title: Pro- and anti-arrhythmic effects of a kappa opioid receptor agonist: a model for the biphasic action of a local hormone in the heart.
abstract: 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.
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Hong Kong, Hong Kong.
authors.forename: X
authors.initials: X
authors.lastname: Yu
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.forename: J
authors.initials: J
authors.lastname: Bian
authors.forename: T M
authors.initials: TM
authors.lastname: Wong
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000188:drug therapy*; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents; D017473:Receptors, Opioid, kappa; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer