Healthy women with the Ile164 allele required a higher isoproterenol dose for 50% venodilation (82.5 vs 15.8 ng/min; P=0.004) and a lower phenylephrine dose for 50% venoconstriction (P=0.02).
Observational (n=26)
Does the Thr164Ile polymorphism of the beta2-adrenoceptor alter in vivo vasodilator and vasoconstrictor sensitivity in healthy women?
The Thr164Ile polymorphism of the beta2-adrenergic receptor shifts adrenergic vascular tone toward vasoconstriction, potentially explaining decreased survival in heart failure patients with this allele.
Absolute Event Rate: 82.5% vs 15.8%
p-value: p=0.004
BACKGROUND: The uncommon Thr164Ile polymorphism of the beta2-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 Ile164 allele. METHODS AND RESULTS: We used the linear variable differential transformer dorsal hand vein technique to compare vasodilation in response to the beta-adrenergic receptor agonist, isoproterenol, and vasoconstriction in response to the alpha-adrenergic receptor agonist, phenylephrine, in healthy homozygous (Thr164/Thr164) (n = 21) and heterozygous Thr164/Ile164 (n = 5) women. The dose of isoproterenol required to achieve 50% venodilation (geometric mean; 95% CI) was significantly higher in women with the Ile164 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 Ile164 allele (151 ng/min; 42-543 ng/min) than those without (540 ng/min; 350-835 ng/min; P = 0.02). CONCLUSIONS: The Thr164Ile polymorphism of the beta2-adrenergic receptor is associated with a five-fold reduction in sensitivity to beta2 receptor agonist-mediated vasodilation; vasoconstrictor sensitivity is increased. The overall effect of the Thr164Ile 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 Thr164Ile polymorphism.
Dishy et al. (2004) conducted an observational in Healthy (n=26). Ile164 allele (Thr164/Ile164 genotype) vs. Thr164/Thr164 genotype was evaluated on Dose of isoproterenol required to achieve 50% venodilation (ng/min) (p=0.004). Healthy women with the Ile164 allele required a higher isoproterenol dose for 50% venodilation (82.5 vs 15.8 ng/min; P=0.004) and a lower phenylephrine dose for 50% venoconstriction (P=0.02).