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Objectives: The objective of this study was to investigate the role of peripheral μ, δ1, δ2, and nociceptin opioid receptors agonists in the regulation of cardiac tolerance to the arrhythmogenic effect of ischemia/reperfusion in rats., Methods: Anesthetized open-chest male Wistar rats were subjected to either 45 minutes of left coronary artery occlusion (phase 1a 10 minutes and phase 2b 35 minutes) and 2 hours of reperfusion in Experiment 1 or 10 minutes of ischemia and 10 minutes of reperfusion in Experiment 2. In Experiment 1, saline or vehicle controls and the mu-specific opioids dermorphin-H (Derm-H) and ([d-Ala2, N-Me-Phe4, Gly-ol5] enkephalin (DAMAGO); the delta-1-specific opioid d-Pen2,5enkephalin (DPDPE); nociceptin; and the delta-2-specific opioids deltorphin-II (Delt-II), Delt-Dvariant (Delt-Dvar), and deltorphin-E (Delt-E) were infused 15 minutes prior to ischemia. In Experiment 2, DPDPE, Delt-D, Delt-Dvar, and Delt-E were infused at 15 minutes prior to ischemia. The universal opioid receptor antagonist naltrexone, the peripherally acting antagonist naloxone methiodide, the selective δ1 antagonist 7-benzylidene naltrexone maleate, and the specific δ2 antagonist naltriben mesylate were infused 25 minutes prior to ischemia., Results: In Experiment 1, pretreatment with the μ opioids Derm-H and DAMGO, DPDPE, and nociceptin at all doses tested did not reduce the incidence of ischemia-induced arrhythmias compared to controls during 45 minutes of ischemia. The δ2 opioids Delt-II (0.12 mg/kg), Delt-Dvar (0.3 mg/kg), and Delt-E (0.18 mg/kg) all demonstrated significant antiarrhythmic effects at the 150 nmol/kg dose compared to saline or vehicle controls. Nine of 19 animals treated with Delt-II were tolerant without ventricular arrhythmias to the arrhythmogenic effect of ischemia during the first 10 minutes of ischemia (phase 1a) and 11 of 19 were without ventricular arrhythmias during the following 35 minutes of ischemia (phase 1b). Delt-II also decreased the incidence of premature ventricular contractions and ventricular tachycardia by almost half during phase 1a. Delt-II did not affect the incidence of ventricular fibrillation (VF). Pretreatment with Delt-Dvar and Delt-E completely blocked the incidence of VF in phase 1b. Delt-E also decreased premature ventricular contractions by 50%, and the incidence of ventricular tachycardia decreased over twofold in phase 1b of ischemia. There was no enhanced tolerance by any of the delta-2 opioids to the arrhythmogenic effect of reperfusion after long-term ischemia. In Experiment 2, after 10 minutes of ischemia and 10 minutes of reperfusion, Delt-II (0.12 mg/kg) reduced the incidence of premature ventricular contractions and ventricular tachycardia compared to controls, and completely blocked the incidence of VF following 10 minutes of reperfusion. Delt-Dvar and Delt-E were without effect, as was DPDPE following 10 minutes of reperfusion. The antiarrhythmic effect of Delt-II during 10 minutes of ischemia and 10 minutes of reperfusion was completely blocked by the peripherally acting opioid receptor inhibitor naloxone methiodide and the selective delta-2 opioid receptor inhibitor naltriben mesylate, but not by the selective delta-1 inhibitor 7-benzylidene naltrexone maleate. The antagonists alone had no effect on arrhythmogenesis., Conclusions: Peripheral delta-2 opioid receptor activation by Delt-II, Delt-Dvar, and Delt-E enhanced cardiac tolerance to the arrhythmogenic effects of ischemia., (© 2013 by the Society for Academic Emergency Medicine.)

