title: Selective inhibitors of cardiac ADPR cyclase as novel anti-arrhythmic compounds.
abstract: ADP-ribosyl cyclases (ADPRCs) catalyse the conversion of nicotinamide adenine dinucleotide to cyclic adenosine diphosphoribose (cADPR) which is a second messenger involved in Ca(2+) mobilisation from intracellular stores. Via its interaction with the ryanodine receptor Ca(2+) channel in the heart, cADPR may exert arrhythmogenic activity. To test this hypothesis, we have studied the effect of novel cardiac ADPRC inhibitors in vitro and in vivo in models of ventricular arrhythmias. Using a high-throughput screening approach on cardiac sarcoplasmic reticulum membranes isolated from pig and rat and nicotinamide hypoxanthine dinuleotide as a surrogate substrate, we have identified potent and selective inhibitors of an intracellular, membrane-bound cardiac ADPRC that are different from the two known mammalian ADPRCs, CD38 and CD157/Bst1. We show that two structurally distinct cardiac ADPRC inhibitors, SAN2589 and SAN4825, prevent the formation of spontaneous action potentials in guinea pig papillary muscle in vitro and that compound SAN4825 is active in vivo in delaying ventricular fibrillation and cardiac arrest in a guinea pig model of Ca(2+) overload-induced arrhythmia. Inhibition of cardiac ADPRC prevents Ca(2+) overload-induced spontaneous depolarizations and ventricular fibrillation and may thus provide a novel therapeutic principle for the treatment of cardiac arrhythmias.
authors.affiliation: Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, G877, 65926 Frankfurt am Main, Germany. aimo.kannt@sanofi.com
authors.forename: Aimo
authors.initials: A
authors.lastname: Kannt
authors.forename: Kerstin
authors.initials: K
authors.lastname: Sicka
authors.forename: Katja
authors.initials: K
authors.lastname: Kroll
authors.forename: Dieter
authors.initials: D
authors.lastname: Kadereit
authors.forename: Heinz
authors.initials: H
authors.lastname: Gögelein
mesh_terms: D036541:ADP-ribosyl Cyclase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002118:Calcium / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000502:physiology; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D066298:In Vitro Techniques; D009206:Myocardium / Q000201:enzymology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D051381:Rats; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000502:physiology; D013552:Swine; D014693:Ventricular Fibrillation / Q000188:drug therapy / Q000503:physiopathology
chemical_list: D000889:Anti-Arrhythmia Agents; D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D006576:Heterocyclic Compounds, 4 or More Rings; C575193:SAN2589; C575194:SAN4825; D036541:ADP-ribosyl Cyclase; D002118:Calcium