u-50488 and Arrhythmias--Cardiac

The role of opioid kappa1 and kappa2 receptors in reperfusion cardiac injury was studied. Male Wistar rats were subjected to a 45-min coronary artery occlusion followed by a 120-min reperfusion. Opioid kappa receptor agonists were administered intravenously 5 min before the onset of reperfusion, while opioid receptor antagonists were given 10 min before reperfusion. The average value of the infarct size/area at risk (IS/AAR) ratio was 43 - 48% in untreated rats. Administration of the opioid kappa1 receptor agonist (-)-U-50,488 (1 mg/kg) limited the IS/AAR ratio by 42%. Administration of the opioid kappa receptor agonist ICI 199,441 (0.1 mg/kg) limited the IS/AAR ratio by 41%. The non-selective opioid kappa receptor agonist (+)-U-50,488 (1 mg/kg) with low affinity for opioid kappa receptor, the peripherally acting opioid kappa2 receptor agonist ICI 204,448 (4 mg/kg) and the selective opioid ?2 receptor agonist GR89696 (0.1 mg/kg) had no effect on the IS/AAR ratio. Pretreatment with naltrexone, the peripherally acting opioid receptor antagonist naloxone methiodide, or the selective opioid kappa2 receptor antagonist nor-binaltorphimine completely abolished the infarct-reducing effect of (-)-U-50,488 and ICI 199,441. Pretreatment with the selective opioid ? receptor antagonist TIPP[psi] and the selective opioid µ receptor antagonist CTAP did not alter the infarct reducing effect of (-)-U-50,488 and ICI 199,441. Our study is the first to demonstrate the following: (a) the activation of opioid kappa2 receptor has no effect on cardiac tolerance to reperfusion; (b) peripheral opioid kappa1 receptor stimulation prevents reperfusion cardiac injury; (c) ICI 199,441 administration resulted in an infarct-reducing effect at reperfusion; (e) bradycardia induced by opioid kappa receptor antagonists is not dependent on the occupancy of opioid kappa receptor.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Administration, Intravenous; Analgesics, Opioid; Animals; Arrhythmias, Cardiac; Disease Models, Animal; Heart Rate; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocytes, Cardiac; Narcotic Antagonists; Piperazines; Pyrrolidines; Rats, Wistar; Receptors, Opioid, kappa; Signal Transduction

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

Acute myocardial ischemia induces electrical and chemical uncoupling of gap junctions, which contributes to conduction abnormalities and re-entrant arrhythmias. We tested the hypothesis that structure and function of Connexin43 may vibrate during acute myocardial ischemia and reperfusion and κ-opioid receptor stimulation may stabilize the alteration of Connexin43.. An animal intervention study was conducted with comparison to a control group.. University preclinical research laboratory.. Age-, weight-, and sex-matched Sprague-Dawley rats.. Adult rat hearts were subjected to ischemia or ischemia/reperfusion, which was induced by temporary occlusion of the left main coronary artery. U50488H was given 10 mins before tissue specimens were taken or before ischemia (1.5 mg/kg, intravenous) and nor-BNI was given 15 mins before tissue specimens were taken or before ischemia (2 mg/kg, intravenous). Tissue samples came from left ventricular myocardium of the rat hearts.. Electrocardiogram, immunohistochemistry, immunoblotting, and reverse transcription-polymerase chain reaction were used to measure changes of arrhythmias, protein, and gene expression of Connexin43, respectively. κ-opioid receptor activation with U50 decreased arrhythmia in a model of myocardial ischemia and reperfusion. In normal hearts, immunohistochemical data showed reduced amount and lateralization of Connexin43 induced by κ-opioid receptor activation, whereas immunoblotting data demonstrated no significant changes between control and U50 group. During ischemia, however, Connexin43 protein underwent dephosphorylation and degradation, and Connexin43 mRNA was upregulated. These alterations were significantly attenuated on κ-opioid receptor stimulation. During ischemia and reperfusion, Connexin43 protein underwent dephosphorylation and degradation and recovered slowly during reperfusion. Activation of κ-opioid receptor accelerated recovery of phosphorylated and total Connexin43.. In normal rat hearts, Connexin43 translocates from intercellular junctions to intracellular locations on κ-opioid receptor activation. In rat hearts experiencing acute myocardial ischemia and reperfusion, protein and gene expression of Connexin43 undergo vibration. This phenomenon is stabilized when κ-opioid receptor is activated and by the fact that κ-opioid receptor produces antiarrhythmic effects.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Arrhythmias, Cardiac; Blotting, Western; Connexin 43; Disease Models, Animal; Female; Gap Junctions; Immunohistochemistry; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Reference Values; Reverse Transcriptase Polymerase Chain Reaction

