Cyclic ADP ribose-mediated Ca super(2+) signaling in mediating endothelial nitric oxide production in bovine coronary arteries

• Published in: American Journal of Physiology: Cell Physiology 2006-03, Vol.290 (3), p.H1172-H1181
• Main Authors: Zhang, Guo, Teggatz, Eric G, Zhang, Andrew Y, Koeberl, Matthew J, Yi, Fan, Chen, Li, Li, Pin-Lan
• Format: Article
• Language: English
• ISSN: 0363-6143; 1522-1563

The present study tested the hypothesis that cyclic ADP ribose (cADPR) serves as a novel second messenger to mediate intracellular Ca super(2+) 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 concentration-dependent vasodilation was significantly attenuated by 8-bromo-cADPR (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 super(2+) transient and nitric oxide (NO) levels in the intact coronary arterial endothelium preparation, 8-bromo-cADPR (30 mu M), ryanodine (50 mu M), and nicotinamide (6 mM) substantially attenuated BK (1 mu M)-induced increase in intracellular [Ca super(2+)] by 78%, 80%, and 74%, respectively, whereas these compounds significantly blocked BK-induced NO increase by about 80%, and inositol 1,4,5-trisphosphate receptor blockade with 2-aminethoxydiphenyl borate (50 mu M) only blunted BK-induced Ca super(2+)-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 beta -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 super(2+) signaling mechanism in CAECs.