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Previous Volume 345:1030-1035 October 4, 2001 Number 14 Next

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ABSTRACT

Background With continuous exposure to ₂-adrenergic agonists, vascular tissue becomes desensitized to agonist-mediated vasodilatation. We studied the effects of two common polymorphisms of the ₂-adrenergic receptor, one at codon 16 and one at codon 27, on agonist-mediated vasodilatation and desensitization in the vascular bed.

Methods We studied 26 healthy subjects who were selected to represent three genotypes: 7 were homozygous for the alleles encoding Arg16 and GIn27, 8 were homozygous for the alleles encoding Gly16 and Gln27, and 11 were homozygous for the alleles encoding Gly16 and Glu27. Vascular responses were assessed by measuring changes in the diameter of a dorsal hand vein. A dose–response curve of the effect of the ₂-adrenergic–receptor agonist isoproterenol was constructed (dose range, 4 to 480 ng per minute). Desensitization was then induced by a 2-hour continuous infusion of isoproterenol, and venodilatation was measured 30, 60, 90, and 120 minutes after the start of the infusion.

Results Subjects who were homozygous for Arg16 had almost complete desensitization; venodilatation in response to isoproterenol in this group decreased from a mean (±SE) of 44±11 percent to 8±4 percent (P=0.006). In contrast, subjects who were homozygous for Gly16 did not have significant desensitization, irrespective of the amino acid encoded by codon 27. Subjects who were homozygous for Glu27 had higher maximal venodilatation in response to isoproterenol than those who were homozygous for Gln27 (86±13 percent vs. 54±8 percent, P=0.03).

Conclusions The Arg16 polymorphism of the ₂-adrenergic receptor is associated with enhanced agonist-mediated desensitization in the vasculature, and the Glu27 polymorphism is associated with increased agonist-mediated responsiveness. Therefore, polymorphisms of the ₂-adrenergic receptor are potentially important determinants of the vascular response to stress.

Source Information

From the Division of Clinical Pharmacology (V.D., G.G.S., H.-G.X., R.B.K., C.M.S., A.J.J.W.) and the General Clinical Research Center (D.W.B.), Vanderbilt University School of Medicine, Nashville.

Address reprint requests to Dr. Wood at the Division of Clinical Pharmacology, Rm. 550, Medical Research Bldg. 1, Vanderbilt University School of Medicine, Nashville, TN 37232-6602.

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