norbinaltorphimine and Arrhythmias--Cardiac

To observe the effects of κ-opioid receptor agonist U50, 488H on myocardial ischemia and reperfusion injury and related mechanism.. Rats were randomly divided into sham operation, myocardial ischemia and reperfusion(I/R, 30 min ischemia followed by 120 min reperfusion), and MI/R+U50, 488H (1.5 mg/kg) and I/R+U50, 488H+ selective κ-opioid receptor antagonist Nor-BNI (2 mg/kg, n = 8 each). The infarction size and the incidence of ventricular arrhythmias were observed.Real-time PCR and DAB staining were used to define the myocardium Toll-like receptor 4(TLR4) expression. Myeloperoxidase level, TNF-α induction and the expression of NF-κB were also examined in rats.. After I/R, the expressions of myocardial TLR4 and NF-κB increased significantly both in ischemia area and area at risk. Compared with I/R, κ-opioid receptor stimulation with U50, 488H significantly attenuated the expressions of TLR4 and NF-κB and reduced myeloperoxidase (MPO) levels, myocardial TNF-α production, myocardial infarct sizes and the incidence of ventricular arrhythmias and arrhythmia score (2.9 ± 0.7 vs. 4.4 ± 0.9, P < 0.05) , above effects of U50, 488H were partly abolished by co-treatment with Nor-BNI.. These data provide evidence for the first time that κ-opioid receptor stimulation could attenuate myocardial I/R injury via downregulating TLR4/NF-κB signaling in rats.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Arrhythmias, Cardiac; Brugada Syndrome; Cardiac Conduction System Disease; Coronary Artery Disease; Down-Regulation; Heart Conduction System; Myocardial Infarction; Myocardial Ischemia; Myocardium; Naltrexone; NF-kappa B; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Reperfusion Injury; Signal Transduction; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Kappa-opioid receptors (κ-OR) and mechanoelectric feedback seem to have common pathways that influence electrophysiological changes resulting from acute myocardial infarction (MI). This study aims to determine the effects of the κ-OR on stretch-induced electrophysiological changes after acute MI.. Male Sprague-Dawley rats were randomly divided into 4 groups: sham operated, MI, U-50488H (a selective κ-OR agonist) -treated MI (MI+U-50488H) and nor-BNI (a selective κ-OR antagonist) -treated MI (MI+nor-BNI). After Langendorff perfusion to maintain stabilization, a transient stretch (5 seconds) was delivered early in diastole. Electrophysiological changes were recorded for 1 minute before and after stretch. Similarly, the 20%, 50% and 90% monophasic action potential duration (MAPD20, MAPD50 and MAPD90, respectively) and stretch-induced arrhythmias were recorded.. MAPD90 significantly increased in all 4 groups. MAPD90 in the MI and MI+nor-BNI groups increased significantly before stretch (P < 0.05) and after stretch (P < 0.01) but was reversed in the MI+U-50488H group (P > 0.05). MAPD90 in the MI group was increased compared with that of the MI+U-50488H group but decreased compared with that of the MI+ nor-BNI group after stretch (P < 0.01). The arrhythmia score in the MI and MI+nor-BNI groups was higher than that of the sham-operated group (P < 0.01), and the arrhythmia score in the MI+nor-BNI group was higher than that in MI group after stretch (P < 0.01). The arrhythmia score of the MI+U-50488H group was lower than that of MI group after stretch (P < 0.01).. The κ-OR could influence the stretch-induced electrophysiological changes and play an antiarrhythmic role in stretch-induced arrhythmias after acute MI.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Action Potentials; Animals; Arrhythmias, Cardiac; Electrophysiological Phenomena; Male; Myocardial Infarction; Naltrexone; Pressoreceptors; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa

