KB-R7943, a selective Na+/Ca2+ exchange inhibitor, protects against ischemic acute renal failure in mice by inhibiting renal endothelin-1 overproduction.

Abstract

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.

• Authors: J Yamashita, M Ogata, M Takaoka, Y Matsumura
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 37 Issue 3 Pg. 271-9 (Mar 2001) ISSN: 0160-2446 [Print] United States
• PMID: 11243417 (Publication Type: Journal Article)

Chemical References

• 2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate
• Endothelin-1
• Sodium-Calcium Exchanger
• Thiourea
• Calcium

Topics

• Acute Kidney Injury (prevention & control)
• Animals
• Calcium (metabolism)
• Endothelin-1 (analysis, antagonists & inhibitors, biosynthesis)
• Ischemia (drug therapy)
• Kidney (drug effects, metabolism)
• Male
• Mice
• Reperfusion Injury (prevention & control)
• Sodium-Calcium Exchanger (antagonists & inhibitors)
• Thiourea (analogs & derivatives, pharmacology, therapeutic use)