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This Article Full Text Full Text (PDF) All Versions of this Article: 290/3/H1172    most recent 00441.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Zhang, G. Articles by Li, P.-L. Search for Related Content PubMed PubMed Citation Articles by Zhang, G. Articles by Li, P.-L.

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

¹Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia; ²Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin; and ³Research Center of Experimental Medicine, Guangxi Autonumous Region People's Hospital, Nanning, Guangxi, People's Republic of China

Submitted 2 May 2005 ; accepted in final form 19 October 2005

The present study tested the hypothesis that cyclic ADP ribose (cADPR) serves as a novel second messenger to mediate intracellular Ca²⁺ 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, Ca²⁺ transient and nitric oxide (NO) levels in the intact coronary arterial endothelium preparation, 8-bromo-cADPR (30 µM), ryanodine (50 µM), and nicotinamide (6 mM) substantially attenuated BK (1 µM)-induced increase in intracellular [Ca²⁺] 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 µM) only blunted BK-induced Ca²⁺-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 Ca²⁺ signaling mechanism in CAECs.

nucleotide; vasodilation; endothelium; endothelium-derived relaxing factor

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