© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Adenosine-mediated early preconditioning in mouse: protective signaling and concentration dependent effects
Heart Foundation Research Centre, School of Health Science, Griffith University Gold Coast Campus, Southport, Queensland 4217, Australia
j.headrick{at}mailbox.gu.edu.au
* Corresponding author. Tel.: +61-7-5552-8292; fax: +61-7-5552-8802.
Objectives: Signaling in adenosine-mediated preconditioning is controversial. We examined roles of mitochondrial (mito) KATP channels, protein kinase C (PKC) and nitric oxide (NO). Methods: Langendorff perfused C57/Bl6 mouse hearts were subjected to 20 min ischemia and 45 min reperfusion. Effects of adenosine-mediated preconditioning were assessed in the absence and presence of signaling inhibitors. Results: Control hearts recovered 70±2 mmHg ventricular pressure, and released 18.1±2.0 IU/g lactate dehydrogenase (LDH). Preconditioning with 10 µM adenosine limited necrosis (10.6±1.4 IU/g) without modifying contractility (72±2 mmHg) whereas 50 µM adenosine reduced necrosis (10.3±1.6 IU/g) and contractile dysfunction (91±2 mmHg). All protective effects of 10 and 50 µM adenosine were abrogated by mito KATP channel blockade with 100 µM 5-hydroxydecanoate (5-HD) during the ‘trigger’ phase, but unaltered by PKC or NO synthase inhibition with 3 µM chelerythrine or 100 µM NG-nitro-L-arginine methyl ester (L-NAME), respectively. Protection against necrosis was eliminated by 5-HD but unaltered by chelerythrine or L-NAME during the ‘mediation’ phase (ischemia–reperfusion). Reduced contractile dysfunction with 50 µM adenosine was partially sensitive to 5-HD and chelerythrine, and only eliminated by co-infusion of the inhibitors. Conclusions: Adenosine-mediated preconditioning is dose-dependent with high level stimulation reducing contractile dysfunction in addition to necrosis. Preconditioning is triggered by a mito KATP channel dependent process independently of PKC and NO. Subsequent protection against necrosis is also mediated by a mito KATP channel dependent process independent of PKC and NO. In contrast, functional protection may be mediated by parallel mito KATP and PKC dependent paths.
KEYWORDS Experimental; Heart; Organ; Pathophysiology
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