Relative contribution of endogenous opioids to myocardial ischemic tolerance

Opioid preconditioning by exogenous opioids experimentally protects the myocardium against ischemia/reflow injury. Additionally, endogenous opioid peptides released during ischemia also enhance ischemic tolerance. Promiscuous opioid receptor agonists conceal the differential contribution of the mu, delta, and kappa opioid subtypes. This study compared the impact of selective delta and kappa opioid receptor antagonists on postischemic functional and metabolic recovery. Also measured were changing levels of peptides dynorphin B and met-enkephalin during ischemia/reflow injury.

Using the rabbit Langendorff model, the functional recovery of control hearts (following 2 h of global ischemia) was compared to hearts pretreated with delta antagonist NTB (1 microM) or kappa antagonist, nor-BNI (1 microM). Measures included percentage of return of isovolumetric developed pressure (LVDP), myocardial oxygen consumption (MVO(2)) and coronary flow (CF). In additional studies, untreated hearts were harvested at baseline, following ischemia, or following 5 or 45 min of reflow. Tissue concentrations of met-enkephalin and dynorphin B were measured by RIA.

After 45 min of reflow, hearts pretreated with either NTB or nor-BNI showed impaired functional recovery by a decrease in LVDP (P < 0.05); however, MVO(2) or CF were unaffected. RIA data shows that baseline levels of both peptides are similar and increase significantly during ischemia, but reflow dynorphin levels drop far below baseline, while met-enkephalin returns to baseline.

Antagonism of both delta and kappa opioid receptor subtypes equally contributes to impaired left ventricular function, independent of altered perfusion or metabolic rate. Endogenous kappa-receptor agonists may contribute primarily during ischemia or early reflow, since low late reflow dynorphin content did not correlate with altered functional recovery.