Opposing effects on infarction of delta and kappa opioid receptor activation in the isolated rat heart: Implications for ischemic preconditioning

δ-Opioid receptors are known to participate in the protection found following ischemic preconditioning (IPC), but the role of κ-receptors in IPC is currently controversial. Langendorff-perfused rat hearts received 35 min regional ischemia and 2 h reperfusion. PC (2 cycles 5 min global ischemia) substantially reduced infarct size. Pharmacological PC with the δ-agonist DADLE (10 nmol/L) had similar protective effects. However, higher dose DADLE (1 μmol/L) had a less beneficial effect, and in conjunction with the δ-antagonist naltrindole unexpectedly increased infarct size (61.5 ± 2.0 %, p<0.05 v 45.9 ± 2.4 % in controls) suggesting a non-δ effect. The universal κ-opioid agonist bremazocine (30 nmol/L) increased infarct size (61.3 ± 1.6 %, p<0.05 v controls), an effect abrogated by the selective κ1-antagonist nor-binaltorphimine (BNI). Since opiates are known to have anti-adrenergic effects, which hypothetically may help to mediate IPC, cyclic AMP levels were measured in DADLE and in bremazocine-treated hearts. Decreased levels of cyclic AMP at the start of the regional ischemic period were found in low dose DADLE hearts (0.485 ± 0/020, n = 8, vs controls, 0.654 ± 0.025 nmol/g wet weight, p<0.001), but not in high dose DADLE nor in bremazocine treated hearts. Thus, in the isolated rat heart κ1-opioid receptor activation exacerbates infarct size through an as yet unknown mechanism, suggesting that there could be an 'anti-preconditioned state'. In contrast, δ-activity mediates protection which may be associated with a reduction of tissue cyclic AMP levels.