Greater inotropic and cyclic AMP responses evoked by noradrenaline through Arg389 β₁‐adrenoceptors versus Gly389 β₁‐adrenoceptors in isolated human atrial myocardium

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 β₁‐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 EC₅₀, M=6.92±0.12) compared to GG homozygotes (n=8, −log EC₅₀, 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 nM noradrenaline 41.4±7.6 n=9, 30 μM noradrenaline 45.2±3.2 n=22, 0.2 mM isoprenaline 48.3±4.2 n=16) compared to GG homozygotes (basal 30.7±4.4 n=5, 300 nM noradrenaline 32.6±6.92 n=5, 30 μM noradrenaline 38.1±3.1 n=8, 0.2 mM 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 β₁‐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 β₁‐adrenoceptor activation depending on its genotype at the 389 position.