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1 Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA, USA
2 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 was designed to determine the production of nicotinic acid adenine dinucleotide phosphate (NAADP) and its role associated with lysosomes in mediating endothelin-1 (ET-1)-induced vasoconstriction in coronary arteries. HPLC assay showed that NAADP was produced in coronary arterial smooth muscle cells (CASMCs) via endogenous ADP-ribosyl cyclase. Fluorescence microscopic analysis of [Ca2+]i in CASMCs revealed that exogenous 100 nM NAADP increased [Ca2+]i by 711 ± 47 nM. Lipid bilayer experiments, however, demonstrated that NAADP did not directly activate ryanodine receptor Ca2+ (RyR/Ca2+)release channels on the sarcoplasmic reticulum (SR). In CASMCs pretreated with 100 nM bafilomycin A1 (Baf), an inhibitor of lysosomal Ca2+ release and vacuolar proton pump function, NAADP-induced [Ca2+]i increase was significantly abolished. Moreover, ET-1 significantly increased NAADP formation in CASMCs and resulted in rise of [Ca2+]i in these cells with a large increase in global Ca2+ level of 1815 ± 84 nM. Before this large Ca2+ increase, interestingly, a small Ca2+ spike with an increase in [Ca2+]i of 529 ± 32 nM was observed. In the presence of Baf (100 nM), this ET-1-induced two-phase [Ca2+]i response was completely abolished, while Rya (50µM) only markedly blocked the ET-1-induced large global Ca2+ increase. Functional studies showed that 100 nM Baf significantly attenuated ET-1-induced maximal constriction from 82.26 ± 4.42 to 51.80 ± 4.36 %. Our results suggest that a lysosome-mediated Ca2+ regulatory mechanism via NAADP contributes to ET-1-induced Ca2+ mobilization in CASMCs and consequent vasoconstriction of coronary arteries.
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