Korean J Anesthesiol.  2008 Dec;55(6):716-722. 10.4097/kjae.2008.55.6.716.

Cardioprotective signaling cascade of A2 adenosine receptor agonist 5'-N-ethylcarboxaminidoadenosine against myocardial reperfusion injury

• Lee YC
• Jang YH
• Kim CJ
• Kim JM

• KMID: 1782548
• DOI: http://doi.org/10.4097/kjae.2008.55.6.716

Abstract

BACKGROUND: This experiments investigated the signaling cascade responsible for anti-infarct effect by an A2 adenosine receptor (AR) agonist 5'-N-Ethylcarboxaminidoadenosine (NECA).
METHODS
Langendorff perfused isolated rat hearts were subjected to 30 minutes of regional ischemia and 120 minutes of reperfusion. Drugs were perfused for a period of 5 minutes before and 60 minutes after reperfusion. For comparison of cardioprotection among groups, area at necrosis (AN) and area at risk (AAR) were measured by triphenyltetrazolium chloride staining.
RESULTS
NECA significantly attenuated AN/AAR (14.1 +/- 1.9%, P < 0.001) compared with control hearts (30.7 +/- 2.8%). Anti-infarct effect by NECA was attenuated by an A(2A)AR antagonist 8-(3-chlorostyryl)caffeine (23.7 +/- 3.4%, P < 0.05) and an A(2B)AR antagonist MRS1706 (29.9 +/- 3.3%, P < 0.001). Cardioprotection by NECA was blocked by a guanylyl cyclase inhibitor (23.1 +/- 2.9%, P < 0.05) and a protein kinase G (PKG) inhibitor KT5823 (30.3 +/- 3.2%, P < 0.001). Glycogen synthase kinase-3beta (GSK-3beta) inhibitor SB216763 attenuated the AN/AAR in both NECA with MRS (17.8 +/- 2.7%, P < 0.01 vs. control) and NECA with KT5823 treated hearts (8.2 +/- 1.8%, P < 0.001 vs. control). The mitochondrial permeability transition pore (mPTP) opener atractyloside also aborted NECA's anti-infarct effect (24.7 +/- 2.4% P < 0.05).
CONCLUSIONS
The signaling pathway by NECA administered at reperfusion involves the activation of both A2AAR and A2BAR and cGMP/PKG pathway, which in turn depends on inactivation of GSK-3beta and inhibition of mPTP opening.

Keyword

adenosine receptor; mitochondria; myocardial infarction; NECA; reperfusion injury

MeSH Terms

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Adenosine
Adenosine-5'-(N-ethylcarboxamide)
Animals
Atractyloside
Caffeine
Carbazoles
Cyclic GMP-Dependent Protein Kinases
Glycogen Synthase
Glycogen Synthase Kinase 3
Guanylate Cyclase
Heart
Indoles
Ischemia
Maleimides
Mitochondria
Mitochondrial Membrane Transport Proteins
Myocardial Infarction
Myocardial Reperfusion
Myocardial Reperfusion Injury
Necrosis
Permeability
Purines
Rats
Receptors, Purinergic P1
Reperfusion
Reperfusion Injury
Tetrazolium Salts
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Adenosine
Adenosine-5'-(N-ethylcarboxamide)
Atractyloside
Caffeine
Carbazoles
Cyclic GMP-Dependent Protein Kinases
Glycogen Synthase
Glycogen Synthase Kinase 3
Guanylate Cyclase
Indoles
Maleimides
Mitochondrial Membrane Transport Proteins
Purines
Receptors, Purinergic P1
Tetrazolium Salts