© 2001 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Adenosine inhibits norepinephrine release in the postischemic rat heart: the mechanism of neuronal stunning
aMedizinische Klinik II, Universitätsklinikum Lübeck, Ratzeburger Allee 160, 23538 Lubeck, Germany
bDeutsches Herzzentrum München, Munich, Germany
* Corresponding author. Tel.: +49-451-500-2420; fax: +49-451-500-6437 gert.richardt{at}medinf.mu-luebeck.de
Objective: Numerous studies support the concept of impaired postischemic sympathetic neurotransmission in the heart. We hypothesized that postischemic neuronal dysfunction (neuronal stunning) is caused by a transient suppression of exocytotic norepinephrine (NE) release from sympathetic nerve terminals. Furthermore, we assessed the role of presynaptic adenosine-receptors and 
2-adrenoceptors in neuronal stunning. Methods and results: Exocytotic NE release was induced by two electrical field stimulations (S1 and S2) in isolated perfused rat hearts. S1 was performed under baseline conditions and S2 either during or following intervention. Results are expressed as mean S2/S1 ratios±S.E.M. Stepwise increase of global ischemic periods (10, 20, and 30 min) induced a progressive suppression of NE release in the postischemic hearts, which was reversible during reperfusion. Both the degree and duration of NE suppression was dependent on the extent of the preceding ischemic period. Following 10-min ischemia complete recovery of NE release was achieved after 5-min reperfusion (1.07±0.12), whereas 5-min reperfusion did not restore NE release after 30 min (0.36±0.07) of ischemia. The adenosine-receptor antagonists 8-phenyltheophylline (8-PT; non-selective) and 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; adenosine A1-receptor subtype selective) significantly increased NE release after 30-min ischemia and 5-min reperfusion (0.78±0.06 and 0.64±0.07), while in the same experimental protocol blockade of 2-adrenoceptors by yohimbine failed to restore the postischemic release (0.24±0.06). In non-ischemic hearts the adenosine analogue R(–)N6-(2-phenylisopropyl)adenosine (R-PIA) resulted in a marked suppression of NE release (0.61±0.07). The inhibitory effect of R-PIA and 2-chloro-N6-cyclopentyladenosine (CCPA; adenosine A1-receptor subtype selective agonist) persisted 5 min after cessation of R-PIA (0.62±0.05) and CCPA (0.58±0.04). Activation of 2-adrenoceptors by 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK 14,304) also caused a reduction of NE release (0.50±0.02), but the release increased to control levels 5 min after cessation of UK 14,304 (0.90±0.06). Conclusions: The results establish the phenomenon of neuronal stunning in terms of a postischemic suppression of exocytotic NE release and provide evidence that neuronal stunning is mediated by endogenous adenosine through activation of presynaptic adenosine A1-receptors.
KEYWORDS Adenosine; Adrenergic (ant)agonists; Ischemia; Reperfusion; Neurotransmitters
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