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In-vivo studies do not support a major functional role for the Gly389Arg β1-adrenoceptor polymorphism in humans

Büscher, Rainerb*; Belger, Heikoa*; Eilmes, Katrin J.b; Tellkamp, Ralphc; Radke, Joachimc; Dhein, Stefana; Hoyer, Peter F.b; Michel, Martin C.d; Insel, Paul A.e; Brodde, Otto-Ericha

Original Article

β1-adrenoceptors play a pivotal role in regulating contractility and heart rate in the human heart. Recently, a polymorphism of the β1-adrenoceptor has been detected: at amino acid position 389 either Gly or Arg has been found with the Gly389 exhibiting reduced responsiveness upon agonist-induced stimulation in vitro. In order to find out whether the Gly389 polymorphism exhibits blunted responsiveness also in vivo we studied, in healthy volunteers, the effects of exercise on heart rate and heart rate-corrected duration of electromechanical systole (QS2c as a measure of inotropism) which, in humans, is mediated by β1-adrenoceptors stimulation. Twenty-four healthy volunteers (12 female, 12 male) homozygous for the Gly389 or Arg389 exercised on a bicycle in supine position (25, 50, 75 and 100 W for 5 min each), and heart rate and QS2c were assessed; in addition, plasma renin activity (PRA) was determined which is also regulated by β1-adrenoceptors in humans. Exercise caused work-load dependent increases in heart rate and PRA, and shortening of QS2c; however, these changes were not significantly different between the Gly389 and Arg389 polymorphism. Thus, these three β1-adrenoceptor responses did not differ between volunteers with the Arg389 versus the Gly389 polymorphism. Intragroup analysis, however, revealed that exercise induced increase in heart rate and shortening of QS2c were higher in female than in male volunteers. In conclusion, our data do not support the idea that the reduced responsiveness of Gly389 against agonist-induced stimulation observed in vitro is of major functional importance in vivo.

aInstitute of Pharmacology, University of Halle, Germany, bDepartment of Pediatric Nephrology, University of Essen, Germany, cDepartment of Anesthesiology, University of Halle, Germany, dDepartment of Internal Medicine, University of Essen, Germany and eDepartment of Pharmacology, University of California at San Diego, La Jolla, CA, USA

Received 3 July 2000; accepted 21 August 2000

Correspondence to Otto-Erich Brodde, Institute of Pharmacology and Toxicology, University of Halle, Magdeburger Strasse 4, D-06097 Halle/Saale, Germany Tel: +49 345 557 1773; fax: +49 345 557 1835

*Both authors contributed equally to this paper

© 2001 Lippincott Williams & Wilkins, Inc.