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

The cardioprotective and antiarrhythmic effects of a selective kappa1-opioid receptor agonist U-50,488 were studied during experimental 45-min total ischemia and 30-min reperfusion of isolated rat heart. The opioid had no effect on the incidence and type of reperfusion arrhythmias. U-50,488 in a concentration of 0.1 microM inhibited reperfusion-induced release of creatine phosphokinase and decreased cAMP concentration in the myocardium by 2 times. These parameters remained unchanged after treatment with U-50,488 in a concentration of 1 microM. The cardioprotective effect of U-50,488 was probably associated with a decrease in cAMP concentration in heart cells. U-50,488 in a concentration of 1 microM produced no cardioprotective effect, which can be explained by its interaction with an unknown non-opioid receptor in cardiomyocytes.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Creatine Kinase; Cyclic AMP; Male; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; 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

The involvement of opioid receptor activation during ischemia-reperfusion is somewhat controversial. While it is generally accepted that activation of the delta-opioid receptor (DOR) is cardioprotective, and may indeed be an important mediator of ischemic preconditioning, the role of the kappa-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.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Antihypertensive Agents; Arrhythmias, Cardiac; Blood Pressure; Heart Rate; Male; Myocardial Infarction; Myocardial Reperfusion; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa

Two series of experiments were performed in the isolated perfused rat heart to determine the role of kappa- and delta-opioid receptors (OR) in cardioprotection of ischemic preconditioning (IP). In the first series of experiments, it was found that IP with two cycles of 5-min regional ischemia followed by 5-min reperfusion each reduced infarct size induced by 30-min ischemia, and the ameliorating effect of IP on infarct was attenuated with blockade of either 5 x 10(-6) mol/l nor-binaltorphimine (nor-BNI), a selective kappa-OR antagonist, or 5 x 10(-6) mol/l naltrindole (NTD), a selective delta-OR antagonist. The second series showed that U50,488H, a selective kappa-OR agonist, or D-Ala(2)-D-leu(5)-enkephalin (DADLE), a selective delta-OR agonist, dose dependently reduced the infarct size induced by ischemia, which mimicked the effects of IP. The effect of 10(-5) mol/l U50,488H on infarct was significantly attenuated by blockade of protein kinase C (PKC) with specific PKC inhibitors, 5 x 10(-6) mol/l chelerythrine or 8 x 10(-7) mol/l calphostin C, as well as by blockade of ATP-sensitive K(+) (K(ATP)) channels with blockers of the channel, 10(-5) mol/l glibenclamide or 10(-4) mol/l 5-hydroxydecanoate. IP also reduced arrhythmia induced by ischemia. Nor-BNI, but not NTD, attenuated, while U50,488H, but not DADLE, mimicked the antiarrhythmic action of IP. In conclusion, the present study has provided first evidence that kappa-OR mediates the ameliorating effects of IP on infarct and arrhythmia induced by ischemia, whereas delta-OR mediates the effects only on infarct. Both PKC and K(ATP) channels mediate the effect of activation of kappa-OR on infarct.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Arrhythmias, Cardiac; Coronary Circulation; Enkephalin, Leucine-2-Alanine; Enzyme Inhibitors; Hemodynamics; In Vitro Techniques; Ischemic Preconditioning, Myocardial; Male; Myocardial Infarction; Potassium Channel Blockers; Protein Kinase C; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, kappa; Signal Transduction

