Abstract P500: Naltrindole And Naltrindole Derivatives Exhibit Potent Cardioprotection In Myocardial Ischemia Reperfusion Injury

Previously, naltrindole (NTI; selective delta opioid receptor antagonist) was shown to improve post-reperfused cardiac function and reduced infarct size when given prior to ischemia (I)/ reperfusion (R) in ex-vivo rat hearts. Conversely, naloxone (NX, broad-spectrum opioid antagonist) and nor-binaltrophine (BNI, selective kappa receptor antagonist) were similar to control hearts. In this study, the effects of NTI derivatives naltriben (NTB, delta receptor antagonist) and guanidonaltrindole (GNTI, kappa receptor antagonist) were compared to NTI, BNI, and NX. Isolated hearts from male SD rats (300g) were subjected to global I(30min)/R(45min). Treatments were given 5 min before I (preconditioning) and during the first 5 min of R. Left ventricular (LV) cardiac function was measured using a pressure transducer. At the end of reperfusion, infarcted heart tissue was compared to total tissue weight. Data were evaluated using ANOVA. As shown in Table 1, NTI, NTB, and GNTI significantly improved post-reperfused cardiac function and reduced infarct size compared to control hearts. NTI and NTB elicited direct effects on cardiac function when given during preconditioning in contrast to all other study groups and were the most robust at reducing infarct size and restoring post reperfusion cardiac function. The negative inotropic effects of NTI and NTB were correlated with a decrease in the rise of ischemic pressure. GNTI also elicited significant improvement in post-reperfused cardiac function and reduction of infarct size compared to BNI which suggests a separate cardioprotective mechanism that this NTI derivative may exert in contrast to kappa opioid receptor inhibition. Results suggest that NTI and derivatives, GNTI and NTB, are cardioprotective against I/R injury resulting in reduced ischemic peak pressure (NTI/NTB) and infarct size. In future studies, we will examine the mechanism of the protective effects of NTI and derivatives in hearts subjected to I/R injury.

Inhibiting Kiss1 Neurons with Kappa Opioid Receptor Agonists to Treat Polycystic Ovary Syndrome and Vasomotor Symptoms

Context Recent evidence suggests that vasomotor symptoms (VMS) or hot flashes in the postmenopausal reproductive state and polycystic ovary syndrome (PCOS) in the premenopausal reproductive state emanate from the hyperactivity of Kiss1 neurons in the hypothalamic infundibular/arcuate nucleus (KNDy neurons). Objective We demonstrate in 2 murine models simulating menopause and PCOS that a peripherally-restricted kappa receptor agonist (PRKA) inhibits hyperactive KNDy neurons (accessible from outside the blood brain barrier) and impedes their down-stream effects. Design Case/control. Setting Academic medical center. Participants Mice. Interventions Administration of peripherally-restricted kappa receptor agonists and frequent blood sampling to determine hormone release, and body temperature. Main Outcome Measures LH pulse parameters and body temperature. Results First, chronic administration of a PRKA to OVX mice with experimentally-induced hyperactivity of KNDy neurons reduces the animals’ elevated body temperature, mean plasma LH level, and mean peak LH per pulse. Second, chronic administration of a PRKA to a murine model of PCOS, having elevated plasma testosterone levels and irregular ovarian cycles, suppresses circulating levels of LH and testosterone and restores normal ovarian cyclicity. Conclusion The inhibition of Kiss1 neuronal activity by activation of kappa receptors shows promise as a novel therapeutic approach to treat both VMS and PCOS in humans.

Abstract 100: Delta Opioid Receptor Blockade Abolishes Exercise-Induced Cardioprotection Against Ischemia-Reperfusion Injury In Vivo

Introduction: Recent studies showed that exercise enhances myocardial tolerance to ischemia-reperfusion (I-R) injury via an opioid receptor-dependent mechanism. However, the specific subtype of opioid receptor involved in this response remains to be determined. Methods: Male Wistar rats were first divided into 2 groups: exercised and control. The exercised group underwent 4 consecutive days of treadmill training (60 min at 70% of maximal oxygen consumption). The exercised group was then divided into 4 subgroups: exercised (Exe; n = 10); exercised + kappa receptor antagonist (Exe + K; n=4); exercised + delta receptor antagonist (Exe + D; n=4); exercised + mu receptor antagonist (Exe + M; n=4). Control group was also divided into 2 groups: control (Ctr; n = 10) and control sham (Sham; n = 10). To induce I-R injury, anesthetized animals were submitted to a left thoracotomy and a 30 min interventricular coronary occlusion followed by 60 min of reperfusion. The hemodynamic parameters were recorded and infarct size was post-mortem determined by double staining using TTC/Evans blue and expressed as a percentage of the area at risk. Results: As shown in the figure, Sham group showed no infarct, Exe group showed a significant reduction in the infarcted area (27.6%) when compared to Ctr group (42.0%). The pretreatment with mu and kappa receptor antagonist did not alter the cardioprotective effect of exercise. However, the pretreatment with delta receptor antagonist prevented the exercise-induced cardioprotection. Conclusions: Endogenous opioid system is involved in cardioprotection conferred by acute exercise, and delta receptor subtype seems to play an important role in this response.