Beta2-adrenoceptor Thr164Ile polymorphism is associated with markedly decreased vasodilator and increased vasoconstrictor sensitivity in vivo.
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.


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.
Division of Clinical Pharmacology and General Clinical Research Center Division of General Internal Medicine, Department of Medicine and the Department of Biostatistics, Vanderbilt University Medical Center, Nashville TN, USA.
Victor
V
Dishy
Ruth
R
Landau
Gbenga G
GG
Sofowora
Hong-Guang
HG
Xie
Richard M
RM
Smiley
Richard B
RB
Kim
Daniel W
DW
Byrne
Alastair J J
AJ
Wood
C Michael
CM
Stein
D058646:Adrenergic alpha-1 Receptor Agonists; D058666:Adrenergic beta-2 Receptor Agonists; D000328:Adult; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007532:Isoleucine / Q000737:chemistry / Q000235:genetics; D007545:Isoproterenol / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011110:Polymorphism, Genetic; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics* / Q000378:metabolism; D013912:Threonine / Q000737:chemistry / Q000235:genetics; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology; D014680:Veins / Q000187:drug effects / Q000502:physiology
D058646:Adrenergic alpha-1 Receptor Agonists; D058666:Adrenergic beta-2 Receptor Agonists; D018340:Receptors, Adrenergic, alpha-1; D018343:Receptors, Adrenergic, beta-2; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D007532:Isoleucine; D010656:Phenylephrine; D013912:Threonine; D007545:Isoproterenol