Intravenous pretreatment with kappa-opioid receptor antagonist (-)-U-50,488 (1 mg/kg) improved heart resistance to the arrhythmogenic effect of coronary occlusion and reperfusion. Selective kappa1-opioid receptor antagonist norbinaltorphimine and nonselective blocker of peripheral opioid receptors methylnaloxone abolished this antiarrhythmic effect. Preliminary blockade of protein kinase C with chelerythrine or inhibition of ATP-dependent K+ channels (K(ATP) channels) with glybenclamide abolished the antiarrhythmic effect of kappa-opioid receptor activation. Selective inhibitor of sarcolemmal K(ATP) channels did not modulate the kappa-opioid receptor-mediated increase in cardiac electrical stability. Our results suggest that protein kinase C and mitochondrial K(ATP) channels play an important role in the antiarrhythmic effect associated with activation of peripheral kappa-opioid receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Alkaloids; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzophenanthridines; Glyburide; Male; Myocardial Reperfusion Injury; Naltrexone; Oxymorphone; Potassium Channels; Protein Kinase C; Rats; Rats, Wistar; Receptors, Opioid, kappa

It was found that pretreatment of rats with selective agonist of kappa1-opioid receptors (OR) (-)--U--50.488 decreased the incidence of ischemic (10 min) and reperfusion (10 min) ventricular arrhythmias. The selective kappa2-OR agonist GR-89696 had no effect on the incidence of ventricular arrhythmias during a 10-min coronary artery occlusion and following reperfusion in anesthetized rats. The effect of (-)--U-50.488 was abolished by the selective kappa1-OR antagonist of non-binaltorphimine and the non-selective peripheral OR antagonist naloxone methiodide. Perfusion of isolated rat heart with (-)--U-50.488 did not affect arrhythmias during ischemia and reperfusion. The authors suggest that stimulation of kappa1-opioid receptors located outside the central nervous system increases heart resistance against arrhythmogenic action of ischemia/reperfusion, antiarrhythmic action of (-)--U-50.488 being mediated through extracardiac opioid receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Myocardial Reperfusion Injury; Myocardium; Naloxone; Naltrexone; Piperazines; Pyrrolidines; Quaternary Ammonium Compounds; Rats; Rats, Wistar; Receptors, Opioid, kappa

Pharmacological preconditioning with kappa-opioid receptor agonists is proarrhythmic and exerts antipreconditioning effects in rats. In swine, it is unknown whether kappa-opioid receptor stimulation plays a role in pharmacological preconditioning. Swine were preconditioned with 1) saline (controls), 2) [d-Ala(2),d-Leu(5)]enkephalin (DADLE), 3) morphine, 4) pentazocine, 5) norbinaltorphimine (nor-BNI), 6) DADLE + nor-BNI, 7) morphine + nor-BNI, or 8) pentazocine + nor-BNI before occlusion (45 min) and reperfusion (180 min) of the left anterior descending coronary artery. Infarct size to area at risk (IS), regional (systolic shortening) and global (pressures and flows) myocardial function, and arrhythmia occurrence were assessed. Only DADLE + nor-BNI preconditioning significantly decreased infarct size compared with controls (47 +/- 13 vs. 65 +/- 5%, P < 0.05); morphine preconditioning was not cardioprotective with or without kappa-opioid receptor blockade (nor-BNI). DADLE preconditioning significantly increased ischemia-induced arrhythmias relative to controls, whereas pentazocine-preconditioned animals (n = 2) experienced intractable ventricular fibrillation during ischemia. kappa-Opioid receptor blockade with DADLE or pentazocine preconditioning alleviated proarrhythmic effects. These results suggest that kappa-opioid receptor activation during pharmacological preconditioning is proarrhythmic in swine.

