Remifentanil post‐conditioning attenuates cardiac ischemia–reperfusion injury via κ or δ opioid receptor activation

Background: Ischemic pre‐ or post‐conditioning of the heart has been shown to involve opioid receptors. Remifentanil, an ultra‐short‐acting selective μ opioid receptor agonist in clinical use, pre‐conditions the rat heart against ischemia–reperfusion injury. This study investigates whether remifentanil post‐conditioning is also cardioprotective. Methods: Remifentanil post‐conditioning (5‐min infusion at 1, 5, 10 or 20 μg/kg/min) or ischemic post‐conditioning (three cycles of a 10 s reperfusion interspersed with a 10 s ischemia) was induced in an open‐chest rat heart model of ischemia and reperfusion injury, in the presence or absence of nor‐binaltorphimine, naltrindole or CTOP, specific κ, δ and μ opioid receptor antagonists, respectively. The same sequence of experiments was repeated in the isolated heart model using the maximal protective dose of remifentanil from the dose–response studies. Results: Both ischemic and remifentanil post‐conditioning reduced the myocardial infarct size relative to the control group in both models. This cardioprotective effect for both post‐conditioning regimes was prevented by the prior administration of nor‐binaltorphimine and naltrindole but not CTOP. The sole administration of the antagonists had no effect on the size of myocardial infarction. Conclusions: These results indicate that remifentanil post‐conditioning protects the heart from ischemia–reperfusion injury to a similar extent as of ischemic post‐conditioning. This protection involves κ and δ but not μ opioid receptor activation. This drug has great potential as a clinical post‐conditioning modality as it can be given in large doses without prolonged opioid‐related side effects.