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Cardiovascular Research 2004 63(4):662-672; doi:10.1016/j.cardiores.2004.05.014
© 2004 by European Society of Cardiology
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Copyright © 2004, European Society of Cardiology

Carvedilol selectively inhibits oscillatory intracellular calcium changes evoked by human {alpha}1D- and {alpha}1B-adrenergic receptors

Taka-aki Koshimizu*,a, Gozoh Tsujimotob, Akira Hirasawaa, Yoko Kitagawaa and Akito Tanouea

aDepartment of Molecular Pharmacology, National Research Institute for Child Health and Development, 3-35-31, Taishido, Setagaya, Tokyo 154-8567, Japan
bDepartment of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University Faculty of Pharmaceutical Sciences, Kyoto University, Yoshida Shimoadachi-cho, Sakyo, Kyoto 606-8501, Japan

* Corresponding author. Tel.: +81-3-3419-2476; fax: +81-3-3419-1252. Email address: tkoshi{at}nch.go.jp

Background: Increasing evidence from clinical trials indicates that carvedilol, an antagonist of {alpha}1- and β-adrenergic receptors (ARs), provides an effective treatment for chronic heart failure, whereas nonselective {alpha}1-AR blockade has an adverse outcome in this disease. It is, however, not clear whether carvedilol exhibits a subtype-dependent impact on three distinct {alpha}1-adrenergic receptors ({alpha}1-ARs). Methods and results: We determined binding properties of human ARs for carvedilol using HEK293 human embryonic kidney cells expressing a single AR subtype. Our results showed that the affinities of {alpha}1D-AR and {alpha}1B-AR for carvedilol are higher than that of the β1-AR subtype, a major target in heart failure treatment. The affinity rank order and pKi values of ARs for carvedilol were as follows: {alpha}1D-AR (8.9)>{alpha}1B-AR (8.6)>β1-AR (8.4)>β2-AR (8.0)>{alpha}1A-AR (7.9)>>{alpha}2C-AR (5.9)>{alpha}2B-AR (5.5)>{alpha}2A-AR (5.3). Furthermore, temporal kinetics of intracellular calcium signaling mediated via {alpha}1D- and {alpha}1B-ARs, but not via {alpha}1A-AR (P<0.01), showed oscillatory patterns with frequencies ranging from 0.3 to 3 per minute in human smooth muscle and HEK293 cells, which were inhibited by the therapeutic concentrations of carvedilol (10 nM) in a subtype-dependent manner. When oscillatory {alpha}1B-AR and non-oscillatory {alpha}1A-AR were co-expressed and heteromer receptors were detected with bioluminescence resonance energy transfer and co-immunoprecipitation, carvedilol suppressed only oscillatory component of global cytosolic free calcium change. Conclusions: These results indicate that in addition to β-ARs, receptor inhibition by carvedilol is directed to {alpha}1-ARs, preferably to {alpha}1D- and {alpha}1B-AR-mediated signaling events, including intracellular calcium oscillations in vascular smooth muscle.

KEYWORDS Adrenergic antagonists; Calcium (cellular); Heart failure; Smooth muscle; Vasoactive agents

Abbreviations: [125I]HEAT, (±)-β-([125I]iodo-4-hydroxyphenyl)-ethyl-aminomethyl-tetralone • [3H]RX821002, (1,4-[6,7(n)-3H]benzodioxan-2-methoxy-2-yl)-2-imidazoline hydrochloride • Gpp(NH)p, 5'-guanylylimidodiphosphate

Time for primary review 27 days


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