Peroxisome‐proliferator‐activated receptor γ mediates the second window of anaesthetic‐induced preconditioning

• Published in: Experimental physiology 2011-03, Vol.96 (3), p.317-324
• Main Authors: Lotz, Christopher, Lange, Markus, Redel, Andreas, Stumpner, Jan, Schmidt, Johannes, Tischer‐Zeitz, Tobias, Roewer, Norbert, Kehl, Franz
• Format: Article
• Language: English
• Subjects: Anesthetics, Inhalation - pharmacology; Anilides - pharmacology; Animals; Arteries - drug effects; Arteries - physiopathology; Coronary Occlusion - drug therapy; DNA-Binding Proteins - metabolism; Heart - drug effects; Heart - physiopathology; Ischemic Preconditioning, Myocardial - methods; Isoflurane - analogs & derivatives; Isoflurane - pharmacology; Myocardial Infarction - diagnosis; Myocardial Infarction - drug therapy; Myocardial Infarction - metabolism; Myocardial Reperfusion - methods; Myocardial Reperfusion Injury - drug therapy; Myocardial Reperfusion Injury - metabolism; Nitric Oxide - metabolism; PPAR gamma - antagonists & inhibitors; PPAR gamma - metabolism; Prostaglandin D2 - analogs & derivatives; Prostaglandin D2 - metabolism; Rabbits; Signal Transduction - drug effects
• ISSN: 0958-0670; 1469-445X
• DOI: 10.1113/expphysiol.2010.055590

The second window of anaesthetic‐induced preconditioning (APC) is afforded by the interplay of multiple signalling pathways, whereas a similar protective response is mediated by peroxisome‐proliferator‐activated receptor γ (PPARγ) agonists. However, a possible role of this nuclear receptor during APC has not been studied to date. We investigated the hypothesis that the second window of APC is mediated by the activation of PPARγ. New Zealand White rabbits (n= 48) were subjected to 30 min of coronary artery occlusion followed by 3 h of reperfusion. The animals received desflurane (1.0 minimal alveolar concentration), the PPARγ antagonist GW9662, as well as the combined application of both, respectively, 24 h prior to coronary artery occlusion. Infarct size was determined gravimetrically; tissue levels of 15‐deoxy‐Δ12,14‐prostaglandin J2 (15d‐PGJ2) and nitrite/nitrate (NOx), as well as PPAR DNA binding were measured using specific assays. Data are presented as means ±s.e.m. Desflurane led to a reduced myocardial infarct size (41.7 ± 2.5 versus 61.8 ± 2.8%, P < 0.05), accompanied by significantly increased PPAR DNA binding (289.9 ± 33 versus 102.9 ± 18 relative light units, P < 0.05), as well as elevated tissue levels of 15d‐PGJ2 (224.4 ± 10.2 versus 116.9 ± 14.2 pg ml−1, P < 0.05) and NOx (14.9 ± 0.7 versus 5.4 ± 0.7 μm, P < 0.05). Pharmacological inhibition of PPARγ abolished these protective effects, resetting the infarct size (56.5 ± 2.9%), as well as PPAR DNA‐binding activity (91.2 ± 31 relative light units) and NOx tissue levels (5.9 ± 0.9 μm) back to control levels. Desflurane governs a second window of APC by increasing the production of 15d‐PGJ2, subsequently activating PPARγ, resulting in a diminished myocardial infarct size by increasing the downstream availability of NO.