title: Inhibition of cADP-ribose formation produces vasodilation in bovine coronary arteries.
abstract: cADP-ribose (cADPR) induces the release of Ca(2+) from the intracellular stores of coronary artery smooth muscle cells. However, little is known about the role of cADPR-mediated intracellular Ca(2+) release in the control of vascular tone. The present study examined the effects of nicotinamide, a specific inhibitor of ADP-ribosylcyclase, on the vascular tone of bovine coronary arteries. A bovine coronary artery homogenate stimulated the conversion of nicotinamide guanine dinucleotide into cGDP-ribose, which is a measure of ADP-ribosylcyclase activity. Nicotinamide significantly inhibited the formation of cGDP-ribose in a concentration-dependent manner: at a concentration of 10 mmol/L, it reduced the conversion rate from 3.34+/-0.11 nmol. min(-1). mg(-1) of protein in control cells to 1.42+/-0.11 nmol. min(-1). mg(-1) of protein in treated cells, a 58% reduction. In U46619-precontracted coronary artery rings, nicotinamide produced concentration-dependent relaxation. Complete relaxation with nicotinamide occurred at a dose of 8 mmol/L; the median inhibitory concentration (IC(50)) was 1.7 mmol/L. In the presence of a cell membrane-permeant cADPR antagonist, 8-bromo-cADPR, nicotinamide-induced vasorelaxation was markedly attenuated. Pretreatment of the arterial rings with ryanodine (50 micromol/L) significantly blunted the vasorelaxation response to nicotinamide. However, iloprost- and adenosine-induced vasorelaxation was not altered by 8-bromo-cADPR. Moreover, nicotinamide significantly attenuated KCl- or Bay K8644-induced vasoconstriction by 60% and 70%, respectively. These results suggest that the inhibition of cADPR formation by nicotinamide produces vasorelaxation and blunts KCl- and Bay K8644-induced vasoconstriction in coronary arteries and that the cADPR-mediated Ca(2+) signaling pathway plays a role in the control of vascular tone in coronary circulation.
authors.affiliation: Departments of Pharmacology and Toxicology and Physiology, Medical College of Wisconsin, Milwaukee 53226, USA.
authors.forename: J
authors.initials: J
authors.lastname: Geiger
authors.forename: A P
authors.initials: AP
authors.lastname: Zou
authors.forename: W B
authors.initials: WB
authors.lastname: Campbell
authors.forename: P L
authors.initials: PL
authors.lastname: Li
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D036541:ADP-ribosyl Cyclase; D000241:Adenosine / Q000494:pharmacology; D000246:Adenosine Diphosphate Ribose / Q000031:analogs & derivatives / Q000096:biosynthesis* / Q000494:pharmacology; D000818:Animals; D002120:Calcium Channel Agonists / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology; D002417:Cattle; D003326:Coronary Circulation / Q000502:physiology; D003331:Coronary Vessels / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D036563:Cyclic ADP-Ribose / Q000031:analogs & derivatives*; D016285:Iloprost / Q000494:pharmacology; D009536:Niacinamide / Q000494:pharmacology; D019761:Phosphorus-Oxygen Lyases / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D012433:Ryanodine / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: C106570:7-deaza-8-bromo-cyclic ADP-ribose; D002120:Calcium Channel Agonists; D015220:Calcium Channels; D014665:Vasodilator Agents; D036563:Cyclic ADP-Ribose; D012433:Ryanodine; D000246:Adenosine Diphosphate Ribose; D009536:Niacinamide; D011189:Potassium Chloride; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D036541:ADP-ribosyl Cyclase; D019761:Phosphorus-Oxygen Lyases; D016285:Iloprost; D000241:Adenosine