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

Kannt A, Sicka K, Kroll K, Kadereit D, Gögelein H - Naunyn Schmiedebergs Arch. Pharmacol. (2012)

Bottom Line: Via its interaction with the ryanodine receptor Ca(2+) channel in the heart, cADPR may exert arrhythmogenic activity.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.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.

View Article: PubMed Central - PubMed

Affiliation: Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, G877, 65926 Frankfurt am Main, Germany. aimo.kannt@sanofi.com

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.

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Representative experimental traces showing the generation of spontaneous action potentials in guinea pig papillary muscle after high-frequency pacing. At t = 0, electrical stimulation was switched off. a Vehicle control and b 3 μM SAN4825
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Fig5: Representative experimental traces showing the generation of spontaneous action potentials in guinea pig papillary muscle after high-frequency pacing. At t = 0, electrical stimulation was switched off. a Vehicle control and b 3 μM SAN4825

Mentions: Out of the potent and selective inhibitors of cardiac ADPR cyclase identified in the experiments described above, the two structurally distinct compounds SAN4825 and SAN2589 were selected for further characterisation in models of ventricular arrhythmia. First, both compounds were tested for their ability to prevent the occurrence of spontaneous action potentials in guinea pig papillary muscle cells following high-frequency electrical stimulation. Representative traces are shown in Fig. 5; the results of the study are summarised in Fig. 6. At 3 μM, SAN4825 significantly reduced the number of delayed after depolarisations within 6 s following rapid pacing from 13.1 ± 2.7 to 2.9 ± 1.9 (n = 10 each, p = 0.004). With vehicle only, the number of spontaneous action potentials was equal to or above 11 in seven out of ten experiments whereas addition of SAN4825 reduced the number of spontaneous electrical activities to equal to or below three in nine out of ten experiments. There was no difference in membrane potential (−81.5 ± 5.3 mV for vehicle versus −77.6 ± 10.2 mV for SAN4825)Fig. 5


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

Kannt A, Sicka K, Kroll K, Kadereit D, Gögelein H - Naunyn Schmiedebergs Arch. Pharmacol. (2012)

Representative experimental traces showing the generation of spontaneous action potentials in guinea pig papillary muscle after high-frequency pacing. At t = 0, electrical stimulation was switched off. a Vehicle control and b 3 μM SAN4825
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3367138&req=5

Fig5: Representative experimental traces showing the generation of spontaneous action potentials in guinea pig papillary muscle after high-frequency pacing. At t = 0, electrical stimulation was switched off. a Vehicle control and b 3 μM SAN4825
Mentions: Out of the potent and selective inhibitors of cardiac ADPR cyclase identified in the experiments described above, the two structurally distinct compounds SAN4825 and SAN2589 were selected for further characterisation in models of ventricular arrhythmia. First, both compounds were tested for their ability to prevent the occurrence of spontaneous action potentials in guinea pig papillary muscle cells following high-frequency electrical stimulation. Representative traces are shown in Fig. 5; the results of the study are summarised in Fig. 6. At 3 μM, SAN4825 significantly reduced the number of delayed after depolarisations within 6 s following rapid pacing from 13.1 ± 2.7 to 2.9 ± 1.9 (n = 10 each, p = 0.004). With vehicle only, the number of spontaneous action potentials was equal to or above 11 in seven out of ten experiments whereas addition of SAN4825 reduced the number of spontaneous electrical activities to equal to or below three in nine out of ten experiments. There was no difference in membrane potential (−81.5 ± 5.3 mV for vehicle versus −77.6 ± 10.2 mV for SAN4825)Fig. 5

Bottom Line: Via its interaction with the ryanodine receptor Ca(2+) channel in the heart, cADPR may exert arrhythmogenic activity.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.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.

View Article: PubMed Central - PubMed

Affiliation: Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, G877, 65926 Frankfurt am Main, Germany. aimo.kannt@sanofi.com

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.

Show MeSH
Related in: MedlinePlus