It has been established that ischemic preconditioning (IP) exerts significant antiarrhythmic effects, as revealed in experiments both in vivo and in vitro. Consequently, processes arising within the myocardium play a key role in adaptive tolerance to ischemia/reperfusion. Preconditioning enhances cardiac electrical stability both in animals and humans. The antiarrhythmic effect of preconditioning is transient, with enhanced tolerance to ischemia-reperfusion triggered arrhythmogenesis dissipating 2-3 after the IP stimulus. The basis of the antiarrhythmic and cardioprotective effects of IP may differ. Preconditioning improves conduction of the cardiac electrical impulse, thereby preventing occurrence of re-entrant arrhythmias. NO-synthase and peroxynitrite play an important role in evolution of the antiarrhythmic effects of IP. Furthermore, intracellular Ca2+ may be a trigger of improved cardiac electrical stability after IP. It has been established that G(i/o)-protein coupled receptors are not involved in antiarrhythmic effects of IP, whereas bradykinin B2 and alpha1 adrenergic receptor activities are involved in IP-dependent improvements in cardiac electrical stability. Adenosine receptors contribute only partially to these effects. In terms of signalling mechanisms, protein kinase C appears essential to the antiarrhythmic effects of IP, whereas PI3-kinase and cyclooxygenase do not appear to be significantly involved. It has also been established that cardiac mast cells are involved in IP effects. Some data indicate that increased cardiac electrical stability with preconditioning depends upon mitoK(ATP) channel opening. Other data provide evidence that antiarrhythmic effects of preconditioning depends upon sarcK(ATP) channel opening. Some data indicate that an increase in electrical stability of heart after preconditioning depends upon mitoK(ATP) channel opening. Other data are evidence that antiarrhythmic effect of preconditioning depends upon sarCK(ATP) channel opening. Further work is needed to fully delineate the mechanistic basis of antiarrhythmic effects of IP.

A course of treatment (16 mg/kg orally during 5 days) by Aralia mandshurica or Rhodiola rosea extracts reduced the incidence of ischemic and reperfusion ventricular arrhythmias during 10-min ischemia and 10-min reperfusion. Extracts of Eleutherococcus senticosus, Leuzea carthamoides, and Panax ginseng did not change the incidence of ischemic and reperfusion arrhythmias. Chronic treatment by aralia, rhodiola, and eleutherococcus elevated the ventricular fibrillation threshold in rats with postinfarction cardiosclerosis. Ginseng and leuzea did not change this parameter in rats with postinfarction cardiosclerosis.

Prophylactic intravenous (i.v.) injections of a selective agonist of ORL1 receptors nociceptin (orphanin FQ) in a dose of 0.4 mg/kg prevented the development of aconitine-induced arrhythmia in rats narcotized with diethyl ether or chloralose. Pretreatment with L-NAME (50 mg/kg) completely abolished this effect of orphanin FQ, while the pretreatment with indomethacin (10 mg/kg) only attenuated the agonist effect, rather than abolished it completely. At the same time, pretreatment with hexamethonium (10 mg/kg) or glibenclamide (3 mg/kg) had no effect on the nociceptin-dependent cardiac tolerance to the arrhythmogenic action of aconitine. Intracerebroventricular (i.c.v.) infusion of orphanin FQ (36 microg) also prevented the onset of aconitine-induced arrhythmia, but this effect was completely abolished by hexamethonium. It is concluded that the antiarrhythmic action of nociceptin with respect to aconitine-induced arrhythmia upon i.v. and i.c.v. administration is explained by different mechanisms. In the former case, the effect of orphanin FQ is related to the activation of NO synthase and cyclooxygenase, while the central action involves the vegetative nervous system.

Preliminary stimulation of opiate receptors (ORs) by intravenous administration of mu agonist DALDA (0.5 mg/kg), delta 1 agonist DPDPE (0.5 mg/kg), and kappa agonist (-)-U-50.488 (1 mg/kg) increases rat myocardial resistance to arrhythmogenic effect of coronary occlusion (10 min) and reperfusion (10 min). Activation of delta 2 ORs (DSLET, 0.5 mg/kg) has no effect on the incidence rate of ischemic and reperfusion arrhythmias. Preliminary administration of glibenclamide (0.3 mg/kg), an inhibitor of KATP channels, blocks the antiarrhythmic effect of DALDA and DPDPE. Repeated short-term exposures of rats to immobilization within two weeks increases the heart tolerance to the arrhythmogenic effect of coronary occlusion and reperfusion. This effect disappears after administration of CTAP (0.5 mg/kg), a mu antagonist, or injection of 5-hydroxydecanoate (5 mg/kg), an inhibitor of mitochondrial KATP channels. The selective antagonists of delta and kappa ORs have no effect on cardiac adaptation-induced resistance to the arrhythmogenic effect of ischemia and reperfusion. We believe that stimulation of mu, delta, and kappa ORs increases myocardial tolerance to the arrhythmogenic effect of ischemia and reperfusion through activation of KATP channels. The antiarrhythmic effect of the adaptation is mediated by stimulation of mu ORs and mitochondrial KATP channels.

