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Cardiovascular Research 2002 54(1):133-139; doi:10.1016/S0008-6363(01)00566-1
© 2002 by European Society of Cardiology
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Copyright © 2002, European Society of Cardiology

Adrenergic activation of cardiac phospholipase D: role of {alpha}1-adrenoceptor subtypes

Kenneth Mier, Dorit Kemken, Hugo A. Katus, Gert Richardt and Thomas Kurz*

Medizinische Klinik II, Medizinische Universität zu Lübeck, Ratzeburger Allee 160, D-23538 Lübeck, Germany

* Corresponding author. Tel.: +49-451-500-2420; fax: +49-451-500-6108 kurz{at}gwsun.medinf.mu-luebeck.de

Objective: Adrenergic stimulation of the heart leads to activation of the phospholipase D signal transduction pathway with formation of the intracellular second messengers phosphatidic acid and diacylglycerol, which may play a role in the development of myocardial hypertrophy by activating mitogen-activated protein kinases and protein kinase C. So far, the adrenergic receptor subtypes mediating activation of cardiac phospholipase D are not known. Methods: We developed an assay for determination of phospholipase D activity in the isolated perfused rat heart. Utilizing the phospholipase D specific transphosphatidylation reaction the stable product phosphatidylethanol (PEtOH) is formed in rat hearts perfused in the presence of 1% ethanol. Myocardial PEtOH formation was used as a marker of phospholipase D activity and was determined by HPLC and evaporative light-scattering detection (PEtOH µg/mg myocardial protein). Results: Basal PEtOH formation in unstimulated hearts was 0.06±0.01 µg/mg. Stimulation of the hearts with norepinephrine resulted in a concentration-dependent phospholipase D activation with a maximum formation of PEtOH (0.17±0.01 µg/mg) at 100 µmol/l norepinephrine. The norepinephrine-induced increase in PLD activity was completely blocked by the {alpha}1-adrenoceptor antagonist prazosin and was unaffected by the β-adrenoceptor antagonist propranolol. Further characterisation of {alpha}1-adrenoceptor subtypes with selective {alpha}1-adrenoceptor antagonists demonstrated a complete inhibition of the norepinephrine-induced phospholipase D activation by WB 4101 ({alpha}1A-selective: 0.06±0.01 µg/mg) and by BMY 7378 ({alpha}1D-selective: 0.07±0.01 µg/mg). In contrast, the {alpha}1B-adrenoceptor antagonist chloroethylclonidine had no inhibitory effect on norepinephrine-stimulated phospholipase D activity (0.14±0.01 µg/mg). Conclusion: Adrenergic activation of the cardiac phospholipase D signal transduction pathway is mediated by {alpha}1-adrenoceptors. Here, the {alpha}1A-adrenoceptor subtype, but not the {alpha}1B-adrenoceptor are coupled to activation of cardiac phospholipase D.

KEYWORDS Adrenergic (ant)agonists; Receptors; Second messengers; Signal transduction


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