12644723

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1

The present study determined the role of cyclic ADP-ribose (cADPR) in mediating vasoconstriction and Ca(2+) release in response to the activation of muscarinic receptors. Endothelium-denuded small bovine coronary arteries were microperfused under transmural pressure of 60 mm Hg. Both acetylcholine (ACh; 1 nmol/L to 1 micromol/L) and oxotremorine (OXO; 2.5-80 micromol/L) produced a concentration-dependent contraction. The vasoconstrictor responses to both ACh and OXO were significantly attenuated by nicotinamide (Nicot; an ADP-ribosyl cyclase inhibitor), 8-bromo-cADPR (8-Br-cADPR; a cADPR antagonist) or ryanodine (Ry; an Ry receptor antagonist). Intracellular Ca(2+) ([Ca(2+)](i)) was determined by fluorescence spectrometry using fura-2 as a fluorescence indicator. OXO produced a rapid increase in [Ca(2+)](i) in freshly isolated single coronary arterial smooth muscle cells (CASMCs) bathed with Ca(2+)-free Hanks' solution. This OXO-induced rise in [Ca(2+)](i) was significantly reduced by pirenzepine (PIR; an M(1) receptor-specific blocker), Nicot, 8-Br-cADPR or Ry. The effects of OXO on the activity of ADP-ribosyl cyclase (cADPR synthase) were examined in cultured CASMCs by measuring the rate of cyclic GDP- ribose (cGDPR) formation from beta-nicotinamide guanine dinucleotide. It was found that OXO produced a concentration-dependent increase in the production of cGDPR. The stimulatory effect of OXO on ADP-ribosyl cyclase was inhibited by both PIR and Nicot. These results suggest that the cADPR signaling pathway participates in the contraction of small coronary arterial smooth muscle and Ca(2+) release induced by activation of M(1) muscarinic receptors.

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pubmed-author:CampbellWilliam BWB, pubmed-author:ChenYa-FeiYF, pubmed-author:GeZhi-DongZD, pubmed-author:LiPin-LanPL, pubmed-author:YiFu-XianFX, pubmed-author:ZhangDavid XDX, pubmed-author:ZouAi-PingAP

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28-36

pubmed-meshheading:12644723-ADP-ribosyl Cyclase, pubmed-meshheading:12644723-Acetylcholine, pubmed-meshheading:12644723-Animals, pubmed-meshheading:12644723-Calcium, pubmed-meshheading:12644723-Calcium Channels, pubmed-meshheading:12644723-Cattle, pubmed-meshheading:12644723-Coronary Vessels, pubmed-meshheading:12644723-Cyclic ADP-Ribose, pubmed-meshheading:12644723-Endothelium, Vascular, pubmed-meshheading:12644723-Enzyme Inhibitors, pubmed-meshheading:12644723-Fluorescent Dyes, pubmed-meshheading:12644723-Fura-2, pubmed-meshheading:12644723-Inositol 1,4,5-Trisphosphate Receptors, pubmed-meshheading:12644723-Muscarinic Agonists, pubmed-meshheading:12644723-Muscle, Smooth, Vascular, pubmed-meshheading:12644723-Muscle Contraction, pubmed-meshheading:12644723-Niacinamide, pubmed-meshheading:12644723-Oxotremorine, pubmed-meshheading:12644723-Receptor, Muscarinic M1, pubmed-meshheading:12644723-Receptors, Cytoplasmic and Nuclear, pubmed-meshheading:12644723-Receptors, Muscarinic, pubmed-meshheading:12644723-Ryanodine, pubmed-meshheading:12644723-Ryanodine Receptor Calcium Release Channel, pubmed-meshheading:12644723-Spectrometry, Fluorescence, pubmed-meshheading:12644723-Vasoconstriction, pubmed-meshheading:12644723-Vasodilator Agents

Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee 53226, USA.