© 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
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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