title: Cyclic ADP-ribose contributes to contraction and Ca2+ release by M1 muscarinic receptor activation in coronary arterial smooth muscle.
abstract: 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.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee 53226, USA.
authors.forename: Zhi-Dong
authors.initials: ZD
authors.lastname: Ge
authors.forename: David X
authors.initials: DX
authors.lastname: Zhang
authors.forename: Ya-Fei
authors.initials: YF
authors.lastname: Chen
authors.forename: Fu-Xian
authors.initials: FX
authors.lastname: Yi
authors.forename: Ai-Ping
authors.initials: AP
authors.lastname: Zou
authors.forename: William B
authors.initials: WB
authors.lastname: Campbell
authors.forename: Pin-Lan
authors.initials: PL
authors.lastname: Li
mesh_terms: D036541:ADP-ribosyl Cyclase / Q000037:antagonists & inhibitors; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels; D002417:Cattle; D003331:Coronary Vessels / Q000502:physiology*; D036563:Cyclic ADP-Ribose / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005456:Fluorescent Dyes; D016257:Fura-2; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018721:Muscarinic Agonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D009536:Niacinamide / Q000494:pharmacology; D010095:Oxotremorine / Q000494:pharmacology; D043643:Receptor, Muscarinic M1; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors; D011976:Receptors, Muscarinic / Q000502:physiology*; D012433:Ryanodine / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects; D013050:Spectrometry, Fluorescence; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D015220:Calcium Channels; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018721:Muscarinic Agonists; D043643:Receptor, Muscarinic M1; D018160:Receptors, Cytoplasmic and Nuclear; D011976:Receptors, Muscarinic; D019837:Ryanodine Receptor Calcium Release Channel; D014665:Vasodilator Agents; D036563:Cyclic ADP-Ribose; D012433:Ryanodine; D009536:Niacinamide; D010095:Oxotremorine; D036541:ADP-ribosyl Cyclase; D000109:Acetylcholine; D002118:Calcium; D016257:Fura-2