Cyclic ADP ribose-mediated Ca²⁺signaling in mediating endothelial nitric oxide production in bovine coronary arteries

Abstract

. Cyclic ADP ribosemediated Ca 2ϩ signaling in mediating endothelial nitric oxide production in bovine coronary arteries. Am J Physiol Heart Circ Physiol 290: H1172-H1181, 2006. First published October 21, 2005 doi:10.1152/ajpheart.00441.2005.-The present study tested the hypothesis that cyclic ADP ribose (cADPR) serves as a novel second messenger to mediate intracellular Ca 2ϩ mobilization in coronary arterial endothelial cells (CAECs) and thereby contributes to endothelium-dependent vasodilation. In isolated and perfused small bovine coronary arteries, bradykinin (BK)-induced concentrationdependent vasodilation was significantly attenuated by 8-bromocADPR (a cell-permeable cADPR antagonist), ryanodine (an antagonist of ryanodine receptors), or nicotinamide (an ADP-ribosyl cyclase inhibitor). By in situ simultaneously fluorescent monitoring, Ca 2ϩ transient and nitric oxide (NO) levels in the intact coronary arterial endothelium preparation, 8-bromo-cADPR (30 M), ryanodine (50 M), and nicotinamide (6 mM) substantially attenuated BK (1 M)-induced increase in intracellular [Ca 2ϩ ] by 78%, 80%, and 74%, respectively, whereas these compounds significantly blocked BKinduced NO increase by about 80%, and inositol 1,4,5-trisphosphate receptor blockade with 2-aminethoxydiphenyl borate (50 M) only blunted BK-induced Ca 2ϩ -NO signaling by about 30%. With the use of cADPR-cycling assay, it was found that inhibition of ADP-ribosyl cyclase by nicotinamide substantially blocked BK-induced intracellular cADPR production. Furthermore, HPLC analysis showed that the conversion rate of ␤-nicotinamide guanine dinucleotide into cyclic GDP ribose dramatically increased by stimulation with BK, which was blockable by nicotinamide. However, U-73122, a phospholipase C inhibitor, had no effect on this BK-induced increase in ADP-ribosyl cyclase activity for cADPR production. In conclusion, these results suggest that cADPR importantly contributes to BK-and A-23187-induced NO production and vasodilator response in coronary arteries through its Ca 2ϩ signaling mechanism in CAECs.nucleotide; vasodilation; endothelium; endothelium-derived relaxing factor CYCLIC ADP RIBOSE (cADPR), endogenously generated from nicotinamide (Ni) adenine dinucleotide, has emerged as a novel intracellular Ca 2ϩ -mobilizing second messenger in a wide variety of mammalian cells. The actions of this signaling nucleotide are completely independent of the inositol 1,4,5-trisphosphate [Ins(1,4,5)P 3 ]-signaling pathway, but it exerts its action by targeting ryanodine (Ry) receptors (RyRs) (8,15,16,(31)(32)(33)44). Elevation of intracellular cADPR levels followed by Ca 2ϩ mobilizition and activation of Ca 2ϩ -dependent effects within cells has been found to be essential for versatile physiological processes, such as cell cycle regulation, cell proliferation, gene expression, egg fertilization, neurotransmitter release, muscle contraction, and nitric oxide signaling (10,29,55). Recent studies (17,35,36,52,55,57) in our laboratory and by others have reported that in va...

Enhanced spontaneous Ca2+ events in endothelial cells reflect signalling through myoendothelial gap junctions in pressurized mesenteric arteries

“…The observation that responses to the endothelial-cell-specific agonist ACh were inhibited as well as the spontaneous events shows that the inhibitors did act on the endothelial cells. Although some studies have suggested that ryanodine receptors and cyclic ADP-ribose contribute to agonist-evoked increases in endothelial cell Ca 2+ increases [35,36], neither ryanodine nor nicotinamide had a significant inhibitory effect on the spontaneous endothelial Ca 2+ events in our study. This concurs with a lack of effect of ryanodine on spontaneous Ca 2+ events in rat ureter endothelial cells in situ [20].…”

Hydrogen peroxide stimulates the Ca2+-activated big-conductance K channels (BK) through cGMP signaling pathway in cultured human endothelial cells

“…Alternatively, different beta-subunit of BK channels expressed in smooth muscle cells and endothelial cells may modify the effect of peroxynitrite on BK channel activity. [38,39]. Related to this speculation is the report that H 2 O 2 has been shown to stimulate NOS and increase NO production in vessels [12,13].…”

Bradykinin‐mediated Ca2+ signalling regulates cell growth and mobility in human cardiac c‐Kit+ progenitor cells

“…These physiological effects or pathophysiological responses may result from different Ca 2+ signalling pathways in different types of cells/organs. In bovine coronary artery, bradykinin‐induced vasodilation is related to endothelial ${\mathrm{Ca}}_{\mathrm{normali}}^{2+}$ increase mediated by cyclic ADP ribose‐RyRs Ca 2+ signalling pathway, but not PLC‐IP3Rs Ca 2+ signalling pathway, because the PLC inhibitor U73122 and the IP3R inhibitor 2‐aminoethoxydiphenyl borate do not affect the ${\mathrm{Ca}}_{\mathrm{normali}}^{2+}$ increase induced by bradykinin 41. However, an earlier study demonstrated that bradykinin induces an increase in inositol 1,4,5‐triphosphate (IP3) in neonatal rat cardiomyocytes42 and bradykinin‐mediated short nocifensive responses is related to activating PLC, followed by Orai1 in afferent sensory neurons 18…”