dynorphins and Arrhythmias--Cardiac

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cats; Dynorphins; Heart; Myocardial Ischemia; Peptide Fragments; Receptors, Opioid, kappa; Sympathetic Nervous System

In acute experiments on Nembutal-anesthetized cats, the effect of opiate receptor agonists DAGO, DSLET, and dinorphin A(1-13) on the incidence of idioventricular rhythm disturbances, including ventricular tachycardia and fibrillation, was studied under conditions of occlusion of circumflex branch of the left coronary artery and stimulation of the sensorimotor cortex. The most pronounced effects were observed with DSLET and dinorphin A(1-13). These preparations completely prevented ventricular fibrillation. DAGO produced a less pronounced protective effect probably because of parallel increase in plasma catecholamine concentration.

Topics: Analgesics, Opioid; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cats; Dynorphins; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine; Motor Cortex; Myocardial Ischemia; Peptide Fragments; Receptors, Opioid

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

In the present study, the relationship between the blockade of kappa-opioid receptor and ischemic preconditioning (IP) was examined and the effect of IP and prolonged ischemia on levels of dynorphin A1-13 (Dyn A1-13) in cardiac muscle in isolated perfused rat heart was investigated. The results are as follows: (1) IP reduced the severity of ischemia/reperfusion arrhythmia (P < 0.05) and infarct size (P < 0.01), but had no significant effect on heart rate and coronary flow (P > 0.05); (2) MR2266, kappa opioid receptor antagonist, reduced the severity of ischemia/reperfusion arrhythmia (P < 0.05) and infarct size (P < 0.01), and also enhanced the recovery of coronary flow, but had no significant effect on heart rate (P > 0.05); and (3) prolonged ischemia decreased the levels of Dyn A1-13 (P < 0.05), which was more marked in the unpreconditioned hearts. The results suggest: (1) MR2266 can "mimic" cardioprotective effect of IP in reducing the severity of arrhythmias and limiting infarct size of cardiac muscle; (2) ischemia causes release of endogenous kappa opioids, which can be attenuated by IP; and (3) the cardioprotective effects of IP in rat heart involves endogenous kappa opioids.

Topics: Animals; Arrhythmias, Cardiac; Benzomorphans; Cardiotonic Agents; Dynorphins; In Vitro Techniques; Ischemic Preconditioning; Male; Myocardium; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa

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

Although the formation of oxygen-derived free radicals (or reactive oxygen species; ROS) and the release of endogenous opioid peptides (EOP) have been independently reported to be the major arrhythmogenic factors in ischemic hearts, possible relations between these two factors have seldom been investigated. Thus, we studied whether the ROS and EOP were related in the progression of ischemia-induced arrhythmias. Isolated rat hearts perfused in the Langendorff mode were treated with dynorphin A1-13 (kappa EOP receptor agonist), and/or allopurinol (xanthine oxidase inhibitor), before the onset of ischemia induced by ligating the left coronary arteries. Ischemic period lasted for 30 min, during which cardiac rhythms were recorded. At the end of ischemia, hearts were analyzed for the glutathione and ascorbate levels. Allopurinol (100 nmoles/heart) was effective in reducing the severity of arrhythmia (arrhythmia score: Mean +/- SEM 3.00 +/- 0.80 for allopurinol, 5.75 +/- 0.41 for placebo, p < 0.01), while dynorphin (10 micrograms/heart) potentiated the arrhythmia (6.71 +/- 0.52, p < 0.05 vs. placebo). Coadministration of allopurinol and dynorphin was capable of reducing arrhythmia (5.57 +/- 0.65) when compared with the administration of dynorphin alone (6.71 +/- 0.52, p < 0.05). Tissue oxidative stress was evaluated by the concentrations of glutathione (GSH) and ascorbate. Allopurinol did not significantly elevate tissue GSH concentrations (1.46 +/- 0.05 mumoles/g wet wt) in ischemic hearts, while dynorphin alone significantly decreased the GSH concentrations (0.96 +/- 0.08, p < 0.05) when compared with the placebo (1.32 +/- 0.03). The dynorphin-induced GSH decrease cannot be reversed by coadministration with allopurinol (0.90 +/- 0.104). Allopurinol significantly elevated tissue ascorbate levels (0.16 +/- 0.01) when compared with placebo (0.10 +/- 0.01, p < 0.05). Interestingly, dynorphin alone also elevated the tissue ascorbate concentrations (0.16 +/- 0.02). Coadministration of allopurinol and dynorphin further spiked the ascorbate levels (0.28 +/- 0.05, p < 0.01). In conclusion, the results suggested that ischemia-induced arrhythmia mechanisms might involve the formation of superoxide and other ROS, which were probably generated from the release of EOP (or EOP/EOP receptor interactions). Superoxide, the formation of which can be inhibited by allopurinol that exerted antiarrhythmic effect, was probably scavenged by ascorbate in myocardial ischemia. The ROS r

