G Protein β3 Subunit 825T Allele and Enhanced Coronary Vasoconstriction on α 2 -Adrenoceptor Activation

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Abstract
—Recently, α2-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 α1- and α2-adrenoceptors reduces coronary blood flow in humans. α2-Adrenoceptors activate pertussis toxin (PTX)-sensitive G proteins, whereas α1-adrenoceptors couple to PTX-insensitive G proteins. Thus, the 825T allele of the β3 subunit of heterotrimeric G proteins, associated with enhanced PTX-sensitive G protein signaling, was expected to determine the α2-adrenoceptor–, but not the α1-adrenoceptor–, mediated reduction in coronary blood flow (CBF). Genotyping was performed on 48 individuals. Twelve of the 48 received the α1-adrenoceptor agonist methoxamine (MTX; 5 mg IC), and 12 received the α2-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). α2-Adrenoceptor coronary vasoconstriction is genetically determined and significantly enhanced in GNB3 825T allele carriers.