title: ATP-sensitive K+ channels mediate the delayed cardioprotective effect of adenosine A1 receptor activation.
abstract: Adenosine A1 receptor stimulation increases myocardial resilience to ischaemia many hours later but the mechanism of protection is unclear. We hypothesized that A1 receptor-induced delayed cardioprotection is mediated by KATP channel opening. Rabbits were pretreated with saline or the selective A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA), 0.1 mg/kg i.v. After 24 h, they were anaesthetized and subjected to 30 min left coronary artery occlusion (CAO) and 120 min reperfusion. Twenty minutes before CAO, either glibenclamide 0.3 mg/kg, sodium 5-hydroxydecanoate (5-HD) 5 mg/kg, or a corresponding volume of vehicle solution were given i.v. Infarct size as a percentage of ischaemic risk volume (I/R%) was assessed by triphenyltetrazolium. In the absence of either glibenclamide or 5-HD, CCPA pretreatment resulted in significant limitation of infarction (I/R 23.4+/-3.3%vs 39.6+/-2.6% in saline pretreated animals, P<0.01). Administration of glibenclamide before CAO abolished this delayed protective effect of CCPA (I/R 37.4+/-4. 7%), as did 5-HD (I/R 48.8+/-3.7%). Neither glibenclamide nor 5-HD significantly modified I/R in saline pretreated animals. Risk volume was similar in all groups (0.8-1.1 cm3). Systemic haemodynamic variables were not markedly different between any of the groups immediately before or during the ischaemia-reperfusion protocol. Thus, delayed protection following transient A1 receptor activation was abolished by pre-ischaemic treatment with either glibenclamide or 5-HD, providing pharmacological evidence that KATP channel opening mediates A1 agonist-induced delayed myocardial protection. The inhibitory effect of 5-HD suggests specific involvement of mitochondrial KATP but the mechanisms of sub-acute regulation of KATP function following A1 receptor stimulation remain to be determined.
authors.affiliation: The Hatter Institute for Cardiovascular Studies, University College London Hospitals & Medical School, London, UK.
authors.forename: G F
authors.initials: GF
authors.lastname: Baxter
authors.forename: D M
authors.initials: DM
authors.lastname: Yellon
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D003652:Decanoic Acids / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D006880:Hydroxy Acids / Q000494:pharmacology; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology; D015221:Potassium Channels / Q000187:drug effects*; D058906:Purinergic P1 Receptor Agonists; D011817:Rabbits; D013997:Time Factors
chemical_list: D000889:Anti-Arrhythmia Agents; D001786:Blood Glucose; D003652:Decanoic Acids; D006880:Hydroxy Acids; D015221:Potassium Channels; D058906:Purinergic P1 Receptor Agonists; C052853:5-hydroxydecanoic acid; D000255:Adenosine Triphosphate; D005905:Glyburide