PHOSPHOLIPASE-C INHIBITORS ATTENUATE ARRHYTHMIAS INDUCED BY KAPPA-RECEPTOR STIMULATION IN THE ISOLATED RAT-HEART

To determine whether the phospholipase C (PLC)/inositol 1,4,5 trisphos phate (IP3)/Ca2+ pathway mediates cardiac arrhythmias induced by kappa -opioid receptor stimulation, the effects of U50,488H, a selective kap pa-opioid receptor agonist, on cardiac rhythm in a isolated perfused r at heart, intracellular calcium ([Ca2+](i)) in a single ventricular my ocyte and IP3 production in myocytes were studied in the presence and absence of PLC inhibitors, U50,488H, the effects of which had been sho wn to be abolished by a selective kappa-receptor antagonist, nor-binal torphimine, induced arrhythmias dose-dependently and increased both [C a2+](i) and 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, t he 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 arr hythmogenic effect of U50,488H. We also determined whether the effects of kappa-receptor stimulation involves a pertussis toxin (PTX)-sensit ive G-protein. We found that pretreatment with PTX at 4 mu g/l for 10 min, a treatment shown to affect PTX sensitive G-protein-mediated func tions, attenuated significantly the U50,488 H-induced arrhythmias. The present study provides evidence that kappa-receptor stimulation-induc ed cardiac arrhythmias involves, at least partly, the PLC/IP3/Ca2+ pat hway as well as a PTX sensitive G-protein. (C) 1998 Academic Press.