The Gln27Glu β2-adrenoceptor polymorphism slows the onset of desensitization of cardiac functional responses in vivo

Studies performed in vitro have shown that the Arg(16)Gly allele in beta(2)-adrenoceptors (beta(2)AR) enhances susceptibility to agonist-induced down-regulation, while the Gln(27)Glu polymorphism diminishes it. In this study, we tested whether similar phenotypes occur in vivo. We assessed 32 volunteers (mean age 25 +/- 2 years) with different genotypes (group A: wild-type beta(2)PAR, n = 16; group B: homozygous Glu(27), n = 10; group C homozygous Gly(16), n = 6) for the effect of 2 weeks treatment with 3 x 5 mg/day oral terbutaline on terbutaline infusion-induced increases in heart rate and contractility (i.e. shortening of heart rate-corrected duration of electromechanical systole, QS(2)c). At baseline, terbutaline infusion increased heart rate and contractility similarly among subjects in the three groups. Treatment with oral terbutaline for 14 days reduced the ability of intravenous (i.v.) terbutaline to increase heart rate and contractility. The extent of this reduction was similar but the time course of desensitization differed among the three groups. While in groups A and C terbutaline infusion-induced increases in heart rate and contractility were reduced within 24 h after oral ingestion of terbutaline, a significant effect on response to terbutaline infusion was not evident for the first 3 days of terbutaline treatment in group B. The Arg(16)Gly and the Gln(27)Glu variants of the beta(2)PAR do not alter the extent of agonist-induced beta(2)PAR desensitization in vivo but Glu(27) homozygotes develop desensitization more slowly. This result may have implications for cardiac side-effects in patients who are Glu(27) homozygotes and who receive beta(2)PAR agonist therapy.