The present study attempted to determine whether the protein kinase C (PKC)/Na(+)-H(+)exchange (NHE) pathway would mediate the arrhythmogenic action of kappa -opioid receptor (OR) stimulation. We first determined the effects of U50,488H, a selective kappa -OR agonist, on PKC activity and cardiac rhythm in the isolated perfused rat heart, and intracellular pH (pH(i)), and Ca(2+)([Ca(2+)](i)) and Na(+)([Na(+)](i)) concentrations in the isolated ventricular myocyte. At 5-40 microm U50,488H concentration dependently increased the particulate PKC activity and pH(i), and induced arrhythmia. 40 microm U50,488H also increased [Na(+)](i)and [Ca(2+)](i). The arrhythmogenic effects of 40 microm U50,488H were abolished by nor-binaltorphimine, a selective kappa -OR antagonist. Blockade of PKC and NHE with respective blockers, 1 microm bisindolylmaleimide I or 0.5 microm calphostin C, and 1 microm 5-[N -methyl- N -isobutyl]amiloride or 1 microm 5-([N -ethyl- N -isopropopyl]amiloride, abolished and significantly attenuated, respectively, the effects of kappa -OR stimulation on pH(i), [Na(+)](i)and [Ca(2+)](i), and arrhythmia. To determine the role of pH(i), we observed U50,488H-induced arrhythmia at pH(i)6.8. At this pH(i), the pH(i)increased gradually both in the presence and absence of 40 microm U50,488H to a similar extent. While the increase in response to U50,488H was significantly less at pH(i)6.8 (from 0.09 to 0.10) than that at pH(i)7.1 (from 0.01 to 0.18), the arrhythmia induced by the agonist was the same at both high and low pHs. On the other hand, 5 microm monensin, a sodium ionophore, increased [Na(+)](i)and [Ca(2+)](i), and induced arrhythmia to similar extents as U50,488H. PKC and NHE inhibitors, that significantly attenuated the effects induced by U50,488H, had no effect on those induced by monensin. In conclusion, kappa -OR stimulation induces arrhythmia via PKC/NHE. [Na(+)](i)and [Ca(2+)](i), but not pH(i), may be directly responsible for arrhythmia induced by kappa -OR stimulation.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Antihypertensive Agents; Arrhythmias, Cardiac; Calcium; Cells, Cultured; Cytosol; Dose-Response Relationship, Drug; Enzyme Inhibitors; Heart; Hydrogen-Ion Concentration; Ionophores; Male; Monensin; Myocardium; Perfusion; Protein Kinase C; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Sodium; Sodium-Hydrogen Exchangers; Spectrometry, Fluorescence; Time Factors

1. The kappa 1 and kappa 2 opioid receptor agonists U-62066 (8 mg/kg, i.p.) and (-)-bremazocine (0.7 mg/kg, i.v.), respectively, both exhibit anti-arrhythmic properties against adrenaline-induced dysrhythmias in rats. 2. In contrast, (+)-bremazocine has no effect on adrenaline-induced dysrhythmias. 3. The kappa 1 opioid receptor agonists U-50488 (110 nmol) and [D-Ala2]-dynorphin A (20 nmol) and the kappa 2 opioid receptor agonist (-)-bremazocine (30 nmol) exhibit pro-arrhythmic properties following intracerebroventricular administration. 4. Prior administration of the kappa opioid receptor antagonist nor-binaltorphimine doses i.c.v. (14 nmol), i.p. (10 mg/kg), completely abolishes the pro-arrhythmic (BNI, i.c.v., 14 nmol) as well as anti-arrhythmic (BNI, 10 mg/kg, i.p.) effects of the kappa opioid receptor agonists. 5. Neither hexamethonium (10 mg/kg, i.v.) nor atropine (1 mg/kg, i.v.) have any effect on the anti-arrhythmic actions of the kappa 1 opioid receptor agonist U-62066 following systemic administration. 6. It is suggested that the anti-arrhythmic effects of U-62066 and (-)-bremazocine are associated with the activation of peripheral kappa opioid receptors and do not depend on the activation of kappa opioid receptors in the autonomic nervous system.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Anti-Arrhythmia Agents; Antihypertensive Agents; Arrhythmias, Cardiac; Benzomorphans; Dynorphins; Male; Pyrrolidines; Rats; Rats, Wistar; Receptors, Opioid, kappa

