Thr164Ile polymorphism of the human β2-adrenoceptor exhibits blunted desensitization of cardiac functional responses in vivo

In subjects heterozygous for Thr164Ile beta(2)-adrenoceptor (beta(2)AR) polymorphism, cardiac responses to beta(2)AR agonist stimulation are blunted. In this study, we investigated agonist-induced desensitization of Thr164Ile beta(2)ARs. For this purpose, we assessed in six subjects with heterozygous Thr164Ile beta(2)ARs and in 10 subjects with homozygous wild-type (WT) beta(2)ARs the effects of 2-wk oral treatment with 3 x 5 mg/day terbutaline on terbutaline infusion-induced increases in heart rate (HR) and contractility [ measured as shortening of HR-corrected duration of electromechanical systole (QS2c)]. Compared with WT beta(2)AR subjects, Thr164Ile subjects exhibited a blunted terbutaline-induced maximum increase in HR (WT 32 +/- 4 beats/min, Thr164Ile 19 +/- 3 beats/ min, P < 0.05) and contractility (WT - 54 +/- 2 ms, Thr164Ile - 37 +/- 6 ms, P < 0.05). Two-week oral terbutaline treatment desensitized cardiac beta(2)AR responses to terbutaline infusion ( increase in HR: WT 10 +/- 2 beats/ min, Thr164Ile 8 +/- 4 beats/ min; increase in contractility: WT - 22 +/- 5 ms Thr164Ile: - 17 +/- 6 ms); however, the extent of desensitization was larger in WT than Thr164Ile beta(2)AR subjects. Thus, after 2-wk oral terbutaline treatment cardiac, beta(2)AR responses did not differ anymore between WT and Thr164Ile beta(2)AR subjects. We conclude that agonist-induced desensitization of cardiac beta(2)ARs is more pronounced in WT than Thr164Ile subjects. Thus cardiac Thr164Ile subjects appear to be somewhat protected against agonist-induced desensitization.