Cardioprotective effects of KB-R7943: a novel inhibitor of the reverse mode of Na⁺/Ca²⁺exchanger

Abstract

The novel inhibitor of the reverse mode of the Na+/Ca2+exchanger (NCE) KB-R7943 (KB) was tested in isolated rat cardiomyocytes exposed to 80 min of simulated ischemia [substrate-free anoxia, extracellular pH (pHo) of 6.4] and 15 min of reoxygenation (pHo 7.4). At pHo 6.4, 20 μmol/l KB was required for complete inhibition of the reverse mode of NCE. Treatment with 20 μmol/l KB only during anoxia did not influence the onset of rigor contracture and intracellular pH (pHi) (monitored with 2′,7′-bis(2-carboxyethyl)-5(6)-carboxyfluorescein) but significantly reduced the cytosolic accumulation of Ca2+ (monitored with fura 2) and Na+ (monitored with sodium-binding benzofuran isophthalate). During reoxygenation, cardiomyocytes developed hypercontracture. This was significantly reduced by anoxic KB treatment. To investigate this protection against reoxygenation-induced injury in the whole heart, we exposed Langendorff-perfused rat hearts to 110 min of anoxia (pHo 6.4) and 50 min of reoxygenation (pHo 7.4). Application of 20 μmol/l KB during anoxia significantly reduced the reoxygenation-induced enzyme release. We conclude that KB offers significant protection of cardiomyocytes against Ca2+ and Na+ overload during anoxia and hypercontracture or enzyme release on reoxygenation.

A quantitative model for linking Na+/Ca2+ exchanger to SERCA during refilling of the sarcoplasmic reticulum to sustain Fameli1, Breemen2, Kuo3 2007Cell Calcium

“…1B. These oscillations were abolished by the application of 10 µM KB-R7943, a NCX reverse-mode inhibitor [15]. We have previously shown that KB-R7943 is highly selective for the reverse mode of NCX in the rabbit IVC [16].…”

Hydroxyl Radical-Induced Acute Diastolic Dysfunction Is Due to Calcium Overload via Reverse-Mode Na + -Ca 2+ Exchange

“…Recently, the isothiourea derivative KB-R7943 has been shown to selectively inhibit the reverse mode of the Na ϩ -Ca 2ϩ exchanger. 38 KB-R7943 has been shown to prevent digitalis-induced calcium overload of cardiomyocytes 21 and was also effective in preventing reoxygenationinduced injury in cardiomyocytes 39 and isolated papillary muscles. 40 The data from the present study show that KB-R7943 could prevent hydroxyl radical-induced acute diastolic dysfunction.…”

Efficacy of selective NCX inhibition by ORM-10103 during simulated ischemia/reperfusion

“…In isolated rat cardiomyocytes exposed to simulated ischemia KB-R7943 reduced the [Ca 2 þ ] i overload and delayed the onset of the contracture (Ladilov et al, 1999). The raise in [Ca 2 þ ] i, induced by the removal of extracellular Na þ , was blocked by 90% in the presence of KB-R7943 (Tokuno et al, 2000).…”