A novel antagonist, No. 7943, of the Na<sup>+</sup>/Ca<sup>2+</sup> exchange current in guinea‐pig cardiac ventricular cells

Watano, Tomokazu; Kimura, Junko; Morita, Tohru; Nakanishi, Hironori

doi:10.1111/j.1476-5381.1996.tb15708.x

Cited by 284 publications

(229 citation statements)

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“…Pharmacological treatments commonly used for blocking reverse NCX-mediated Ca 2ϩ uptake include the removal of external Ca 2ϩ (0 Ca 2ϩ ) and the addition of the isothiourea derivative KB-R7943 at low micromolar concentrations, which preferentially blocks the reverse mode of Ca 2ϩ uptake cata- lyzed by NCX1 (Iwamoto et al 1996;Watano et al 1996). The divalent cation Ni 2ϩ has also been shown to block Ca 2ϩ uptake via NCX1 and NCX2 with an IC 50 of ϳ50 M (Iwamoto and Shigekawa 1998).…”

Section: Resultsmentioning

confidence: 99%

Role of Na⁺/Ca²⁺exchanger in Ca²⁺homeostasis in rat suprachiasmatic nucleus neurons

Wang

Chen

Cheng

et al. 2015

Journal of Neurophysiology

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Wang YC, Chen YS, Cheng RC, Huang RC. Role of Na ϩ /Ca 2ϩ exchanger in Ca 2ϩ homeostasis in rat suprachiasmatic nucleus neurons. J Neurophysiol 113: 2114 -2126, 2015. First published January 7, 2015 doi:10.1152/jn.00404.2014 is critical to the central clock of the suprachiasmatic nucleus (SCN). However, the role of Na ϩ /Ca 2ϩ exchanger (NCX) in intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) homeostasis in the SCN is unknown. Here we show that NCX is an important mechanism for somatic Ca 2ϩ clearance in SCN neurons. In control conditions Na ϩ -free solution lowered [Ca 2ϩ ] i by inhibiting TTX-sensitive as well as nimodipine-sensitive Ca 2ϩ influx. With use of the Na ϩ ionophore monensin to raise intracellular Na ϩ concentration ([Na ϩ ] i ), Na ϩ -free solution provoked rapid Ca 2ϩ uptake via reverse NCX. The peak amplitude of 0 Na ϩ -induced [Ca 2ϩ ] i increase was larger during the day than at night, with no difference between dorsal and ventral SCN neurons. Ca 2ϩ extrusion via forward NCX was studied by determining the effect of Na ϩ removal on Ca 2ϩ clearance after high-K ϩ -induced Ca 2ϩ loads. The clearance of Ca 2ϩ proceeded with two exponential decay phases, with the fast decay having total signal amplitude of ϳ85% and a time constant of ϳ7 s. Na ϩ -free solution slowed the fast decay rate threefold, whereas mitochondrial protonophore prolonged mostly the slow decay. In contrast, blockade of plasmalemmal and sarco(endo)plasmic reticulum Ca 2ϩ pumps had little effect on the kinetics of Ca 2ϩ clearance. RT-PCR indicated the expression of NCX1 and NCX2 mRNAs. Immunohistochemical staining showed the presence of NCX1 immunoreactivity in the whole SCN but restricted distribution of NCX2 immunoreactivity in the ventrolateral SCN. Together our results demonstrate an important role of NCX, most likely NCX1, as well as mitochondrial Ca 2ϩ uptake in clearing somatic Ca 2ϩ after depolarization-induced Ca 2ϩ influx in SCN neurons. Ca 2ϩ homeostasis; Ca 2ϩ imaging; circadian rhythm; Na ϩ /Ca 2ϩ exchanger; suprachiasmatic nucleus

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Section: Resultsmentioning

confidence: 99%

Role of Na⁺/Ca²⁺exchanger in Ca²⁺homeostasis in rat suprachiasmatic nucleus neurons

Wang

Chen

Cheng

et al. 2015

Journal of Neurophysiology

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“…In 1996, Watano et al reported that KB-R7943 inhibits I NCX in a direction-dependent manner in guineapig ventricular myocytes (6). In this experiment, a unidirectional outward I NCX was induced by suddenly raising external Ca 2+ in the presence of Na + in the pipette solution, and a uni-directional inward I NCX was induced by suddenly raising external Na + in the presence of Ca 2+ in the pipette solution.…”

Section: Selective Benzyloxyphenyl Ncx Inhibitorsmentioning

confidence: 98%

“…4). KB-R7943 was developed by Kanebo as the first specific NCX inhibitor (5,6) and is now used as an experimental pharmacological tool (56). SEA0400 is the second and more potent NCX inhibitor than KB-R7943 developed by Taisho Pharmaceutical (7).…”

Section: Selective Benzyloxyphenyl Ncx Inhibitorsmentioning

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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“…A Ca 2ϩ -dependent inactivation of stretch-activated channel activity has been described (68), and activation of the delayed rectifier K ϩ current and of the Na ϩ /Ca 2ϩ exchanger is also regulated by intracellular Ca 2ϩ concentration (3,25,59). Thus, besides the effects of substances that block the stretch-activated channels, other substances can modulate the electrophysiological effects of stretch through different mechanisms that affect Ca 2ϩ handling by myocytes.The present study analyzed and compared the acceleration of ventricular fibrillation (VF) activation frequency produced by acute stretch (8) under the influence of three substances: the Na ϩ /Ca 2ϩ exchanger blocker 23,38,67), the ␤-blocker propranolol, and the adenosine A 2 receptor antagonist SCH-58261 (71). In relation to the first of these drugs, the inactivation of the Na ϩ /Ca 2ϩ exchanger results in a decrease in the slow force response to stretch and in the magnitude of Ca 2ϩ transients (69), although there is little information about its effects upon the electrophysiological modifications induced by stretch.…”

mentioning

confidence: 99%

Pharmacological modifications of the stretch-induced effects on ventricular fibrillation in perfused rabbit hearts

