![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
|
|
|
|
|
||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Received for publication April 30, 2004.
Revised June 30, 2004.
Accepted for publication July 1, 2004.
SEA0400 (2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline) has recently been described as a potent and selective inhibitor of Na+-Ca2+ exchange in cardiac, neuronal, and renal preparations. The inhibitory effects of SEA0400 were investigated on the cloned cardiac Na+-Ca2+ exchanger, NCX1.1, expressed in Xenopus laevis oocytes to gain insight into its inhibitory mechanism. Na+-Ca2+ exchange currents were measured using the giant excised patch technique using conditions to evaluate both inward and outward currents. SEA0400 inhibited outward Na+-Ca2+ exchange currents with high affinity (IC50's = 78 ± 15 nM and 23 ± 4 nM for peak and steady state currents, respectively). Considerably less inhibitory potency (i.e., µM) was observed for inward currents. The inhibitory profile was re-examined after proteolytic treatment of excised patches with 
-chymotrypsin, a procedure that eliminates ionic regulatory mechanisms. After this treatment, an IC50 value of 1.2 ± 0.6 µM was estimated for outward currents, whereas inward currents became almost insensitive to SEA0400. The inhibitory effects of SEA0400 on outward exchange currents were evident at both high and low concentrations of regulatory Ca2+, although distinct features were noted. SEA0400 accelerated the inactivation rate of outward currents. Based on paired pulse experiments, SEA0400 altered the recovery of exchangers from the Na+i-dependent inactive state, particularly at higher regulatory Ca2+i concentrations. Finally, the inhibitory potency of SEA0400 was strongly dependent on the intracellular Na+ concentration. Our data confirm that SEA0400 is the most potent inhibitor of the cardiac Na+-Ca2+ exchanger described to date and provide a reasonable explanation for its apparent transport mode selectivity.
Key words:
SEA0400, giant excised patch, inhibition, ionic regulation, mode selectivity, sodium calcium exchange
This article has been cited by other articles:
|
|
 |
|
  G. Antoons and K. R. Sipido Targeting calcium handling in arrhythmias Europace, December 1, 2008; 10(12): 1364 - 1369. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Hryshko What regulates Na+/Ca2+ exchange? Focus on "Sodium-dependent inactivation of sodium/calcium exchange in transfected Chinese hamster ovary cells" Am J Physiol Cell Physiol, October 1, 2008; 295(4): C869 - C871. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Ozdemir, V. Bito, P. Holemans, L. Vinet, J.-J. Mercadier, A. Varro, and K. R. Sipido Pharmacological Inhibition of Na/Ca Exchange Results in Increased Cellular Ca2+ Load Attributable to the Predominance of Forward Mode Block Circ. Res., June 6, 2008; 102(11): 1398 - 1405. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Savelieva and J. Camm Anti-arrhythmic drug therapy for atrial fibrillation: current anti-arrhythmic drugs, investigational agents, and innovative approaches Europace, June 1, 2008; 10(6): 647 - 665. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Birinyi, A. Toth, I. Jona, K. Acsai, J. Almassy, N. Nagy, J. Prorok, I. Gherasim, Z. Papp, Z. Hertelendi, et al. The Na+/Ca2+ exchange blocker SEA0400 fails to enhance cytosolic Ca2+ transient and contractility in canine ventricular cardiomyocytes Cardiovasc Res, June 1, 2008; 78(3): 476 - 484. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. P. Sergeant, M. A. Hollywood, N. G. McHale, and K. D. Thornbury Ca2+ signalling in urethral interstitial cells of Cajal J. Physiol., November 1, 2006; 576(3): 715 - 720. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Bradley, M. A. Hollywood, L. Johnston, R. J. Large, T. Matsuda, A. Baba, N. G. McHale, K. D. Thornbury, and G. P. Sergeant Contribution of reverse Na+-Ca2+ exchange to spontaneous activity in interstitial cells of Cajal in the rabbit urethra J. Physiol., August 1, 2006; 574(3): 651 - 661. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Iwamoto Vascular Na+/Ca2+ exchanger: implications for the pathogenesis and therapy of salt-dependent hypertension Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2006; 290(3): R536 - R545. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Dipolo and L. Beauge Sodium/Calcium Exchanger: Influence of Metabolic Regulation on Ion Carrier Interactions Physiol Rev, January 1, 2006; 86(1): 155 - 203. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Beauge and R. DiPolo SEA-0400, a potent inhibitor of the Na+/Ca2+ exchanger, as a tool to study exchanger ionic and metabolic regulation Am J Physiol Cell Physiol, June 1, 2005; 288(6): C1374 - C1380. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
