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May 1998
Ischemic preconditioning in the intact rat heart is mediated by delta1- but not mu- or kappa-opioid receptors
Schultz JEJ, Hsu AK and Gross GJ; Circulation 1998; 97:1282-89.
[ see abstract below ]
While anesthesiology practitioners are comparative experts on the concepts of opioid receptor agonists and antagonists in analgesia, it may not be fully appreciated how much laboratory and clinical research is in process regarding the "other" possible roles of various opioid receptors in health and disease.
This journal article emphasizes some interesting work related to the role(s) of various opioid receptor types in cardioprotection during ischemia. By way of introduction the authors remind us that multiple opioid receptors is now a generally accepted concept: mu, delta and kappa receptors have been relatively well characterized. Now it is recognized that delta opioid receptors may be classified further into delta1 and delta2 subtypes. The delta opioid receptor has been associated with a protective influence on the myocardium following stress by hypoxia, ischemia, temperature and pH challenges.
In this regard, and of potential clinical interest, reference is made to the observation that the time before organ (presumably heart) transplantation could be expanded from 6 hours to 48 hours with the administration of a synthetic delta-opioid agonist. The authors of the present article point out that their purpose in this study was to focus on determining the role of the four known opioid subtypes in mediating the cardioprotective effect of ischemic preconditioning in an intact rat heart model. In this model, all animals were subjected to 30 minutes of coronary artery occlusion and 2 hours of reperfusion. Ischemic preconditioning was produced by three 5-minute coronary occlusion period interspersed with 5 minutes of reperfusion. Using various agonists and antagonists to each of the opioid subtypes the authors concluded from this study that delta1 opioid receptors play a key role in mediating the beneficial, cardioprotective, effects observed with intervals of preconditioning ischemia.
The authors provide some realistic perspective on the interpretation of this study and the possible applications in patient care: "The results of this study suggest that there may be significant clinical potential for stimulating delta1 receptors with regard to treating cardiac ischemia in patients with coronary artery disease; however, more studies need to the perfrormed to demonstrate a universal role for delta1-opioid receptors in ischemic preconditioning in all species. Opioids have been used clinically to manage pain after surgery. The demonstration that opioid receptors, most notably delta1-opioid receptors, which not only have analgesic properties but may have the potential to protect the myocardium during cardiac surgical interventions, suggests a possible new pharmacological approach for the treatment of patients with acute myocardial infarction."
Although this study is relatively simple in design, the results are impressive, and warrant our continued attention as subsequent work in this area develops.
Return to the Current Literature Review Front Page, or read the abstract:
ABSTRACT
Background: Our laboratory has previously shown that delta-opioid receptors are involved in the cardioprotective effect of ischemic preconditioning in the rat heart. However, this class of receptors consists of two subtypes, delta1 and delta2 and mu- or kappa-opioid receptors may also exist in the heart. Therefore, the purpose of the present study was to test the hypothesis that ischemic preconditioning is mediated through stimulation of one or both delta-opioid receptor subtypes.
Methods and Results: Anesthetized, open-chest, male Wistar rats were assigned to 1 of 14 groups. All animals were subjected to 30 minutes of occlusion and 2 hours of reperfusion. Ischemic preconditioning was elicited by three 5-minute occlusion periods intersperse with 5 minutes of reperfusion. Two doses of 7-benzylidenaltrexone (BNTX; 1 and 3 mg/kg IV), a selected delta1-opioid receptor antagonist, or naltriben (NTB; 1 and 3 mg/kg IV), a selective delta2-opioid receptor antagonist were given before ischemic preconditioning. To test for a role of mu-opioid receptors, rats were pretreated with beta-funaltrexamine (beta-FNA; 15 mg/kg SC), an irreversible mu-opioid receptor antagonist, 24 hours before ischemic preconditioning or given the mu-opioid receptor agonist D-Ala2, N-Me-Phe4, glycerol5-enkephalin (DAMGO) as three 5-minute infusions (1, 10, and 100 µg/kg per infusion IV, respectively) interspersed with 5-minute drug-free periods before the prolonged ischemic and reperfusion periods (lowDAMGO, medDAMGO, and hiDAMGO, respectively).
The involvement of kappa-opioid receptors was tested by administering one of two doses of nor-binaltorphimine (nor-BNI; 1 and 5 mg/kg IV) before ischemic preconditioning. Infarct size (IS) as a percent of the area at risk (AAR) was measured by triphenyltetrazolium stain. Ischemic preconditioning markedly reduced IS/AAR (14 +/-4%, P <.05) compared with control (55+/-4%). NTB, beta-FNA, and nor-BNI were unable to block the cardioprotective effect of ischemic preconditioning. In addition, DAMGO had no effect on IS/AAR. However, the high dose of BNTX (3mg/kg IV) significantly attenuated the cardioprotective effect of ischemic preconditioning (39+/-5%; P <.05 versus control and ischemic preconditioning).
Conclusions: These results indicate that delta1-opioid receptors play an important role in the cardioprotective effect of ischemic preconditioning in the rat heart.
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