Adenosine-mediated early preconditioning in mouse: protective signaling and concentration dependent effects.

Abstract

OBJECTIVES:

Signaling in adenosine-mediated preconditioning is controversial. We examined roles of mitochondrial (mito) K(ATP) 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 microM adenosine limited necrosis (10.6+/-1.4 IU/g) without modifying contractility (72+/-2 mmHg) whereas 50 microM adenosine reduced necrosis (10.3+/-1.6 IU/g) and contractile dysfunction (91+/-2 mmHg). All protective effects of 10 and 50 microM adenosine were abrogated by mito K(ATP) channel blockade with 100 microM 5-hydroxydecanoate (5-HD) during the 'trigger' phase, but unaltered by PKC or NO synthase inhibition with 3 microM chelerythrine or 100 microM N(G)-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 microM 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 K(ATP) channel dependent process independently of PKC and NO. Subsequent protection against necrosis is also mediated by a mito K(ATP) channel dependent process independent of PKC and NO. In contrast, functional protection may be mediated by parallel mito K(ATP) and PKC dependent paths.

• Authors: Jason Peart, John P Headrick
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 58 Issue 3 Pg. 589-601 (Jun 01 2003) ISSN: 0008-6363 [Print] England
• PMID: 12798432 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Alkaloids
• Benzophenanthridines
• Calcium Channel Blockers
• Decanoic Acids
• Enzyme Inhibitors
• Hydroxy Acids
• Phenanthridines
• Phenethylamines
• Potassium Channels
• Receptors, Purinergic P2
• 2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine
• Xanthine
• Hypoxanthine
• Nitric Oxide
• Inosine
• Adenosine Diphosphate
• 5-hydroxydecanoic acid
• chelerythrine
• L-Lactate Dehydrogenase
• Nitric Oxide Synthase
• Protein Kinase C
• Adenosine
• Diazoxide
• NG-Nitroarginine Methyl Ester

Topics

• Adenosine (analogs & derivatives, pharmacology)
• Adenosine Diphosphate (pharmacology)
• Alkaloids
• Animals
• Benzophenanthridines
• Calcium Channel Blockers (pharmacology)
• Decanoic Acids (pharmacology)
• Diazoxide (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Hydroxy Acids (pharmacology)
• Hypoxanthine (pharmacology)
• Inosine (pharmacology)
• Ischemic Preconditioning, Myocardial (methods)
• L-Lactate Dehydrogenase (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mitochondria, Heart (metabolism)
• Myocardial Contraction (drug effects)
• Myocardial Infarction (metabolism, pathology, physiopathology)
• NG-Nitroarginine Methyl Ester (pharmacology)
• Necrosis
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase (antagonists & inhibitors)
• Perfusion
• Phenanthridines (pharmacology)
• Phenethylamines (pharmacology)
• Potassium Channels (metabolism)
• Protein Kinase C (metabolism)
• Receptors, Purinergic P2 (drug effects)
• Signal Transduction (drug effects, physiology)
• Xanthine (pharmacology)