Topics: Allopurinol; Animals; Arrhythmias, Cardiac; Ascorbic Acid; Dynorphins; Female; Free Radicals; Glutathione; In Vitro Techniques; Models, Cardiovascular; Myocardial Ischemia; Opioid Peptides; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species

The endogenous opioid peptide (EOP) dynorphin and opioid receptors have been found in the heart. This opioid system plays important roles in cardiovascular regulation and is involved in the pathophysiology of shock, heart failure and myocardial ischaemia. The aim of this study was to evaluate whether the EOP dynorphin modulates or potentiates ischaemia-induced arrhythmias and whether its effects are prevented by the opiate antagonist naloxone. Following coronary artery occlusion, all rats in the control group developed ischaemia-induced arrhythmias, bradycardia and hypotension, which were significantly potentiated by pre-treatment with dynorphin and attenuated by treatment with naloxone. The results clearly indicate that EOPs may be released when myocardial ischaemia occurs, thus causing arrhythmias, bradycardia and hypotension. Dynorphin and naloxone, by virtue of their opioid agonistic and antagonistic actions, respectively, potentiate and attenuate these fatal complications secondary to myocardial ischaemia. This suggests that EOPs play an important part in ischaemic heart disease.

Topics: Animals; Arrhythmias, Cardiac; Bradycardia; Dynorphins; Female; Heart Conduction System; Hypotension; Male; Myocardial Ischemia; Naloxone; Rats; Rats, Sprague-Dawley; Shock, Cardiogenic

The objectives of this study were to test the hypothesis that dynorphin in the central nervous system modulates epinephrine-induced cardiac arrhythmias and that central cholinergic mechanisms are operative in this action of dynorphin. Cardiac arrhythmias were produced by continuous intravenous infusion of epinephrine, in Wistar rats, previously instrumented with catheters in the lateral cerebral ventricle, femoral vein and femoral artery. Epinephrine produced ventricular premature complexes and later the development of fatal ventricular fibrillation. Dynorphin A (1-13), 5 or 20 micrograms (3 or 12 nM) administered into the lateral cerebral ventricle (ICV), significantly (P less than 0.05) increased the threshold for development of cardiac arrhythmias. Dynorphin A (1-13), 20 micrograms, increased the epinephrine dose at the occurrence of ventricular premature beats to 171 +/- 8 (mean +/- 1 S.E.M.) compared to 120 +/- 5 micrograms epinephrine/kg in the control group and increased the dose at the onset of fatal arrhythmias to 186 +/- 8 compared to 141 +/- 10 micrograms epinephrine/kg in the control group. The action of dynorphin was significantly (P less than 0.05) antagonized by the kappa opioid antagonist MR2266. Atropine sulfate, administered ICV or intravenously, produced a dose dependent antagonism of this action of dynorphin A (1-13). This was not due to the peripheral effects of atropine, as atropine methylnitrate, which does not cross the blood brain barrier, did not oppose the effects of dynorphin A (1-13). These data indicate (i) dynorphin A (1-13) increases the threshold for or suppresses the manifestations of epinephrine-induced ventricular arrhythmias, (ii) dynorphin's action on cardiac arrhythmias is mediated through central cholinergic rather than peripheral parasympathetic mechanisms (iii) dynorphin may play a role as an endogenous opioid within the brain that modulates cardiac arrhythmias in circumstances of elevated circulating epinephrine concentration.

