The involvement of opioid receptor activation during ischemia-reperfusion is somewhat controversial. While it is generally accepted that activation of the δ-opioid receptor (DOR) is cardioprotective, and may indeed be an important mediator of ischemic preconditioning, the role of the κ-opioid receptor (KOR) is less well understood. To this end, we examined three different KOR agonists and their effects upon infarct size and arrhythmia development. Male Sprague-Dawley rats were subjected to 30 minutes of occlusion followed by 90 minutes of reperfusion. Opioid receptor agonists were administered 10 minutes before the onset of ischemia, while the opioid antagonists were given 20 minutes before occlusion. Untreated rats exhibited an infarct size (IS/AAR%) of 52.4 ± 2.7%. Pretreatment with the DOR agonist, BW373U86, limited infarct development to 37.2 ± 1.8%, which was reversed by the selective DOR antagonist, BNTX. All three KOR agonists studied, U50,488, ICI 204,448, and BRL 52537 significantly reduced infarct size to levels comparable to that of BW373U86. The infarct-sparing effects of U50,488 and ICI 204,448 were abolished by the selective KOR antagonist, nor-BNI. Nor-BNI failed to inhibit the cardioprotective effects of BRL 52537. Furthermore, U50,488 and BRL 52537, but not ICI 204,448, significantly reduced the incidence of arrhythmias. These effects were not blocked by nor-BNI.
These data demonstrate that KOR activation provides a similar degree of infarct size reduction as DOR activation. KOR agonists also reduced arrhythmogenesis; however, these responses appear to be independent of KOR activation.
Myocardial binding studies demonstrate that κ- and δ-opioid receptors (KORs and DORs, respectively) are present on adult ventricular myocytes of rats and humans, 1,2 while μ-opioid receptors are absent.
Schultz et al 3 first reported that activation of opioid receptors may induce acute cardioprotection. Following these initial studies, exogenous opioids have been shown to afford cardioprotection against both stunning and infarction. 4,5 Similarly, it has been reported that endogenous opioids have a role in the triggering and maintenance of both early and delayed preconditioning against myocardial infarction.
Opioid antagonists, both non-selective and selective for the DOR, have been demonstrated to attenuate the cardioprotective effects of ischemic preconditioning (IPC) in both rat and rabbit hearts. 6,7 Moreover, subtype selective δ1 opioid receptor (D1OR) agonists have been shown to provide pronounced cardioprotective actions in both intact animals and isolated myocytes via activation of Gi/o proteins, protein kinase C, and the mitochondrial KATP channel. 5,8 The cardioprotective effects provided by DOR activation manifest immediately following receptor activation and reappear 24 to 48 hours posttreatment in rats and rabbits. 9,10
While it is generally accepted that DOR activation affords cardioprotection, data regarding the KOR are conflicting with many papers reporting cardioprotection from KOR activation while others report no effect or protection after KOR blockade. While KOR activation appears not to be involved in acute IPC, recent data suggest that activation of the KOR is indeed protective in an isolated rat model. 11 Furthermore, treatment with the KOR agonist U50,488 leads to a preconditioning-like effect in isolated myocytes. 12 However, Huh et al 13 showed no protection via KOR in isolated chick myocytes while Aitchison et al 14 demonstrated that stimulation of KOR augmented infarct development. Indeed the data provided by Aitchison et al are supported by several earlier reports examining the arrhythmogenic effects of KOR agonists in which these compounds were shown to exacerbate ischemia/reperfusion-induced arrhythmias while KOR antagonists were found to attenuate arrhythmogenesis. Furthermore, it has been suggested that some of the actions of KOR agonists are due to direct effects on ion channels, independent of KOR activation.
Therefore, in light of the controversies surrounding the effects of KOR activation in the ischemic myocardium, the goal of this study was to examine and compare the effects of 3 selective KOR agonists, U50,488, ICI 204,448, and BRL 53527, on infarct size and the incidence of arrhythmias in an intact rat model of myocardial infarction.