Pre- or post- ischemic treatment with a novel Na+/Ca2+ exchange inhibitor,KB-R7943, shows renal protective effects in rats with ischemic acute renalfailure

We investigated the effects of pre- or post-ischemic treatment with KB-R794 3, a new Na+/Ca2+ exchange inhibitor, on ischemic acute renal failure (ARF) in rats, and these were compared with the effects of verapamil. Ischemic A RF was induced by clamping the left renal pedicle for 45-min followed by re perfusion, 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/reperf usion-induced renal dysfunction was overcome by post-ischemic treatment wit h KB-R7943 but not with verapamil. Histopathological examination of the kid ney of ARF rats revealed severe renal damage, and suppression of the damage was seen with post-ischemic treatment with KB-R7943. KB-R7943 markedly sup pressed 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 p rotein expression in renal tissue were observed with 45-min ischemia, 6 h a fter reperfusion and KB-R7943 treatment. These results suggest that Ca2+ ov erload via the reverse mode of Na+/Ca2+ exchange, followed by ET-1 overprod uction, 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 ag ent for cases of ischemic ARF.