Conservation of the cardiostimulant effects of (-)-norepinephrine across Ser49Gly and Gly389Arg beta(1)-adrenergic receptor polymorphisms in human right atrium in vitro.
OBJECTIVE
The goal of this study was to determine whether the cardiostimulant effects of the endogenous beta(1)-adrenergic receptor (AR) agonist, (-)-norepinephrine are modified by polymorphic (Serine49Glycine [Ser49Gly], Glycine389Arginine [Gly389Arg]) variants of beta(1)-ARs in the nonfailing adult human heart.


BACKGROUND
Human heart beta(1)-ARs perform a crucial role in mediating the cardiostimulant effects of (-)-norepinephrine. An understanding of the significance of Ser49Gly and Gly389Arg polymorphisms in the human heart is beginning to emerge, but not as yet in adult patients who have coronary artery disease (CAD).


METHODS
The potency and maximal effects of (-)-norepinephrine at beta(1)-ARs (in the presence of beta(2)-AR blockade with 50 nM ICI 118,551 [erythro-DL-1(7-methylindan-4-yloxy)-3-isopropylamino-butan-2-ol]) for changes in contractile force and shortening of contractile cycle duration were determined in human right atrium in vitro from 87 patients undergoing coronary artery bypass grafting who were taking beta-blockers before surgery. A smaller sample of patients (n = 20) not taking beta-blockers was also investigated. Genotyping for two beta(1)-AR polymorphisms (Ser49Gly and Gly389Arg) was determined from a sample of blood taken at the time of surgery.


RESULTS
(-)-Norepinephrine caused concentration-dependent increases in contractile force and reductions in time to reach peak force and time to reach 50% relaxation. There were no differences in the potency or maximal effects of (-)-norepinephrine in the right atrium from patients with different Ser49Gly and Gly389Arg polymorphisms.


CONCLUSIONS
The cardiostimulant effects of (-)-norepinephrine at beta(1)-ARs were conserved across Ser49Gly and Gly389Arg polymorphisms in the right atrium of nonfailing hearts from patients with CAD managed with or without beta-blockers.
Molenaar
Peter
P
National Heart Foundation and Prince Charles Hospital Foundation Cardiovascular Research Centre, Department of Medicine, University of Queensland Chermside, Queensland, Australia. p.molenaar@mailbox.uq.edu.au
Rabnott
Glenn
G
Yang
Ian
I
Fong
Kwun M
KM
Savarimuthu
Santiyagu M
SM
Li
Li
L
West
Malcolm J
MJ
Russell
Fraser D
FD
D058665:Adrenergic beta-1 Receptor Agonists; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000368:Aged; D019943:Amino Acid Substitution / Q000235:genetics*; D016275:Atrial Function; D003131:Combined Modality Therapy; D001026:Coronary Artery Bypass; D003327:Coronary Disease / Q000235:genetics* / Q000503:physiopathology* / Q000628:therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000235:genetics / Q000502:physiology; D009638:Norepinephrine / Q000008:administration & dosage / Q000502:physiology*; D011110:Polymorphism, Genetic / Q000235:genetics*; D013566:Sympathomimetics / Q000008:administration & dosage; D013997:Time Factors
D058665:Adrenergic beta-1 Receptor Agonists; D000319:Adrenergic beta-Antagonists; D013566:Sympathomimetics; D009638:Norepinephrine