Topics: Animals; Arrhythmias, Cardiac; Coronary Circulation; Enkephalin, Leucine-2-Alanine; Hemodynamics; Ischemic Preconditioning, Myocardial; Morphine; Myocardial Infarction; Myocardial Ischemia; Naltrexone; Narcotic Antagonists; Narcotics; Pentazocine; Receptors, Opioid, kappa; Swine

Topics: Adaptation, Physiological; Animals; Arrhythmias, Cardiac; Enkephalin, Leucine; Epinephrine; Heart; Hypoxia; Immobilization; Male; Naltrexone; Narcotic Antagonists; Plant Extracts; Rats; Rats, Wistar

During myocardial ischaemia the beta-adrenoceptor is activated, which contributes, at least partly, to cardiac arrhythmias via inducing [Ca2+]i oscillations. Since beta-adrenoceptor is negatively modulated by the kappa-opioid receptor in the heart, the present study attempted to determine if kappa-opioid receptor stimulation modulates the arrhythmogenic action of beta-adrenoceptor stimulation and to delineate the underlying mechanism. The effect of U50,488H, a selective kappa-opioid agonist, on arrhythmias in the isolated perfused rat heart subjected to low flow and 10(-6)mol/l norepinephrine (NE) were determined. Low flow induced arrhythmias, which were potentiated by NE, but not by 10(-6)mol/l U50,488H. The arrhythmia-potentiating effect of NE was antagonized by 10(-6)mol/l propranolol, a beta-adrenoceptor antagonist. U50,488H at 10(-6)mol/l also abolished the potentiation in arrhythmias by NE without affecting the arrhythmias induced by low flow. The anti-arrhythmic action of the kappa-opioid receptor agonist was abolished by 10(-6)mol/l nor-binaltorphimine, a selective kappa-opioid receptor antagonist, but not by 10(-7)mol/l calphostin C, an inhibitor of protein kinase C. Similarly, kappa-opioid receptor stimulation with U50,488H also abolished the NE-induced [Ca2+]i oscillations which are believed to cause cardiac arrhythmias, in ventricular myocytes. To determine whether the inhibitory actions of U50,488H against the effects of beta-adrenoceptor stimulation was via a cAMP-dependent or a cAMP-independent pathway, we determined the effects of U50,488H on NE-enhanced cAMP production and [Ca2+]i oscillations induced by either forskolin, an activator of adenylate cyclase, or Bay K-8644, a selective L-type Ca2+ channel agonist, in the ventricular myocytes. We found that U50,488H abolished the effect of forskolin, but did not alter the effect of Bay K-8644, on [Ca2+]i oscillations in the ventricular myocyte. In addition, U50, 488H also attenuated significantly the NE-induced elevation in cAMP in the heart. The observations suggest that kappa-opioid receptor stimulation abolishes the effect of beta-adrenoceptor stimulation on arrhythmias and [Ca2+]i oscillation via a cAMP-dependent pathway. The finding may be useful for the prevention and treatment of ischaemic heart diseases.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Adrenergic beta-Antagonists; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium; Colforsin; Cyclic AMP; Cytosol; Electric Stimulation; Electrocardiography; Heart; Heart Rate; In Vitro Techniques; Male; Myocardial Contraction; Naltrexone; Norepinephrine; Propranolol; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa

