mr-2266 and Arrhythmias--Cardiac

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 purpose of this study was to determine whether the opioid receptor agonist ethylketocyclazocine (EKC) modulates the development of cardiac arrhythmias by an action within the central nervous system. Catecholamine-induced ventricular arrhythmias were produced in the rat by continuous infusion of epinephrine, at incremental doses, until the development of fatal arrhythmias that were usually ventricular fibrillation. EKC, 1 mg/kg, intravenously (IV) significantly (p < 0.05) accentuated the manifestations of or reduced the threshold for epinephrine-induced arrhythmias. The effect of EKC was prevented by the kappa opioid antagonist MR 2266 in a dose-dependent manner. To determine whether the central nervous system is a site of this action of EKC, rats received injection of either EKC or the diluent (control) into the lateral cerebral ventricle (ICV). EKC, 100 and 200 micrograms/kg ICV, significantly (p < 0.05) altered the dose-effect relationship between epinephrine and arrhythmias so that EKC accentuated the development of cardiac arrhythmias. These data indicate that EKC, through an action in the brain, modulates cardiac arrhythmias and suggests a role for opioid receptor agonists, such as EKC, in cardiac arrhythmias and perhaps sudden cardiac death in man.

Topics: Animals; Arrhythmias, Cardiac; Benzomorphans; Blood Pressure; Brain; Dose-Response Relationship, Drug; Electrocardiography; Epinephrine; Ethylketocyclazocine; Injections; Male; Narcotic Antagonists; Rats; Rats, Wistar

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

Cardiac opioid receptors have been shown to be involved in the genesis of arrhythmias during ischemia and reperfusion. The present study was aimed at elucidating the receptor subtype(s) involved in arrhythmogenesis. Two series of experiments were conducted. In the first, effects of prototype opioid agonists, namely, (D-Ala2, NMe4, Gly-ol)-Enkephalin (DAGO), U50,488H and (D-Pen2, Pen5)-Enkephalin (DPDPE) and (D-Ala2, D-Leu2)-Enkephalin (DADLE), representing mu-, kappa- and delta-agonists, respectively, in disturbing the normal cardiac rhythm in the isolated perfused rat heart were investigated. Both DAGO and U50,488H were arrhythmogenic, whereas the effects of the delta-agonists, DPDPE and DADLE at a same dose range (44-396 nmol/heart) as that of DAGO were almost negligible. U50,488H was by far the most potent as it induced ventricular arrhythmias including frequent PVC and VT even at a dose (44 nmol/heart) at which other agonists either produced no or negligible effect. In the second series of experiments, the antiarrhythmogenic effects of mu-antagonist (naloxone) and kappa-antagonist (MR 2266) against arrhythmias arising during ischemia and reperfusion were compared. The effects of MR 2266 were significantly greater than that of naloxone. Results of the present study suggest that the cardiac kappa-receptors are the most likely receptor-subtype involved in arrhythmogenesis during ischemia and reperfusion.

Topics: Animals; Arrhythmias, Cardiac; Benzomorphans; Coronary Disease; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalin, Leucine-2-Alanine; Enkephalins; Female; In Vitro Techniques; Myocardial Reperfusion Injury; Myocardium; Perfusion; Rats; Rats, Inbred Strains; Receptors, Opioid