Effects of SEA0400, a Na+/Ca2+ exchange inhibitor, on ventricular arrhythmias in the in vivo dogs

Nagasawa, Yoshinori; Zhu, Bing-Mei; Chen, Jianguang; Kamiya, Kazunori; Miyamoto, Shigeki; Hashimoto, Keitaro

doi:10.1016/j.ejphar.2004.11.011

Cited by 37 publications

(29 citation statements)

References 25 publications

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“…This provides pharmacological evidence that NCX plays a crucial role in ouabain-induced arrhythmogenesis. It was also reported that SEA0400 attenuated ouabain-induced arrhythmia in a canine in vivo model (18) and in isolated Purkinje fibers (24). The effect of SEA0400 on other types of arrhythmia has also been investigated.…”

Section: Discussionmentioning

confidence: 99%

“…Concerning the action of cardiac glycosides, inhibition by SEA0400 of digitalis-induced arrhythmias in canine models was reported (18), but the mechanisms of cardiac glycoside-induced inotropy and arrhythmogenesis has not been examined in the isolated working myocardium with this selective inhibitor. The present study was performed to obtain pharmacological evidence for the involvement of NCX in cardiac glycosideinduced inotropy and arrhythmogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Involvement of the Na+/Ca2+ Exchanger in Ouabain-Induced Inotropy and Arrhythmogenesis in Guinea-Pig Myocardium as Revealed by SEA0400

et al. 2007

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Abstract. Involvement of the Na + / Ca 2+ exchanger in ouabain-induced inotropy and arrhythmogenesis was examined with a specific inhibitor, SEA0400. In right ventricular papillary muscle isolated from guinea-pig ventricle, 1 µM SEA0400, which specifically inhibits the Naexchanger by 80%, reduced the ouabain (1 µM)-induced positive inotropy by 40%, but had no effect on the inotropy induced by 100 µM isobutyl methylxantine. SEA0400 significantly inhibited the contracture induced by low Na + solution. In HEK293 cells expressing the Naexchanger, 1 µM ouabain induced an increase in intracellular Ca 2+, which was inhibited by SEA0400. The arrhythmic contractions induced by 3 µM ouabain were significantly reduced by SEA0400. These results provide pharmacological evidence that the Na2+ exchanger is involved in ouabain-induced inotropy and arrhythmogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Involvement of the Na+/Ca2+ Exchanger in Ouabain-Induced Inotropy and Arrhythmogenesis in Guinea-Pig Myocardium as Revealed by SEA0400

et al. 2007

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“…SN-6 protects against cardiac ischemia / reperfusion injury and also acts as an oxygen radical scavenger (73). On the other hand, SEA0400 and KB-R7943 do not reduce significantly mortality from ischemia / reperfusion injury, ouabain-induced arrhythmia, and coronary reperfusion-induced arrhythmia (71,74). Further studies are necessary to establish NCX inhibitors as therapeutic agents.…”

Section: Discussionmentioning

confidence: 99%

Topics on the Na+/Ca2+ Exchanger: Pharmacological Characterization of Na+/Ca2+ Exchanger Inhibitors

2006

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Abstract. Using the whole-cell voltage clamp, we examined acute effects of various agents on Na + / Ca 2+ exchange current (I NCX ) in guinea-pig cardiac ventricular cells and transfected cells. Among the antiarrhythmic drugs, amiodarone, bepridil, dronedarone, cibenzoline, azimilide, and aprindine inhibited I NCX in a concentration-dependent manner. We also investigated the effects on NCX of 2,3-buanedione monoxim (BDM) and selective NCX inhibitors such as KB-R7943, SEA0400, and SN-6. The presence of trypsin in the pipette solution attenuated the inhibitory effects on NCX of amiodarone, bepridil, and BDM, suggesting that these drugs inhibit NCX from the cytosolic side. In contrast, the trypsin-insensitive NCX inhibitors were aprindine, azimilide, dronedarone, cibenzoline, KB-R7943, SEA0400, and SN-6. KB-R7943, SEA0400, and SN-6 suppressed the uni-directional outward I NCX more potently than the uni-directional inward I NCX . The mechanism of this mode-dependency is unknown, but is suggested to be related to intracellular Na + concentration.

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“…Experimental data on the antiarrhythmic effects of SEA0400 are sparse and contradictory, although mostly positive [47][48][49][50], while similar data for ORM-10103 have become available only very recently [41,51,52]. SEA0400 has a moderate inhibitory effect on the L-type Ca 2+ channels [40], while ORM-10103 has a minor effect on IKr; neither of these pleiotropic effects could substantially modulate the observed antiarrhythmic efficacy of the NCX inhibition.…”

Section: Regional Ischaemiamentioning

confidence: 99%

“…Recent experimental data demonstrate that these pathological processes are tightly linked to the abnormal activities of two vital sarcolemmal ion transporters, the Na [57,58]. In the majority of related experimental studies, the inhibition of one of these transporters could reduce the incidence and/or severity of ventricular arrhythmias [32,33,49,59,60]. Therefore, restoring the normal levels of their activities via pharmacological intervention is generally considered a highly feasible therapeutic strategy to prevent, or at least substantially reduce, reperfusioninduced arrhythmogenesis.…”

Section: Rationalementioning

confidence: 99%

Prevention of intracellular calcium overload by blocking NCX

Szepesi¹

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b.) Conference presentations related to PhD topic Szepesi J, Sebők Zs, Tóth A Effect of NCX and NHE inhibition on the development and duration of postischemic arrhythmias (NCX és NHEgátlás hatása posztiszkémiás aritmiák kialakulására és időtartamára) CARDIOLOGIA HUNGARICA 42:(Suppl.A) p. A37. (2012) Szepesi J The effect of combined NCX1 and NHE1 blockade in acute ischemia/reperfusion injury in rat SEMINAR FOR YOUNG RESEARCHERS The physiology, pathophysiology and pharmacology of the cardiovascular system (2012) Posters Szepesi J The effect of NCX and NHE inhibition on the development and duration of post-ischemic arrhythmias  Sudden Cardiac Death & Cardioprotection conference and advanced workshop (2012) EHRA .......................................................................................................................... 51 10 ACKNOLEDGEMENTS ..............................................................................................

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Effects of SEA0400, a Na+/Ca2+ exchange inhibitor, on ventricular arrhythmias in the in vivo dogs

Cited by 37 publications

References 25 publications

Involvement of the Na+/Ca2+ Exchanger in Ouabain-Induced Inotropy and Arrhythmogenesis in Guinea-Pig Myocardium as Revealed by SEA0400

Involvement of the Na+/Ca2+ Exchanger in Ouabain-Induced Inotropy and Arrhythmogenesis in Guinea-Pig Myocardium as Revealed by SEA0400

Topics on the Na+/Ca2+ Exchanger: Pharmacological Characterization of Na+/Ca2+ Exchanger Inhibitors

Prevention of intracellular calcium overload by blocking NCX

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