title: Signal transduction mechanisms involved in ischemic preconditioning in the rat retina in vivo.
abstract: Ischemic preconditioning (IPC) protects the rat retina against the injury that ordinarily follows severe ischemia. We showed previously that release of adenosine and de novo protein synthesis were required for IPC protection. The mechanisms of IPC were studied in the rat retina by examining the signal transduction mediators responsible, in particular, those theorized to be downstream of adenosine receptors. In addition, we examined the hypothesis that nitric oxide and hydroxyl radicals were involved in the IPC protective phenomenon. Retinal ischemia was produced for 60 min in ketamine/xylazine-anesthetized Sprague-Dawley rats, and recovery was measured using electroretinography. We tested the effects on the protective effect of IPC resulting from antagonism of protein kinase C, potassium ATP channels, nitric oxide synthase, or hydroxyl radicals. The effects of the inhibition of de novo protein synthesis or of protein kinase C, and blockade of potassium ATP channels on the mimicking of IPC by adenosine receptor agonists was examined.IPC protection was strongly attenuated by inhibition of protein kinase C and by blockade of potassium ATP channels, but unaffected by the inhibition of hydroxyl radicals. Blockade of nitric oxide synthase produced a trend toward enhancement of IPC protection. Mimicking of IPC protection by adenosine receptor agonists was inhibited by blockade of protein synthesis or of protein kinase C, as well as by potassium ATP channel antagonism. These results demonstrate that protein kinase C and potassium ATP channels are mediators of the protective effect produced by IPC. In addition, the results show that stimulation of adenosine receptor subtypes A1 and A2a is responsible for IPC protection via downstream stimulation of protein kinase C, the opening of potassium ATP channels, and de novo protein synthesis.
authors.affiliation: Department of Anaesthesia and Critical Care, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: B
authors.initials: B
authors.lastname: Li
authors.forename: C
authors.initials: C
authors.lastname: Yang
authors.forename: D M
authors.initials: DM
authors.lastname: Rosenbaum
authors.forename: S
authors.initials: S
authors.lastname: Roth
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D003513:Cycloheximide / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004596:Electroretinography; D004789:Enzyme Activation; D004791:Enzyme Inhibitors; D005905:Glyburide / Q000494:pharmacology; D015640:Ion Channel Gating; D019194:Ischemic Preconditioning / Q000379:methods*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D010627:Phenethylamines / Q000494:pharmacology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D058906:Purinergic P1 Receptor Agonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D012171:Retinal Vessels / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011500:Protein Synthesis Inhibitors; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D019335:Nitroarginine; D000255:Adenosine Triphosphate; C038983:1,3-dimethylthiourea; D003513:Cycloheximide; D019001:Nitric Oxide Synthase; D011493:Protein Kinase C; D013890:Thiourea; D000241:Adenosine; D005905:Glyburide; D004121:Dimethyl Sulfoxide