Pre- or Post-Ischemic Treatment with a Novel Na+/Ca2+ Exchange Inhibitor, KB-R7943, Shows Renal Protective Effects in Rats with Ischemic Acute Renal Failure
- Junji Yamashita,
- Makoto Itoh,
- Toshihiko Kuro,
- Yutaka Kobayashi,
- Masaya Ogata,
- Masanori Takaoka and
- Yasuo Matsumura
Abstract
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.
Footnotes
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Send reprint requests to: Yasuo Matsumura, Ph.D., Department of Pharmacology, Osaka University of Pharmaceutical, Sciences 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan. E-mail:matumrh{at}oysun01.oups.ac.jp
- Abbreviations:
- ARF
- acute renal failure
- NCX
- Na+/Ca2+ exchanger
- ET-1
- endothelin-1
- UN
- uninephrectomized
- MAP
- mean arterial pressure
- HR
- heart rate
- BUN
- blood urea nitrogen
- Pcr
- plasma creatinine concentration
- Ccr
- creatinine clearance
- UF
- urine flow
- UOsm
- urinary osmolality
- FENa
- fractional excretion of sodium
- UNaV
- urinary excretion of sodium
- PNa
- plasma sodium concentration
- RIA
- radioimmunoassay
- KB-R7943
- 2-[2-[4-nitorobenzyloxy]phenyl]ethyl)isothioureamethanesulfonate
- SDS
- sodium dodecyl sulfate
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- Received August 1, 2000.
- Accepted October 16, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
