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Am J Physiol Heart Circ Physiol 282: H1229-H1236, 2002. First published November 29, 2001; doi:10.1152/ajpheart.00736.2001
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Vol. 282, Issue 4, H1229-H1236, April 2002

Role of ADP-ribose in 11,12-EET-induced activation of KCa channels in coronary arterial smooth muscle cells

Pin-Lan Li, David X. Zhang, Zhi-Dong Ge, and William B. Campbell

Departments of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

We recently reported that cADP-ribose (cADPR) and ADP-ribose (ADPR) play an important role in the regulation of the Ca2+-activated K+ (KCa) channel activity in coronary arterial smooth muscle cells (CASMCs). The present study determined whether these novel signaling nucleotides participate in 11,12-epoxyeicosatrienoic acid (11,12-EET)-induced activation of the KCa channels in CASMCs. HPLC analysis has shown that 11,12-EET increased the production of ADPR but not the formation of cADPR. The increase in ADPR production was due to activation of NAD glycohydrolase as measured by a conversion rate of NAD into ADPR. The maximal conversion rate of NAD into ADPR in coronary homogenate was increased from 2.5 ± 0.2 to 3.4 ± 0.3 nmol · min-1 · mg protein-1 by 11,12-EET. The regioisomers of 8,9-EET, 11,12-EET, and 14,15-EET also significantly increased ADPR production from NAD. Western blot analysis and immunoprecipitation demonstrated the presence of NAD glycohydrolase, which mediated 11,12-EET-activated production of ADPR. In cell-attached patches, 11,12-EET (100 nM) increases KCa channel activity by 5.6-fold. The NAD glycohydrolase inhibitor cibacron blue 3GA (3GA, 100 µM) significantly attenuated 11,12-EET-induced increase in the KCa channel activity in CASMCs. However, 3GA had no effect on the KCa channels activity in inside-out patches. 11,12-EET produced a concentration-dependent relaxation of precontracted coronary arteries. This 11,12-EET-induced vasodilation was substantially attenuated by 3GA (30 µM) with maximal inhibition of 57%. These results indicate that 11,12-EET stimulates the production of ADPR and that intracellular ADPR is an important signaling molecule mediating 11,12-EET-induced activation of the KCa channels in CASMCs and consequently results in vasodilation of coronary artery.

nicotinamide adenine dinucleotide glycohydrolase; K+ channels; epoxyeicosatrienoic acid; endothelium-derived hyperpolarization factor


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