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CLINICAL STUDY

Conservation of the cardiostimulant effects of (–)-norepinephrine across Ser49Gly and Gly389Arg beta₁-adrenergic receptor polymorphisms in human right atrium in vitro

Peter Molenaar, PhD^*,*, Glenn Rabnott, BSc(Hons), Ian Yang, MBBS, FRACP, Kwun M. Fong, MBBS, PhD, FRACP, Santiyagu M. Savarimuthu, MSc, Li Li, MD^*, Malcolm J. West, MBBS, PhD, FRACP^* and Fraser D. Russell, PhD^*

^* National Heart Foundation and Prince Charles Hospital Foundation Cardiovascular Research Centre, Department of Medicine, University of Queensland, Queensland, Australia
Division of Thoracic Medicine, The Prince Charles Hospital, Chermside, Queensland, Australia

Manuscript received August 6, 2001; revised manuscript received May 13, 2002, accepted June 27, 2002.

^* Reprint requests and correspondence: Dr. Peter Molenaar, The National Heart Foundation and Prince Charles Hospital Foundation Cardiovascular Research Centre, Department of Medicine, University of Queensland, The Prince Charles Hospital, Chermside, Queensland, 4032, Australia.
p.molenaar{at}mailbox.uq.edu.au

OBJECTIVES: The goal of this study was to determine whether the cardiostimulant effects of the endogenous beta₁-adrenergic receptor (AR) agonist, (–)-norepinephrine are modified by polymorphic (Serine49Glycine [Ser49Gly], Glycine389Arginine [Gly389Arg]) variants of beta₁-ARs in the nonfailing adult human heart.

BACKGROUND: Human heart beta₁-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 beta₁-ARs (in the presence of beta₂-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 beta₁-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 beta₁-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.

Abbreviations and Acronyms   AR   adrenergic receptor   Arg   arginine   bp   base pair   CABG   coronary artery bypass graft   CAD   coronary artery disease   DMSO   dimethyl sulphoxide   DNA   deoxyribonucleic acid   Gly   glycine   HF   heart failure   HR   heart rate   LV   left ventricular   PCR   polymerase chain reaction   Ser   serine

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