvascular
constrictions of human coronary vessels are
augmented and can then induce myocardial
ischemia.5 Although these findings account for
part of the pathophysiological role of
-adrenergic coronary vasoconstriction, a common gene
variation, such as the C825T polymorphism at GNB3, which
determines G protein signaling, might account for the wide range of
interindividual variability of -adrenoceptor–mediated
coronary constrictor responses.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Patients
Forty-eight white individuals undergoing coronary angiography due to chest pain of unknown cause were enrolled consecutively in this study after providing written informed consent. Enrollment was completed when the diagnostic coronary angiography and intravascular ultrasound examination yielded either a normal left coronary artery or single-vessel disease that was suitable for quantitative evaluation. Normal coronary arteries were defined when patients had no plaques or had plaques with <10% area stenosis in the major left coronary arteries on intravascular ultrasound examination. Demographic data are given in Table 1
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Twelve individuals received the selective
1-adrenoceptor agonist methoxamine
(MTX) and 12 individuals received the selective
2-adrenoceptor agonist BHT-933 (BHT), both
intracoronarily (IC) and in random order. Twenty-four additional
individuals received both MTX and BHT in random order during the same
investigational procedure. Individuals were divided into 4 groups
depending on the -agonist they received and on the presence or
absence of coronary artery disease (CAD).
Study Protocol
The study protocol was approved by the local ethics committee of
the University of Essen Medical School. With the exception of 100 mg/d
aspirin, all medication was stopped 24 hours before cardiac
catheterization. Aortic pressure measurement, biplane
left ventricular angiography, intravascular ultrasound
examination, and coronary catheterization were
performed and intracoronary Doppler flow velocity
measurements were made as previously described.5 One
individual of the BHT group had to be excluded from further
analysis because the quality of the Doppler signal was not
satisfactory.
After the intravenous injection of 1 mg atropine to prevent
reflex bradycardia, the respective -adrenoceptor agonists were
administered in a dose of 5 mg IC each as a bolus via the guiding
catheter. Based on our previous study, a dose of 5 mg of each agonist
was expected to result in clear coronary vasomotor
effects.5 Doppler flow velocity, arterial
blood pressure, and ECG were recorded continuously.
Occurrence of Myocardial Ischemia
Drug-related ischemia was assumed if chest pain was
reported or if ST-segment depression of 
0.2 mV occurred on the ECG
within 10 minutes after the injection of the respective drug.
Genotyping
DNA extraction and genotyping were performed in a blinded
fashion as previously described.1
Statistical Analysis
The results are expressed as mean±SEM. Data were
analyzed with the use of the SPSS software package 8.0.0G (SPSS
Inc). Categorical data were compared with the use of the
2 test or the Fisher exact test, where
appropriate. An exact test was used to determine whether the null
hypothesis of an odds ratio of 1 for the occurrence of ischemic
events could be rejected. Intragroup variations, as well as comparisons
between groups with regard to mean aortic blood pressure (MAP), heart
rate (HR), and cholesterol levels, were performed with the
use of the Student t test.6 Because
several factors were reported to influence coronary vasomotion,
a general linear model was used that included cholesterol
levels,7 MAP,8 HR,9 10 and the
presence or absence of CAD5 to test the influence of
genotype on CBF reduction after BHT or MTX, respectively. A
value of P
0.05 was considered to indicate statistical
significance.
An expanded Materials and Methods section is available online at http://www.circresaha.org.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Demographic and clinical data for individuals with different genotypes at GNB3 in each drug group were comparable (Table 1
). Genotyping yielded 2 individuals who were homozygous,
23 individuals who were heterozygous for the 825T allele, and 23
individuals who were homozygous for the 825C allele. HR and MAP
values were comparable among groups at baseline and remained unchanged
when the local coronary vasoconstrictor responses were
measured. MAP subsequently increased, however, due to the recirculation
of study drugs, and HR decreased. Under baseline conditions, average
peak velocity, cross-sectional area in the Doppler segment, and CBF
did not differ among groups, regardless of genotype and CAD
status (Table 2).
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2-Adrenoceptor Activation
The CBF reduction induced by BHT was significantly larger in
825T allele carriers than in homozygous C825 allele carriers
(58±4% versus 28±4%, P=0.001; Figure 1) and significantly enhanced in patients
with CAD compared with patients without CAD (53±5 versus 30±5%,
P=0.04; Figure 2).
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In individuals with the homozygous CC genotype, CBF was
markedly reduced in response to 2-adrenoceptor
activation and further reduced in the presence of CAD (39±8% versus
20±3%, P=0.02. Although CBF reduction was even greater in
825T allele carriers, the additional effect of CAD was rather
moderate (64±5% versus 48±7%, P=0.07).
In 8 patients with an average CBF reduction of 55±10%, clinical signs
of acute ischemia, as represented by ST-segment
depression or symptoms of angina pectoris, were observed in response to
BHT (Table 2). This effect was almost exclusively observed in
heterozygous 825T allele carriers with (3 TC and 1 CC) and without
(4 TC) CAD. The resulting odds ratio for ischemia in response
to BHT was significantly increased in 825T allele carriers (odds
ratio, 14.0; 95% confidence interval, 1.5 to 132; P=0.01;
Table 3).