To determine whether the phospholipase C (PLC)/inositol 1,4,5 trisphosphate (IP3)/Ca2+ pathway mediates cardiac arrhythmias induced by kappa-opioid receptor stimulation, the effects of U50,488H, a selective kappa-opioid receptor agonist, on cardiac rhythm in a isolated perfused rat heart, intracellular calcium ([Ca2+]i) in a single ventricular myocyte and IP3 production in myocytes were studied in the presence and absence of PLC inhibitors. U50,488H, the effects of which had been shown to be abolished by a selective kappa-receptor antagonist, nor-binaltorphimine, induced arrhythmias dose-dependently and increased both [Ca2+]i and IP3-production in the heart. More importantly, the effects of U50,488H were blocked by PLC inhibitors, neomycin and streptomycin. To further confirm the selectivity of action of the PLC inhibitor, the effects of another PLC inhibitor U73122 and its inactive structural analog, U73343, on cardiac rhythm in the isolated perfused rat heart were compared. The former did, while the latter did not, block the arrhythmogenic effect of U50,488H. We also determined whether the effects of kappa-receptor stimulation involves a pertussis toxin (PTX)-sensitive G-protein. We found that pretreatment with PTX at 4 microg/l for 10 min, a treatment shown to affect PTX sensitive G-protein-mediated functions, attenuated significantly the U50,488H-induced arrhythmias. The present study provides evidence that kappa-receptor stimulation-induced cardiac arrhythmias involves, at least partly, the PLC/IP3/Ca2+ pathway as well as a PTX sensitive G-protein.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Arrhythmias, Cardiac; Calcium; Enzyme Inhibitors; Estrenes; Heart Rate; In Vitro Techniques; Inositol 1,4,5-Trisphosphate; Male; Naltrexone; Narcotic Antagonists; Neomycin; Pertussis Toxin; Pyrrolidinones; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Signal Transduction; Streptomycin; Type C Phospholipases; Virulence Factors, Bordetella

The effect of kappa receptors agonists and antagonists was studied in the model of epinephrine induced arrhythmias. Kappa receptor agonists U-50,488 and [D-Ala2]-Dynorphin A (1-13) administered I.C.V. potentiate the arrhythmogenic effect of epinephrine. The effect of U-50,488 was completely blocked by kappa receptor antagonist, nor-binaltorphine. Administration of N-cholinergic receptor inhibitor, hexamethonium, prevented pro-arrhythmic effects of U-50,488 and [D-Ala2]-Dynorphin A (1-13). The data support the hypothesis that central kappa opioid receptors play an important role in the arrhythmogenesis.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Arrhythmias, Cardiac; Dynorphins; Epinephrine; Hexamethonium; Male; Naloxone; Naltrexone; Narcotic Antagonists; Peptide Fragments; Pyrrolidines; Rats; Rats, Wistar; Receptors, Opioid, kappa

Topics: Animals; Arrhythmias, Cardiac; Blood-Brain Barrier; Brain; Dynorphins; Ganglionic Blockers; Heart; Hexamethonium; Injections, Intraventricular; Male; Naloxone; Naltrexone; Narcotic Antagonists; Parasympathetic Nervous System; Rats; Rats, Wistar; Receptors, Opioid, kappa

The antiarrhythmic activities of 16-methylcyprenorphine (M8008), nor-binaltorphimine (NBT) and naltrexone, which are relatively specific opioid receptor antagonists for delta, kappa and mu receptors, respectively, were examined during the 30 min following coronary artery occlusion in anaesthetised rats. The haemodynamic and electrocardiographic effects of the opioid receptor agonists [D-Ala2,D-Leu5]enkephalin (DADLE) (relatively selective for delta receptors), ICI-204448 (kappa) and glyol (mu) were also investigated over the 30-90 min post ligation period. When administered intravenously 5 min before ligation, M8008 (0.5 mg kg-1 and 2.5 mg kg-1) reduced the number of ventricular ectopic beats but had no effect on the incidence or duration of ventricular fibrillation. NBT and naltrexone were not antiarrhythmic at a dose of 0.5 mg kg-1 but at 2.5 mg kg-1 (a concentration at which both drugs block kappa receptors) the number of ventricular ectopic beats, the incidence of ventricular fibrillation and mortality were all reduced. All of the opioid receptor agonists caused a transient decrease in heart rate and in arterial blood pressure but none exhibited an arrhythmogenic effect. These studies suggest that the delta and kappa opioid receptor antagonists used may be antiarrhythmic as a result of blockade of the action of endogenously released peptides acting on these receptors or that they have a non-specific 'direct' antiarrhythmic action.

Topics: Animals; Arrhythmias, Cardiac; Coronary Disease; Coronary Vessels; Electrophysiology; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine-2-Alanine; Enkephalins; Hemodynamics; Male; Morphinans; Naltrexone; Narcotic Antagonists; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu