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.