It has been found that intravenous administration of nociceptin (0.4 mg/kg) prevents development of aconitine-induced arrhythmias but has no effect on the incidence of occlusion, reperfusion, CaCl2-induced arrhythmias, and exacerbates epinephrine-evoked dysrhythmias. Pretreatment with hexamethonium, atropine, guanethidine and naloxone did not abolish the arrhythmic effect of nociceptin. Intracerebroventricular infusion of orphanin FQ was shown to increase cardiac tolerance of arrhythmogenic influence of aconitine, but this effect is completely abolished by hexamethonium administration. It has been suggested that stimulation of both central and peripheral ORL1 receptors increases cardiac resistance against arrhythmogenic effect of aconitine via different mechanisms.

It has been found that pretreatment with ATP-dependent potassium channel (KATP-channel) opener, BMS 180448 (3 mg/kg, intravenously), increases cardiac resistance against arrhythmogenic action of coronary artery occlusion and reperfusion in anaesthetized rats. However, BMS 180448 induced a decrease in ventricular fibrillation threshold in rats postinfarction cardiac fibrosis. This effect was completely abolished by administration of the KATP-channel inhibitor, glibenclamide. By contrast, coadministration of BMS 180448 and selective sarcolemmal KATP-channel inhibitor, HMR 1098, promoted an increase in ventricular fibrillation threshold in rats with postinfarction cardiac fibrosis before normal value. The selective mitochondrial KATP-channel opener, diazoxide, also exacerbated a decrease in ventricular fibrillation threshold induced by postinfarction cardiac sclerosis. But after depletion of endogenous catecholamine storage by pretreatment with guanthidine, diazoxide, on the contrary, elevated the ventricular fibrillation threshold. It has been suggested that stimulation of mitochondrial ATP-sensitive potassium channels promotes an elevation in electrical stability of the heart, whereas opening of sarcolemmal KATP-channel increases a possibility of ventricular arrhythmias.

During aconitine-induced arrhythmias the antiarrhythmic effect of DALDA (Tyr-D-Arg-Phe-Lys-NH2) and nociceptin (orphanin FQ) administered intravenously depended on activation of nitric oxide synthase. K(ATP) channels were not involved in the realization of this effect. Endogenous prostanoids played a minor role in the antiarrhythmic effect of nociceptin and did not contribute to the protective influence of DALDA. The antiarrhythmic effect of orphanin FQ administered intravenously did not depend on functional activity of the autonomic nervous system. However, the effect of orphanin FQ after intracerebroventricular infusion was determined by changes in the state of this system.

Preliminary intravenous injection of peptide agonist of delta1-opioid receptors DPDPE (0.5 mg/kg) decreased the incidence of occlusion (10 min) and reperfusion (10 min) arrhythmias in rats. By contrast, delta2-opioid receptor agonist DSLET produced no effect on the incidence of arrhythmias provoked by coronary occlusion and reperfusion. Preliminary injection of selective delta-receptor antagonist ICI 174,864 (2.5 mg/kg) or TIPP[y] (0.5 mg/kg) completely abolished the antiarrhythmic effect of DPDPE. Stimulation of cardiac delta1-opioid receptors with DPDPE added to perfusion saline in concentrations of 0.1 and 0.5 mg/liter decreased the incidence of reperfusion arrhythmias. Addition of DPDPE to perfusion saline in a concentration of 0.1 mg/liter prevented reoxygenation destruction of cardiomyocytes. By contrast, no cardioprotective effect of this peptide was observed at a concentration of 0.5 mg/liter in perfusion saline or when it was injected intravenously. It is concluded that the cardioprotective and antiarrhythmic effects of DPDPE are caused by activation of cardiac delta1-opioid receptors.

It has been found that prior intravenous administration of the endocannabinoid anandamide (10 mg/kg) or its synthetic analogue R-(+)-methanadamide (5 mg/kg) prevents a development of ischemic and reperfusion arrhythmias in rats. The prior injection of the CB1 receptor antagonist, SR 141716A (3 mg/kg), did no affect the antiarrhythmic action of both cannabinoids. Pretreatment with the CB2 receptor antagonist, SR 144528 (1 mg/kg), completely abolished antiarrhythmic effect of anandamide and R-(+)-methanandamide. Both CB antagonist had no effect on the arrhythmias itself. Pretreatment with the NO-synthase inhibitor, L-NAME (50 mg/kg), had no effect on the antiarrhythmic action of cannabinoids. We therefore conclude that CB2 receptor stimulation increases the heart tolerance to ischemic and reperfusion arrhythmias.

