Phospholipase C Inhibitors Attenuate Arrhythmias Induced byκ-receptor Stimulation in the Isolated Rat Heart

To determine whether the phospholipase C (PLC)/inositol 1,4,5 trisphosphate (IP3)/Ca2+pathway mediates cardiac arrhythmias induced byκ-opioid receptor stimulation, the effects of U50,488H, a selectiveκ-opioid receptor agonist, on cardiac rhythm in a isolated perfused rat heart, intracellular calcium ([Ca2+]i) in a single ventricular myocyte and IP3production in myocytes were studied in the presence and absence of PLC inhibitors. U50,488H, the effects of which had been shown to be abolished by a selectiveκ-receptor antagonist, nor-binaltorphimine, induced arrhythmias dose-dependently and increased both [Ca2+]iand IP3-production in the heart. More importantly, the effects of U50,488H were blocked by PLC inhibitors, neomycin and streptomycin. To further confirm the selectivity of action of the PLC inhibitor, the effects of another PLC inhibitor U73122 and its inactive structural analog, U73343, on cardiac rhythm in the isolated perfused rat heart were compared. The former did, while the latter did not, block the arrhythmogenic effect of U50,488H. We also determined whether the effects ofκ-receptor stimulation involves a pertussis toxin (PTX)-sensitive G-protein. We found that pretreatment with PTX at 4μg/l for 10 min, a treatment shown to affect PTX sensitive G-protein-mediated functions, attenuated significantly the U50,488H-induced arrhythmias. The present study provides evidence thatκ-receptor stimulation-induced cardiac arrhythmias involves, at least partly, the PLC/IP3/Ca2+pathway as well as a PTX sensitive G-protein.