Article date: January 2003
By: A J Sandilands, K M O'Shaughnessy, M J Brown in Volume 138, Issue 2, pages 386-392
We studied the biochemical and contractile responses of isolated human myocardial tissue expressing native receptor variants of the 389G>R β1‐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 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.
We studied the biochemical and contractile responses of isolated human myocardial tissue expressing native receptor variants of the 389G>R β1‐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 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.
British Journal of Pharmacology (2003) 138, 386–392. doi:10.1038/sj.bjp.0705030
DOI: 10.1038/sj.bjp.0705030
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