Bedeutung genetischer Polymorphismen im Beta-1-Adrenorezeptor für die Wirkungen von Metoprolol und Carvedilol

Bedeutung genetischer Polymorphismen im Beta-1-Adrenorezeptor für die Wirkungen von Metoprolol und Carvedilol

The Role of Genetic Polymorphisms Within the Beta-1-Adrenoceptor Regarding the Effects of Metoprolol amd Carvedilol

Julia-Patricia Kaup

Doctoral thesis

Date of Examination: 2014-09-16

Date of issue: 2014-08-08

Advisor: Brockmöller, Jürgen Prof. Dr.

Referee: Brockmöller, Jürgen Prof. Dr.

Referee: Nikolaev, Viacheslav Dr.

Persistent Address: http://hdl.handle.net/11858/00-1735-0000-0022-5F47-9

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Abstract

English

Beta blockers are some of the most-prescribed medications in modern medicine regarding cardiovascular diseases. Their main molecular target ist the beta-1-adrenoceptor, a seven transmembrane helical proteine, belonging to the subspecies of G proteine-coupled receptors. It has been shown that there are two common polymorphisms – Arg389Gly and Ser49Gly – existing within the Beta-1-adrenoceptor, which lead to conformational differences. We examined if there were polymorphism-dependent differences in resting or exercise heart rate, blood pressure, orthostatic reaction and intensity of side effects under metoprolol or carvedilol. For that reason, we performed a study with 135 healthy volunteers, who underwent ergometric and orthostatic testing with and without influence of metoprolol and carvedilol. Our results showed that the Ser49 genotype seems to have a reducing influence on resting heart rate both under metoprolol and carvedilol and without drug influence. Without medication as well as under influence of carvedilol, this could be shown for exercise heart rate as well. Furthermore it was shown that the Ser49 genotype was associated with a higher maximum load during ergometries without drug influence. Concerning the Arg389Gly polymorphism, a clear influence regarding heart rate could not be shown. Furthermore we could not observe any polymorphism-dependent influence on blood pressure or intensity of side effects.

Keywords: ADRB1; Metoprolol; Carvedilol; Polymorphism