Delayed uncoupling is related to cardioprotection induced by κ-agonist U-50,488H in rat heart

Objectives. To determine whether the kappa-opioid receptor agonist U50,488H affects electrical uncoupling during prolonged ischemia and, if so, whether the changes are associated with its cardioprotective action. Design. The isolated rat heart was perfused in a Langendorff apparatus. Formazan content, lactate dehydrogenase (LDH) and hemodynamic parameters were measured to confirm the cardioprotective effect of U50,488H. The effects of U50,488H on electrical coupling during prolonged ischemia were also measured. Results. U50,488H concentration-dependently increased formazan content and reduced LDH release, and the ameliorating effect of 10(-5) mol/L U50,488H was abolished by 5 x 10(-6) mol/L norbinaltorphimine (nor-BNI), a selective kappa-opioid receptor antagonist, or 10(-4) mol/L 5-hydroxydecanoate (5-HD), a selective mitochondrial ATP-sensitive K+ (KATP) channel blocker. The onset of electrical uncoupling during prolonged ischemia was delayed by U50,488H, and the delay was not only abolished, but also advanced by nor-BNI or 5-HD relative to the control group. Conclusions. These results demonstrate that delayed uncoupling during prolonged ischemia is associated with the cardioprotection of U50,488H, and these effects of U50,488H are mediated by mitochondrial KATP channels.