Chorro

Trapero²,

Such-Miquel

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Stretch induces modifications in myocardial electrical and mechanical activity. Besides the effects of substances that block the stretch-activated channels, other substances could modulate the effects of stretch through different mechanisms that affect Ca 2ϩ handling by myocytes. Thirty-six Langendorff-perfused rabbit hearts were used to analyze the effects of the Na ϩ /Ca 2ϩ exchanger blocker KB-R7943, propranolol, and the adenosine A 2 receptor antagonist SCH-58261 on the acceleration of ventricular fibrillation (VF) produced by acute myocardial stretching. VF recordings were obtained with two epicardial multiple electrodes before, during, and after local stretching in four experimental series: control (n ϭ 9), KB-R7943 (1 M, n ϭ 9), propranolol (1 M, n ϭ 9), and SCH-58261 (1 M, n ϭ 9). Both the Na ϩ /Ca 2ϩ exchanger blocker KB-R7943 and propranolol induced a significant reduction (P Ͻ 0.001 and P Ͻ 0.05, respectively) in the dominant frequency increments produced by stretching with respect to the control and SCH-58261 series (control ϭ 49.9%, SCH-58261 ϭ 52.1%, KB-R7943 ϭ 9.5%, and propranolol ϭ 12.5%). The median of the activation intervals, the functional refractory period, and the wavelength of the activation process during VF decreased significantly under stretch in the control and SCH-58261 series, whereas no significant variations were observed in the propranolol and KB-R7943 series, with the exception of a slight but significant decrease in the median of the fibrillation intervals in the KB-R7943 series. KB-R7943 and propranolol induced a significant reduction in the activation maps complexity increment produced by stretch with respect to the control and SCH-58261 series. In conclusion, the electrophysiological effects responsible for stretch-induced VF acceleration in the rabbit heart are reduced by the Na ϩ /Ca 2ϩ exchanger blocker KB-R7943 and by propranolol but not by the adenosine A2 receptor antagonist SCH-58261. cardiac electrophysiology; mechanical stretch; Fourier analysis STRETCH induces the modulation of electrical and mechanical activity in myocytes. The modulation of electrical activity, also referred to as mechanoelectrical feedback (14,35), includes the depolarization of the resting potential (2,17,21,27,28,31,70), alterations of the shape and duration of action potentials (3,11,21,27,28,31,47,57,70), changes in refractoriness (4,7,9,11,27,36,47,48), and the induction of afterdepolarizations (16,18,34). These electrophysiological changes have been related to the generation of different types of cardiac arrhythmias (7, 9, 13-15, 24, 26, 35, 40, 47). The mechanical effects of stretch consist of an immediate and slow increase in force (45, 64), involving changes in myofilament Ca 2ϩ sensitivity, in the concentrations of intracellular Ca 2ϩ , and in the magnitude of Ca 2ϩ transients (1,3,29,33,58,69). These changes have been related to several mechanisms, including the actions of 1) endogenous angiotensin II (1, 46); 2) the Na ϩ /H ϩ exchanger (1, 3, 46, 66); 3) the Na ϩ /Ca 2ϩ exchanger (3,...

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A novel antagonist, No. 7943, of the Na⁺/Ca²⁺ exchange current in guinea‐pig cardiac ventricular cells

Abstract: other currents as a competitive inhibitor with external Ca2+. This effect is in contrast to DCB which preferentially inhibits the inward rather than the outward Na+/Ca2+ exchange current.

Cited by 284 publications

References 38 publications

Role of Na⁺/Ca²⁺exchanger in Ca²⁺homeostasis in rat suprachiasmatic nucleus neurons

Role of Na⁺/Ca²⁺exchanger in Ca²⁺homeostasis in rat suprachiasmatic nucleus neurons

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

Pharmacological modifications of the stretch-induced effects on ventricular fibrillation in perfused rabbit hearts

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A novel antagonist, No. 7943, of the Na+/Ca2+ exchange current in guinea‐pig cardiac ventricular cells

Abstract: other currents as a competitive inhibitor with external Ca2+. This effect is in contrast to DCB which preferentially inhibits the inward rather than the outward Na+/Ca2+ exchange current.

Cited by 284 publications

References 38 publications

Role of Na+/Ca2+exchanger in Ca2+homeostasis in rat suprachiasmatic nucleus neurons

Role of Na+/Ca2+exchanger in Ca2+homeostasis in rat suprachiasmatic nucleus neurons

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

Pharmacological modifications of the stretch-induced effects on ventricular fibrillation in perfused rabbit hearts

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A novel antagonist, No. 7943, of the Na⁺/Ca²⁺ exchange current in guinea‐pig cardiac ventricular cells

Role of Na⁺/Ca²⁺exchanger in Ca²⁺homeostasis in rat suprachiasmatic nucleus neurons

Role of Na⁺/Ca²⁺exchanger in Ca²⁺homeostasis in rat suprachiasmatic nucleus neurons