Greater inotropic and cyclic AMP responses evoked by noradrenaline through Arg389 β 1 ‐adrenoceptors versus Gly389 β 1 ‐adrenoceptors in isolated human atrial myocardium

We studied the biochemical and contractile responses of isolated human myocardial tissue expressing native receptor variants of the 389G>R β 1 ‐adrenoceptor polymorphism. Right atrial appendage was obtained from homozygous RR patients ( n =37) and homozygous GG patients ( n =17) undergoing elective cardiac surgery. The positive inotropic effect of noradrenaline in these tissues, mediated through β 1 ‐adrenoceptors, was studied using electrically stimulated (1 Hz) atrial strips, as well as the effects of noradrenaline on cyclic AMP levels and cyclic AMP‐dependent protein kinase. Tissue from RR homozygotes ( n =14) showed significantly increased inotropic potency to noradrenaline (−log EC 50 , M =6.92±0.12) compared to GG homozygotes ( n =8, −log EC 50 , M =6.36±0.11, P <0.005). This difference was not dependent on tissue basal force. Tissue cyclic AMP levels (pmol mg −1 ) were also greater in RR homozygotes (basal 34.8±3.7 n =12, 300 n M noradrenaline 41.4±7.6 n =9, 30 μ M noradrenaline 45.2±3.2 n =22, 0.2 m M isoprenaline 48.3±4.2 n =16) compared to GG homozygotes (basal 30.7±4.4 n =5, 300 n M noradrenaline 32.6±6.92 n =5, 30 μ M noradrenaline 38.1±3.1 n =8, 0.2 m M isoprenaline 42.6±5.2 n =6, P =0.007). There were no differences between the variants in terms of cyclic AMP‐dependent protein kinase activity. These data provide the first evidence that enhanced G‐protein coupling of the R389 β 1 ‐adrenoceptor variant reported in rodent fibroblast expression systems is also present in native human receptors. The functional consequence of this is to significantly alter the inotropic potency of β 1 ‐adrenoceptor activation depending on its genotype at the 389 position.British Journal of Pharmacology (2003) 138 , 386–392. doi: 10.1038/sj.bjp.0705030