ISCHEMIC PRECONDITIONING IN THE INTACT RAT-HEART IS MEDIATED BY DELTA(1)-OPIOID BUT NOT MU-OPIOID OR KAPPA-OPIOID RECEPTORS

Background-Our laboratory has previously shown that delta-opioid recep tors are involved in the cardioprotective effect of ischemic precondit ioning in the rat heart. However, this class of receptors consists of two subtypes, delta(1) and delta(2), and mu- or kappa-opioid receptors may also exist in the heart. Therefore, the purpose of the present st udy was to test the hypothesis that ischemic preconditioning is mediat ed through stimulation of one or both delta-opioid receptor subtypes. Methods and Results-Anesthetized, open chest, male Wistar rats were as signed to I of 14 groups. All animals were subjected to 30 minutes of occlusion and 2 hours of reperfusion. Ischemic preconditioning was eli cited by three 5-minute occlusion periods interspersed with 5 minutes of reperfusion. Two doses of 7-benzylidenenaltrexone (BNTX; 1 and 3 mg /kg IV), a selective delta(1)-opioid receptor antagonist, or naltriben (NTB; 1 and 3 mg/kg IV), a selective delta(2)-opioid receptor antagon ist, were given before ischemic preconditioning. To test for a role of mu-opioid receptors, rats were pretreated with beta-funaltrexamine (b eta-FNA; 15 mg/kg SC), an irreversible mu-opioid receptor antagonist, 24 hours before ischemic preconditioning or given the mu-opioid recept or agonist D-Ala,N-2-Me-Phe,(4)glycerol(5)-enkephalin (DAMGO) as three 5-minute infusions (1, 10, and 100 mu g/kg per infusion IV, respectiv ely) interspersed with 5-minute drug-free periods before the prolonged ischemic and reperfusion periods (lowDAMGO, medDAMGO, and hiDAMGO, re spectively). The involvement of kappa-opioid receptors was tested by a dministering one of two doses of nor-binaltorphimine (nor-BNI; 1 and 5 mg/kg IV) before ischemic preconditioning. Infarct size (IS) as a per cent of the area at risk (AAR) was measured by triphenyltetrazolium st ain. Ischemic preconditioning markedly reduced IS/AAR (14+/-4%, P<.05) compared with control (55+/-4%). NTB, beta-FNA, and nor-BNI were unab le to block the cardioprotective effect of ischemic preconditioning. I n addition, DAMGO had no effect on IS/AAR. However, the high dose of B NTX (3 mg/kg IV) significantly attenuated the cardioprotective effect of ischemic preconditioning (39+/-5%; P<.05 versus control and ischemi c preconditioning). Conclusions-These results indicate that delta(1)-o pioid receptors play an important role in the cardioprotective effect of ischemic preconditioning in the rat heart.