Delta opioid agonists and volatile anesthetics facilitate cardioprotection via potentiation of K ATP channel opening

ABSTRACT Opioids and volatile anesthetics produce marked cardioprotective effects against myocardial infarction via the activation of ATP‐sensitive potassium (K ATP ) channels, however, the effect of combined treatment with both drugs is unknown. We examined the hypothesis that opioids and volatile anesthetics potentiate cardiac K ATP channel opening, thereby enhancing cardioprotection. Rats were treated with the delta opioid agonists, TAN‐67 or BW373U86, or isoflurane, together or alone with and without diazoxide, a mitochondrial K ATP channel opener. Glibenclamide, a non‐selective K ATP channel blocker, was used to further characterize the signaling mechanism involved. Myocardial infarct size (IS) was determined by tetrazolium staining and was expressed as a percent of the area at risk (AAR). High doses of TAN‐67 (10 mg/kg), diazoxide (10 mg/kg), and isoflurane (1 MAC) produced a significant reduction in IS compared with the control group (30±3%, 36±5%, and 42±2 vs. 58±2%, respectively), whereas lower doses of the drugs had no effect except for the low dose of isoflurane (0.5 MAC). The combination of TAN‐67 and diazoxide or isoflurane and diazoxide resulted in a marked reduction in IS compared with controls in the presence of high (9±3% and 14±3%) and low (17±7% and 31±7%) dose combinations, respectively. The combination of TAN‐67 or BW373U86 and isoflurane also caused a striking reduction in IS/AAR (16±7% and 7±2%, respectively). To date, this is the first demonstration that opioids and volatile anesthetics work in conjunction to confer protection against myocardial infarction through potentiation of cardiac K ATP channel opening.