Enhanced production and action of cyclic ADP-ribose during oxidative stress in small bovine coronary arterial smooth muscle.
Recent studies in our lab and by others have indicated that cyclic ADP-ribose (cADPR) as a novel second messenger is importantly involved in vasomotor response in various vascular beds. However, the mechanism regulating cADPR production and actions remains poorly understood. The present study determined whether changes in redox status influence the production and action of cADPR in coronary arterial smooth muscle cells (CASMCs) and thereby alters vascular tone in these arteries. HPLC analyses demonstrated that xanthine (X, 40 microM)/xanthine oxidase (XO, 0.1 U/ml), a superoxide-generating system, increased the ADP-ribosyl cyclase activity by 59% in freshly isolated bovine CASMCs. However, hydrogen peroxide (H2O2, 1-100 microM) had no significant effect on ADP-ribosyl cyclase activity. In these CASMCs, X/XO produced a rapid increase in [Ca2+]i (Delta[Ca2+]i=201 nM), which was significantly attenuated by a cADPR antagonist, 8-Br-cADPR. Both inhibition of cADPR production by nicotinamide (Nicot) and blockade of Ca2+-induced Ca2+ release (CICR) by tetracaine (TC) and ryanodine (Rya) significantly reduced X/XO-induced rapid Ca2+ responses. In isolated, perfused, and pressurized small bovine coronary arteries, X at 2.5-80 microM with a fixed XO level produced a concentration-dependent vasoconstriction with a maximal decrease in arterial diameter of 45%. This X/XO-induced vasoconstriction was significantly attenuated by 8-Br-cADPR, Nicot, TC, or Rya. We conclude that superoxide activates cADPR production, and thereby mobilizes intracellular Ca2+ from the SR and produces vasoconstriction in coronary arteries.
Zhang
Andrew Y
AY
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Yi
Fan
F
Teggatz
Eric G
EG
Zou
Ai-Ping
AP
Li
Pin-Lan
PL
D036541:ADP-ribosyl Cyclase / Q000378:metabolism; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D002417:Cattle; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism*; D036563:Cyclic ADP-Ribose / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D009536:Niacinamide / Q000494:pharmacology; D018384:Oxidative Stress; D012433:Ryanodine / Q000494:pharmacology; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology*; D013481:Superoxides / Q000378:metabolism; D013748:Tetracaine / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014969:Xanthine Oxidase / Q000378:metabolism
C493642:8-bromo-cyclic-ADP-ribose; D013748:Tetracaine; D013481:Superoxides; D036563:Cyclic ADP-Ribose; D012433:Ryanodine; D009536:Niacinamide; D006861:Hydrogen Peroxide; D014969:Xanthine Oxidase; D036541:ADP-ribosyl Cyclase