Cyclooxygenase-2 does not mediate late preconditioning induced by activation of adenosine A1 or A3 receptors. Am J Physiol Heart Circ Physiol 2001 Aug;281(2):H959-68
Date
07/17/2001Pubmed ID
11454603DOI
10.1152/ajpheart.2001.281.2.H959Scopus ID
2-s2.0-0034880998 (requires institutional sign-in at Scopus site) 33 CitationsAbstract
Recent studies have demonstrated that the adenosine A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA) and the adenosine A3 receptor agonist N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA) produce a delayed phase of protection against infarction similar to the late phase of ischemic preconditioning (PC). However, the mechanism for adenosine A1 or A3 receptor-induced late PC remains unknown. The goal of this study was to determine whether the delayed cardioprotective effects of adenosine A1 or A3 receptors are mediated by cyclooxygenase-2 (COX-2), which is an obligatory mediator of ischemic PC. We found that COX-2 protein expression (Western blotting) did not increase 24 h after the administration of either CCPA (100 microg/kg iv) or IB-MECA (300 microg/kg iv) compared with controls. To probe the role of constitutive COX-2 expression, conscious rabbits were subjected to 30-min coronary occlusion followed by 72-h reperfusion. Twenty-four hours before the occlusion, the rabbits were pretreated with CCPA (100 microg/kg iv) or IB-MECA (300 microg/kg iv). Both CCPA and IB-MECA resulted in a marked (approximately 47%) reduction in infarct size vs. controls [36.2 +/- 4.0% of the risk region (n = 9), 31.2 +/- 4.7% (n = 9), and 59.5 +/- 3.8% (n = 9), respectively; P < 0.05], similar to that induced by the late phase of ischemic PC [31.8 +/- 3.2% (n = 9)]. The selective COX-2 inhibitor N-(2-[cyclohexyloxy]4-nitrophenyl)methanesulfonamide (NS-398, 5 mg/kg), which abolished the protective effect of ischemic late PC, failed to block the protection of either CCPA or IB-MECA, indicating that COX-2 does not mediate the delayed protection of either CCPA or IB-MECA [CCPA + NS-398, 29.1 +/- 3.4% (n = 7); IB-MECA + NS-398, 34.9 +/- 2.9% (n = 8)]. NS-398 in itself did not affect infarct size [54.9 +/- 3.7% (n = 9)]. Taken together, these results demonstrate that, in contrast to ischemia-induced late PC, the mechanisms of adenosine A1 or A3 receptor-induced late PC is independent of COX-2.
Author List
Kodani E, Shinmura K, Xuan YT, Takano H, Auchampach JA, Tang XL, Bolli RAuthor
John A. Auchampach PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCyclooxygenase 2
Heart Rate
Ischemic Preconditioning, Myocardial
Isoenzymes
Male
Prostaglandin-Endoperoxide Synthases
Rabbits
Receptor, Adenosine A3
Receptors, Purinergic P1