dynorphins and Myocardial-Ischemia

During myocardial ischemia, the cranial cervical spinal cord (C1-C2) modulates the central processing of the cardiac nociceptive signal. This study was done to determine 1) whether C2 SCS-induced release of an analgesic neuropeptide in the dorsal horn of the thoracic (T4) spinal cord; 2) if one of the sources of this analgesic peptide was cervical propriospinal neurons, and 3) if chemical inactivation of C2 neurons altered local T4 substance P (SP) release during concurrent C2 SCS and cardiac ischemia. Ischemia was induced by intermittent occlusion of the left anterior descending coronary artery (CoAO) in urethane-anesthetized Sprague-Dawley rats. Release of dynorphin A (1-13), (DYN) and SP was determined using antibody-coated microprobes inserted into T4. SCS alone induced DYN release from laminae I-V in T4, and this release was maintained during CoAO. C2 injection of the excitotoxin, ibotenic acid, prior to SCS, inhibited T4 DYN release during SCS and ischemia; it also reversed the inhibition of SP release from T4 dorsal laminae during C2 SCS and CoAO. Injection of the kappa-opioid antagonist, nor-binaltorphimine, into T4 also allowed an increased SP release during SCS and CoAO. CoAO increased the number of Fos-positive neurons in T4 dorsal horns but not in the intermediolateral columns (IML), while SCS (either alone or during CoAO) minimized this dorsal horn response to CoAO alone, while inducing T4 IML neuronal recruitment. These results suggest that activation of cervical propriospinal pathways induces DYN release in the thoracic spinal cord, thereby modulating nociceptive signals from the ischemic heart.

Topics: Animals; Brain Stem; Coronary Vessels; Dynorphins; Electric Stimulation; Excitatory Amino Acid Agonists; Ibotenic Acid; Image Processing, Computer-Assisted; Immunohistochemistry; Male; Myocardial Ischemia; Naltrexone; Narcotic Antagonists; Neural Pathways; Neurons; Posterior Horn Cells; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Spinal Cord; Substance P

Electrostimulatory forms of therapy can reduce angina that arises from activation of cardiac nociceptive afferent fibers during transient ischemia. This study sought to determine the effects of electrical stimulation of left thoracic vagal afferents (C(8)-T(1) level) on the release of putative nociceptive [substance P (SP)] and analgesic [dynorphin (Dyn)] peptides in the dorsal horn at the T(4) spinal level during coronary artery occlusion in urethane-anesthetized Sprague-Dawley rats. Release of Dyn and SP was measured by using antibody-coated microprobes. While Dyn and SP had a basal release, occlusion of the left anterior descending coronary artery only affected SP release, causing an increase from lamina I-VII. Left vagal stimulation increased Dyn release, inhibited basal SP release, and blunted the coronary artery occlusion-induced release of SP. Dyn release reflected activation of descending pathways in the thoracic spinal cord, because vagal afferent stimulation still increased the release of Dyn after bilateral dorsal rhizotomy of T(2)-T(5). These results indicate that electrostimulatory therapy, using vagal afferent excitation, may induce analgesia, in part, via inhibition of the release of SP in the spinal cord, possibly through a Dyn-mediated neuronal interaction.

Topics: Afferent Pathways; Animals; Blood Pressure; Dynorphins; Female; Heart Rate; Male; Myocardial Ischemia; Nerve Fibers; Rats; Rats, Sprague-Dawley; Spinal Cord; Substance P; Thoracic Vertebrae; Vagus Nerve

To examine the receptor specificity and the mechanism of opioid peptide-induced protection, we examined freshly isolated adult rabbit cardiomyocytes subjected to simulated ischemia. Cell death as a function of time was assessed by trypan blue permeability. Dynorphin B (DynB) and Met5-enkephalin (ME) limitation of cell death (expressed as area under the curve) was sensitive to blockade by naltrindole (NTI, a delta-selective antagonist) and 5'-guanidinyl-17-(cyclopropylmethyl)-6,7-dehydro-4,5alpha-epoxy-3,14-dihydroxy-6,7-2',3'-indolomorphinan (GNTI dihydrochloride, a kappa-selective antagonist): 85.7 +/- 2.7 and 142.9 +/- 2.7 with DynB and DynB + NTI, respectively (P < 0.001), 94.1 +/- 4.2 and 164.5 +/- 7.3 with DynB and DynB + GNTI, respectively (P < 0.001), 111.9 +/- 7.0 and 192.1 +/- 6.4 with ME and ME + NTI, respectively (P < 0.001), and 120.2 +/- 4.3 and 170.0 +/- 3.3 with ME and ME + GNTI, respectively (P < 0.001). Blockade of ATP-sensitive K+ channels eliminated DynB- and ME-induced protection: 189.6 +/- 5.4 and 139.0 +/- 5.4 for control and ME, respectively (P < 0.001), and 210 +/- 5.9 and 195 +/- 6.1 for 5-HD and ME + 5-HD, respectively (P < 0.001); 136.0 +/- 5.7 and 63.4 +/- 5.4 for control and ME, respectively (P < 0.001), and 144.6 +/- 4.5 and 114.6 +/- 7.7 for HMR-1098 and ME + HMR-1098, respectively (P < 0.01); 189.6 +/- 5.4 and 139.0 +/- 5.4 for control and ME, respectively (P < 0.001), and 210 +/- 5.9 and 195 +/- 6.1 for 5-HD and ME + 5-HD, respectively (P < 0.001); and 136.0 +/- 5.7 and 63.4 +/- 5.4 for control and ME, respectively (P < 0.001), and 144.6 +/- 4.5 and 114.6 +/- 7.7 for HMR-1098 and ME + HMR-1098, respectively (P < 0.01). We conclude that opioid peptide-induced cardioprotection is mediated by delta- and kappa-receptors and involves sarcolemmal and mitochondrial ATP-sensitive K+ channels.

Topics: Adenosine Triphosphate; Animals; Benzamides; Cardiotonic Agents; Dose-Response Relationship, Drug; Dynorphins; Endorphins; Enkephalin, Methionine; Guanidines; Ischemic Preconditioning, Myocardial; Male; Mitochondria; Morphinans; Myocardial Ischemia; Myocytes, Cardiac; Naltrexone; Narcotic Antagonists; Potassium Channels; Rabbits; Receptors, Opioid, delta; Receptors, Opioid, kappa; Sarcolemma

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

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