To evaluate catecholaminergic responses without systemic counterregulation, we infused graded concentrations of
tyramine, an indirect presynaptic
norepinephrine releaser, into dorsal hand veins of 49 normotensive men and women of 5 ethnicities. Vascular responses were coupled to common (minor allele frequency >10%) single-nucleotide polymorphisms at
adrenergic target loci within presynaptic pathways. Significance was set at P<0.003 after Bonferroni correction. Generalized analysis of molecular variance (GAMOVA) was performed to determine whether genetic admixture contributed to results. Venoconstriction progressed to 47% with increasing concentrations of
tyramine (0.129 to 25.8 mmol/L; P<0.001). Family history of
hypertension (P<0.001) and female sex (P=0.02) predicted blunted
tyramine responses. Two genetic loci significantly predicted vascular response:
chromogranin B, which encodes a
protein that catalyzes
catecholamine vesicle formation (CHGB, exon 4, Glu348Glu; P=0.002), and
cytochrome b-561 (CYB561, intron 1, C719G; P<0.001), an electron shuttle for
catecholamine synthesis. Stepwise regression suggested important effects for the CHGB locus, with polymorphisms for the
vacuolar-ATPase beta-subunit (ATP6V1B1, exon 1, Ile30Thr) and
flavin-containing monooxygenase-3 (
FMO3, exon 3, Lys158Glu, P=0.002). GAMOVA did not show a significant relationship between overall genetic profile and hand-vein constriction (P=0.29), which indicates that population stratification did not contribute to this phenotype.
CONCLUSIONS: Locally infused
tyramine produced dose-dependent pressor responses, predicted by family history of
hypertension, sex, and genetic variants at loci, particularly CHGB, that encode the biosynthesis, storage, and metabolism of
catecholamines. Such variants may influence the complex heritability of
adrenergic responses and perhaps
hypertension.