We have found that intravenous administration of cannabinoid receptor (CB) agonist HU-210 (0.05 mg/kg), increases cardiac resistance against arrhythmogenic effect of epinephrine, aconitine, coronary artery occlusion and reperfusion in rats. Pretreatment with CB2-receptor antagonist, SR144528 (1 mg/kg), completely abolished the antiarrhythmic effect of HU-210. However this effect of HU-210 was not attenuated by pretreatment with CB1-receptor antagonist, SR141716A (3 mg/kg). We also found that HU-210 (0.05 mg/kg) decreased the relationship between infarction size and area of ischemia. It is concluded that CB2 receptor stimulation promotes an increase in the cardiac resistance against arrhythmogenic influences and probably increases myocardial tolerance of both ischemic and reperfusion damages in rats.

Stimulation of cannabinoid receptors with endogenous cannabinoid anandamide and its enzyme-resistant analogue R-(+)-methanandamide improved cardiac resistance to arrhythmias induced by coronary occlusion and reperfusion. This antiarrhythmic effect was not associated with activation of NO synthase, since pretreatment with NG-nitro-L-arginine methyl ester had no effect on the incidence of ischemia/reperfusion-induced arrhythmias. Blockade of ATP-dependent K+ channels with glybenclamide did not abolish the antiarrhythmic effect of R-(+)-methanandamide. Antiarrhythmic activity of endogenous cannabinoids is probably associated with their direct effects on the myocardium.

It has been found that stimulation of delta-1 opioid receptors by intravenous administration of DPDPE (0.5 mg/kg) decreases the incidence of ischemic and reperfusion-induced arrhythmias and also increases myocardial tolerance to the arrhythmogenic action of epinephrine in rats. Pretreatment with a selective delta-2 agonist, DSLET, had no antiarrhythmic effect. The inhibition of the enzymatic breakdown of endogenous enkephalins by intravenous administration of acetorphan decreased the incidence of epinephrine-induced arrhythmias. Pretreatment with a selective delta opioid receptor antagonist, ICI-174.868, completely abolished this antiarrhythmic effect. Adaptation of rats to repeated immobilization stress during 12 days increased myocardial tolerance to the arrhythmogenic action of coronary artery occlusion (10 min) and reperfusion (10 min). Pretreatment with a selective delta opioid receptor antagonist, TIPP(Psy), did not abolish the antiarrhythmic effect of adaptation to immobilization stress. It seems that endogenous agonists of delta opioid receptors are not involved in the antiarrhythmic effect resulting from adaptation to stress.

Preliminary administration of the delta 1-opioid receptor (delta 1-OR) peptide agonist DPDPE (0.5 mg/kg, i.v.) decreased the incidence of occlusion (10 min) and reperfusion (10 min) arrhythmias in rats. The delta 2-OR agonist DSLET did not affect arrhythmias upon the coronary artery occlusion and reperfusion. Pretreatment with the selective delta-antagonists ICI 174,864 (2.5 mg/kg) or TIPP[psi] (0.5 mg/kg) completely eliminated the antiarrhythmic effect of DPDPE. Uncapable of crossing the blood brain barrier, the nonselective OR antagonist naloxone methiodide (5 mg/kg) also abolished this effect. At the same time, hexametonium (10 mg/kg) did not antagonize the antiarrhythmic effect of DPDPE. Pretreatment with the KATP channel blocker glibenclamide (0.3 mg/kg) completely eliminated the protective effect of the delta 1-OR stimulation. It was concluded that the delta 1-OR stimulation prevents the ischemic and reperfusion arrhythmias by means of the KATP channel activation.

It is demonstrated that intravenous administration of the kappa 1-opioid receptor (OR) agonists (-)-trans-(1S,S)-U-50,488 and (+)-trans-(1R,2R)-U-50,488 increases heart tolerance to the arrhythmogenic effect of epinephrine in rats. This antiarrhythmic effect was completely abolished by preliminary kappa-OR blocking with norbinaltorphimine. Preliminary administration of of a high-affinity kappa 1-OR agonist (-)-trans-(1S,S)-U-50,488 significantly reduced the incidence of ventricular arrhythmias upon coronary artery occlusion and reperfusion in vivo. The low-affinity (+)-trans-(1R,2R)-U-50,488 does not show antiarrhythmic activity under ischemia and reperfusion of myocardium. It is concluded that the antiarrhythmic action of kappa 1-OR agonists in the adrenal, ischemic, and reperfusion arrhythmia models has a receptor-specific character.

