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Articles in PresS, published online ahead of print November 29, 2001
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00736.2001
Submitted on August 17, 2001
Accepted on November 21, 2001
1 Pharmacology & Toxicology and Physiology, Medical College of Wisconsin, Milwaukee, WI, USA
* To whom correspondence should be addressed. E-mail: pli{at}mcw.edu.
We have recently reported that cyclic ADP-ribose (cADPR) and ADP-ribose (ADPR) play an important role in the regulation of the 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. Using HPLC analysis, 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 nmol/min/mg to 3.4 ± 0.3 nmol/min/mg protein by 11,12-EET. By Western blot analysis, a 42 kDa protein was recognized by a monoclonal antibody against CD38 protein in smooth muscle cells. The removal of CD38 by immunoprecipitation significantly decreased the basal enzyme activity and completely abolished 11,12-EET-induced activation of NAD glycohydrolase. Using cell-attached patch clamp method, 11,12-EET (100 nM) increase 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 inhibitions 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.
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