kb-r7943 and Acute-Kidney-Injury

The Na+-Ca2+ exchange (NCX) system plays a pivotal role in regulating intracellular Ca2+ concentration in cardiomyocytes, neuronal cells, kidney and a variety of other cells. It performs a particularly important function in regulating cardiac contractility and electrical activity. One of the leading NCX inhibitors is KB-R9743 (KBR) that appears to exhibit selectivity for Ca2+-influx-mode NCX activity (reverse mode of NCX). In this article we reviewed pharmacology of KBR and provide a brief summary of studies with other NCX inhibitors, such as SEA0400 (SEA) and SN-6 (SN). Potential clinical usefulness of KBR and other NCX inhibitors is still controversial but the reviewed findings may be helpful in designing more selective and clinically useful NCX inhibitors for the treatment of cardiac, neuronal and kidney diseases.

Topics: Action Potentials; Acute Kidney Injury; Animals; Anti-Arrhythmia Agents; Humans; Reperfusion Injury; Sodium-Calcium Exchanger; Thiourea

The precise mechanisms underlying radiocontrast nephropathy (RCN) are not well understood. Intracellular Ca(2+) overload is considered to be a key factor in RCN. The Na(+)/Ca(2+) exchanger (NCX) system is one of the main pathways of intracellular Ca(2+) overload. We investigated whether intracellular Ca(2+) overload via the NCX system was involved in contrast-induced renal tubular cytotoxicity.. NRK-52E cells were exposed to ioversol (100 mg iodine/ml) for 4 h. KB-R7943 (inhibitor of reverse mode of NCX, 4 × 10(-5), 4 × 10(-6)M) was added 1 h before incubation with ioversol. Cell viability and permeability were determined by 3-(4,5-dimethyldiazol-2-yl)-2,5-diphenyl tetrazolium bromide and lactate dehydrogenase assay. Apoptosis was determined by flow cytometry. Intracellular Ca(2+) concentration ([Ca(2+)](i)] and reactive oxygen species (ROS) were detected by confocal microscopy. The expression of NCX1 mRNA and caspase-3 protein was evaluated by reverse transcription-polymerase chain reaction and Western blot, respectively.. Ioversol exposure induced significantly increased lactate dehydrogenase release and decreased 3-(4,5-dimethyldiazol-2-yl)-2,5-diphenyl tetrazolium bromide conversion in NRK-52E cells. Significantly increased apoptosis and caspase-3 protein expression were observed in the NRK-52E cells exposed to ioversol for 4 h. Ioversol treatment induced a significant increase in [Ca(2+)](i) and intracellular ROS. KB-R7943 dose-dependently and significantly suppressed the increase in [Ca(2+)](i), intracellular ROS and caspase-3 overexpression induced by ioversol and attenuated the contrast-induced NRK-52E cell apoptosis. No significant changes in NCX1 mRNA expression were observed following contrast exposure.. Intracellular Ca(2+) overload via the reverse mode of NCX, followed by ROS overproduction and caspase-3 overexpression played an important role in the contrast-induced renal tubular cytotoxicity. The reverse mode of the NCX inhibitor KB-R7943 attenuated contrast-induced renal tubular cytotoxicity.

Topics: Acute Kidney Injury; Animals; Apoptosis; Calcium; Cell Survival; Cells, Cultured; Contrast Media; Epithelial Cells; Kidney Tubules; Permeability; Rats; Reactive Oxygen Species; Sodium-Calcium Exchanger; Thiourea; Triiodobenzoic Acids

We investigated the effects of pre- or post-ischemic treatment with KB-R7943, a new Na+/Ca2+ exchange inhibitor, on ischemic acute renal failure (ARF) in rats, and these were compared with the effects of verapamil. Ischemic ARF was induced by clamping the left renal pedicle for 45-min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function markedly decreased 24 h after reperfusion. Pre-ischemic treatment with KB-R7943 or verapamil attenuated the ARF-induced renal dysfunction. The ischemia/reperfusion-induced renal dysfunction was overcome by post-ischemic treatment with KB-R7943 but not with verapamil. Histopathological examination of the kidney of ARF rats revealed severe renal damage, and suppression of the damage was seen with post-ischemic treatment with KB-R7943. KB-R7943 markedly suppressed the increment of endothelin-1 (ET-1) content in the kidney at 2, 6, and 24 h after reperfusion. No significant changes in Na+/Ca2+ exchanger protein expression in renal tissue were observed with 45-min ischemia, 6 h after reperfusion and KB-R7943 treatment. These results suggest that Ca2+ overload via the reverse mode of Na+/Ca2+ exchange, followed by ET-1 overproduction, seems to play an important role in the pathogenesis of the ischemia/reperfusion-induced ARF. KB-R7943, which is effective in both cases of pre- and post-ischemic treatments, may prove to be an effective therapeutic agent for cases of ischemic ARF.

Topics: Acute Kidney Injury; Animals; Blood Pressure; Blood Urea Nitrogen; Blotting, Western; Calcium Channel Blockers; Endothelin-1; Heart Rate; Hemodynamics; Homeodomain Proteins; Kidney Function Tests; Male; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sodium-Calcium Exchanger; Thiourea; Verapamil

We investigated whether the preischemic or postischemic treatment with KB-R7943, a novel and selective Na+/Ca2+ exchange inhibitor, has renal protective effects in mice with ischemic acute renal failure (ARF). Ischemic ARF was induced by clamping the left renal pedicle for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function was markedly diminished 24 h after reperfusion. Preischemic treatment with KB-R7943 attenuated the ARF-induced renal dysfunction. The ischemia/reperfusion-induced renal dysfunction was also overcome by postischemic treatment with KB-R7943. Histopathologic examination of the kidneys of ARF mice revealed severe renal damage such as tubular necrosis, proteinaceous casts in tubuli, and medullary congestion. Histologically evident damage and Ca2+ deposition in necrotic tubular epithelium were improved by preischemic treatment with KB-R7943. In addition, preischemic treatment with KB-R7943 significantly suppressed the increment of endothelin-1 (ET-1) content in the kidney at 2, 6, and 24 h after reperfusion. These findings suggest that Ca2+ overload via the reverse mode of Na+/Ca2+ exchange, followed by renal ET-1 overproduction, plays an important role in the pathogenesis of the ischemia/reperfusion-induced ARF. KB-R7943 may prove to be an effective therapeutic agent for cases of ischemic ARF in humans.

Topics: Acute Kidney Injury; Animals; Calcium; Endothelin-1; Ischemia; Kidney; Male; Mice; Reperfusion Injury; Sodium-Calcium Exchanger; Thiourea

The effects of KB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea methanesulfonate), a novel Na+/Ca2+ exchange inhibitor, on ischemic acute renal failure (ARF) in rats were examined. ARF was induced by clamping the left renal pedicle for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function was markedly diminished in ARF rats. Pretreatment with KB-R7943 (10 mg/kg, i.v.) markedly attenuated the ARF-induced renal dysfunction. Histopathological examination of the kidney of ARF rats revealed severe renal damage, which was suppressed by KB-R7943. Activation of the reverse mode of Na+/Ca2+ exchange seems to play an important role in the pathogenesis of ARF. A selective Na+/Ca2+ exchange inhibitor may be useful in cases of ARF.

Topics: Acute Kidney Injury; Animals; Blood Urea Nitrogen; Creatine; Kidney; Kidney Function Tests; Male; Rats; Rats, Sprague-Dawley; Renal Circulation; Reperfusion Injury; Sodium-Calcium Exchanger; Thiourea