TITLE

Selective inhibitors of cardiac ADPR cyclase as novel anti-arrhythmic compounds

AUTHOR(S)
Kannt, Aimo; Sicka, Kerstin; Kroll, Katja; Kadereit, Dieter; Gögelein, Heinz
PUB. DATE
July 2012
SOURCE
Naunyn-Schmiedeberg's Archives of Pharmacology;Jul2012, Vol. 385 Issue 7, p717
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
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 mobilisation from intracellular stores. Via its interaction with the ryanodine receptor Ca 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 overload-induced arrhythmia. Inhibition of cardiac ADPRC prevents Ca overload-induced spontaneous depolarizations and ventricular fibrillation and may thus provide a novel therapeutic principle for the treatment of cardiac arrhythmias.
ACCESSION #
76339073

 

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