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1-Adrenoceptor Activation
The MTX-induced CBF reduction was not significantly different
between genotypes at the GNB3 locus (CC, 46±5%;
TC, 31±6%; P=0.2; Figure 1) but strongly enhanced
in patients with CAD (53±4 versus 19±5%; P=0.003;
Figure 2). Three patients (2 TC, 1 CC) displayed clinical
signs of ischemia (mean CBF reduction, 36±27%; Table 3).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the experimental setting,
-adrenergic coronary
constriction is overcome by metabolic dilation under
physiological circumstances11 but is
sufficiently powerful to reduce CBF when local regulatory mechanisms
are impaired by endothelial dysfunction,12
atherosclerosis,13 autoregulatory
escape,14 or distal to severe
stenoses.15 16 In patients with CAD, isometric
exercise and reflex sympathetic activation can induce ischemic
myocardial dysfunction and angina pectoris, which are in part
caused by -adrenergic coronary
vasoconstriction.17 18 19 Both 1-
and 2-adrenoceptor activation play an
important role in coronary vasoconstriction. In our previous
study, in normal coronary arteries, CBF was mainly reduced
through the activation of 2-adrenoceptors,
whereas in atherosclerotic coronary arteries, both
1- and 2-adrenoceptor
activation contributed equally to the reduction in blood
flow.5 Somewhat different from our previous investigation
but consistent with the study of Lorenzoni et
al,20 in the present study, we found a small but
significant decrease in blood flow in normal human coronary
vessels on 1-adrenoceptor activation. This
difference can most likely be explained from a statistical point of
view, because the number of patients in the previous study was probably
not sufficient to achieve significance in differentiation between
several doses of the 1-agonist. We observed a
large interindividual variability in vasoconstrictor responses to
-adrenoceptor activation. Given the enhanced responsiveness of
PTX-sensitive G proteins in individuals carrying the GNB3
825T allele, we hypothesized that a large fraction of the
variability seen on 2-adrenoceptor, but not
1-adrenoceptor, activation is determined by
genotype. In fact, we could now demonstrate that the presence
of an 825T allele was a strong predictor of selective
2-adrenergic coronary
vasoconstriction, independent of MAP, HR, and cholesterol
levels. Even more remarkable was that this effect was independent of
coronary artery status, which also contributed to CBF reduction
in response to BHT, potentially through impaired coronary
vasodilator capacity in the presence of endothelial
damage. However, with the use of a descriptive analysis, the
impact of CAD was markedly lower in 825T allele carriers.
As expected, no differences occurred with respect to genotype
at GNB3 on selective 1-adrenoceptor
activation, whereas the CBF reduction was significantly enhanced in
patients with CAD, in line with our previous
observations.5
In response to BHT, the 825T allele carriers also significantly
more often displayed clinical signs of ischemia, which was most
likely due to the greater CBF reduction, because further
analysis of data from our previous study5
indicated that the decrease in myocardial lactate extraction, as an
indicator of myocardial ischemia, is significantly correlated
to the reduction of CBF in response to 5 mg IC of the respective study
drug (Spearman’s R=0.725, P=0.008).
Interestingly, we recently reported that the presence of an 825T
allele also increases the likelihood for myocardial infarction in
individuals with CAD.21 Although these findings
improve our pathophysiological understanding,
especially of patients with abnormal vascular reactions and angina
pectoris symptoms in the absence of any flow-limiting epicardial
coronary stenosis, the
physiological importance of this observation
remains to be defined. No investigation has been performed in vivo,
with the use of norepinephrine as the
endogenous adrenoceptor activator or physical
activity, to evaluate the distinct impact of
1- and
2-adrenoceptors on CBF under
physiological circumstances in humans.
The molecular basis of the observed association between
2-adrenergic activation and genotype
at GNB3 has yet to be determined.
2-Adrenoceptors regulate vascular tone via 2
distinct mechanisms. First, they may mediate vasoconstriction through
the inhibition of adenylyl cyclases and activation of phospholipase C,
with the latter process involving G protein ß
subunits.22 23 Second,
2-adrenoceptor activation mediates
vasodilation, which is assumed to be secondary to the release of nitric
oxide from the endothelium.24 Thus, one
could speculate that the enhanced blood flow reduction in 825T
allele carriers may be counteracted by a concomitantly increased
vasodilation. However, 2-adrenoceptor
activation in vivo usually causes vasoconstriction that is not overcome
by vasodilation, with the latter mainly observed under in vitro
conditions (eg, in preconstricted, isolated arteries). Furthermore,
although 2-adrenoceptor–mediated vasodilation
seems to involve nitric oxide formation via PTX-sensitive G proteins in
large conductance arteries,24 in other vascular beds, such
as in coronary arteries,25 cerebral
arteries,26 or mesenterial resistance
arteries,27 nitric oxide either seems to have no effect or
inhibits 2-adrenoceptor–mediated
vasodilation. Not much is known about the mechanisms of the nitric
oxide–independent, 2-adrenoceptor–mediated
vasodilation, although a very recent report suggests the involvement of
smooth muscle Ca2+-operated
K+ channels.27
Conclusions
Beyond the augmentation of 1- and
2-adrenergic coronary vasoconstriction
in the presence of coronary atherosclerosis,
the response to 2-adrenoceptor activation is
likely genetically determined and is strongly associated with the 825T
allele at GNB3. The enhanced coronary
vasoconstrictor response in 825T allele carriers with and without
CAD was accompanied by a higher rate of signs and symptoms of
myocardial ischemia.
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Acknowledgments |
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This work was supported by the Deutsche Forschungsgemeinschaft (DFG Si 393/12-2) and the IFORES-Program of the University of Essen (Essen, Germany). We thank Johannes Hüsing for his statistical advice.
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Footnotes |
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1 Both authors contributed equally to this study.
Received February 5, 1999; accepted September 7, 1999.
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