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Adrenergic activation of cardiac phospholipase D: role of alpha(1)-adrenoceptor subtypes.
- Source :
-
Cardiovascular research [Cardiovasc Res] 2002 Apr; Vol. 54 (1), pp. 133-9. - Publication Year :
- 2002
-
Abstract
- 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.<br />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 microg/mg myocardial protein).<br />Results: Basal PEtOH formation in unstimulated hearts was 0.06+/-0.01 microg/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 microg/mg) at 100 micromol/l norepinephrine. The norepinephrine-induced increase in PLD activity was completely blocked by the alpha(1)-adrenoceptor antagonist prazosin and was unaffected by the beta-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 microg/mg) and by BMY 7378 (alpha(1D)-selective: 0.07+/-0.01 microg/mg). In contrast, the alpha(1B)-adrenoceptor antagonist chloroethylclonidine had no inhibitory effect on norepinephrine-stimulated phospholipase D activity (0.14+/-0.01 microg/mg).<br />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.
- Subjects :
- Adrenergic alpha-Antagonists pharmacology
Adrenergic beta-Antagonists pharmacology
Animals
Clonidine pharmacology
Dioxanes pharmacology
Male
Norepinephrine pharmacology
Perfusion
Piperazines pharmacology
Prazosin pharmacology
Propranolol pharmacology
Rats
Rats, Wistar
Receptors, Adrenergic, alpha-1 drug effects
Stimulation, Chemical
Cardiomegaly metabolism
Clonidine analogs & derivatives
Myocardium enzymology
Phospholipase D metabolism
Receptors, Adrenergic, alpha-1 physiology
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 0008-6363
- Volume :
- 54
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cardiovascular research
- Publication Type :
- Academic Journal
- Accession number :
- 12062369
- Full Text :
- https://doi.org/10.1016/s0008-6363(01)00566-1