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  • Title: Signal transduction mechanism(s) involved in prostacyclin production elicited by acetylcholine in coronary endothelial cells of rabbit heart.
    Author: Kan H, Ruan Y, Malik KU.
    Journal: J Pharmacol Exp Ther; 1997 Jul; 282(1):113-22. PubMed ID: 9223547.
    Abstract:
    The purpose of this study was to elucidate the mechanism by which acetylcholine (ACh) promotes prostacyclin (PGI2) production in cultured coronary endothelial cells (CEC) of the rabbit heart. ACh-induced production of PGI2, measured as immunoreactive 6-keto-PGF1alpha, was enhanced by increasing the extracellular calcium (Ca++) concentration and reduced by Ca++ depletion. The receptor-operated Ca++ channel blocker SK&F96365, but not the voltage-dependent Ca++ channel blockers verapamil or nifedipine, attenuated ACh-induced 6-keto-PGF1alpha production and the associated rise in cytosolic Ca++. Thapsigargin, which depleted Ca++ accumulation from the intracellular Ca++ store, did not prevent the ACh-induced rise in cytosolic Ca++. In the absence of extracellular Ca++, ACh and ATP increased cytosolic Ca++ but did not alter 6-keto-PGF1alpha production. In permeabilized CEC, guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S) but not ACh enhanced 6-keto-PGF1alpha synthesis. ACh increased 6-keto-PGF1alpha production in the presence of GTP-gamma-S. These effects of GTP-gamma-S were attenuated by guanosine 5'-O-(2-thiotriphosphate). In the absence of extracellular Ca++, ACh or ATP increased cytosolic Ca++ in cells permeabilized with beta-escin and loaded with GTP-gamma-S; this effect was attenuated by guanosine 5'-O-(2-thiotriphosphate). The effect of ATP but not ACh to mobilize intracellular Ca++ or increase 6-keto-PGF1alpha was inhibited by pertussis toxin. The phospholipase C inhibitor D609, which attenuated ACh- and ATP-induced mobilization of intracellular Ca++, did not alter 6-keto-PGF1alpha production. The NO synthase inhibitor N-monomethyl-arginine also failed to alter ACh-induced 6-keto-PGF1alpha synthesis. These data suggest that, in CEC of the rabbit heart, ACh stimulates prostacyclin production via a pertussis toxin-insensitive G protein and by increasing the influx of extracellular Ca++ through a G protein-independent receptor-operated Ca++ channel.
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