β₂-adrenoceptor Thr164lle polymorphism is associated with markedly decreased vasodilator and increased vasoconstrictor sensitivity in vivo

Background: The uncommon Thr164lle polymorphism of the β₂- adrenoceptor is associated with profoundly altered responses to agonist in vitro; however its effects on vascular responses in vivo are not known. Altered adrenergic vascular sensitivity may contribute to the decreased survival observed in patients with congestive heart failure carrying the lle164 allele. Methods and results: We used the linear variable differential transformer dorsal hand vein technique to compare vasodilation in response to the β-adrenergic receptor agonist, isoproterenol, and vasoconstriction in response to the α-adrenergic receptor agonist, phenylephrine, in healthy homozygous (Thr164/Thr164) (n = 21) and heterozygous Thr164/lle164 (n = 5) women. The dose of isoproterenol required to achieve 50% venodilation (geometric mean; 95% CI) was significantly higher in women with the lle164 allele (82.5 ng/min; 17.3-394 ng/min) than those without (15.8 ng/min; 11-25 ng/ min; P = 0.004). The maximum response to isoproterenol was not different (102 ± 1% and 102 ± 3%, respectively, P = 0.9). The dose of phenylephrine needed to induce 50% venoconstriction was significantly lower in women with the lle164 allele (151 ng/min; 42-543 ng/min) than those without (540 ng/min; 350-835 ng/min; P = 0.02). Conclusions: The Thr164lle polymorphism of the β₂-adrenergic receptor is associated with a five-fold reduction in sensitivity to β₂ receptor agonist-mediated vasodilation; vasoconstrictor sensitivity is increased. The overall effect of the Thr164lle polymorphism is to shift the balance of adrenergic vascular tone toward vasoconstriction. This suggests a mechanistic explanation for the clinical observation of decreased survival in patients with congestive heart failure heterozygous for the Thr164lle polymorphism.