Greater inotropic and cyclic AMP responses evoked by noradrenaline through Arg389 beta 1-adrenoceptors versus Gly389 beta 1-adrenoceptors in isolated human atrial myocardium.
1. We studied the biochemical and contractile responses of isolated human myocardial tissue expressing native receptor variants of the 389G>R beta(1)-adrenoceptor polymorphism. 2. 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 beta(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. 3. 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. 4. 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 micro M 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 micro M 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. 5. These data provide the first evidence that enhanced G-protein coupling of the R389 beta(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 beta(1)-adrenoceptor activation depending on its genotype at the 389 position.
Sandilands
A J
AJ
Clinical Pharmacology Unit, University of Cambridge, Box 110, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QQ. ajs@medschl.cam.ac.uk
O'Shaughnessy
K M
KM
Brown
M J
MJ
D058665:Adrenergic beta-1 Receptor Agonists; D000368:Aged; D000704:Analysis of Variance; D001120:Arginine / Q000235:genetics / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D014644:Genetic Variation / Q000187:drug effects / Q000502:physiology; D005838:Genotype; D005998:Glycine / Q000235:genetics / Q000378:metabolism; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D009206:Myocardium / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology*; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics / Q000502:physiology*; D013268:Stimulation, Chemical
D058665:Adrenergic beta-1 Receptor Agonists; D018342:Receptors, Adrenergic, beta-1; D001120:Arginine; D000242:Cyclic AMP; D005998:Glycine; D009638:Norepinephrine