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1 Department of Pharmacology and Toxicology, Medical College of Virginia, Richmond, VA, USA; Research Center of Experimental Medicine, Guangxi Autonumous Region People Hospital, Nanning, Guangxi, China; Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA
2 Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA
3 Department of Pharmacology and Toxicology, Medical College of Virginia, Richmond, VA, USA
4 Department of Pharmacology and Toxicology, Medical College of Virginia, Richmond, VA, USA; Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA
* To whom correspondence should be addressed. E-mail: pli{at}mail1.vcu.edu.
The present study tested the hypothesis that cADP-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-dependant 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 [Ca2+]i by 78%, 80% and 74%, respectively, while these compounds significantly blocked BK-induced NO increase by about 80%, whereas IP3 receptor blockade with 2-APB (50 µM) only blunted BK-induced Ca2+-NO signaling by about 30%. Using cADPR cycling assay, it was found that inhibition of ADP- ribosylcyclase by nicotinamide substantially blocked BK-induced intracellular cADPR production. Furthermore, HPLC analysis showed that the conversion rate of 
-NGD into cyclic GDP ribose dramatically increased by stimulation with BK, which was blockable by nicotinamide. However, U73122, a phospholipase C inhibitor, had no effect on this BK-induced increase in ADP-ribosylcyclase activity for cADPR production. In conclusion, these results suggest that cADPR importantly contributes to BK- and A23187-induced NO production and vasodilator response in coronary arteries through its Ca2+ signaling mechanism in CAECs.
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