Many patients have advanced cardiac disease, necessitating complicated cardiac surgery or transplantation. During cardiac surgery, including transplantation, the heart is rendered ischemic; and blood flow to the heart is stopped either to undertake the surgery or to transport the organ, which is currently limited to 4-6 hours. In order for the patient to be removed from cardiopulmonary bypass and return to activity, the heart has to function well following cardiac surgery. Any enhancement in myocardial energy preservation will increase the number of positive outcomes for patients and improve the quality of patient care. Interestingly, hibernating animals can preserve up to 90% of the energy required during normal euthermic metabolism. The mechanism of this energy preservation during hibernation is currently unknown; however, many studies point to an opioid """"""""trigger"""""""" molecule, which has been termed the hibernation induction trigger or HIT. The opiate nature of HIT is well established, as HIT can be reversed or retarded by opiate antagonists. Evidence indicates that HIT initiates its potential metabolic inhibitory effects through specific membrane opioid receptors, particularly delta receptors. Delta opioids have been shown in many models and the investigators' preliminary results to produce profound behavioral, physiological and metabolic inhibitory effects favoring survival at the whole animal, the organ and the cellular level. The proposed study will investigate the mechanisms of action of delta opioids at both the organ and subcellular levels. These studies could result in extended safe cardiac ischemic time with potential application to cardiac surgery and cardiac transplantation. In these proposed isolated heart studies, the investigators will determine if delta opioids provide enhanced myocardial protection during ischemia. The investigators will also seek to elucidate the intracellular mechanism by which the delta opioids protect the ischemic myocardium. The ability of the delta opioids to effect myocardial protection suggests that the use of these molecules may be valuable in many clinical scenarios resulting in ischemia.
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| Seymour, Elisabeth M; Wu, Shu-Yung James; Kovach, Melissa A et al. (2003) HL-1 myocytes exhibit PKC and K(ATP) channel-dependent delta opioid preconditioning. J Surg Res 114:187-94 |
| Bolling, S F; Badhwar, V; Schwartz, C F et al. (2001) Opioids confer myocardial tolerance to ischemia: interaction of delta opioid agonists and antagonists. J Thorac Cardiovasc Surg 122:476-81 |
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