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PRO‐ AND ANTI‐ARRHYTHMIC EFFECTS OF A κ OPIOID RECEPTOR AGONIST: A MODEL FOR THE BIPHASIC ACTION OF A LOCAL HORMONE IN THE HEART
Author(s) -
Yu XIAOCHUN,
Zhang WEIMIN,
Bian JINSONG,
Wong TAK MING
Publication year - 1999
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1046/j.1440-1681.1999.03143.x
Subject(s) - endocrinology , medicine , agonist , κ opioid receptor , chemistry , stimulation , receptor , forskolin
SUMMARY 1. The effects of κ opioid receptor stimulation on cardiac rhythm and the underlying signal pathways were investigated in the rat. 2. Stimulation of κ opioid receptors with 40–50 μmol/L U50 488H, a selective κ opioid receptor agonist, induced dysrhythmias and increased inositol 1,4,5‐trisphosphate (IP 3 ) production in rat isolated, perfused heart. The pro‐arrhythmic effects of U50 488H were abolished by 5 μmol/L nor‐ binaltorphimine (nor‐BNI), a specific κ opioid receptor antagonist. 3. The effect of U50 488H on cardiac dysrhythmia and IP 3 production were abolished by 1 mmol/L neomycin and streptomycin, phospholipase C (PLC) inhibitors. 4. At 1 μmol/L, U50 488H, which itself has no effect on cardiac rhythm and IP 3 production, significantly attenuated the potentiating effect of 1 μmol/L noradrenaline (NA) on dysrhythmias, which were induced by low flow in the isolated heart. The effects of U50 488H were abolished by 1 μmol/L nor‐BNI. Cytosolic cAMP production was augmented by 1 μmol/L NA and this was significantly attenuated by 1 μmol/L U50 488H. 5. At 1 μmol/L, U50 488H also reduced [Ca 2+ ] i oscillations induced by 0.5 μmol/L NA and 0.5 μmol/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/IP 3 pathway, while the latter was mediated via the AC/cAMP pathway.