The cardioselective KATP channel activator BMS 180448 (3 mg/kg) administered intravenously 15 min before the coronary artery occlusion (10 min) decreased the incidence of ischemic and reperfusion arrhythmias in rats. A similar antiarrhythmic effect was observed when BMS 180448 was infused 2 min before reperfusion. Pretreatment with BMS 180448 also prevented the occurrence of CsCl induced arrhythmias, but but did not affect the incidence of epinephrine induced arrhythmias. On the contrary, BMS 180448 potentiated the arrhythmogenic action of CaCl2. The mechanism of the antiarrhythmic activity of BMS 180448 is discussed.

Peripheral administration of the mu- or kappa-receptor agonists or sigma-receptor antagonists produced a significant receptor-dependent increase in the ventricular fibrillation threshold in rats with postinfarction cardiosclerosis. The effect was not observed upon administration of the epsilon-receptor agonist beta-endorphin. The receptor and molecular mechanisms of the observed effects are discussed.

It has been found that in vivo pretreatment of rats with the sigma receptor antagonist DuP 734 (1 mg/kg) resulted in an increase in the heart tolerance to ischemic and reperfusion arrhythmias both in vivo and ex vivo. Administration of DuP 734 (1 mg/liter) directly in the perfusion solution of isolated rat heart 10 min before total ischemia also promoted a decrease in the incidence of reperfusion arrhythmias. The normoxic perfusion of isolated rat heart at a dose of 1 mg/liter had no effect on the action potential. It was concluded that antiarrhythmic effect of DuP 734 might depend on the decrease in the Ca2+ overload but not on K+ and Na+ channel blockade.

It has been found that the sigma 1- and sigma 3-receptor antagonists, DuP 734 intraperitoneally and XJ 448 intravenously, had antiarrhythmic effects against epinephrine-induced arrhythmias in rats. The ED50 for antiarrhythmic effect of DuP 734 was 0.157 mg/kg after intraperitoneal administration. Other sigma-receptor antagonists (rimcazole, BMY 14802, haloperidol) did not affect the incidence of epinephrine-induced arrhythmias. sigma 1-Receptor agonists (DTG, N-allyl-normetazocine, (+)-3-PPP, (-)-3-PPP) had proarrhythmic effect after systemic administration. The sigma-agonist N-allyl-normetazocine and sigma-antagonist XJ 488 had no effect on the incidence of epinephrine-induced arrhythmias after intracerebroventricular administration. Therefore, it appears that the central nervous system does not play a significant role in the antiarrhythmic or proarrhythmic effects of sigma ligands. We hypothesize that these effects of sigma ligands might be dependent on their action on cardiac sigma receptors.

Stimulation of peripheral delta-opioid receptors exerted no effect on arrhythmias, whereas that central delta 1- and delta 2-receptor activation decrease the heart susceptibility to arrhythmogenic action of epinephrine. Pre-treatment with the delta-opioid receptor antagonist ICI 174 prevented the antiarrhythmic effect of the central delta-receptors stimulation. The findings suggest that the heart decreased vulnerability to epinephrine-induced arrhythmias following the central delta-receptors stimulation is mediated by an enhanced vagal activity.

Adaptation of rats to hypoxia increased the heart resistance against arrhythmogenic effects. The Met-enkephaline-Arg6-Phe7 contant increased in the hypothalamus of the adapted animals. The blockers of mu- and delta-opioid receptors reduced the antiarrhythmic effect of the adaptation, whereas chi-receptor inhibitor, nor-binaltorphimine, completely abolished it. The findings suggest the antiarrhythmic effect depends on an increase of the endogenous opioids level and modulated effect of these peptides upon autonomous nervous system.

Blockade of the mu and delta receptors exerted no effect upon the heart resistance against arrhythmogenic influences. Stimulation of the delta receptors increased the myocardial resistance against arrhythmogenic influences. Autonomic nervous system seems to take no part in this effect.

It was established that selective ligands of the mu-opioid receptors DAGO and DALDA exhibit antiarrhythmic activity on a model of CACl2-induced arrhythmias when infused intravenously in a dose of 0.2 mg/kg. The autonomic nervous system does not take part in realization of the antiarrhythmic effect of DAGO and DALDA. It is supposed that this effect of DAGO and DALDA is associated with activation of cardiac mu-opioid receptors.