Topics: Animals; Arrhythmias, Cardiac; Atropine; Atropine Derivatives; Benzomorphans; Blood Pressure; Brain; Cardiac Complexes, Premature; Dynorphins; Epinephrine; Heart Rate; Injections, Intraventricular; Male; Narcotic Antagonists; Parasympatholytics; Peptide Fragments; Rats; Rats, Wistar; Receptors, Cholinergic; Tachycardia, Ventricular

The effects of the opioid receptor agonists morphine and dynorphin on digoxin-induced arrhythmias were examined in guinea pigs that had received intravenous digoxin (50 mu/kg bolus plus 500 mu/kg/hr intravenously). Animals received either morphine (50 or 100 micrograms/kg) or dynorphin A(1-13) (50 or 100 micrograms/kg) or saline (the diluent) into the lateral cerebral ventricle (intracerebroventricularly) prior to digoxin. Morphine and dynorphin produced significant (P < 0.05) dose-dependent increases in the threshold of digoxin-induced arrhythmias. The mean digoxin dose at the development of fatal arrhythmias was 775 +/- 42 micrograms/kg in the control group but was significantly higher namely 958 +/- 45 micrograms/kg after 100 micrograms/kg of morphine ICV, and 984 +/- 47 micrograms/kg after 100 micrograms/kg of dynorphin A (1-13) intracerebroventricularly. In the absence of digoxin, the highest doses of each of these opioids did not produce arrhythmias. Changes in blood pressure and heart rate were unlikely explanations for the observed actions of these opioids as morphine accentuated the increase in blood pressure that accompanied digoxin while dynorphin was associated with a lower blood pressure with digoxin, despite similar effects on arrhythmias. In the control group, fatal digoxin-induced arrhythmias were ventricular tachyarrhythmias in two-thirds of cases and complete heart block in the rest. Morphine and dynorphin reduced the development of ventricular tachyarrhythmias. The role of the cholinergic system was explored, with morphine, utilizing atropine sulfate which crosses the blood brain barrier and atropine methylnitrate which does not enter the CNS. Atropine sulfate but not atropine methylnitrate reversed the effects of morphine on digoxin-induced arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arrhythmias, Cardiac; Blood Pressure; Brain; Digoxin; Dose-Response Relationship, Drug; Dynorphins; Guinea Pigs; Heart Rate; Injections, Intraventricular; Male; Morphine

We have studied the effects of a daily morphine injection for 2 weeks on induction of naloxone-reversible arrhythmias in the Langendorff isolated rat heart preparation caused by dynorphin1-13 or myocardial ischemia and reperfusion. Chronic morphine treatment significantly reduced the incidence and severity of arrhythmias and increased recovery following both administration of dynorphin and myocardial ischemia and reperfusion. The results support the notion that myocardial ischemia and reperfusion induce cardiac arrhythmias via endogenous opioid peptides.

Topics: Animals; Arrhythmias, Cardiac; Coronary Disease; Dynorphins; Female; Heart Ventricles; Morphine; Peptide Fragments; Perfusion; Rats; Rats, Inbred Strains

We have studied the effects of dynorphin1-13 on cardiac rhythm and cAMP levels in the isolated perfused rat heart. The standard Langendorff isolated heart preparation was used. The myocardial cAMP levels and the incidence of cardiac arrhythmias were determined after injection of dynorphin1-13. Dynorphin1-13 caused simultaneously cardiac arrhythmias and an increase in myocardial cAMP levels in a dose-dependent manner, and both effects were antagonized by naloxone. Further studies are needed to determine whether myocardial cAMP mediates the dynorphin-induced cardiac arrhythmias.

Topics: Animals; Arrhythmias, Cardiac; Cyclic AMP; Dynorphins; Female; Heart; In Vitro Techniques; Myocardium; Peptide Fragments; Rats; Rats, Inbred Strains