Copyright © 2005, European Society of Cardiology
Alterations of the preproenkephalin system in cardiac hypertrophy and its role in atrioventricular conduction
aMedizinische Klinik II des Universitätsklinikums Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany
bInstitut für Experimentelle und Klinische Pharmakologie und Toxikologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstrasse 17, 91054 Erlangen, Germany
cInstitut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universitäts-Krankenhaus Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
dKlinik für Innere Medizin-Nephrologie, Universitäts-Krankenhaus Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
* Corresponding author. Tel.: +49 451 500 2421; fax: +49 451 500 2363. Email address: joachim.weil{at}innere2.uni-luebeck.de
Objective: The goal of this study was to investigate alterations of the endogenous opioid system in cardiac hypertrophy, to elucidate mechanisms of preproenkephalin (ppENK) gene expression, and to assess effects of endogenous opioids on myocardial contractility and atrioventricular conduction.
Methods: Hypertrophy was induced by ligation of a renal artery (2K1C) or chronic isoprenaline infusion (ISO). ppENK and opioid receptor (µ-, 
-, 
-OR) mRNA expression was quantified by Northern blot and quantitative RT-PCR, respectively. Isolated cardiac myocytes and non-myocytes from neonatal rat heart were used for cell culture experiments.
Results: Overall expression of OR in the heart was markedly lower than in brain tissue, with -OR being the most abundant isoform in the heart. We did not observe differences in -OR expression in ventricular and atrial myocardium. In contrast, -OR expression was markedly higher in atria than in ventricles. µ-OR expression in the heart was below the detection limit of the developed qRT-PCR assay. In left ventricular myocardium, ppENK mRNA levels were significantly increased in 2K1C rats but decreased in ISO rats. Cell culture experiments from neonatal rat hearts revealed that myocytes and non-myocytes express ppENK mRNA. In these cells, receptor-dependent and -independent stimulation of the β-adrenergic signalling pathway caused an increase in ppENK mRNA. Furthermore, inactivation of inhibitory G-proteins by pertussis toxin increased basal and noradrenaline-stimulated ppENK mRNA expression. The physiological significance of myocardial opioids was investigated in isolated perfused rat hearts. Opioid receptor antagonists (nor-BNI, naltrindol) and the enkephalinase inhibitor CPL had no effect on contractility but significantly altered atrioventricular conduction.
Conclusion: These observations suggest that the cardiac opioid system is activated in cardiac hypertrophy. Pressure overload and stimulation of the β-adrenergic signalling pathway have been identified as a possible mechanism leading to increased ppENK expression, which may contribute to opioid system activation. Finally, endogenous opioids modulate the dromotropic response to catecholamine stimulation. The latter finding raises the possibility that endogenous opioids may contribute to the pathogenesis of arrhythmias.
KEYWORDS Hypertrophy; Gene expression; AV-node
Time for primary review 21 days
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