Remifentanil preconditioning protects against ischemic injury in the intact rat heart

Abstract

Background: Opioid receptors mediate cardiac ischemic pre-conditioning. Remifentanil is a new, potent ultra-short-acting phenylpiperidlne opioid used in high doses for anesthesia. The authors hypothesize that pretreatment with this drug confers cardioprotection. Methods: Male Sprague-Dawley rats were anesthetized and the chest was opened. All animals were subjected to 30 min of occlusion of the left coronary artery and 2 h of reperfusion. Before the 30-min occlusion, rats received either preconditioning by ischemia (ischemic preconditioning, 5-min occlusion, 5-min reperfusion × 3) or pretreatment with remifentanil, performed with the same regime (3 × 5-min infusions) using 0.2, 0.6, 2, 6, or 20 μg·-kg-1·min -1 intravenously. The experiment was repeated with naltrindole (a selective δ-opioid receptor antagonist, 5 mg/kg), nor-binaltorphimine (a selective κ-OR antagonist, 5 mg/kg), or CTOP (a selective μ-opioid receptor antagonist, 1 mg/kg) administered before remifentanil-induced preconditioning or ischemic preconditioning, respectively. Infarct size, as a percentage of the area at risk, was determined by 2,3,5-triphenyltetrazolium staining. Results: There was a dose-related reduction in infarct size/area at risk after treatment with remifentanil that was similar to that seen with ischemic preconditioning. This effect was prevented or significantly attenuated by coadministration of a μ, κ, or δ-opioid antagonist. The infarct-sparing effect of ischemic preconditioning was abolished by blockade of κ-opioid receptors or δ-opioid receptors but not by μ-opioid receptors. Conclusion: Remifentanil mimics cardioprotection via all three opioid receptors. This differs from ischemic preconditioning, which confers cardioprotection via κ- and δ-, but not μ-opioid receptors. Part of the protective effect of remifentanil may be produced by μ-agonist activity outside the heart.