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

1. The effects of kappa opioid receptor stimulation on cardiac rhythm and the underlying signal pathways were investigated in the rat. 2. Stimulation of kappa opioid receptors with 40-50 mumol/L U50 488H, a selective kappa opioid receptor agonist, induced dysrhythmias and increased inositol 1,4,5-trisphosphate (IP3) production in rat isolated, perfused heart. The pro-arrhythmic effects of U50 488H were abolished by 5 mumol/L norbinaltorphimine (nor-BNI), a specific kappa opioid receptor antagonist. 3. The effect of U50 488H on cardiac dysrhythmia and IP3 production were abolished by 1 mmol/L neomycin and streptomycin, phospholipase C (PLC) inhibitors. 4. At 1 mumol/L, U50 488H, which itself has no effect on cardiac rhythm and IP3 production, significantly attenuated the potentiating effect of 1 mumol/L noradrenaline (NA) on dysrhythmias, which were induced by low flow in the isolated heart. The effects of U50 488H were abolished by 1 mumol/L nor-BNI. Cytosolic cAMP production was augmented by 1 mumol/L NA and this was significantly attenuated by 1 mumol/L U50 488H. 5. At 1 mumol/L, U50 488H also reduced [Ca2+]i oscillations induced by 0.5 mumol/L NA and 0.5 mumol/L forskolin, an activator of adenylate cyclase (AC). 6. In conclusion, U50 488H exerted pro- and anti-arrhythmic actions at high and lower concentrations, respectively. The former effect was mediated via the PLC/IP3 pathway, while the latter was mediated via the AC/cAMP pathway.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Anti-Arrhythmia Agents; Antihypertensive Agents; Arrhythmias, Cardiac; Heart; Male; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Signal Transduction

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

The antiarrhythmic actions of low and high doses of U-50,488H, a selective kappa-receptor agonist, were examined in pentobarbitone-anaesthetized rats subjected to occlusion of the left anterior descending coronary artery. At a high dose (16 mumol/kg) U-50,488H reduced blood pressure, heart rate and prolonged the P-R and QRS intervals of the electrocardiogram. This dose reduced the incidence of ventricular arrhythmias produced by occlusion. The blood pressure, heart rate, ECG and antiarrhythmic actions of a high dose of U-50,488H were not antagonized by 8 mumol/kg naloxone, a dose which had no cardiovascular or ECG actions. Naloxone alone reduced arrhythmia incidence but to a lesser extent than U-50,488H. A low dose (0.2 mumol/kg) of U50,488H in the absence or presence of naloxone had no effect on arrhythmias. Thus, U-50,488H had antiarrhythmic actions at a high dose which were independent of opioid receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atenolol; Blood Pressure; Coronary Disease; Dose-Response Relationship, Drug; Drug Interactions; Electrocardiography; Heart Rate; Male; Naloxone; Potassium; Pyrrolidines; Rats; Rats, Inbred Strains

The aim was to evaluate the effects of an opiate agonist (U50,488H) and an opiate antagonist (naloxone) in myocardial ischaemia.. A left thoracotomy was performed and the left coronary artery was ligated in adult Sprague-Dawley rats of either sex (350-400 g). Blood pressure, heart rate and electrocardiogram were measured before and after injections of U50,488H or naloxone and throughout the 30 min postligation period.. Following coronary artery occlusion, all rats in the control group developed arrhythmias, bradycardia, and hypotension. U50,488H potentiated and naloxone attenuated the ischaemia induced arrhythmias, bradycardia, and hypotension.. The potentiating and blocking effects of U50,488H and naloxone, respectively, suggest that endogenous opioid peptides are involved in the pathophysiology of myocardial ischaemia and play an important role in ischaemic heart disease.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Arrhythmias, Cardiac; Blood Pressure; Coronary Disease; Disease Models, Animal; Female; Heart Rate; Male; Naloxone; Pyrrolidines; Rats; Rats, Inbred Strains

1. The effects of a range of opioid receptor agonists and antagonists with differing opioid receptor selectivities on ischaemia-induced arrhythmias in anaesthetised rats was investigated. 2. Naloxone was antiarrhythmic only at doses expected to antagonise kappa- and delta-receptors in addition to mu-receptors. 3. The opioid receptor antagonist Mr 2266, which is twice as potent at kappa-receptors as at mu-receptors dose-dependently reduced the incidence and severity of the arrhythmias resulting from coronary artery occlusion. 4. The opioid receptor antagonist M 8008 (1 mg kg-1), which is twice as potent at delta-receptors as at mu-receptors but has very little affinity for the kappa-receptor, did not exhibit any beneficial antiarrhythmic properties. 5. MrZ 2593, a quarternary complex of naloxone which does not readily cross the blood brain barrier, was antiarrhythmic which implies that the antiarrhythmic actions of opioid receptor antagonists may be mediated via peripheral opioid receptors. 6. The agonists, diamorphine, [Leu] enkephalin and U-50,488H exhibited no significant arrhythmogenic effects under the present experimental conditions. 7. It is tentatively suggested that blockade of peripheral kappa-receptors during acute myocardial ischaemia may result in an antiarrhythmic effect.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Coronary Disease; Coronary Vessels; Enkephalin, Leucine; Heart Rate; Heroin; Male; Naloxone; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Time Factors